Subject: BETA #22 Date: Sep 1 1994 (8271 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Bulletin of Experimental Treatments for AIDS &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& BETA (Bulletin of Experiment Treatments for AIDS) -- No. 22 Published by the San Francisco AIDS Foundation -- September 1994 CONTENTS: [items are separated by "*****" for this display] Treatment Updates from Yokohama New Drug for Herpes Zoster Preventive Vaccine Studies Falter BETA Readership Survey Results Recommendations on AZT Use in Pregnancy Food-Based Nutrients as Therapy BETA Online ***** Individualized Therapy: An Emerging New Treatment Strategy Ronald Baker, PhD Ronald Baker is editor of BETA. Recent media reports have painted a relentlessly gloomy picture of the status of AIDS drug development. Yet much useful information on treatment emerged at the 10th International Conference on AIDS in Yokohama, Japan (August 7-12, 1994). Encouraging treatment developments presented in Yokohama include the following: * Recombinant human growth hormone therapy significantly increases weight gain as represented by fat-free lean body mass among people with AIDS-related wasting. * AZT treatment dramatically reduces the rate of HIV transmission from mother to infant. * Acyclovir co-treatment with anti-HIV therapy significantly increases survival time among people with AIDS. * Oral ganciclovir appears to be an effective primary prophylaxis for cytomegalovirus disease. * The protease inhibitor drug saquinavir reduces viral load and increases CD4 cell counts significantly more when used in a triple combination with AZT and ddC compared to 2 double combinations (AZT plus ddC or saquinavir plus AZT). * Quantitative polymerase chain reaction (PCR) and branched chain DNA (bDNA) testing for measuring HIV load is expected to become a major new tool to help guide individual treatment decisions and to evaluate anti-HIV therapies in clinical studies. While it is important to recognize these treatment-related accomplishments, it is equally important to acknowledge the pressing need for a more effective strategy for the treatment of HIV infection and AIDS. AIDS researchers, community physicians and activists are working together to achieve this goal. The end result hoped for is better care and improved clinical benefits for HIV positive individuals. --------- Individualized Therapy Today, a handful of physicians are already offering to their patients components of a new treatment strategy~initially termed "Individualized Therapy." Within 6 months, more community physicians will offer elements of Individualized Therapy to their HIV positive patients, as access increases to powerful new diagnostic technologies and to more effective treatment regimens. By the end of 1995, the majority of patients cared for by mainstream physicians likely will have access to the primary ingredients of this new treatment strategy. There are 5 key components of Individualized Therapy: 1) wider access to HIV RNA testing, a new medical technology that provides an accurate measure of HIV load in the blood plasma of HIV-infected patients; 2) tailoring anti-HIV treatment to each individual patient, based primarily on periodic measurement of HIV load; 3) accelerated approval of and wider access to protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTI), 2 new classes of anti-HIV drugs that show promise when used in combination with the nucleoside analogues; 4) more widespread use of 3- or 4-drug regimens that combine different classes of drugs; 5) early initiation of drug treatment, while the immune system is still relatively intact and capable of a strong response to HIV infection. To better elucidate the emerging paradigm of Individualized Therapy, it will be helpful to describe briefly what is currently known about the pathogenesis of HIV disease and its implications for treatment approaches. --------- Pathogenesis of HIV disease Scientists do not yet have a clear understanding of how HIV causes disease, but there is continuing progress in this area. David Ho, MD, and Robert Coombs, MD, published articles in 1989 suggesting that HIV actively replicates during the earliest stages of infection and continues to do so throughout all stages of the disease. Ho and Coombs and colleagues also found a direct correlation between increasing viral replication and disease progression. In 1993, Anthony Fauci, MD, and Giuseppe Pantaleo, MD, of the National Institute of Allergy and Infectious Diseases (NIAID) further elucidated these groundbreaking findings. They discovered that HIV was present and actively replicating in the lymphoid tissues of HIV positive individuals throughout the course of HIV disease. Following initial infection, the amount of HIV in the body ("viral burden") rises rapidly. In response, the immune system mounts a vigorous defense that dramatically and quickly reduces the viral load, but does not eliminate it. Fauci and Pantaleo demonstrated that, over the long course of HIV disease, through mechanisms that are incompletely understood, the proper functioning of the lymph nodes and other lymphoid tissue critical to normal immunity becomes gradually impaired. At the 1994 Yokohama AIDS Conference, Ashley Haase, MD, of the University of Minnesota presented evidence that corroborates the findings of Ho, Coombs, Fauci and Pantaleo concerning HIV pathogenesis. In addition, Haase presented data showing for the first time that HIV infects a huge reservoir of CD4 T-lymphocytes in the lymphoid tissue. Using in situ hybridization polymerase chain reaction (PCR) with a double-labeled probe, Haase found that, following the initial immune response, a large reservoir~about 25%~of CD4 T-lymphocytes within lymphoid tissue are "latently" infected by HIV in the earliest stage of HIV disease. The "resting" state of HIV inside these lymphocytes allows it to evade detection by the host~s immune defenses. Only 1% of HIV-infected lymphocytes in the lymph nodes are actively replicating at any one time, according to Haase. However, there is low-level, but continuing HIV gene expression in the large reservoir of latently infected cells. Over time, these cells become activated, creating a cascade of new viral replication and an increased viral load that eventually results in disease progression. There is a slow but relentlessly progressive depletion of CD4 T-cells, the body~s white blood cells responsible for initiating the immune system~s primary defense against invading microorganisms. Immune system defenses are gradually weakened by this process, and in time the immune system collapses entirely, leaving the body vulnerable to opportunistic infections, malignancies and cancers. Haase's observation that in early disease 25% of the CD4 T- cells in the lymph nodes and other lymphoid tissue are covertly infected with HIV is extraordinarily significant. This means that about 100 billion latently infected CD4 cells reside in the lymphoid tissue, undetected by immune system defenses. One percent of CD4 cells/mm3 actively infected translates into 1 billion productively infected CD4 cells that contribute to the viral load in the blood stream. Perhaps the most important conclusion to draw from Haase~s findings is that the total HIV burden, comprised of latently and actively infected cells in an infected individual, is enormous, and is rapidly established in the earliest stage of infection (after the initial immune response). "This puts great emphasis on our ability to institute long-term, effective antiretroviral treatment in the early stages of HIV infection," Haase told the Yokohama delegates, "and there is a need for multiple types of [viral] inhibitors and combination therapy." --------- HIV RNA Assays and Viral Load Both the reliability of HIV RNA testing and its practical applications have expanded dramatically in recent years. Already HIV RNA testing has become a significant tool in AIDS research. Within a matter of months these powerful assays may be a major new tool for guiding the course of treatment for HIV infection. Because of the ability of this new technology to detect minute quantities of genetic material, it has many potential applications in medicine. What is HIV RNA? RNA stands for ribonucleic acid, the genetic information of HIV present within virus particles. After HIV infects human cells, its genetic information (RNA) is transcribed into DNA (deoxyribonucleic acid), the substance in human cells that contains their genetic information. HIV then "takes over" the machinery of the host cell. When activated, the virus uses the host cell to replicate, producing virions (new virus particles). These viral progeny then spread to infect new cells in the bloodstream or tissue of the human host. The new tests measure the RNA of HIV, which reflects how much viral replication is going on in the individual. This is commonly referred to as "viral load," "viral burden" or "HIV load," which is determined by measuring free viral particles. When tested in blood samples, the test findings are expressed as the number of copies of HIV RNA in each milliliter of blood plasma. A test value (result) of 50,000 copies means the individual has 50,000 copies of HIV RNA per milliliter of blood plasma at the time the sample was drawn. A test result of 50,000 copies is regarded anecdotally as "medium" viral load, not dangerously "high," but also not as "low" as might be wished. A test result of 100,000 copies is regarded anecdotally as a relatively high viral load. (These are rough guidelines based on preliminary findings, but the lower the number of copies per milliliter of blood plasma, the better!) Work remains to be done in the development and validation of these tests to ensure that they give accurate, reliable and repeatable results. At the present time, the tests are not standardized, and results may be inconsistent. Scientists have not yet determined precisely how HIV load values correlate with disease stage (although they have a rough idea), nor can they rely with complete confidence on the viral load result to predict clinical outcome. Yet several studies using these tests suggest that HIV load predicts clinical outcome (e.g., decreases in viral load due to treatment correlate with a clinical benefit). Further studies will be necessary to verify these preliminary findings. Several companies are working to produce assays that measure viral load. Hoffmann-La Roche (Roche Molecular Systems) and Chiron Corporation are the 2 companies farthest along in developing standardized assay kits for widespread use by researchers and physicians. The Roche product is called "quantitative polymerase chain reaction" or more commonly "quantitative PCR. " The Chiron product is called "branched chain DNA" or, more commonly, branched DNA (bDNA). Researchers have found that both tests give comparable results in measuring HIV RNA. There are advantages and disadvantages to each of the 2 tests. For example, the Chiron bDNA assay cannot measure HIV burden if the value is below 5,000 copies of HIV RNA per milliliter, whereas the Roche quantitative PCR can measure HIV load as low as 200 copies of HIV RNA per milliliter. Some researchers prefer the Chiron bDNA because it is simpler to operate, others prefer the Roche quantitative PCR because it is more sensitive. At this stage of their development, the tests appear to offer equally reliable and consistent results. PCR and bDNA are sensitive and fast techniques that can detect and amplify minute genetic fragments (RNA and DNA). The genetic fragments of microorganisms present in infected individuals can be identified quickly and the quantity of the microorganism in blood plasma or tissue measured. Within a few hours source DNA can be amplified a billion-fold so that scientists can recognize it. The ability of these tests to quantify the amount of the organism inside host cells is important to AIDS researchers and clinicians, offering an easy method for accurately measuring HIV load in infected individuals. This new tool may change significantly the treatment of HIV disease in many ways. It has already changed the way that researchers are testing the effectiveness of AIDS drugs in clinical trials. Instead of relying heavily on CD4 count changes as a surrogate marker for disease progression or drug effectiveness, researchers are now employing HIV RNA testing, which tells them with reasonable accuracy how much HIV is in the circulating blood of individual patients. Preliminary evidence suggests that HIV load correlates with clinical benefit (the lower the HIV load, the better the clinical prognosis). High viral burden appears to presage disease progression and clinical decline. Within a short time these tests may become an accepted method for demonstrating how well a particular drug (or drug regimen) is working in individual patients. Eventually, when these tests are standardized and approved by FDA, community physicians will be able to order them from local laboratories. Using quantitative PCR or bDNA tests, physicians almost everywhere will be able to determine whether viral load in each individual patient is increasing, decreasing or remaining stable. With this critically important information in hand, drug treatment can be "individualized" for each patient. As a result, recommendations can be made about continuing, halting, changing or adding drug treatment early, before patients experience significant CD4 loss and clinical decline. CD4 loss is thought to be a relatively late result of increased viral replication. Therefore, it is considered more beneficial to make treatment decisions based on the patient's viral load. Using HIV RNA testing in clinical trials to assess the HIV load in patients on various treatment regimens, researchers may be able to predict which drugs will work best for a particular patient or subset of patients. Assays of viral burden also may dramatically shorten the amount of time necessary to test the effectiveness of experimental therapies~antiretroviral drugs, gene therapies, immunomodulating agents and other treatments. By significantly decreasing the amount of time required to evaluate these therapies, millions of dollars in research costs may be saved. These tests also can be employed to evaluate the effect of alternative therapies on viral burden. Therapies with no effective anti-HIV activity could be identified quickly and abandoned. --------- Access to HIV RNA Tests Both the Chiron bDNA and the Roche quantitative PCR are available to researchers and clinicians now, but in order to be accessible to large numbers of community physicians, these tests must receive FDA approval, and be manufactured and distributed to local laboratories. To receive approval, FDA requires that the manufacturers create a standardized kit that must be evaluated in clinical trials. The standardized kits, once certified by FDA, will yield consistent results when run by different laboratories. It is unknown how long it will take for Roche and Chiron to create kits that will win FDA approval. No one from the companies involved will predict a specific timeline, but this should be accomplished within the next 12 months, possibly sooner. In the meantime, physicians can order the tests from certain laboratories, with the most reliable likely to be those operated or licensed by Roche and Chiron. To order the quantitative PCR test from a Roche-licensed laboratory, physicians may call 1-800-533-0567, 8 am -- 6 pm Eastern Time. To order a bDNA test from Chiron, physicians may call the Nichols Institute at 1-800-553-5445. The cost per test is currently about $200. When commercially available in standardized kit format, the cost for the test is expected to drop significantly. It is important to understand that, much like CD4 T- lymphocyte testing, the result of a single HIV RNA test is less valuable than tracking changes over time. Studies show that monotherapy with AZT is able to produce a ten-fold (1-log) decrease in viral load in antiretroviral-naive patients. If therapy is stopped, viral load returns to baseline values. It has been suggested by some scientists that what is needed for effective viral suppression is a drug regimen capable of reducing viral load by 100-fold (a 2-log drop) for an extended period of time. No currently available single-agent drug can produce this desired decrease in viral load. --------- The Limitations of Monotherapy in HIV Disease If the model of HIV disease pathogenesis discussed earlier is accurate~early and massive presence of HIV in the lymph nodes and other lymphoid tissue~then beginning antiretroviral treatment at the earliest possible time seems the most appropriate treatment strategy. Postponement of treatment allows the viral burden to increase unchecked, which further damages immune function and results in the patient's clinical decline. The critically important question is not whether early antiretroviral treatment will benefit HIV positive individuals, but rather, can currently available anti-HIV drugs arrest HIV replication in the lymph nodes and decrease viral burden in early HIV infection? The answer may be ~yes,' if these drugs are used in combination. There is growing evidence to suggest that monotherapy with currently licensed antiretrovirals cannot effectively interfere with viral activity in the lymphoid tissue during the earliest stages of HIV infection. This notion is supported by the results of 2 studies presented at the Yokohama AIDS Conference. Paul Volberding, MD, presented results from the part of the ACTG 019 trial that enrolled over 1,600 patients with CD4 counts greater than 500 cells/mm3. Participants received 1,500 or 500 mg/day AZT monotherapy or placebo. Unfortunately, over the mean followup period of 2.6 years, no additional benefit in reducing time of progression to AIDS nor in extending survival time was seen in those patients receiving AZT monotherapy. Oren Cohen, MD, of the NIAID presented in Yokohama results of an 8-week study that examined the effect of AZT monotherapy on HIV in the lymph nodes of people with early HIV disease (average CD4 count of 654). Using quantitative PCR to measure HIV replication and viral load, his research team concluded that AZT monotherapy had no detectable effect on the amount of HIV in the lymphoid tissue nor in certain mononuclear white blood cells of these individuals. Researchers believe that use of monotherapy with any available drug in HIV infection inevitably leads to the development of viral resistance, which in turn may seriously compromise the effectiveness of the drug. Resistance may occur within weeks or years, depending on the individual patient's viral strain, viral load and the particular drug used. Most likely, nearly complete suppression of HIV replication needs to be achieved to prevent the emergence of resistant virus. --------- Double Combination Therapy In contrast to those in early-stage HIV disease on AZT monotherapy, patients in the NIAID study with more advanced disease (average CD4 count of 394) who added ddI to their AZT regimen experienced decreased HIV replication in their lymphoid tissue and a decline in plasma viral load. However, these reductions were temporary and not statistically significant, according to the researchers. Yet the study did not address the potential benefit of combination treatment with ddI plus AZT in individuals with early HIV disease (nor was this approach tested in ACTG 019). It is possible that initiating antiretroviral treatment with 2 or more agents in patients with early HIV infection could produce a significant reduction in viral burden in the circulating blood as well as reduce HIV replication in the lymphoid tissues. The results of several studies suggest a survival benefit for patients on 2-drug antiretroviral therapy, compared to those on monotherapy. Neil Graham, MD, presented data from the Multicenter AIDS Cohort Study (MACS) demonstrating a survival advantage from combining AZT and ddI over switching from AZT monotherapy to ddI monotherapy. Graham told Yokohama delegates that combining therapy is far better than alternating therapy. Melanie Thompson, MD, of the AIDS Research Consortium of Atlanta presented data in Yokohama showing that the survival benefit of double combination antiretroviral therapy is significantly greater than that of sequential therapy. In addition, starting AZT treatment at higher CD4 counts is correlated with an increased survival benefit, according to Thompson. Several small studies have suggested that AZT in a double combination with ddI, ddC or 3TC provides an advantage over any of these agents used alone. This may be due to the ability of these combinations to reduce the development of resistant strains of HIV. Although the mechanism of action of all 3 drugs is the same, they have different toxicities and therefore probably represent a useful clinical combination. However, reliance on only 2 agents of the same drug class in the treatment of HIV infection is unlikely to suppress HIV replication for an extended period of time, due to the extreme mutability of the virus. In addition, the viral load in many HIV-infected patients, especially those with advanced disease, is extremely high, and the 2-drug combination probably cannot reduce it to a level that will halt or significantly delay disease progression. --------- Triple Combination Therapy: Best Hope for Maximal Clinical Benefit Three-drug combinations hold the most promise for effective, sustained control of viral activity. Historically, 3- or 4-drug combinations have been necessary for the effective treatment of certain chronic infections and other diseases. For example, state-of-the-art treatment for M. tuberculosis calls for early, initial treatment with 4 chemotherapeutic agents. In therapy for various cancers and malignancies, treatment with 3 or more chemotherapeutic agents is commonly the standard of care. In HIV disease, laboratory studies of certain 3-drug combinations have demonstrated complete control of HIV replication at drug concentrations that can safely be attained in the blood. The in vitro combinations of AZT plus ddI plus 3TC and AZT plus ddC plus nevirapine produce a synergistic effect that reduces HIV activity to almost zero, according to David Barry, MD, of Burroughs Wellcome. While in vitro data may not translate into in vivo benefit, the fact that these triple antiretroviral combinations can completely suppress viral activity in laboratory cultures suggests that 3-drug combinations hold promise for providing patients with a clinical advantage over monotherapy and double combinations. It is also important to note that the drugs that constitute these promising combinations are available now, and could be approved by FDA for marketing within a matter of months through the accelerated approval program. In the near-term, these combinations likely will be comprised of nucleoside reverse transcriptase inhibitors (e.g., AZT, ddI, ddC, d4T, 3TC), non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine) and a protease inhibitor. It is hoped that saquinavir (Inverase), the protease drug farthest along in development, will receive accelerated approval from FDA within the next 6-9 months. Three-drug combinations using protease inhibitors plus the reverse transcriptase inhibitors are currently the best hope for improved, sustained clinical benefits among HIV-infected individuals. Over time (24-36 months), patients may have increased access to other types of anti-HIV therapies for use in combination with the nucleoside analogues and protease inhibitors. These include immunomodulating therapies such as the treatment vaccines and autologous CD8+ cell infusion, passive hyperimmune therapy and interleukin-2, as well as other novel therapeutic approaches now in the research pipeline. --------- 3-Drug Combinations with a Protease Inhibitor Hoffmann-La Roche released in May 1994 preliminary results of a government-sponsored clinical study (ACTG 229) showing that the triple combination of saquinavir (a protease inhibitor), AZT and ddC significantly reduces HIV load and produces a transient, but significant increase in CD4 counts in patients with 50-300 CD4 cells/mm3. This first-ever study that combines a protease inhibitor with nucleoside analogues compared the safety and activity of the 3-drug combination to 2 double combinations: ddC plus AZT and saquinavir plus AZT. Ann Collier, MD, of the University of Washington, presented the ACTG 229 study results in Yokohama. The data show that the triple combination was significantly better than the 2 double combinations in reducing viral load and in increasing CD4 counts. With 302 participants, ACTG 229 is the largest study of an HIV protease inhibitor yet completed. Participants had used AZT for at least 4 months before enrollment. While the study results do not prove a clinical benefit from use of the 3-drug combination studied, the significant decreases achieved in viral load (as measured by quantitative PCR) and the significant increases in CD4 counts suggest that this and other triple combinations may delay disease progression and improve survival. The benefit may be even greater if 3-drug combination regimens are initiated in patients at earlier stages of HIV disease (greater than 500 CD4 cells/mm3). --------- The Inter-Company Collaboration for AIDS Drug Development Almost everyone with a stake in AIDS drug development~companies, researchers, clinicians, regulators, patients and activists~agree that new approaches are needed for the clinical testing of combination regimens that show promise in the laboratory. There are now 4 FDA-approved anti-HIV drugs: AZT, ddI, ddC and d4T plus 3 drugs with anti-HIV activity that are FDA-approved for other indications: alpha interferon, foscarnet and ribavirin. In addition, 3TC is available through the parallel track program. This translates into 56 possible 3- drug combinations that might be tested in clinical studies. In addition, protease inhibitors, non-nucleoside reverse transcriptase inhibitors and treatment vaccines are emerging from Phase II studies in the coming months, raising the number of potential 3-drug combinations to several thousand. If the potential clinical benefits of 3-drug combinations are to be made available to patients desperately in need of new therapies, it is imperative to design and implement a new, streamlined AIDS drug research program. One such approach is already in place, a collaborative program between a group of the world's leading pharmaceutical companies. The Inter-Company Collaboration for AIDS Drug Development, a consortium of 15 pharmaceutical companies, will begin a program in the fall of 1994 to test the efficacy of various triple antiretroviral drug combinations. The 3-drug regimens will be tested among HIV positive, asymptomatic individuals who have never used anti-HIV medication. The goal of the collaboration is to accelerate research into antiretroviral drugs by sharing information and compounds, and by conducting joint research. The major objective of the program is to identify triple drug combinations that demonstrate strong activity against HIV. Regimens that show early promise will then be evaluated in traditional trials. The collaborators have designed a "Master Protocol" to quickly evaluate currently feasible 3-drug combinations and to allow for the addition of new drugs as they become available. The design of these studies is such that the information they provide can be quickly put into clinical practice. These protocols are designed as pilot Phase II studies, but if results show a clinical benefit, the drugs could be made widely available to patients through the existing FDA accelerated approval and parallel track systems. If a study shows negative results, then that combination would be dropped from the options recommended for patients. The first 4 triple combinations to be studied using this protocol have been selected: (1) AZT plus ddC plus saquinavir; (2) AZT plus ddI plus nevirapine; (3) AZT plus ddI plus 3TC; and (4) AZT plus ddC plus nevirapine. These combinations have been selected first because they demonstrate in vitro evidence of synergistic anti-HIV activity and no evidence of overlapping toxicities. (For a complete review of the Inter-Company Collaboration and a detailed introduction to the Master Protocol, see the article by David Barry, MD, in the June 1994 issue of BETA, pp. 46-48.) --------- Toward a New Definition of Early Intervention As mentioned earlier, laboratory studies of antiretroviral drugs demonstrate clearly that 2 drugs are better than one (in suppressing viral activity) and that 3 drugs are better than 2. In addition, anti-HIV therapy appears to work best when the viral load is low. Can these laboratory findings guide physicians and patients in choosing the most effective time to initiate treatment as well as the most effective drug regimen(s)? If certain 3-drug combinations offer the most promise for suppressing viral activity, and if viral burden is lowest during early-stage infection, then initiating a 3-drug combination as early as possible in infected individuals may be the most effective treatment strategy available to patients today. In this case, early intervention would no longer mean initiation of AZT monotherapy among asymptomatics with 200-500 CD4 cells/mm3, but rather initiation of a 3-drug treatment regimen at the earliest possible moment following the initial immune response to acute infection. While it will be necessary to conduct clinical trials to test for the effectiveness of 3- drug combinations in early-stage infection, existing laboratory and clinical data are sufficient to warrant serious consideration of such an approach now. --------- Accelerated Approval To improve the likelihood for a 3-drug combination to provide a prolonged clinical benefit, one of the 3 drugs used likely would be a protease inhibitor. The protease inhibitor farthest in development is saquinavir (Inverase), manufactured by Hoffmann-La Roche. Saquinavir is just now entering Phase III trials in the U.S. and Europe. It is important that the drug be made available through the FDA accelerated approval program as soon as possible so that it can be used in combination regimens. A compelling argument can be made that saquinavir has already fulfilled the requirements for accelerated approval. It fills an "unmet need" in that it belongs to a new class of drugs with a distinctly different mechanism of action against HIV than currently licensed drugs. Its toxicity profile is favorable. No serious adverse reactions have been reported in Phase I or Phase II trials of the drug. Equally important, the results of ACTG 229 suggest that, in a triple combination with AZT and ddC, the drug significantly reduces viral burden and significantly increases CD4 counts in individuals with advanced disease (50-300 CD4 cells/mm3). Thus, already-completed saquinavir studies meet the FDA accelerated approval requirement of providing "...evidence of the drug's effect on a surrogate endpoint [in this case, CD4 counts and viral burden] that reasonably suggests clinical benefit to patients..., pending completion of studies to establish and define the degree of clinical benefits to patients." ("Accelerated Approval." Federal Register. December 11, 1992). In addition, given the desperate need of thousands of AIDS patients who have failed on all approved anti-HIV therapies, it may be unethical to deny them access to saquinavir, which has shown no undue toxicities and has demonstrated a reasonable promise of efficacy for patients in intermediate to advanced stages of HIV disease. --------- The FDA and Accelerated Approval The FDA will play a critical role on several levels in determining how quickly Individualized Therapy becomes a reality in HIV disease. First, FDA must collaborate with Roche and Chiron to ensure the timely design and implementation of studies to test the reliability of the HIV RNA assays and the potential of these assays to evaluate treatment regimens and shorten the duration of clinical studies of AIDS therapies. Most importantly, FDA must continue its policy of granting accelerated approval to experimental AIDS therapies that show reasonable safety and reasonable promise of benefit. Unfortunately, the agency is now considering proposals to make more stringent requirements for accelerated approval of new AIDS drugs, specifically the protease inhibitors. In the opinion of many researchers, clinicians and activists, such action would represent a major step backwards for people with HIV/AIDS in their continuing struggle to gain earlier access to promising new therapies. Changing the standard for accelerated approval also will send a chilling message to drug developers, large and small. The end result of making it more difficult, time consuming and expensive to bring products to market could be a retreat by these companies from the development of new AIDS drugs. Until a protease inhibitor receives FDA approval, there is no possibility of their use in 3-drug combinations outside of clinical trials. Yet triple combination regimens offer the current best chance for prolonged viral suppression and improved clinical benefits. Raising the regulatory hurdle for accelerated approval of the protease inhibitors (and other experimental AIDS drugs) will make widespread access to Individualized Therapy an unobtainable goal for the foreseeable future. It is to be hoped that FDA will not revise the existing standards for accelerated approval for AIDS drugs, and thus undermine the medical needs of individual patients who require the earliest possible access to new treatments. --------- Conclusion Individualized Therapy is an emerging new treatment strategy for HIV infection that differs from the current "cookbook" approach which relies almost exclusively on CD4 cell counts and clinical symptoms to guide treatment decisions. The essential elements of Individualized Therapy include the use of powerful new tests for (1) measuring HIV load to determine disease stage, (2) evaluating treatment regimens and (3) guiding the timing and choice of changing therapy. The concept of early antiretroviral treatment in HIV disease, also a component of Individualized Therapy, is supported by the finding that, after the initial immune response to acute infection, 25% of CD4 T-lymphocytes in the lymph nodes are infected with HIV. Furthermore, it is now well established that HIV is actively replicating in the lymph nodes and other lymphoid tissue throughout the asymptomatic stage of HIV disease. Since monotherapy with AZT in early disease appears to have no significant effect on HIV load in the lymph nodes, early treatment with double and triple combination regimens using nucleoside reverse transcriptase inhibitors plus a protease inhibitor offer the possibility of producing prolonged suppression of viral replication and improved clinical benefits for patients. Before Individualized Therapy can be put into widespread practice, the following ongoing developments require completion: (1) Clinical trials now in progress must be completed and new ones must be designed and implemented to show conclusively that viral load measurement using quantitative PCR and branched chain DNA assays correlates with clinical outcome. (2) Standardized kits of these 2 assays must be developed and approved by FDA to ensure consistent results when the tests are run by different laboratories. (3) New drugs currently in the research pipeline, most notably the protease inhibitors (e.g., saquinavir) and the non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine), must become available as soon as possible for use in 3- or 4-drug combination regimens. (4) FDA must maintain the current standards for accelerated approval of promising new AIDS drugs, namely that these drugs demonstrate "reasonable" safety and a "reasonable" promise of efficacy. Sample HIV-1 RNA Quantitation Cumulative Report Social Security Chiron Nichols Date HIV-1 RNA CD4 Time Drug Number Reference # Reference # Collected Quantitation Count Point Therapy 549-34-8976 940001 4089878923 3/1/90 110200 177 Pre-Therapy None 940008 4089908767 6/1/90 87720 198 During Therapy AZT 940015 4089938611 9/1/90 19880 250 During Therapy AZT 940022 4089968455 12/1/90 <10000 223 During TherapyAZT 940029 4089998299 3/1/91 37800 245 Post-Therapy None 940036 4090028143 8/17/92 >1600000 190 Post-TherapyNone Source: Chiron Reference Testing Laboratory ****** Treatment Updates from the X International Conference on AIDS In Yokohama, Japan Harvey S. Bartnof, MD Since 1985, Dr. Bartnof has served as course coordinator for "AIDS/HIV Overview and Update" at the University of California at San Francisco (UCSF) School of Medicine. He is also a member of the San Francisco AIDS Foundation's Scientific Advisory Committee. Except for 1991, Dr. Bartnof has attended and/or presented papers at every International AIDS Conference since 1985. Twelve thousand four hundred seventeen (12,417) participants (2,178 media representatives) from 130 countries attended the Yokohama AIDS Conference (August 7-12, 1994), including 5,737 Japanese citizens. There were a total of 3,400 abstracts submitted to the Conference, including 600 oral and 2,800 poster presentations. In the following article, Dr. Bartnof summarizes the most important Conference presentations on treatment developments. Treatment Highlights --------- Growth Hormone Increases Lean Body Weight in AIDS-Related Wasting Morris Schambelan, MD, from UCSF-affiliated San Francisco General Hospital reported on the results of a Phase III multicenter, double-blind, placebo-controlled study of 178 patients with AIDS-related wasting syndrome who were treated daily for 3 months with recombinant human growth hormone. The treatment group gained a mean of 2.9 kg of lean body (muscle) mass when compared to the placebo group, which had a 0.1 kg lean weight loss. The treatment group and placebo groups lost 1.7 kg and 0.2 kg of body fat, respectively. Total mean weight gain during the 3 months was 1.4 kg for the treatment group and 0.2 kg for the control group. Both the lean muscle and total weight gains in the treatment group were statistically significant. The body compositions were measured by Dual Energy X-Ray Absorptiometry (DEXA). Upon entering the study, the patients had a mean HIV-related weight loss of 11.2 kg and 14% of ideal weight. Average dosage of recombinant human growth hormone was 6 mg/day, administered subcutaneously, with subsequent adjustments for toxicity. There were 172 men and 6 women in the study. Mean age was 39 years. Mean CD4 T-lymphocyte count was 84/mm3 at entry. Treadmill work performance was significantly improved in the treatment group when compared with the control group. Changes in lean body mass were correlated with changes in treadmill work performance. However, AIDS progression, based upon clinical events and CD4 and p24 antigen counts, was similar in the treatment and control groups. Serious events, dropouts and deaths were similar between the treatment and control groups. Side effects potentially due to growth hormone were usually mild or moderate in severity and responded to dose reduction. Side effects included musculoskeletal discomfort, edema (fluid retention), elevated blood glucose or triglycerides, parasthesias (numbness), nausea and carpel tunnel syndrome in the wrists. Even though the cost of the dosage used in the study is prohibitively expensive, the 13 clinical investigators of the study conclude that recombinant human growth hormone appears to be safe and effective as a therapy for AIDS-related wasting syndrome. References Schambelan M and others. Growth hormone therapy of AIDS wasting. X International Conference on AIDS. Yokohama, August 1994. Abstract 423B and oral presentation. --------- Oral Ganciclovir Beneficial for Primary Prophylaxis of Cytomegaloviral (CMV) Disease An independent Data Safety Monitoring Board (DSMB) for the Syntex ICM 1654 study evaluating the potential benefit of oral ganciclovir for prevention of CMV disease has recommended ending the placebo arm due to a highly statistically significant difference in the incidence of and time of development to CMV disease in the treatment arm. All patients in the placebo arm have been offered active drug. Approximately one-half of the enrollees had completed 10 months of therapy at the interim analysis. The study was designed as a double-blind, placebo- controlled multicenter Phase III trial that began enrollment in November 1992. Enrollment of 725 participants was completed in December 1993. The entry criteria included HIV seropositivity, CMV seropositivity and a CD4 lymphocyte count less than 50/mm3, or less than 100/mm3 and history of an AIDS-defining opportunistic infection. Two-thirds of enrollees were randomized to receive active drug while the other third received placebo. The treatment arm dosage was 1,000 mg 3 times a day of oral ganciclovir. Follow-up has included eye examinations by an ophthalmologist every 2 months along with CMV cultures and other laboratory measurements. The primary endpoint was diagnosis of CMV disease, while secondary endpoints included survival and quality of life. The study will continue as an open-label unblinded one to monitor the patients for further safety and efficacy. While a formal presentation of the data was not given in Yokohama, an information sheet was made available by Mary Jean Stempien, MD, from Syntex. Stempien and colleagues anticipate an analysis of the data will be released at the upcoming International Conference on Anti-Microbial Agents and Chemotherapies (ICAAC) meetings. The ICM 1654 study is similar though not identical to the Community Programs for Clinical Research on AIDS (CPCRA) 023 study of oral ganciclovir for primary CMV prophylaxis. That study completed enrollment of approximately 995 patients in June 1994. The CPCRA study has an endpoint of symptomatic CMV disease, while the Syntex study included an endpoint of asymptomatic CMV disease. References Syntex information sheet. Oral ganciclovir CMV prevention study 1654. X International Conference on AIDS. Yokohama, August 1994. Stempien MJ, Syntex Corporation. Personal Communication. August 1994. --------- Oral Ganciclovir for Treatment of CMV Retinitis Oral ganciclovir is much more convenient than the intravenous (IV) route and is a viable alternative to IV ganciclovir for maintenance treatment of retinitis. Time to progression of CMV retinitis averages 5-12 days faster on oral compared to IV. The safety profile is better for the oral form: fewer catheter-related events, less sepsis and less neutropenia. The data were reviewed by David Hardy, MD, of the UCLA School of Medicine. References Hardy WD. HIV-associated opportunistic infections: new progress in treatment and prophylaxis. Presented at Treatment of HIV Disease: Advances and Future Challenges, University of California at Los Angeles (UCLA) satellite symposium. X International Conference on AIDS. Yokohama, August 1994. --------- Atovaquone for Relapse or Resistant Toxoplasma Encephalitis In patients with AIDS-related toxoplasmic encephalitis relapse or intolerance to standard regimen or pyrimethamine and a sulphonamide, atovaquone therapy for 6 weeks led to a 64% clinical response rate and a 61% radiologic response rate. The study was presented by Ramon Gabriel Torres, MD, from New York Medical College. References Gabriel Torres RA. Atovaquone in toxoplasmosis. Presented at New Strategies for Treatment and Prevention of HIV Disease, a Wellcome Foundation satellite symposium. X International Conference on AIDS. Yokohama, August 1994. --------- Atovaquone for Microsporidiosis Eight homosexual men treated with atovaquone 750 mg tablets thrice daily for 13 days had a mean weight gain of 9.5 pounds and a 70% decrease in the number of daily stools from a mean of 10 to 3, according to Ramon Gabriel Torres, MD, from New York Medical College. References Gabriel Torres RA. Atovaquone in toxoplasmosis. Presented at New Strategies for Treatment and Prevention of HIV Disease, a Wellcome Foundation satellite symposium. X International Conference on AIDS. Yokohama, August 1994. --------- HIV Drug Interactions * Rifabutin causes a 30% decrease in serum zidovudine [AZT] level. * Rifabutin causes a 50% decrease in serum clarithromycin level. * Rifabutin causes a 30-50% increase in serum fluconazole level. * Oral ganciclovir causes a 15-38% increase in serum zidovudine [AZT] level. * Oral ganciclovir causes a 50-80% increase in serum didanosine [ddI] level. * Didanosine [ddI] causes a 25% decrease in oral ganciclovir level. Data were presented and reviewed by David Hardy, MD, of the UCLA School of Medicine. References Hardy WD. HIV-associated opportunistic infections: new progress in treatment and prophylaxis. Presented at Treatment of HIV Disease: Advances and Future Challenges, University of California at Los Angeles (UCLA) satellite symposium. X International Conference on AIDS. Yokohama, August 1994. Gaines K and others. Pharmacokinetic interactions with oral ganciclovir, zidovudine, didanosine, probenecid. X International Conference on AIDS. Yokohama, August 1994. Abstract 004B and oral presentation. --------- Treatment for Pneumocystis carinii Pneumonia (PCP) Causes Drop in PCP as AIDS Indicator Disease In the U.S. in 1993, PCP was the AIDS indicator disease in 16% of AIDS patients compared to 43% in 1992, 50% in 1990 and 57% in 1988, according to data presented by David Hardy, MD, of the UCLA School of Medicine. References Hardy WD. HIV-associated opportunistic infections: new progress in treatment and prophylaxis. Presented at Treatment of HIV Disease: Advances and Future Challenges, University of California at Los Angeles (UCLA) satellite symposium. X International Conference on AIDS. Yokohama, August 1994. --------- Mycobacterium avium Complex (MAC) is the Leading Opportunistic Infectious Cause of Death In ACTG 021 in the U.S., MAC disease accounted for 13% of AIDS deaths compared to PCP, which only accounted for 3% of AIDS deaths, according to a review by David Hardy, MD, of the UCLA School of Medicine. References Hardy WD. HIV-associated opportunistic infections: new progress in treatment and prophylaxis. Presented at Treatment of HIV Disease: Advances and Future Challenges, University of California at Los Angeles (UCLA) satellite symposium. X International Conference on AIDS. Yokohama, August 1994. --------- Oral Prednisolone Stabilizes Immune Deterioration in Asymptomatic HIV Disease Forty-four (44) asymptomatic HIV-infected patients at Laennec Hospital in France were treated with oral prednisolone, an immune suppressing glucocorticoid for 6 months at a dose of 0.5 mg/kg, followed by another 6 months at a dose of 0.3 mg/kg. The mean entry CD4 T-lymphocyte count among the patients was 421/mm3, with a range of 207-775/mm3. Treatments while on the study also included 1,200 mg potassium daily to offset steroid side effects and Bactrim prophylaxis 3 times a week. Some patients were prescribed fluconazole, and one-fourth of the patients had some AZT therapy. J. M. Andrieu, MD, and colleagues noted that after 1 year of prednisolone therapy: (1) CD4 lymphocytes increased more than 100/mm3 (median); (2) CD8 lymphocyte counts decreased somewhat; (3) no progression to symptomatic AIDS-defining disease occurred; (4) viral load (HIV, DNA and RNA) remained unchanged; (5) lymphadenopathy as well as seborrheic dermatitis decreased or disappeared; (6) markers of immune activation (beta-2 microglobulin, immune globulins, CD4+DR+ and CD4+CD25+ cells) decreased, and; (7) T-cell apoptosis (premature cell death) decreased significantly. Lu W and others. Glucocorticoids rescue CD4+ T cells from activation-induced apoptosis triggered by HIV-1. X International Conference on AIDS. Yokohama, August 1994. Abstract 021A and oral presentation. --------- Oral Valaciclovir Passes Phase I Trials Seventeen (17) HIV-infected patients with a mean CD4 lymphocyte count of 44/mm3 completed the Phase I Study of oral valaciclovir, 4 times a day with 1,000 mg or 2,000 mg for 1 month. Valaciclovir is a prodrug of acyclovir that significantly increases serum levels of acyclovir. There were few side effects. With the higher dosage, serum levels of the active metabolite acyclovir were 5-fold greater than levels achieved with the highest dose of oral acyclovir (800 mg 5 times a day). Such levels hold promise in the prevention and treatment of HIV- related CMV, varicella-zoster virus (VZV), herpes simplex virus (HSV) and possibly human herpesvirus 6 (HHV-6) infection. The lead author is Mark Jacobson, MD, of UCSF/San Francisco General Hospital. References Jacobson MA and others. Phase I trial of valaciclovir, the l- valyl ester of acyclovir, patients with advanced human immunodeficiency virus disease. Antimicrobial Agents and Chemotherapy 38(7): 1534-1540. July 1994. --------- Benefits for AZT Therapy for Acute Retroviral Syndrome Seventy-two (72) patients with various HIV behavioral risk factors were treated for 6 months with AZT 250 mg twice daily or placebo, during or shortly after the onset of their acute HIV infection illness, the flu-like symptoms which occur prior to the immune response and within a few weeks after HIV infection (in the majority of patients). After a mean follow-up of 15.4 months, a trend was observed toward higher CD4 lymphocyte counts (553/mm3 versus 460/mm3 in placebo after 12 months), higher CD8 lymphocyte counts and lower HIV RNA viremia. There were fewer clinical events in the treatment group, when compared to controls (oral candidiasis, herpes zoster, hairy leukoplakia), which was statistically significant. The lead author was Luc Perrin, MD, from the Central Laboratory of Virology in Switzerland. References Perrin L. Treatment of HIV infection during primary infection. Presented at New Strategies for Treatment and Prevention of HIV Disease, a Wellcome Foundation satellite symposium. X International Conference on AIDS. Yokohama, August 1994. --------- No Clinical Benefit for AZT With CD4 Count Over 500 In ACTG 019, when AZT was given to asymptomatic patients with a CD4 lymphocyte count of greater than 500/mm3, there was no added clinical benefit when compared to starting at a CD4 count of less than 500/mm3, according to Paul Volberding, MD, of UCSF/SF General Hospital. He noted that it would be difficult to measure a beneficial effect at such high CD4 counts because the risk of disease at that time is low. References Volberding PA and others. Zidovudine in early asymptomatic HIV disease: a controlled trial in subjects with greater than 500 CD4+ cells/microliter. X International Conference on AIDS. Yokohama, August 1994. Abstract 355B and oral presentation. Volberding PA. Considerations in the initiation of antiretroviral therapy. X International Conference on AIDS. Yokohama, August 1994. Abstract PS17 and oral presentation. --------- Acyclovir Survival Advantage Acyclovir at a dose of 400 mg twice a day along with anti- HIV therapy increases survival in HIV-infected patients with less than 150 CD4 lymphocytes/mm3, according to the European- Australian and Multicenter AIDS Cohort Study (MACS) studies. However, a Maryland study to be presented at the upcoming ICAAC meetings may indicate otherwise, according to researchers at Johns Hopkins School of Medicine. References Cooper D. Acyclovir cotherapy in advanced HIV disease. Presented at New Strategies for Treatment and Prevention of HIV Disease, a Wellcome Foundation satellite symposium. X International Conference on AIDS. Yokohama, August 1994. Stein DS and others. The effect of the interaction of acyclovir with zidovudine on progression to AIDS and survival. Annals of Internal Medicine 121(2): 100-108. July 15, 1994. --------- Triple Therapy Leads to Highest CD4 Counts and Lowest Mononuclear Cell HIV Levels In ACTG 229, the results of a randomized, 3-arm, double- blind (with open-label AZT), 24-week trial among 300 patients were reviewed by Ann Collier, MD, from the University of Washington. Two arms included the proteinase inhibitor saquinavir (saq), while all 3 arms included the reverse transcriptase inhibitors AZT with or without ddC. After 24 weeks, the percentage of baseline CD4 count was lowest in the AZT/ddC group at 90%, intermediate in the saq/AZT group at 100%, and highest in the triple-therapy group at 109% of baseline. More impressive were the results of the mean HIV levels in peripheral mononuclear cells: lowest in the triple-therapy group at 30% of baseline, intermediate in the ddC/AZT group at 62% of baseline, and highest in the saq/AZT group at 140% of baseline. Moderate-to-severe adverse experiences were not different statistically when comparing the 3 groups, ranging from 31-40%. References Collier AC and others. Comparative study of Ro 31-8959 and zidovudine vs ZDV and zalcitabine vs Ro 31-8959, ZDV and ddC. X International Conference on AIDS. Yokohama, August 1994. Abstract 058 and oral presentation. Collier AC. Advances in retroviral therapy. Presented at Treatment of HIV Disease: Advances and Future Challenges, University of California at Los Angeles (UCLA) satellite symposium. X International Conference on AIDS. Yokohama, August 1994. --------- Survival Advantage in Combination Anti-HIV Therapy Neil Graham, MD, from Johns Hopkins University presented an interim analysis from the MACS involving 853 gay or bisexual men with intermediate-stage HIV disease who either: continued AZT as monotherapy (ZMT), switched to ddC or ddI (sequential monotherapy = SMT), or added ddC or ddI (combination anti-retroviral therapy = CART). Those patients who took CART had a 34% survival advantage (i.e., 66% risk of death) when compared to either SMT or ZMT regimens. The results were adjusted for disease stage, other therapies and time on AZT. References Graham NMH. Survival in ZDV-experienced patients: combination antiretroviral therapy vs ddI/ddC monotherapy vs continued ZDV montherapy. Presented at New Strategies for Treatment and Prevention of HIV Disease, a Wellcome Foundation satellite symposium. X International Conference on AIDS. Yokohama, August 1994. --------- Survival Advantage in Switch to ddI Associated With Decreased Viral Load Ann Collier, MD, from the University of Washington reviewed the NWCS 032 analysis of ACTG 116b/117 Trial in which patients were switched to ddI or maintained on AZT after 4 weeks or more of prior AZT therapy. For those who switched to ddI, a 32% decrease in the relative risk of disease progression was associated with a 50% decrease in the HIV viral burden (RNA). Furthermore, regardless of the assignment group, there was a 178% increased risk of disease progression or death and a 278% increase in the risk of death alone associated with AZT resistance at study entry. References Collier AC. Advances in retroviral therapy. Presented at Treatment of HIV Disease: Advances and Future Challenges, University of California at Los Angeles (UCLA) satellite symposium. X International Conference on AIDS. Yokohama, August 1994. --------- Viral Burden Predicts Outcome on AZT William O'Brien, MD, presented findings from the Veterans Affairs Cooperative Study #298A, which indicate that baseline plasma HIV viral burden (RNA count) was strongly correlated with clinical response to AZT therapy, in addition to the CD4 lymphocyte percent and absolute count. He also reported that the decrease in HIV RNA copy number over 6 months after initiation of AZT therapy can be used to predict clinical outcome. The log HIV RNA explained a greater percent of treatment effect than the CD4 lymphocyte count and beta-2 microglobulin combined. References O'Brien WA and others. Plasma HIV RNA and beta-2 microglobulin as surrogate markers. X International Conference on AIDS. Yokohama, August 1994. Abstract 254B and oral presentation. --------- Viral Burden Associated with Death and AZT Resistance Maryanne T. Vahey, MD, and colleagues from the Walter Reed Army Institute of Research in Maryland presented their findings from the RV43 Study Group, which consisted of 95 HIV-infected patients with a mean entry CD4 lymphocyte count of 252/mm3 placed on AZT monotherapy for 2 to 3 years. Their findings indicated that viral burden (HIV RNA/ml plasma) is strongly associated with death and the development of AZT resistance in patients on long- term AZT therapy. Risk of adverse events increased directly with increasing plasma HIV RNA levels. Patients with 107 plasma HIV RNA copies/ml had a 7-fold increased risk of death when compared to those with less than 103 copies/ml. References Vahey MT and others. Plasma RNA predicts clinical outcome of AZT therapy. X International Conference on AIDS. Yokohama, August 1994. Abstract 253B and oral presentation. --------- Decreased Viral Burden with Combination Therapy David Barry, MD, from Burroughs Wellcome Company, presented the results of a laboratory study comparing the viral burden after initiation of AZT with or without one other nucleoside analog, either ddC or ddI. After 48 weeks of drug therapy, AZT treatment led to a median 70% of baseline RNA copies/ml, whereas therapy with AZT and either ddC or ddI led to a median 30% of baseline RNA copies/ml. References Barry D. Triple combinations and future research direction. Presented at New Strategies for Treatment and Prevention of HIV Disease, a Wellcome Foundation satellite symposium. X International Conference on AIDS. Yokohama, August 1994. --------- Viral Burden to Help Determine Initiation of Anti-HIV Therapy Clifford Lane, MD, of the NIAID has proposed that it may be useful to use viral burden measurements, along with CD4 lymphocyte counts, to determine when to initiate anti-HIV therapy. He noted that in HIV-infected patients with a viral burden of more than 50,000 RNA copies/ml by the bDNA test, CD4 lymphocyte counts were lower (280 cells/mm3) when compared to those with less than 10,000 RNA copies/ml (340 cells/mm3). When the 2 groups were followed over 8 months, the group with the higher viral burden had a steep decline in the CD4 count to 185/mm3, while those in the low viral burden group decreased only slightly to 330/mm3. He proposed that the viral burden marker may be even more important than the CD4 count. References Lane HC. When to start antiretroviral treatment. X International Conference on AIDS. Yokohama, August 1994. Round-table session. --------- Developing Anti-HIV Drug Strategy Similar to Tuberculosis (Tb) Drug Development In a plenary session called "Update on Antiretroviral Strategy," Stefano Vella, MD, from the Instituto Superiore in Italy declared, "If anti-Tb drugs had been developed the way we currently develop anti-HIVs, we would not know now that tuberculosis is a treatable condition." He continued, "One ~Concorde Trial' on INH [isoniazid] would have proven the drug to be fairly useless." Prior to the advent of antibiotics in the 1940s, tuberculosis was difficult to treat and often fatal. When streptomycin was first made available for Tb treatment, resistance to the drug developed in many cases. The current strategy for active Tb treatment includes 4 antibiotics, each of a different type. References Vella S. Update on antiretroviral therapy. X International Conference on AIDS. Yokohama, August 1994. Abstract PS3 and plenary session oral presentation. --------- AZT Decreases HIV Transmission from Mother to Newborn While the results of ACTG 076 had already been released before Yokohama, the CDC published their recommendations for AZT therapy in HIV-infected pregnant women and their newborns during the week of the Yokohama Conference. Hence, several sessions addressed different aspects of the study and the recommendations. An African study showed that HIV transmission from mothers to their newborns occurs: 31% intrauterine (during pregnancy), 58% intrapartum (during delivery), and 11% postpartum (after delivery). Increasing risk of transmission is associated with maternal viral burden, higher p24 antigenemia and lower CD4 lymphocyte counts. As of December 1993, an interim analysis of ACTG 076, a Phase III, double-blind, placebo-controlled trial were as follows. Four hundred seventy-seven (477) women with a median age of 25 years, a median CD4 count of 550 cells/mm3, and no prior AZT exposure (during the current pregnancy) were enrolled. The race/ethnic background was 50% African-American, 29% Hispanic and 19% Caucasian/non-Hispanic. Daily oral AZT 500 mg (100 mg 5 times a day) was given to the pregnant women after 14 weeks gestation and continued until the onset of labor. At the start of labor, an IV loading dose of 2 mg/kg of AZT was given, followed by a continuous IV infusion at the rate of 1 mg/kg/hour. The infant was treated with 2 mg/kg orally 4 times a day until age 6 weeks. There were 364 infants born with known HIV status. Of the 180 mother/infant pairs who received AZT, there were 13 HIV- infected infants, an 8.3% transmission rate. Of the 184 mother/infant pairs who received placebo, there were 40 infected infants, a 25.5% transmission rate. Therefore, there was a 67.5% reduction in HIV transmission from mother to newborn in the treatment group. This result was highly statistically significant (p=0.000056). Dr. Yvonne Bryson from UCLA School of Medicine stated that there was no significant toxicity in either the mothers or their infants. A slightly decreased hemoglobin in some infants resolved by age 3 months. There were no obvious teratogenic effects. Based on these results, the U.S. Public Health Service, via the CDC, has published the recommended guidelines for AZT treatment of HIV-infected mothers after the 14th week of gestation, during labor, and to their infants up to age 6 weeks. The doses are the same as those used during the ACTG 076 Study above. Mothers and fathers need to understand that the long-term effects to the infant are unknown, including possible future carcinogenic and/or reproductive effects, as well as physical and mental growth abnormalities. Several comments were voiced in Yokohama that the expense of AZT precludes the vast majority of HIV-infected women or their infants in developing countries from access to the drug. References Balsey J. Mother-to-child infection. X International Conference on AIDS. Special recent report session SR-2. Yokohama, August 1994. Oral presentation. Blanche S. Materno-fetal HIV transmission. X International Conference on AIDS. Yokohama, August 1994. Abstract PS11 and plenary session oral presentation. Bryson Y. Protective role of zidovudine in reduction of maternal-fetal HIV transmission during pregnancy. Presented at New Strategies for Treatment and Prevention of HIV Disease, a Wellcome Foundation satellite symposium. X International Conference on AIDS. Yokohama, August 1994. Rogers M. Prevention of maternal-fetal transmission of HIV. Presented at Treatment of HIV Disease: Advances and Future Challenges, University of California at Los Angeles (UCLA) satellite symposium. X International Conference on AIDS. Yokohama, August 1994. U.S. Department of Health and Human Services. Recommendations of the U.S. Public Health Service Task Force on the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus. Morbidity and Mortality Weekly Report 43(RR-11). August 5, 1994. --------- Pregnancy Hormone for AIDS-Related Kaposi's Sarcoma? Robert Gallo, MD, of the National Institute of Health (NIH) has suggested using beta-human chorionic gonadotropin (b-HCG) to treat AIDS-related Kaposi's sarcoma (KS). He and his co-workers have observed that KS cells failed to grow in vitro when b-HCG was added and that in an immunodeficient-mouse model with KS, treatment with HCG led to KS tumor regression. Clinicians have also noted that KS tumors among HIV-infected women resolved when they became pregnant, only to return after their babies were born. References Gallo RC. Presented at HIV Ten Years On: Research Findings and Future Prospects, tenth anniversary special session. X International Conference on AIDS. Yokohama, August 1994. --------- Hydoxyurea for HIV Infection? Just as he did at the IX International Conference on AIDS in Berlin, Robert Gallo, MD, has called for trials to evaluate the cancer chemotherapy agent hydroxyurea as an anti-HIV co-therapy along with a reverse transcriptase (RT) inhibitor(s). He stated that it would decrease the nucleoside pool (DNA building blocks) available for incorporation into HIV DNA, thereby allowing the RT inhibitors to be more effective. Hydroxyurea is an FDA-approved drug for use in chronic leukemia and other cancers. It is inexpensive, orally available, crosses the blood-brain barrier, and would synergize with AZT, ddI and/or ddC. References Gallo RC. Presented at HIV Ten Years On: Research Findings and Future Prospects, tenth anniversary special session. X International Conference on AIDS. Yokohama, August 1994. --------- Oral Ulcers and ddC Use Deborah and John Greenspan, MD, from UCSF presented a study on the incidence of oral ulcerations following zalcitabine (ddC) therapy. They reported that the increased risk of oral ulcers from ddC peaks between 3 and 6 months after starting therapy. They also found that the risk is higher for non-smokers compared to smokers. However, considering previous reports of negative effects of smoking among those infected with HIV, the benefits of stopping cigarette smoking far outweigh the potential avoidance of oral ulcers while taking ddC. References Greenspan D and others. Association between oral ulcers and zalcitabine. X International Conference on AIDS. Yokohama, August 1994. Abstract 200B and oral presentation. --------- Magnesium Supplement Beneficial for Peripheral Neuropathy Sally Stroud, MD, and colleagues at the Houston Immunological Institute reported on the benefits of giving supplemental magnesium to AIDS patients with peripheral neuropathy and hypomagnesemia (low serum magnesium). Sixty-eight (68) HIV-infected patients, including 59 with AIDS, had histories and physical examinations consistent with sensory dysfunction. Electromyographic (EMG) nerve studies were performed on 46: 38 had peripheral neuropathy. Neurotoxic drugs, diabetes and alcohol usage were excluded as causes. All patients had a decreased serum magnesium level, with normal B-12 and thyroid function tests. Patients received IV magnesium initially, with subsequent oral magnesium supplements (doses not stated). Response was measured by improved vibration sensation and pinprick, increased ankle reflex, decreased subjective pain and decreased usage of pain medications. 78% had improvement in symptoms within 24-48 hours; 32% (22 patients) showed no initial improvement. However, 7 of those 22 did show improvement after a mean of 14 days taking oral magnesium. After 12 months, 81% of the patients continued to demonstrate improvement in symptoms from baseline, excluding 13 patients lost to follow-up. References Stroud S. Magnesium and peripheral neuropathy. X International Conference on AIDS. Yokohama, August 1994. Abstract PBO235 and poster presentation. --------- Long-Term Non-Progressors (LTN) and Long-Term Survivors (LTS) Several speakers addressed the topic of long-term non- progressors. Susan Buchbinder MD, from the SF City Department of Public Health presented an update from the San Francisco City Clinic Cohort. She and her colleagues have determined that the progression to AIDS after HIV seroconversion is: 1% progression by 2 years; 11% by 5 years; 51% by 10 years; and 79% by 15 years. For 552 patients infected with HIV for 10-16 years, 6.9% still have CD4 counts greater than 500 cells/mm3 and are classified as "non-progressors." The non-progressors had broadly reactive cytotoxic T-lymphocyte responses in vitro, and had certain human leukocyte antigen (HLA) markers in both Class I and Class II more frequently than progressors. Ongoing studies in the non- progressors include viral burden, lymph node assays, qualitative CD8 functioning and apoptosis measurements. Jay Levy, MD, from UCSF reviewed the findings of his laboratory's studies of long-term survivors (LTS). He defines such individuals as: infected with HIV for 10 or more years; clinically healthy; having a stable CD4 count of greater than 500/mm3; and taking no anti-HIV therapy. He and others have acknowledged that the CD8 antiviral factor is strong in the LTS. The CD8 antiviral factor appears to be mediated by a novel factor; is observed in activated CD8+CD28+ cells; is active against HIV-l, HIV-2 and SIV; blocks HIV RNA expression, and; does not work by a lytic mechanism (i.e., does not cause cells to break up and die). He also reviewed selected cytokine secretion and functioning in relation to an altered THl-TH2 immune response in LTS when compared to those with HIV disease progression. Levy and co-workers have discovered an exciting breakthrough in an animal AIDS model. They have determined that HIV-2 causes an AIDS-like disease in baboons. These baboons demonstrate CD4+ cell 1086; lymphoid depletion; lymphoid interstitial pneumonitis (similar to pediatric AIDS); and skin lesions. Having an AIDS- like animal model will help researchers' efforts to uncover safe and effective HIV therapies and vaccines. David Ho, MD, from the Aaron Diamond AIDS Research Center in New York reviewed his findings among 10 LTS referred to his laboratory. He defines LTS as: HIV infection for longer than 12 years; no HIV symptoms; and normal and stable CD4 lymphocyte counts. His 10 patients include: 9 men and 1 woman; 7 homosexual men, 2 IVDU men and 1 heterosexual woman. HIV infection was documented for over 12 to 15 years. The age range was 38-47 years. Ho has found that the viral burden, as measured by plasma HIV RNA and HIV DNA in peripheral blood mononuclear cells, among LTS is low. They have strong neutralizing antibody responses and strong CD8 antiviral responses, associated with control of HIV replication. He found evidence for HIV strains in LTS which are attenuated (weakened), i.e., they do not grow well in the laboratory even when the CD8 antiviral factor is removed. He also found no evidence of a host-cell resistance to HIV. Ho believes that LTS "have distinctive virologic and immunologic features to suggest that they are not merely one extreme of a normal distribution curve." In his studies of rapid HIV progressors, he found that they have increased viral load in blood and tissues, and that about half have syncytium-inducing (SI) viruses. Anthony Fauci, MD, and colleagues from the NIH presented their findings of 7 long-term non-progressors (LTN) followed at the NIH. Their definition for LTN is the one used in the MACS: HIV seropositivity at study entry; CD4 T-lymphocyte measurements for greater than 7 years, with a CD4 cell slope greater than or equal to zero (i.e., not declining); and no anti-HIV therapy. Their 11 patients included 10 men and 1 woman, with an age range of 32 to 46 years. His laboratory performed various measurements on lymph node biopsies from the LTN. They found that the germinal center area in the lymph nodes of LTN was the same as for HIV negative controls, but was abnormally elevated in HIV-infected progressors. When comparing the viral burden (DNA) in mononuclear cells found in lymph nodes, there was a lower viral burden in the LTN than in progressors. A similar pattern was observed in the DNA in mononuclear cells in peripheral blood, though the difference was not as striking. More impressive were the plasma viral burden (RNA) measurements comparing the 2 groups. LTN had a mean of 77,061 HIV RNA copies/mm3 of plasma (standard deviation 77,540), whereas 8 HIV progressors had a mean of 1,676,001 HIV RNA copies/mm3 of plasma (standard deviation 2,522,009). Fauci believes that it will be important to determine what allows for the maintenance of normal germinal centers in the lymph nodes of LTN. The disruption of normal germinal center architecture, he believes, is an important early event in HIV disease, long before the onset of CD4 T-lymphocyte decrease and AIDS disease symptoms. References Buchbinder S. Healthy long-term HIV positives: viral burden and cell-mediated immunity. X International Conference on AIDS. Yokohama, August 1994. Abstract 007C and oral presentation. Fauci AS. Host factors in immunopathogenesis. X International Conference on AIDS. Yokohama, August 1994. Abstract PS2 and plenary session oral presentation. Ho DD. Long-term non-progressors. X International Conference on AIDS. Yokohama, August 1994. Abstract PS10 and plenary session oral presentation. Ho DD. Presented at Treatment of HIV Disease: Advances and Future Challenges, University of California at Los Angeles (UCLA) satellite symposium. X International Conference on AIDS. Yokohama, August 1994. Levy JA. Presented at HIV Ten Years On: Research Findings and Future Prospects, tenth anniversary special session. X International Conference on AIDS. Yokohama, August 1994. Developments in Basic Science 100 Billion CD4 Cells Have HIV DNA Ashley Haase, MD, from the University of Minnesota Medical School gave an impressive plenary session oral presentation. Haase has developed a new in situ PCR technique to measure viral burden in resting cells in lymphoid tissue. He has found that "...during the early symptomatic stages... approximately 25% or more of the CD4 positive cells (and macrophages in lymphoid tissue and spleen) harbour HIV DNA, yet only about 1 in a 100 of these are actively productive." Haase continued, "If 25% of CD4 cells are infected~this translates into approximately 100 billion covertly infected CD4 cells. If only 1% of these are productively infected, this gives rise to one billion productively infected cells, which can account for the viral loads in the peripheral blood at one time." He felt that this indicated a need for "long-term effective anti-HIV treatment in the early stages of HIV infection~and a need for multiple types of inhibitors and combination therapy." References Haase AT. New molecular technology in HIV research. X International Conference on AIDS. Yokohama, August 1994. Abstract PS16 and oral presentation. Miscellaneous Presentations Pap Smears for HIV Positive Women as Effective as Colposcopy for CIN Carol Brosgart, MD, and colleagues of UCSF and the East Bay AIDS Center in Berkeley, CA, have determined that an adequately performed Pap smear of the uterine cervix in women is as effective as colposcopy for the detection of cervical intraepithelial neoplasia (CIN), a precancerous condition found more commonly in HIV-infected women. Colposcopy, less widely available than the Pap smear, traditionally has been thought to be more specific for the detection of CIN. References Brosgart C and others. Papanicolaou (Pap) smears versus colposcopy as screening tests for cervical intraepithelial neoplasis (CIN) in HIV-seropositive women. X International Conference on AIDS. Yokohama, August 1994. Abstract 079B and oral presentation. --------- Rectal Pap Smears for Men and Women With Rectal Sex History Joel Palefsky, MD, of UCSF reported on the prevalence of human papillomavirus (HPV) isolated from the rectums of 57 homosexual men with symptomatic HIV disease. HPV is associated with the development of anal cancer, which has been increasing in the AIDS epidemic. Early detection of a precancerous lesion would allow for earlier treatment and prolonged survival. After 1 year, the prevalence of HPV in the study increased from 67% at baseline to 84%. Dr. Palefsky said that although he used PCR testing, rectal Pap smears might also be useful. Rectal Pap smears might also be indicated in women who had engaged in receptive anal intercourse. References Palefsky JM and others. Anal infection with multiple HPV types in men with symptomatic HIV disease. X International Conference on AIDS. Yokohama, August 1994. Abstract 081B and oral presentation. --------- Subset of Gay Men Possibly Resistant to HIV Infection Roger Detels, MD, and co-workers from the UCLA School of Public Health have compared 23 gay men with multiple exposures to HIV over 21 years, who remained persistently HIV antibody- negative, to 137 gay men who seroconverted to HIV. The men were from the MACS. A subset of the groups were evaluated. For 90- 100% of 10 different clinic visits, the "HIV-resistant" men had higher numbers of white blood cells including lymphocytes and neutrophils. They also had higher numbers of leukocytes positive for the CD3, CD4 and CD8 markers, compared to the men who seroconverted to HIV. In addition, the HIV-resistant men had an increased frequency in the class-1 human leukocyte antigen markers A26, B38 and TAP1.4. The HIV-resistant men also had an increased prevalence of CD25+CD8+ cells. These findings could have applicability to vaccine and/or therapeutic research. References Detels R and others. Persistently seronegative men from whom HIV-1 has been isolated are genetically and immunologically distinct. X International Conference on AIDS. Yokohama, August 1994. Abstract 163A and oral presentation. --------- Increased Funding for Vaginal HIV Microbicide Research Several sessions on issues for women addressed the need for research into preventive female-controlled microbicides which could be placed into the vagina prior to intercourse to help prevent HIV transmission. William Paul, MD, from the Office of AIDS Research at the NIH indicated that his office is committed to providing research dollars for finding anti-HIV vaginal microbicides. Paul delivered a plenary presentation entitled, "A Turning Point in AIDS Research: the Search for New Frontiers." References Elias C. Presented at Female-controlled Prevention, special session SS2. X International Conference on AIDS. Yokohama, August 1994. Abstract SS7 and oral presentation. Paul WE. A turning point in AIDS research: the search for new frontiers. X International Conference on AIDS. Yokohama, August 1994. Abstract PS9 and plenary session oral presentation. Stein ZA. Women helping themselves. X International Conference on AIDS. Yokohama, August 1994. Abstract PS5 and plenary session oral presentation. Weiss E. Presented at Female-controlled Prevention, special session SS2. X International Conference on AIDS. Yokohama, August 1994. Abstract SS9 and oral presentation. --------- Cesarean Delivery to Help Prevent HIV Infection in Infants Martha Rogers, MD, reviewed a meta-analysis of 11 studies that evaluated the potential lower risk of HIV transmission from mother to newborn when delivered by cesarean section. Six studies showed a lower risk of transmission, while 4 showed a higher risk (and one revealed no difference). However, when the mother-infant pairs from all 11 studies were tallied for the meta-analysis however, there was a 20% lower risk of HIV transmission from cesarean section versus vaginal delivery. References Rogers M. Prevention of maternal-fetal transmission of HIV. Presented at Treatment of HIV Disease: Advances and Future Challenges, University of California at Los Angeles (UCLA) satellite symposium. X International Conference on AIDS. Yokohama, August 1994. --------- One-Third of World Population Infected With Tb Of the 5.7 billion people on the planet, one-third or 1.9 billion people are infected with Tb. Those who are co-infected with HIV and Tb number 5.6 million. Yet tuberculosis is considered a low priority in the world, according to Arata Kochi, MD, the Tb Program Manager for the World Health Organization. References Kochi A. Tb, a global emergency: World Health Organization report on the Tb epidemic. X International Conference on AIDS. Yokohama, August 1994. Oral presentation. --------- HIV Infection Worldwide (Cumulative HIV as of January 1, 1994) Adults Men Women Children Total 1 North America 1,123,000 963,000 160,000 4,000 1,138,000 2 Westem Europe 654,000 545,000 109,000 6,000 660,000 3 Oceania 27,000 24,000 3,000 < 1,000 27,000 4 Latin America 1,252,000 1,002,000 250,000 61,000 1,313,000 5 Sub-Saharan Africa 13,463,000 6,411,000 7,052,000 1,996,000 15,459,000 6 Caribbean 376,000 225,000 150,000 26,000 402,000 7 Eastern Europe 28,000 25,000 3,000 < 1,000 28,000 8 SE Mediterranean 57,000 47,000 9,000 2,000 58,000 9 North East Asia 93,000 77,000 15,000 1,000 94,000 10 Southeast Asia 2,952,000 1,968,000 984,000 68,000 3,020,000 Total World 20,025,000 11,287,000 8,737,000 2,175,000 22,200,000 Source: Global AIDS Policy Coalition, AIDS in the World, vol. II (Oxford University Press, 1995, forthcoming) --------- Aggressive Treatment for HIV Infection The following is an edited transcript of 3 BETA LIVE! telephone teleconferences held July 12, 14 and 19, 1994. Participants included Ronald Baker, PhD, Mark Feinberg, MD, PhD, Thomas Merigan, MD, David Katzenstein, MD and Mary Romeyn, MD. Dr. Mark Feinberg is Director of the Virology Research Laboratory at San Francisco General Hospital, where he also cares for patients at the hospital's world-renowned AIDS clinic. Dr. Thomas Merigan is Professor of Medicine at Stanford University, where he also directs the University's AIDS Clinical Trials Unit (ACTU). The Stanford program is part of a government-funded coalition of medical centers across the country that conduct human studies of AIDS treatments. Dr. David Katzenstein is Associate Medical Director of the AIDS Clinical Trials Unit of Stanford University. He is also co-directing a large government-sponsored trial (ACTG 175), a study among 2,500 people that is comparing the effectiveness of immediate versus deferred double- combination treatment for HIV infection. Dr. Mary Romeyn is an internist and community physician with an HIV practice in San Francisco. She has a special interest in nutrition and has written a book entitled, Nutrition and AIDS: A New Model for Treatment, scheduled for publication next year. Ronald Baker is editor of BETA. BAKER: Dr. Feinberg, let's start with a question for you. As you know, there's considerable controversy among physicians, researchers and even patients about the most appropriate time to begin anti-HIV treatment. Could you describe for us what is now known about the pathogenesis of HIV disease and how our understanding of this process may affect the decision of when to start drug treatment? FEINBERG: The understanding of the pathogenesis of HIV infection, or how the virus causes disease, is an incredibly important thing to consider when you're trying to figure out how best to treat it. Earlier in the course of the epidemic, after HIV had been identified as the cause of AIDS, the tools to detect how much viral replication was going on in HIV-infected people were really quite insensitive. As a result of that, there was a tremendous under-estimation of how much viral replication was going on throughout the course of the disease. It was believed that there was little viral replication going on during the asymptomatic period of HIV infection, and that viral replication would only be seen in the later stages of the disease, when people started showing signs of immunodeficiency, such as developing opportunistic infections. If there's not much viral replication going on, it seemed to make sense that you don't really need to treat people during the asymptomatic phase of the disease. As a result, a lot of the therapies were reserved for people in later stages of disease. We now appreciate that notion was fundamentally wrong. What allows us to say this are technological advances that have changed the way we think about the disease process. In the future, this new medical technology will have direct application to the care of HIV positive people, and will probably improve the outcome of that care. We now have tools that are very sensitive at detecting HIV replication in people. Studies using these tools of how much viral replication is going on in different stages of the disease give clear and striking answers. It's clear now that there is much more replication of HIV going on throughout the disease process from the time that one is first infected with the virus, during the asymptomatic period and increasingly in the later stages of the disease process. This leads one to an important theoretical conclusion: if the replication of the virus is what causes the disease (and we now have reason to believe that this is true) then it makes sense to try to intervene early, perhaps very early in the disease, when you first identify someone as being HIV positive. You want to preserve their immune function when it is maximal and the amount of virus replication is as low as it is ever going to be found in that individual. Unfortunately, as I'm sure everyone listening today knows, the results of the recent Concorde study of when to intervene with zidovudine [AZT] were not what everyone had hoped. The study conclusions were not a ringing endorsement for early intervention. It's important for us to think about why that might be the case. Is that because the notion of early intervention is wrong, or is it because AZT, when used by itself, is not a particularly potent anti-HIV drug? We now have ways to document if antiviral therapy is effective and beneficial. We also can apply those tools to try to individualize therapy: to identify which are the most active drugs for a given individual, to decide when those drugs may no longer be benefiting that person, and to know specifically when to change to another drug. I hope this will be translated into improved outcomes in the care of people, prolonging the quantity and improving the quality of their lives. The means to do this are not available today. It's going to take a lot of effort to make that happen. I hope it will be happening with increased vigor over the course of the next year. BAKER: Dr. Merigan, first, thank you for taking time from your vacation to join us. Mark mentioned the concept of individualized therapy. Could you explain what that concept means in the context of HIV disease? MERIGAN: For many years, even with imperfect tools, physicians have tried to monitor the impact of the drugs they're giving, and to avoid toxicity. Determining for example, whether a patient might have peripheral neuropathy, you could choose to use or not use a given drug. CD4 counts [T-cell counts] have been monitored as another way of determining whether the immune system was being protected. The problem is that CD4 cell loss is a relatively late result of increased changes in viral replication. It's better to look at the viral load itself. Our first efforts to look at viral load were by culturing the virus from plasma or cells. We found that people in advanced disease had higher levels than people with earlier disease, and that drug therapy reduced those levels. Now we have RNA detection methods for measuring viral load in the serum of patients. I think these techniques promise to be able to give day-to-day, minute-to-minute information as to whether we're suppressing virus in the patient. We actually want to move one more step closer. We want to see whether the drug is active or not by looking at the important drug-sensitivity loci, to see whether there is the smallest percentage of mutant virus arising in the patient. I've noticed that a patient sometimes develops a mutant virus at very low viral loads. So if you can identify those mutational changes, you can move even closer to the action of the drug. What we want to do is to use these drugs as long as they're active in a given patient. When we look at mutation rates, we see that some patients don't become mutant for 3 or 4 years, while others may do so in a few months. BAKER: Dr. Feinberg, both you and Dr. Merigan have mentioned "new tools." What are these tools, and what can we expect from them? FEINBERG: The new tools that I think are most promising are ones that measure the amount of HIV RNA (the genetic material of the virus that's found in the virus particles that are present in the blood) in the plasma of people who are HIV positive. There is enough HIV RNA present throughout the course of the disease process to be detected by the sensitive methods that are now available. T-cell counts drop after the amount of virus replication in an individual has already started to increase. Ideally, you would prevent that sort of damage before it happened. What these new tools do is permit us to look directly at the amount of virus in an individual. The amount of virus in an individual is frequently referred to as the viral load. Basically, these methods basically amplify a signal that is there so that you can detect minute quantities of HIV RNA. One of the methods to detect that signal is the so-called polymerase chain reaction or PCR, which is a very sensitive technique that amplifies the numbers of RNA copies. With certain modifications you can actually estimate the precise number there. So, ideally, if you had someone with 100,000 copies of HIV RNA in their blood, you would start them on treatment. You would want to see that number fall significantly, maybe down to 10,000 or 1,000. You could monitor the level of the HIV RNA in their blood at intermittent periods. If the drugs were losing their effectiveness, you would expect to see the copy number of RNA increase, which would tell you that it's time to change to another drug. These tools allow you to really individualize therapy. There are a number of versions of PCR in development. Hopefully, they will soon be available in a format that can be used in clinical labs and by physicians. They aren't validated for that use yet, so it's not going to be something that someone can go and ask their physician for tomorrow, but maybe next year. There's another technique that measures the genetic material of the virus, or HIV RNA, called a branched DNA assay [bDNA]. It works in a different way. It uses very sensitive probes to detect limited quantities of HIV RNA in the plasma. The bDNA test is probably closer to clinical usefulness. It's not as sensitive as PCR, but it's easier to use and slightly further along in its development. Hopefully, again, both tests will be available for clinical practice soon. But before that, it's going to be important to validate that, yes, this notion of individualizing therapy by decreasing viral load actually gives you a clinical benefit. MERIGAN: The tests will probably become available before they're completely validated. Probably next year, both the PCR and the bDNA tests will be available to more practicing physicians, but we will only have them document where we are with a given patient, and that's different than knowing that you can use it usefully. We're going to have to set up clinical trials with the final forms of the tests, and then show that knowing the information [HIV load] allows you to do better than if you don't know the information. We're having a lot of trouble designing those trials at present, but we are all committed to doing them. Another approach is to actually look at the key mutations of the virus. In ACTG 244 we're monitoring for the key mutation in AZT resistance, which takes place before the CD4 count drops, and we're seeing if switching drugs based on that really has an advantage for the patient. We're randomizing patients to continue AZT or combinations to see if the rational shifting of the drug based on what we think is the key mutation defends the immune system longer against destruction by the virus. BAKER: Thank you, Tom. Let's take a few questions now. San Diego, California? SAN DIEGO, CA: Good afternoon. Several different labs here in California are evaluating whether it's better to look at PCR as a qualitative or a quantitative test. Is there anyone out there who has done clinical trials to test this PCR, if it's going to be the surrogate marker of choice in the future? MERIGAN: We went back to specimens from ACTG 019 and ACTG 016 and looked at viral load. In some of the original AZT trials, we saw that using PCR you can measure quantitative viral load, and that when that rises in the patient on AZT, CD4 counts fall. We think that viral load is closely associated with CD4 changes, but it's a more precise measurement. If you look at patients on a day-to-day, week-to-week basis, it's much more steady as a signal, and we're talking about changes, as Mark said, from 10 to the 6 down to 10 to the 2. With the best drug combinations, you can get 2 and 3 changes. And as long as those continue, I think you're doing well with the drug, but we have to find that out, and that's why this validation phase is necessary. FEINBERG: I think that there is accumulating information about the utility of these tests. For instance, Tom referred to looking back at studies that had already been completed to see if you could learn more by applying these RNA tests, and he found that the answer was yes. There are other examples. For instance, studies of the Merck non-nucleoside RT [reverse transcriptase] inhibitor, the so called L-drug [L-554], where resistance was found to develop quite rapidly. You can see a dramatic fall in RNA levels, which then shortly afterward increase again because the virus has become resistant to the drug. PCR really does allow you to monitor in real terms the amount of replication going on in a patient. But the caller raises an important question: a number of these assays are being explored now in research laboratories to try to figure out what is best. I don't know that those are yet available to the average practicing clinician. It's important that these tests be performed by people who know what they're doing. Otherwise, the information you get can be very misleading, and I think that would be a disservice to the patient. MERIGAN: Two diagnostic companies, Hoffman-La Roche and Chiron, are very serious about this. Both are on a development track toward licensing their own kind of assay for looking at viral load. ACTG has gone through a number of prospective and retrospective studies with them. I think that these assays are going to be convincing enough for the FDA to license them. More and more drug companies are now using them in their trials of new drugs. That these assays are now available only in research labs is a necessary but temporary phase. In this disease we have to move quickly to make them available to practicing physicians. MIAMI BEACH, FL: Hi. This is for Dr. Merigan. I was one of the original participants in the ACTG O19 AZT study in 1985- 86. What is the outcome of ACTG 019, and what has it shown, generally, compared to the Concorde AZT trial? I believe that the conflicting results of these trials are keeping people off of AZT, when they may benefit from treatment early on. Thank you. MERIGAN: Well, I think you're certainly right that the release of the Concorde AZT information confused a lot of people. Concorde was basically not so much a direct comparison of drug to placebo, but rather a comparison of delayed versus immediate treatment. Once the 019 results were released, the patients in the Concorde AZT trial could start themselves, and their doctors could start them on therapy [AZT], even if they were in a placebo limb. The Concorde trial shows a more transient impact from AZT therapy on disease than we thought, based on data from the 019 study. The Concorde study indicated that the main impact of AZT was for the first 1-3 years of use, and it was better at higher CD4 levels than it was at lower CD4 levels. All of us who were in the original 019 study knew we wanted to get an active drug out there, and we thought we had seen a permanent, durable AZT effect. What has been disappointing, really, is that we've been slow to develop the followup drugs or the drugs to use in combination. It isn't because people weren't working on it, but that there were difficulties. A lot of drugs have fizzled out in late-stage testing. We're starting to develop a new class of drugs, the protease inhibitors. I think the protease inhibitors will meld in with the nucleoside analogs, [AZT, ddI, ddC, 3TC and d4T] and probably will only be used in combination. Some people like yourself, perhaps, did well with early initiation of AZT. On the other hand, the average patient probably gets a benefit from AZT of 1-2 to maybe 3 years. What we need to learn is when to move on to other drugs, or how to maximize the durable impact of AZT by combining it with other drugs. And I think we're continuing to learn more about both of those issues, as well as these diagnostic tests to help drive rational therapy. I know that people were looking for something that would completely normalize the process, like insulin for diabetics. Instead, it's more likely to be a matter of changing drugs periodically. My hope is to normalize the lifetime of an HIV- infected person. That's the driving principle in the field and what all of us want. I think it can happen, but it's going to take more drugs, more testing and new methods to evaluate drug activity. BAKER: Dr. Romeyn, a question for you. If an HIV positive patient who is asymptomatic or mildly symptomatic comes to you and says, "I want to pursue a very proactive, aggressive treatment strategy," what practical advice can you offer him/her in terms of drug therapy and other possible interventions? ROMEYN: Given what we've learned over the past couple of years about HIV, my own bias is more and more in favor of early and aggressive antiretroviral therapy. We saw in the European/Australian collaborative group study that people with high CD4 counts actually benefitted from antiretroviral therapy, and they had 650 CD4 cells on average. That's a powerful indication that there's value to early treatment. So given that, and given the fact that people with HIV don't have time to wait to be sure of what the results are going to be, I think when people ask for it, it's appropriate to offer treatment regardless of CD4 count. We now know that AZT has a more lasting effect before resistance develops in a less advanced population, and I think it seems reasonable for people to push that as far as possible while waiting for definitive data. We also know we have new drugs coming, something we just talked about. So if a patient wants to take an aggressive approach, and if the medicines are available, I think it's reasonable to throw everything we can at the virus right from the beginning. In my practice many patients start with combination antiretroviral therapy right from the beginning. We already have some evidence that this type of therapy is more successful in people with lower CD4 counts, and I think we'll look with interest at the results of ACTG 175 to find out what it does at an earlier stage. But for now, if a patient wants to jump right in with both feet, I offer both. We offer AZT in combination with ddI or ddC right from the beginning. We usually start the AZT at half dose, or about 100 mg 3 times a day, and we check with the patient by phone in about 2 weeks. If he or she is comfortable with the drug by then, and any side effects have been managed, we push the dose up to 500 or 600 a day. When they come back 2 weeks later, we start the next drug. That way if we have a problem, we have a better sense of which drug caused it, and we don't lose access to the other. Acyclovir also may have some value. It's been shown to increase survival in late-stage patients and I think there's some interest in using it in the early phases. Again, this is an aggressive approach, as we don't have proof of its impact on progression in early stages. But I think it's worthwhile to consider. In later stages we routinely recommend acyclovir. But what I'd really like to talk about is the whole picture of HIV treatment. I think of us as sort of getting ready for a marathon. If you go into training, you last longer, and you feel better while you do it. So we try to get our patients to prepare, to be stronger for what's coming up. Alcohol, for instance, has been shown to increase viral replication in vitro, so we discourage it. We recommend not smoking cigarettes. We particularly discourage methamphetamine and cocaine. We stress safe-sex activities to protect the HIV negative partner and, in the HIV positive patient, to avoid infection with other organisms which might trigger the acute phase response. As you can tell from the title of my book, Nutrition and AIDS: A New Model for Treatment, I have a special interest in maintaining nutritional competence. We've seen from the early Cotler studies that there's a clear correlation between the degree of wasting and the timing of death. This suggests that prevention and attenuation of the wasting process may give us a shot at longer survival, and I don't think any of us would question that it improves quality of life. So as soon as a patient walks in the door, we get a nutritional consult. We assess their lean body mass, urge them to pay attention to what they eat and how much, and to stay alert for abnormalities in their absorption. We continue to monitor their nutritional markers all the way through their disease course. We also recommend antioxidants, and everybody in the practice takes multivitamins and trace elements. For those who are asymptomatic or mildly symptomatic, such as you suggested, Ron, I prescribe progressive resistance exercises in the hope of adding to lean body mass while we can. We don't yet have information on the value of exercise in later stages. We also ask patients to watch closely for signs of infection, and to alert us quickly so we can get ahead of things. We stress hygiene and ways to avoid common infections. We stress sleep and recreation. We ask about stress and major areas in people's lives that are the focus for pain. I think some of these can be changed easily, and I think others should be considered for change over the long term. There are other things, too, you can do to be proactive. There are studies in cancer showing that survival can be increased by belonging to support groups. I think this should be suggested to patients. There have been some writings by Frankel on survivors of German concentration camps, who noted that probably a critical element to the people who survived was that they were dedicated to something outside of themselves. I think there's a real good way to apply that here, and to join the fight against HIV on a bigger level. We suggest that people participate in trials or studies whenever it could be to their advantage. We always urge membership in an observational database. We also suggest volunteering or political activity targeted to HIV. That's how we get started; then we go on to the drugs. BALTIMORE, MD: I am at a late stage of HIV disease. I have very low T-cell counts, in the single digits, and I have been on AZT for over a year. I'm considering changing to another drug. One of the suggestions that my physician had was d4T [Zerit], which was recently approved. But I have several friends who've had negative experiences with d4T, ddI and ddC, so I'm a little hesitant about going on d4T. Could any of the panelists talk about this? MERIGAN: I'll take a quick stab at it. I think d4T is a good drug for patients with advanced HIV infection. We don't have, however, a lot of experience with it in patients who aren't having problems with AZT or ddI or ddC. I think that the safety of d4T is pretty good. d4T is the one of these drugs [nucleoside analogs] where we have not yet seen a mutation pathway. I think the risk of neuropathy from d4T is less than 5%, and if you can catch it early, it's completely reversible. That's the downside. The potential rise in CD4 and arrest of virus replication is the upside. FEINBERG: I would agree with what Tom just said. The worst thing probably that would happen is you would try the drug for a brief period of time and find that it didn't suit you, that you experienced neuropathy. If you and your physician are aware of it, the drug could be stopped as soon as possible, and the neuropathy should go away. At this point, it might be a reasonable treatment to consider trying. ROMEYN: I'd like to say one thing. I think one consideration would be the possibility of continuing the AZT, and adding ddI or ddC. While it's true that there are resistant mutants that develop that still need attention, we continue to have a suppressed, wild-type virus in people who've been on AZT, and I'd rather not let that get away from us. I guess I'm more concerned about this in people with low CD4 counts, based on some of the suggestions that AZT prevents or at least greatly reduces the cytopathic changes in the brain on autopsy in late-stage HIV patients. I guess my own interest, if the virus had escaped AZT, might be in adding something, rather than changing to something. BAKER: Dr. Katzenstein, you're directing a large government-sponsored study that's comparing the effectiveness of early versus deferred combination treatment. If you were HIV positive and you had made the decision to start drug treatment, would you start with a combination of anti-HIV drugs or would you use only one drug? Please explain the reasons for your decision. KATZENSTEIN: Sure, and I welcome the opportunity to talk about decision-making in this, because that's what so many people are spending so much time doing. I think there are some fundamental principles in the world of infectious disease, which is where I trained, that are as applicable to HIV infection as to any other serious bacterial, fungal or viral infection. In terms of drug management, it's a very good idea for patients and HIV positive people to try to do one thing at a time so you can really assess what effect that one thing is having. This is a simple principle but one I have to constantly reinforce in the course of doing infectious disease consultations and talking to patients. It's a very important one with antiretroviral therapies, prophylactic therapies and, perhaps as Mary will be talking about later, even nutritional or alternative therapies. It's easy to embark on a course of treatment where there are multiple drugs or alternative immunotherapeutic agents, and then become embroiled in a very difficult situation where you're not sure which of the many things you may be trying is producing either a good or an ill effect. I don't think there's any compelling argument at the moment that shows that bringing all the elements and even combination therapy together at once in an individual patient achieves anything greater than the sum of their sequential addition. My advice to people is to certainly initiate at the point where they want to initiate antiretroviral therapy. Most experts recommend beginning somewhere below 500 CD4 cells. Most people recommend beginning with AZT, and to see how that affects you, your CD4 count and any of the different parameters which can either be measured at the moment or may be measurable in the future, such as viral load. In answer to your question, Ron, I would start AZT, wait a period of time, and then probably add a second antiretroviral drug, unless I was extremely happy with the response that I was getting from AZT alone. I think people should assess antiretroviral therapy the way they would almost any other therapeutic relationship with a drug. That is, if it makes you feel much worse, perhaps it's not the best drug for you, even if it's recommended at that phase of the disease. Some of the problems we've seen in people initiating AZT, including severe nausea or headache, are the kind of thing which I don't think should be tolerated for long periods of time. There's often a 1 or 2 month period of getting used to the drug, after which these side effects go away, so I encourage people to give it some time to be sure that they can or can't tolerate AZT. Perhaps to play with the dose to reduce it a bit if they're having a great deal of difficulty taking it. The second step would be to add a second antiretroviral. The jury is certainly still out as to whether it's best to start with combination therapy or to take monotherapy with AZT or potentially ddI initially, and then to move to a combination. We may have better information next spring about initiating single- agent vs combination therapy. ACTG 175 is scheduled to close in April 1995 and we'll begin analyzing all the data. BAKER: When is your Data and Safety Monitoring Board (DSMB) taking a look at the data? The trial has been going on for about 2 years now, hasn't it? KATZENSTEIN: That's right. And they've been looking essentially twice a year. At our upcoming DSMB meeting [August 1994] the blinded data will be revealed to the DSMB by the protocol statistician. It's possible, if there's a particularly dramatic difference, that the DSMB would tell us to stop the study. But it's more likely that we will continue until April 1995. We've tried to incorporate all the experiences of the last few years in terms of looking at endpoints. We began this study convinced that we could use the falling CD4 cells as an endpoint. Now, we use it as a means of deciding to switch people from monotherapy to combination, or if they're on combination, switch them to a different combination, based on a 50% fall in their CD4 count. In the wake of results from the Concorde AZT trial and concern about the importance of clinical as opposed to the surrogate marker endpoints, we made our constraints on stopping the study tighter. We said we wanted to see some difference in clinical endpoints before stopping the study. Now, because we started with a large group of people, but nevertheless a largely healthy group of people, we're not likely to see big differences in clinical endpoints. So, again, I suspect that we will continue until April '95. We should have very interesting comparisons in the rate of CD4 cell decline and the frequency with which people on monotherapy or combination have a loss of CD4 cells, but I can't tell you exactly how it's going to turn out. FREEHOLD, NJ: I have a question for Dr. Feinberg. Considering vital resistance factors, how would you treat patients who are on combination ddI and AZT who are failing that treatment? FEINBERG: I can make certain recommendations but it's currently difficult to know exactly what the right choice is. With the availability of d4T and, in many places, 3TC, adding to the list of the other approved nucleoside analogs such as AZT, ddI and ddC, people do have options. Things to consider would be trying to switch to an alternative of nucleoside therapy or, if possible, entering into a clinical trial of another agent, such as a protease inhibitor. BAKER: One immediate option that comes to mind is perhaps switching to Zerit (d4T), which will be available by prescription in mid-August. You might also want to consider combination therapy with ddI and d4T. There's a pilot study of ddI plus d4T that's recruiting now. FEINBERG: But it is important to see that study through, because both drugs can cause neuropathy. BAKER: Absolutely. Your physician would want to monitor you carefully for peripheral neuropathy, on that combination. A call from Detroit, Michigan. DETROIT, MI: The first question I'd like to ask is for Dr. Romeyn. If you found a patient who has been prescribed Bactrim to be allergic to it, would you consider desensitizing that patient as opposed to switching to dapsone, which may have a higher breakthrough rate than Bactrim? ROMEYN: Initially I probably would have already done a G6PD test, and I'd go ahead and try the dapsone, but frequently somebody who has a problem with Bactrim is also going to have a problem with dapsone. I am interested in Bactrim desensitization, and we've had a lot of luck with it, though I don't know that we call it desensitization any more. Initially we thought this [side effect from Bactrim] was an allergy, but now what we're finding is that it has to do with the body's inappropriate capacity to break down the drug. There are some metabolites that can make trouble if it's present in high doses. We have certainly had good luck working with the Bactrim suspensions, starting in low doses and eventually getting people up to the equivalent of one double-strength tablet, 3 times a week without much problem. Some new information has come out suggesting that the problem with the metabolism of Bactrim is part of the whole glutathione reductase process. Part of why we're doing so well with Bactrim may be because we're swarming our patients with antioxidants. BAKER: Any comments from the other panelists on desensitization for Bactrim/Septra? KATZENSTEIN: At Stanford we're using Dr. Marcus Conant's protocol, which was worked out with some of the pharmacologists at UCSF. I favor trying this desensitization regimen over switching because I think there's value to Bactrim prophylaxis that extends outside of PCP, in the world of other bacterial infections. Bactrim is a useful antibacterial agent against a number of common problems that might be listed among those that cause a lot difficulties for people with HIV, such as sinusitis and pneumococcus. BAKER: A recent study at UCSF showed that Bactrim not only was the best prophylaxis for PCP, but also for toxoplasmosis. That certainly would be an added advantage of using the drug, if people can tolerate it. WASHINGTON, DC: I have 2 questions. The first question is for Dr. Romeyn on her comment about acyclovir. I wanted her to clarify whether or not she suggests acyclovir should be used in all patients and if so, just as a suppressive regimen, or just in people with positive histories of shingles or genital herpes. ROMEYN: There have been studies that show that the daily use of acyclovir significantly increases the lifespan of people with HIV and AIDS who are also on AZT. In the atmosphere of managed care in San Francisco, I certainly would be happy to find a diagnosis that gave me an excuse to prescribe acyclovir. My interest would be in using acyclovir at any rate. There are many herpesviruses present in the body, possibly even some that we don't yet know about, but we do have evidence that some herpesviruses do act as cofactors in disease progression, others even than HSV-1 and HSV-2 or Epstein-Barr virus. I tend to test routinely when people come in for the presence of herpes-1 and-2 antibodies. It's very, very rare that I don't find them. Another indication for acyclovir that one can use to get the medicine for a patient is hairy leukoplakia. KATZENSTEIN: I think it may be important to note that the studies demonstrating the utility of acyclovir were in patients with low CD4 cell counts, and I think the caller's question, if I heard it correctly, was whether the use of acyclovir would be recommended at all CD4 levels or stages of HIV infection. WASHINGTON, DC: Yes, that's correct, Dr. Katzenstein. KATZENSTEIN: Although it's hard to come up with an argument against instituting it early, other than the $2,000 or $3,000 a year that it costs, I'm not sure that we have any real indications that for someone without recurrent herpes who's asymptomatic otherwise, and who has high CD4 cell counts, that we get any extra boost or bang out of adding chronic acyclovir to their regimen. Dr. Romeyn's quite right that the Australian study implied that people with CD4 cell counts of, I believe it was less than 100 and/or an AIDS diagnosis, seemed to benefit from being on chronic acyclovir. There isn't any evidence of efficacy of a combined regimen in asymptomatics, and certainly as part of early intervention it could be proposed, but there's little data to base it on. Is that a fair summary, Dr. Romeyn? ROMEYN: I would agree with that. I do think, though, that people who have HIV now sometimes are willing to base their behavior and their choices on theoretical or potential advantage, and I guess in this office we tend to operate from the "couldn't hurt" mentality once in a while. There's another study that showed a remarkably high amount and frequency of viral shedding from the oropharynx of persons with HIV who had positive antibody tests for herpes, but who had no idea that they had it. My real interest is in dampening the fires of the cytokine response, which essentially causes the conversion of monocytes to macrophages and the release of HIV which into the body, which increases viral replication. I would imagine we probably are on the aggressive side in this area. FEINBERG: I would also like to respond to that question. We need to understand exactly what the role for acyclovir in the treatment of HIV positive people is both mechanistically and practically. Dr. Romeyn's concerns about activating HIV replication by having these sort of ongoing chronic immune stimuli is a very important subject. If true, it has implications for all kinds of other infections that would be going on [in HIV positive people.] I would prefer to try to sort that out rather than just assume that it's true. Otherwise everyone who's HIV positive is going to end up taking multiple drugs, some of which they may not need. I think we need more information to really understand, if acyclovir does have a survival benefit, how it is mediated. GAINESVILLE, FL: Yes, I was wondering about protease inhibitors and also about peripheral neuropathy. KATZENSTEIN: Well, we now have a little experience with them in combination. There was an AIDS Clinical Trials Group study [ACTG 229], which you summarized in the most recent BETA very nicely, Ron, where there were clearly some short-term benefits, in terms of surrogate markers, to using protease inhibitors in combination with AZT and ddC. I think the protease inhibitors are going to be very useful for people who have experienced peripheral neuropathy on ddC, ddI or d4T, because they represent an alternative. SAN FRANCISCO, CA: In 1985 I only had 40 T-cells, and today I only have 10. I'm still alive. My question is, why hasn't there been an effort to develop a recombinant human T-cell growth factor? I know it's been used in laboratory experiments in virology to keep human T-cells growing in the test tube. Without the substance it's very difficult to culture CD4 cells outside of the body. But when you have this ingredient, the rate of success is much higher. So my question is, why hasn't somebody tried to develop a product like Neupogen, which is a recombinant granulocyte cell-colony stimulating factor? I think Neupogen infusions could be clinically useful. MERIGAN: Well, this is a 2-sided coin you're talking about. That is, activating the cells can also make them more able to replicate virus. Mark, I'm sure you could say something interesting about that. FEINBERG: There actually is a recombinant human T-cell growth factor. It's known as interleukin-2 (IL-2). Interleukin-2 has been evaluated in HIV positive people for [its possible] benefit. Some of those studies were conducted by Tom Merigan's group at Stanford, and he may want to talk about that. There are more recent trials that have some intriguing preliminary evidence about infusions of IL-2 being able to increase T-cell counts in people in the range of 200 or so, or higher than the caller's. But, as Tom said, it's a 2-sided sword. We don't really know whether those increases are beneficial, but we do know that HIV replication is activated by things that activate T-cells, IL-2 being one of them. It looks like there are short bursts of increased viral replication after you give someone IL-2. Whether that causes them any harm or not, we don't know, but it will have to be answered in clinical trials. It's important that trials with IL-2 move ahead. The problem with IL-2 being given to people with advanced HIV disease is not analogous to giving Neupogen to someone with advanced HIV disease. Not only does HIV damage T- cells, but it also damages the architecture of the lymph nodes, the thymus and other important lymphoid organs that are necessary for the maturation and development of T-cells. I don't think it's going to be so simple as just giving back the growth factor. We're going to have to figure out ways to fix or reverse the damage that HIV causes to the structures of the immune system as well. MERIGAN: And what we do may be very disease stage-specific. In our studies of IL-2, people also took AZT. One of the reasons we were one of the first groups to measure RNA viral load was that we had to do it because of the interleukin-2 studies. We were afraid that something that increased virus replication in vitro would do it in vivo. As Mark said, there's a small burst with each infusion, but we don't know whether that's bad or good. It does mean we have to go a little slower. Once patients have less than 100 CD4 cells, we haven't seen a big increase in their CD4 cell numbers with interleukin-2. It's really only from 100 to 200 that we might get a 25% increase, whereas some phenomenal increases of 200% and 400% have been seen in patients who had over 200, or over 300 CD4 cells. But we don't know whether those lymphocytes are educated and knowledgeable, whether they'll do anything to microorganisms, or anything useful for the patient. You have to know, are those dumb or smart lymphocytes, can they do the job lymphocytes have to do? Rebuilding the immune system is a new game, and we have to go at it thoughtfully. KATZENSTEIN: Interleukin-2 is a cytokine that is probably very important in the stimulation of T-cell replication, T-cell signalling and communication between macrophages and T-cells within the immune system. It's kind of a growth factor for CD4 cells, thought to promote their division and certainly their movement into the peripheral blood. Some promising results came from our laboratory as long as 2 or 3 years ago, as well as from the NIH and Dr. Cohen in New York, and one of his associates, Heady Kepler. All have published on CD4 increases in people receiving interleukin-2. That's the good news. The bad news is this is a difficult drug to take because it causes a myriad of systemic changes. It changes the vascular permeability of the lungs, causing the "6-hour flu-from-hell" syndrome in which people have a lot of watering of their eyes, stuffiness in their sinuses. A lot of interleukin-2 is presumably produced in the course of viral infection, so you get a kind of viral syndrome associated with high doses of it. Another thing that hasn't been sorted out yet is the duration of the effect on CD4 cells that has been documented in some patients receiving IL-2. Although people's CD4 counts go bouncing up, is IL-2 perhaps just causing a shift in the location of CD4 cells in the body? Is it causing a lot of CD4 cells to move out of the lymph nodes and the spleen, and into the peripheral blood, where they can be counted; do they then sort of disappear back from whence they came? Or are we really increasing the number of immunologically active CD4 cells [with IL-2 treatment]? There's a lot of encouraging work saying that people have somewhat better immune responses in vitro after receiving IL-2, but again, these effects tend to be fairly short-lived. The drug is fairly hard to tolerate, but it seems that it's not dangerous. By that I mean that people were also very worried about IL-2 being a sort of "pouring-gasoline-on-a-fire" kind of drug. We use it in the laboratory all the time to keep CD4 cells activated and replicating so they can grow virus [for us to use in experiments]. We've done PCR measurements of viral load in people receiving interleukin-2, and so far we're comfortable with its safety. We've always done this in people who are simultaneously receiving antiretrovirals. We require all of the patients to whom we give IL-2 to at least also take AZT, and often another antiretroviral as well, because of the concern that unopposed CD4 activation could cause a lot of virus replication, and make things worse. Also, IL-2 is expensive. So I guess that's the good news/bad news. It would be an experimental therapy that you'd have to do with a physician; there's no guaranteed information about whether it's going to help or not, but it's something which can be done. You can follow your own CD4 cell counts after receiving IL-2 and see how it makes you feel, and look at the range of side effects that are occurring and ask yourself, is it tolerable? Those are all possibilities as long as you're on an antiretroviral. From the work that's been done in several laboratories that have tried to look at changes in viral load, I don't think IL-2 poses the danger that was initially one of the concerns about it. ROMEYN: One of the concerns that I have about interleukin-2 is that we also know it as one of the metabolic or immunoregulatory triggers for the anorexia and the metabolic disregulation that contribute to the wasting response. I may be particularly attuned to that because we work so hard to maintain lean body mass here. Since we are working with weak cytokine blockers now to block or attenuate IL-2 and other cytokines, I have a concern about giving IL-2 to the same organism that on the other end of the spectrum we're trying to protect from IL-2. SHELBYVILLE, IN: I'd like to know about the benefits versus the detriments of using AZT and ddI together in people with CD4 counts over 500. ROMEYN: We offer it. If a patient is anxious to take their one shot in the absence of confirmed information as to what that one shot should be, and if we're willing to monitor them carefully, and be sure that what we're doing isn't going to harm them, then I'm comfortable with that. We actually have a couple of people in our practice on AZT and ddI who have CD4 counts over 800. BAKER: Any other comments on using double-combination treatment in early disease? FEINBERG: Right now it's impossible to give someone an honest answer to the question about whether it's beneficial or not. Right now I would agree with Dr. Romeyn that it's really a personal decision, and that if someone wants to go ahead with it, it wouldn't be unreasonable. But, quite honestly, it would be a decision for which the available clinical data has no real guidance. BROOKLYN, NY: Hello. I'm wondering why the Centers for Disease Control added cancer as a criteria for AIDS. Is there a higher incidence of it in HIV-infected women? KATZENSTEIN: I can talk about what we're starting to do at Stanford. It's a difficult area because the risk factors associated with cervical cancer or genital neoplasia in general are often the same risk factors associated with the acquisition of HIV: having early sexual activity, having many sexual partners. Herpes simplex used to be associated with cervical cancer; now the papillomavirus is much more closely linked to cervical neoplasia. And all of those things are increasingly common in the general population, and probably somewhat increased among women who are HIV positive, often because of other things that have taken place in their life that may or may not have much to do with the HIV. There is an increased frequency of abnormal Pap smears in HIV positive women, so we recommend Pap smears every 3 or at least 6 months, with prompt referral to a gynecologist who can look carefully at the cervix when there are abnormal results. We're working right now to better understand how changes in the cervix and/or the presence of other papillomaviruses impact HIV replication and, potentially, relate to maternal fetal transmission of HIV. These and many other phenomena in HIV in women are not well understood, because we haven't studied a large number of HIV positive women in this country. ROMEYN: I would agree with that. I would also like to note that not only is there an increasing frequency of abnormal Pap smears, but there is a truly alarming increase in the rate of change of an abnormal Pap smear. We may already be seeing progression in the patient who doesn't keep her appointment for colposcopy and who gets a repeat Pap smear in 4 to 6 weeks. When it does occur, it looks as though the progression from initial dysplasia to cervical carcinoma is very rapid. If you are a woman with HIV it's important to maintain good vaginal and genital hygiene to try to prevent infections and bacterial imbalances, which can promote a low-grade chronic activation of immune response. NEW YORK, NY: I'm HIV positive and currently asymptomatic. I wanted to ask the panelists what they see as being the next generation in HIV management. I'm looking at antiviral therapy and combination therapy, and I'm curious to know what might be in the research pipeline. MERIGAN: Two things that are really starting to take off now are cell and gene therapy. An article in today's New York Times that discusses a chimpanzee transplant is an example of how imaginatively we're willing to think. In that spirit, new kinds of immunotherapy and gene therapy to block deterioration of the immune system, match donors or even animal transplants are being considered. We're beginning to get a good strategy for early intervention, but patients present at a variety of stages of infection. And, patients who have been treated for a long time can get to very low immune cell numbers, and we've got to have a strategy to try and reverse that. This is a new but important undertaking, and we're going to push very hard. Perhaps some of you've heard of Project Restore Immune Function, sponsored by Project Inform. I think it's made a lot of investigators realize that we need to work on the lower end of the CD4 spectrum, to come up with new ideas. It's a complex undertaking because we really don't know enough about the immune system. We're like the transplanters 30 years ago. I was an internist then, and I remember thinking how radical those surgeons were, and now that's all become standard, accepted practice. IRVINE, CA: I don't think I have wasting syndrome, but what signs should I look out for? I've lost a lot of weight, and I have a low CD4 count. No OI [opportunistic infections] ever, just shingles. What do I look for? ROMEYN: Well, I think the first thing I would do if I were you is get a nutritional consult. What you look for is, number one, how much and what kinds of food you are taking in. People who are HIV positive tend to eat less than people who are negative, and people who have secondary infections or OI as well tend to eat even less. Secondly, you may want to rely less on dairy products for your nutritional needs, as lactase deficiency and therefore lactose intolerance is an early factor in HIV. I would also try to determine what your absorption is like. If you are not absorbing well, that can be addressed. In addition, I would pay attention to your triglyceride counts. If they're going up, it's time to begin to look aggressively for occult opportunistic infections which can activate your immune system in such a way that they cause your body to inappropriately use those nutrients that you take in, using them to make fat and spending your protein. I would suggest to you that weight loss is not only enough to raise a concern about wasting, but is one of the later manifestations of wasting. It would be worthwhile to get an idea of what your lean body mass is. If you're healthy and essentially asymptomatic, progressive resistance exercise may be a helpful way for you to put on weight. Otherwise, there are supplements that can be taken. There are several standard nutritional interventions to the wasting syndrome, but you have to start by knowing you have it before you can treat it. BALTIMORE, MD: This is for Dr. Romeyn, about nutrition. You said, in an aggressive diet, cut out all processed foods, go to freshly cooked food, etc. ~do you have any other comments on that? ROMEYN: To eat things that taste good certainly does a lot for quality of life. What I'm really concerned more about, in terms of aggressive supplementation of diet, is if you can take in calories properly and if you can absorb properly. RANCHO MIRAGE, CA: Is there a place for alpha interferon or even a combination of alpha interferon and 3TC in treating a patient who has pretty much run the gamut of the neucleosides, including Zerit? FEINBERG: I don't know if Tom Merigan wants to address that; I can comment on it. There's really no clear indication that that specific combination would be beneficial or that alpha interferon administered in the long term would be beneficial. It does seem to have an antiviral effect, but unfortunately we don't know as much about that as I think would be good to know. Certainly alpha interferon can have side effects that make it less than optimal to take on an ongoing basis. BAKER: Another problem is that 3TC is available only through expanded access. HONOLULU, HI: I have a question for Dr. Romeyn. I'm a nutritionist that works with small children. How do your treatment recommendations, as far as nutrition, exercise and the use of antioxidants differ for small children, as compared to adults? ROMEYN: That's a good question. I actually researched it extensively in the process of hoping to write a book on pediatric nutrition in kids and in women, but I found there has not been a lot of work done on that. I will say that the antioxidant studies which have been done in vitro are interesting in their ability to slow the replication of the virus. We know this isn't going to hurt adults. We know it isn't going to hurt kids. It's inexpensive and appears to me to be a wise approach. I don't treat children so I don't know about doses, but certainly if I had a child who was HIV positive, I would be aggressive with antioxidant therapy and with vitamin therapy, as well. SAN FRANCISCO, CA: Hello. My question also has to do with antioxidants. A lot of people seem to be recommending beta carotene, but there's a lot of variance in the recommended dosage. Do any of you, perhaps Dr. Romeyn in particular, have any suggestions about adult dosage of beta carotene or any other antioxidants? ROMEYN: I have some suggestions, but the fact is we don't have any answers. Some studies have been done at a level of 60 mg a day, but very little work has been done. Certainly 60 mg a day is not likely to hurt you. I do monitor my patients to make sure they don't turn orange. We recommend 30 to 60 mg/day. My guess is it may be possible to go higher. But we're guessing at this time in terms of making practical applications of antioxidant therapy. We do have our cookbook recipe that we recommend to people, but I'm not sure that any validity has been assigned to those numbers at this time. SAN FRANCISCO, CA: I also wanted to know how milligrams [mg] translate into international units [IU], which is how they seem to measure it when you buy it at the market. ROMEYN: I think 15 mg of betacarotene is 25,000 units of vitamin A. I'm hope I'm right. BAKER: I would refer the caller to the March '94 issue of BETA. There's an extensive article there on the use of nutrients, including antioxidants, in HIV infection, along with a comprehensive chart of suggested dosing. AUSTIN, TX: This is for any of the panelists. What would you recommend for people who declined to take antiretroviral medication? FEINBERG: I feel that it's most important to honor people's feelings about how they want to approach therapy. I would want to make sure that they had all the information that was available or, if something new became available, that they were informed of it so that they could reevaluate their decision, but I do think that it's a decision that a patient can make. If my patients choose to make that decision, I respect their ability. ROMEYN: I'd like to add something to that. My own bias is in favor of aggressive treatment, but it's true that it's important not to impose your bias on patients. My sense of the people who refuse antiretrovirals is that they fall into 2 categories. One is a group of people who don't trust the establishment or don't trust doctors, and the other is a group of people whose personal life philosophy involves leading a life of great delicacy and health orientation. If it's a matter of not trusting doctors, you can spend time with these people, and do a lot of listening as well as talking. I make my pitch once with everybody. If they feel that it is criminal to assault their body with antiretrovirals, then we're in a position to urge them to be extraordinarily responsible about other aspects of their health care, which include exercise, stress education, antioxidants, getting the calories in, whatever it takes that are basic health practices. If that's all we have to work with, I try to work with them very hard. MERIGAN: I'd like to add to that. Another point that is important is appropriate prophylaxis. When the patient drops to low CD4 levels, we know we can get benefit and predictable impact. You really can cut the risk for opportunistic infections with appropriate prophylaxis for people with low CD4 cell counts. AKRON, OH: This question is for Dr. Romeyn. Have you had any experience with testosterone or the transcrotal patches they're using for wasting syndrome? ROMEYN: Well, we do have a lot of interest in testosterone supplementation. We do testosterone supplementation in this office but only when we have a testosterone level that documents hypogonadism. In late-stage HIV this is common. I do not have experience with the new scrotal patch. I have one patient who swears that he will be our test case. My own experience here is that people would rather come in for a shot every 3 weeks than place a patch on their scrotum. So far we haven't had a whole lot of takers. I'd be interested in the experience of others with it. BAKER: What about the potential benefit of using testosterone to treat wasting syndrome? ROMEYN: Morris Schambelan and Marc Hellerstein, who did the growth hormone study at San Francisco General, did trial runs with testosterone and with growth hormone when they were deciding what to study. They decided that growth hormone was the one to go with. There is a lot of interest in testosterone, though, and there is actually a study, I believe, in formation at San Francisco General Hospital. We don't have any results yet beyond theory to tell us that there is definitely going to be a benefit to lean body mass from testosterone supplementation. There seems to be an increased sense of well-being from the testosterone injections, but I haven't been doing them long enough yet to know if that's a placebo effect. I think we will have to look to the clinical studies to tell us exactly what the benefits are. Theoretically, testosterone could produce an increased sense of well-being and an opportunity to maintain lean body mass. MONTEREY, CA: This is a question for Dr. Romeyn. It's on the same level as the last question. Can you talk about using growth hormone for wasting syndrome? ROMEYN: A few small studies have been published. Growth hormone has been used previously in non-HIV people who showed a deficit of lean body mass, and was helpful in laying down lean body mass. With the exception of the studies on progressive resistance exercise in early asymptomatic people, we really haven't come up with anything yet that helps build lean body mass as opposed to holding on to it. These growth hormone studies seem to show that it may do that. The effect, which appears to be significant, seems to be more profound during the early part of treatment. However, the product [human growth hormone] is extremely expensive and moderately inconvenient, and there have been 1 or 2 cases of side effects. In fact, one person developed diabetes, although I believe that was resolved with cessation of treatment. Ongoing treatment with growth hormone right now would be enormously costly. I'm not sure that we see that the benefits are maintained if the injections are not maintained, nor have we yet seen if continuing treatment involves continuing, increasing benefit. However, growth hormone is incredibly exciting. I think that Kathy Mulligan and the other people who have been working on this feel that if enough benefit is shown, if there's an indication for it, and if enough people want it, we could get the cost down. It's still only available in research settings. I was actually fortunate to be around when a pilot study was beginning in 1988. It's only anecdotal, and there's not enough research yet, but I can't tell you what it looks like to watch people put on 2.2 kg in the space of a week. It just knocks your socks off. If I had HIV and were wasting, I'd be in a hurry to get my hands on some of that stuff. PHOENIX, AZ: This question could be for any of the panelists. Just to give us all some hope with this disease, what do you see as the most promising treatment in the future and do you anticipate a cure or a vaccine? FEINBERG: There are a number of advances that I'm optimistic about. The availability of the protease inhibitors is an important step in the right direction. Not that these drugs will necessarily be panaceas but, as Tom Merigan suggested, protease is another target in the virus that we can attack, which gives us more choices. The way the protease inhibitors are being developed now is an interesting process, i.e., going about it by understanding what the target is and trying to specifically focus a therapy on that target. We are better able to do that with the protease drugs than we've been able to do with the reverse transcriptase drugs like AZT, ddI, d4T, ddC and 3TC. Even if these drugs [protease inhibitors] don't work the first time around, it will be possible to improve their design. Having more targets and having more drugs is beneficial but, in and of itself, it isn't enough. What you need is a way of knowing whether these drugs are working. You need to be able to identify the best time to intervene, and the best combinations of drugs for a given individual, and know when to switch the therapies. That is something that will be standard of practice in the next year or so. For me, these are really hopeful signs. I don't know that there's going to be a cure for this disease, although I certainly hope there will be. Perhaps a more feasible goal to pursue now would be if we could simply turn this into a disease that was really a bit more like diabetes, where people can lead normal lives for long periods of time. Do I think there's going to be a vaccine? That's a hard question to answer, because to make a vaccine for HIV you would have to be able to do things that no other vaccine has been able to do for other diseases. For all the diseases for which there are successful vaccines, there is what's called natural immunity. If someone gets exposed, their body can fight it off, eliminate that agent, never to be infected with it again. The fact that HIV causes a chronic infection that the immune system can't get rid of is a major challenge that we don't know enough about yet. MERIGAN: I agree with Mark's outline and his sense of where we're beginning to succeed. I'd add one more component: in addition to chemotherapy, we should be able to set up specific and nonspecific immunotherapy that will be effective against the virus. In years to come, it will be, as Mark said, a matter of chronic suppressive therapy. We have no means at the present time of getting rid of the virus for now so we just have to suppress it, and know where we are in that process all the time. BAKER: Thank you all for your excellent questions. I want to report briefly now on recent AIDS drug developments, and to mention important open studies that are actively recruiting for volunteers. One recent and welcome development mentioned earlier in the program is that the U.S. Food and Drug Administration has granted accelerated approval to the experimental drug called d4T. Its tradename or brandname is Zerit. It appears to be about as effective against HIV infection as AZT, and has a different toxicity profile. FDA approval of Zerit is a welcome development, because it offers people with AIDS a new anti-HIV treatment option. In approving Zerit, the FDA has suggested that the drug be used only by people who have failed all other approved drugs, i.e., who have failed or are intolerant to AZT, ddI and ddC. But now that Zerit is FDA-approved, physicians can prescribe it for any HIV positive patient. You may want to speak with your doctor about whether Zerit can benefit you. The drug's manufacturer, Bristol-Myers Squibb, has said that Zerit will be available in pharmacies by August 15th. The wholesale cost of Zerit will be about $6 a day for a daily dose of 40 mg taken twice daily. The cost to consumers (patients) will be higher, and will vary depending on where you buy it. --------- Accelerated Approval for Protease Drug As many of you have read in BETA and elsewhere, probably the most promising anti-HIV drugs that are likely to be approved in the near future are the protease inhibitors, a new class of anti-HIV drugs. About a dozen pharmaceutical companies are now developing protease drugs. The protease drug that is farthest along in development is called Inverase. The results of a government-sponsored study of this drug were released earlier this summer [June 1994]. The most promising results of this study were among people who took Inverase in a triple combination of Inverase plus AZT plus ddC. Individuals using these 3 drugs together had greater increases in their CD4 T-cell counts and greater decreases in the amount of HIV in their bodies, compared to other people in the study who took the double combinations of AZT plus ddC or Inverase plus AZT. Simply stated, it looks like taking these 3 drugs together may produce more benefit than taking only 2 of them together or one of them alone. Based on these and other study results, it's likely that the FDA will be asked to grant accelerated approval to Inverase. This would mean that doctors could write prescriptions for Inverase for their HIV positive patients. The drug would be widely accessible. Without accelerated approval from the FDA, Inverase probably will not be available by prescription for several years. If you support accelerated approval for this promising new protease drug, it's important that the FDA hear from you. I urge you to write or fax the Commissioner of the FDA. His name is Dr. David Kessler; his office address is 5600 Fishers Lane, Rockville, Maryland, 20857. Or you may want to fax Dr. Kessler. His office fax number is 301-443-3100. Your letter or fax could be short and simple. Simply let Dr. Kessler know that you support accelerated approval for Inverase because people with AIDS need access to promising new drugs as soon as possible. --------- Open Studies I want to mention some studies that are now open to enrollment. First, the largest enrollment openings currently are for Phase III trials of Inverase. They are open to enrollment for up to 1,800 volunteers at 40 sites in the United States and Puerto Rico. In Europe, about 1,200 people will be enrolled in Inverase Phase III trials. For the location of individual study sites, and for information about entry criteria for this study, call Hoffmann-La Roche at the following toll-free number: 1- 800-526-6367. In addition to the Inverase trials, human studies of 6 other protease drugs are also ongoing. There are 2 protease drugs from Abbott Laboratories, 2 from Merck, and 2 from Searle. But right now, only the Hoffmann-La Roche and Abbott protease drug studies are open and actively recruiting. [Since the teleconference, enrollment into Abbott protease studies has ended.] --------- Aspirin, Tagamet, Zantac One interesting experiment managed by the Community Research Initiative in New York City, is an 8-week study of aspirin using 1,000 mg a day of aspirin among 50 asymptomatic individuals with 50 to 350 CD4 cells. Researchers are also recruiting for a 12- week and a 16-week study of Tagamet and Zantac, both commonly used drugs for stomach ulcers, that may have some benefit for HIV positive individuals. These studies will enroll 400 asymptomatic or symptomatic volunteers with 200 to 700 CD4 cells. There are a number of sites for this study, including New York City, Boston, Milwaukee, Houston and others. Curcumin is also being studied. This is an orange-yellow substance found in the spice turmeric. This new study will enroll 40 volunteers in the greater Boston area. A one-year pilot study of Zerit plus ddI is now open; the study is designed to test the Zerit/ddI combination among 75 people who have had no previous use of AZT or ddI, and no history of pancreatitis or peripheral neuropathy. The study sites are New York City, Los Angeles and San Francisco. Earlier in the program, Dr Feinberg discussed recombinant human growth hormone. There is an open study comparing human growth hormone to insulin-like growth factor. These are both genetically engineered products. The study will enroll 30 HIV positive children aged 6 months to 18 years who exhibit failure to grow. The antioxidant NAC (N-acetylcysteine) is being studied in the San Francisco Bay area. Participants in this 8-week, Stanford University-sponsored study, may have between 0 and 500 CD4 cells, and be taking AZT, ddI, ddC or d4T for at least 4 months. [Since the teleconference, enrollment has closed.] There are several large, open studies of nevirapine in double and triple combinations with AZT, ddI and ddC. About 1,600 people are being recruited for these 3-year Phase II/II studies at 52 medical centers. [Accrual into nevirapine trials has been suspended, pending results of an FDA review. For more information, see the report in this edition of Research Notes.] Passive hyperimmune therapy. This treatment involves taking plasma from healthy HIV positive donors who have high levels of HIV-neutralizing antibodies. The plasma has been processed to inactivate HIV, and it is then infused into patients with AIDS. This is a 2-year Phase III trial that's recruiting 600 volunteers with 50-400 CD4 cells. Finally, thymopentin, also known as TP5. This is a one-year study at 22 sites with 2,100 asymptomatic individuals who are also using some other anti-HIV drug. TP5 is self-administered by subcutaneous injection. The telephone number to call for more information on all open AIDS clinical studies in the United States is toll-free, 1- 800-874-2572. Dr. Merigan, Dr. Feinberg, Dr. Katzenstein and Dr. Romeyn, thank you for participating in today's teleconference. Many thanks as well to Hoffmann-La Roche for providing the educational grant that supports these free BETA LIVE! teleconferences. ****** Accelerated Approval for New AIDS Drugs Faces Uncertain Future Ronald Baker, PhD Ronald Baker is editor of BETA. The New York-based treatment activist organization Treatment Action Group (TAG) has generated considerable controversy in the AIDS community by asking FDA to slow the approval process for new AIDS drugs. In addition, TAG has lobbied FDA to deny early approval to saquinavir, the promising protease inhibitor drug from Hoffmann-La Roche (Roche). In discussions with FDA and others, TAG has argued that saquinavir is not a suitable candidate for accelerated approval because the drug has been studied in too few patients for too short a time. For this reason, its safety for humans is uncertain, according to TAG. In addition, TAG argues, the use of surrogate markers (e.g., CD4 count and viral load) to evaluate the effectiveness of the protease inhibitors is untested and therefore suspect. Current FDA policy allows drug sponsors to use surrogate marker endpoints (such as increases in CD4 counts) as data to support a drug's candidacy for early approval. Roche had been expected to apply before the end of 1994 for accelerated approval of saquinavir in combination with AZT and ddC, based primarily on promising surrogate marker results from ACTG 229. This Phase II study among 302 participants compared saquinavir in a triple combination with AZT and ddC to 2 double combinations: ddC plus AZT and saquinavir plus AZT. Results show that the 3-drug combination is significantly better than the 2-drug combinations in reducing viral load and in increasing CD4 counts. Although neither FDA nor Roche will comment on their discussions concerning saquinavir, reliable sources say that FDA has asked Roche not to apply for accelerated approval of the drug at this time. Many community activists believe that TAG opposition to early approval of saquinavir influenced FDA's decision. "Placebo-controlled trials of drugs for life-threatening illnesses are considered unethical by many community members and physicians." --------- The TAG Proposals In a letter to FDA Commissioner David Kessler in June, and in a closed meeting with top agency officials in July, TAG has argued against considering saquinavir for accelerated approval: "Saquinavir is not yet an appropriate candidate for an accelerated NDA [New Drug Application]....We feel that such an approval would penalize people with AIDS/HIV by setting an inappropriately low standard of evidential requirements that would govern the regulation of this entire class of therapies. We urge you not to invite Hoffmann-La Roche to apply for accelerated approval of saquinavir until we can complete further discussion between FDA, its advisory committee, the company and people with AIDS/HIV. " (TAG letter to FDA Commissioner David Kessler. June 20, 1994.) The TAG letter argues further that in order to receive accelerated approval, the protease inhibitors first must demonstrate clinical benefits (e.g., significantly delayed disease progression or significantly increased survival time). To evaluate the clinical benefits of the protease inhibitors, TAG has proposed implementing a large simple trial (LST) that would attempt to enroll within one year 18,000 participants taking a protease inhibitor or placebo, with 3-4 years of follow-up. The primary endpoint of the trial would be an AIDS-defining event or death. --------- Concerns About Large Simple Trials for AIDS Drugs There are several reasons for widespread community concerns about the TAG proposals: (1) There is no evidence that a LST will provide more or better data on AIDS drugs. (2) Placebo- controlled trials of drugs for life-threatening illnesses are considered unethical by many community members and physicians, especially in studies that have AIDS-defining conditions or death as clinical endpoints. (3) An LST of protease inhibitors with one-third of participants expected to take placebo likely would never enroll enough participants to yield meaningful data. (4) The manufacturers of protease inhibitors would be unwilling to provide free drug to thousands of participants in a lengthy study. (5) Several community groups oppose LST because of the difficulties related to recruiting people of color into trials scheduled to run for several years. LST cannot gather meaningful data reasonably quickly and economically. The most cost- and time-effective way to evaluate AIDS drugs is in smaller studies that enroll fewer people for less time. Moreover, future studies of AIDS drugs likely will rely heavily on the use of powerful new diagnostic technology~quantitative PCR and branched chain DNA (bDNA) assays. Widespread use of these new tests may change dramatically the design of clinical studies of AIDS drugs. When used to best advantage, these tests promote an efficient use of financial and human resources in clinical trials while still yielding important information in a relatively short period of time. Many researchers believe that this fast, sensitive technology will promote a better assessment of drug effectivenss in individual patients and to a more reliable and faster evaluation of anti-HIV AIDS therapies in clinical trials. --------- AIDS Community Reactions Many AIDS advocates, including this writer, regard the TAG proposals as well-intentioned, but unfortunately, also outdated, unworkable and too costly. Most importantly, implementation of these proposals would be devastating to people with AIDS whose pressing medical needs require that they have the earliest possible access to new therapies. Early access to promising new drugs such as saquinavir is a fundamental right for people who no longer benefit from available treatments. As Martin Delaney of Project Inform wrote in a consensus statement addressed to FDA: "People with HIV and AIDS in recent years fought aggressively for the right to earlier and broader access to new therapies than was afforded by clinical trials. This hard-won right must not be threatened or rescinded by efforts to solve other possible problems in the drug development process." Many AIDS researchers, clinicians and activists believe that 3- and possibly 4-drug combinations that include at least 1 protease inhibitor currently offer the best hope for effective, sustained control of HIV activity. Without early approval of a protease inhibitor, patients remain restricted to monotherapy or combination regimens comprised of nucleoside analogues, a class of drugs that offers limited clinical benefits for a limited time. "Early access to promising new drugs such as saquinavir is a fundamental right for people who no longer benefit from available treatments." In August, Merck and Company announced that it will not seek accelerated approval for its lead protease drug, L-524. In addition, Merck said it may take up to 3 years to bring L-524 to market, due to a limited drug supply and other difficulties. Within 3 years, thousands of people with AIDS may die awaiting access to a protease inhibitor that might help to improve the quality of their lives and extend their survival. With increasing frequency, patients are calling physicians and AIDS hotlines to ask how and when they can get a protease inhibitor. Because saquinavir is the protease inhibitor farthest along in development, the demand for access to this particular drug will increase dramatically in the coming weeks and months. There are 3 mechanisms through which patients might gain access to saquinavir: clinical trials, parallel track and accelerated approval. (1) Clinical trials: Many if not most HIV positive individuals do not qualify for enrollment in clinical trials of the protease inhibitors because of their prior use of other anti-HIV drugs. (2) Parallel track: The high costs of producing the protease inhibitors makes it extremely unlikely that these drugs will become available though parallel track, an FDA program through which drug companies provide experimental drugs free to patients who have failed on all approved therapies. (ddI and d4T first became widely available through the parallel track.) (3) Accelerated approval: For the vast majority of people with AIDS, the accelerated approval program is the only hope for access to saquinavir and other promising new drugs. Established by FDA 5 years ago, this program provides promising AIDS drugs to patients through the simple mechanism of a prescription written by a physician. FDA could make saquinavir available by prescription within the next 6 months if the agency would evaluate the drug using existing criteria for accelerated approval. Because early studies show that saquinavir demonstrates "reasonable" safety and a "reasonable" promise of clinical benefit, it appears to meet current FDA standards for early approval. Under prevailing FDA rules, drugs for life-threatening illnesses need not demonstrate clear clinical benefits in order to win early approval. Rather, the clinical efficacy of these drugs are determined in post- marketing studies that follow accelerated approval. The FDA can revoke approval and remove the drug from the market if it fails these evaluations. --------- Drug Company Perspective A recent front-page article in the financial magazine Barron's entitled "Do We Have Too Many Drugs for AIDS?" carries the subtitle, "In a turnabout, some AIDS activists are now asking the government to slow down its drug approval process." The article suggests that FDA intends to revise its accelerated approval policies, making it more difficult for new AIDS drugs to get to market. Raising the hurdle for accelerated approval of promising new AIDS drugs will send a chilling message to AIDS drug developers large and small. The content of that message reads something like this: "Spend millions on developing experimental AIDS drugs that may or may not be approved for marketing after up to 5 years of clinical testing. And remember, no early marketing of compounds unless they show clear clinical benefits!" This misguided policy may provoke a discontinuation of AIDS drug research and development by both large pharmaceutical firms and the smaller biotechnology companies that now are risking huge financial investments on AIDS research. If these companies cannot bring promising therapies to market early through the mechanism of accelerated approval, there will be little incentive for them to develop new AIDS drugs. --------- FDA Responsibilities When FDA grants accelerated approval to drugs based on surrogate marker endpoints, the drug's sponsor is required by FDA to conduct "post-approval" clinical studies to verify the drug's clinical benefit. If these studies are not carried out, or if the studies fail to show a clinical benefit for the therapy in question, FDA may withdraw approval and remove the drug from the market. It is the responsibility of FDA to ensure that these post-marketing studies are adequately designed and implemented. FDA itself has determined the rules governing accelerated approval, and also decides which drugs are appropriate candidates for early approval. However, individuals and communities most affected by the AIDS epidemic, in particular people living with HIV infection and AIDS, should have significant input regarding these issues. FDA has the responsibility to weigh carefully the views and suggestions of diverse community organizations and individuals before altering existing guidelines on accelerated approval for new AIDS therapies. When the FDA Antiviral Advisory Committee meets on September 12 and 13, 1994, the topic for consideration will be "Early Access to Drugs for Life-threatening Illness: Improving the Process." The purpose of the meeting is to hear comments from people living with HIV infection and AIDS, the pharmaceutical industry and the advisory committee on all aspects of the current mechanisms for early access. --------- Community Consensus Statement A coalition of community groups is gathering signatures on a consensus statement that calls on FDA to retain existing standards for accelerated approval of the protease inhibitors and other promising AIDS drugs. The coalition is comprised of the following community organizations and publications: Project Inform, San Francisco AIDS Foundation's BETA, ACT-Up Golden Gate, AIDS Treatment News, ACT-UP New York, ACT-UP NY~Treatment and Data, Positive Awareness Coalition (PAC), Community Consortium, Direct Action for Treatment Access, Mobilization Against AIDS, National Association of People with AIDS, ACT-UP San Francisco, ACT-UP East Bay, Search Alliance Los Angeles, AIDS Foundation of San Diego, Physicians Association of AIDS Care (PAAC), PWA Coalition of Dallas, The Committee of Ten Thousand, Atlanta Buyers Club, AIDS Survival Project, Atlanta, Los Angeles City AIDS Commission, Robert Smith Medical Group, Housing Works. Other community groups are expected to sign the document as they become aware of the important issues involved. --------- A Role for BETA Readers It is important for BETA readers who support existing FDA guidelines for accelerated approval to send a signal of support for this policy to FDA. Consider making a personal contribution to the community effort to preserve early access by signing and mailing the "Dear Dr. Kessler" card inserted in the September issue of BETA. Also consider asking your friends, healthcare providers or other concerned individuals to fax or write a brief note to Dr. Kessler in support of accelerated approval for saquinavir and other promising AIDS drugs. Write or fax: David Kessler, MD, FDA Commissioner, 5600 Fishers Lane, Rockville, Maryland 20857. FDA FAX: 1-301-443-1863. ***** The Implications of AIDS for the Development of Therapies and Vaccines: A Pharmaceutical Industry Perspective R. Gordon Douglas, Jr., MD R. Gordon Douglas is President of the Merck Vaccine Division of Merck & Co., Inc. This article is based on a presentation made at the AIDS History Group Conference on "AIDS and the Public Debate," held at the National Institutes of Health in Bethesda, Maryland, on October 28, 1993. A fully documented version will appear in the conference proceedings: Caroline Hannaway, Victoria Harden, and John Parascandola, eds., AIDS and the Public Debate: Historical and Contemporary Perspectives (Amsterdam, The Netherlands: IOS Press, 1994). Finding effective treatments for those infected with HIV is clearly one of the top priorities for biomedical research today. This worldwide effort involves thousands of researchers in the basic and clinical sciences at academic, government and industrial laboratories, including Merck. Indeed, a 1993 survey by Pharmaceutical Research and Manufacturers of America (PhRMA) reports that 103 medicines and vaccines are in development by 74 different companies. This essay discusses Merck's efforts to develop new therapies and vaccines for AIDS and places those efforts in the context of the pharmaceutical industry's overall approach to the problem. I'll discuss the critical success factors involved in the assault on AIDS, some of the difficulties we face in clinical research and regulatory review, and the challenges of distributing new therapies to the patients who need them around the world. I'll conclude with a brief overview of the Inter-Company Collaboration for AIDS Drug Development, an unprecedented consortium of 15 leading pharmaceutical companies designed to help hasten the process of finding effective treatments. First, let me note that Merck's objectives are to develop the most effective therapies and vaccines for AIDS in the most efficient manner possible, and get them licensed and delivered as quickly as we can to patients whose lives depend on them. In the best of times, drug or vaccine discovery and development is a risky business. But because HIV is such an intricate virus and AIDS is such a complicated and deadly condition, they present extraordinary challenges to the global medical community. Nonetheless, I'm confident that we will succeed in finding treatments and preventives for AIDS, but it will take cooperation between the private and public sectors, and it will not be easy. Despite the strength of our commitment, resources are finite, and there are limitations on what industry can realistically do, or be expected to do. Government's role~and responsibility~in this search is to fund some of the basic scientific research that provides a foundation for the development of new antivirals, immunostimulants and vaccines. Government should also work with industry to overcome the hurdles inherent in bringing these products to the marketplace. The pharmaceutical industry's role is to discover, develop, manufacture and market new vaccines and therapies. Working together, government and industry need to overcome a number of major hurdles. --------- Critical Success Factors in the Assault on AIDS There are 4 basic critical factors to consider in developing effective treatments and preventives for AIDS: technical feasibility, sustaining incentives for innovative research and development (R&D), overcoming difficulties in clinical research and regulatory review, and how to distribute the new therapies to people in need. --------- Technical Feasibility Available therapies so far have been hampered by toxicity and limited effectiveness. For example, patients on AZT face the threat of anemia; ddI patients can develop pancreatitis; and ddC patients sometimes experience peripheral neuropathy. An allied problem with current therapies as well as many of those in early clinical trials is the rapid onset of resistance. This has led to a strategy of trying to develop combination therapies (discussed in more detail below). But HIV has proven to be remarkably adaptable, making it impervious to many of the weapons now available to fight it. There are 2 key aspects to this adaptability. First, the virus mutates rapidly in the face of challenges from different antiviral agents. That property alone would not necessarily be a problem, if the mutant strains were not robust enough to survive and if they did not remain virulent. However, HIV's turnover time is so fast, its mutation rate so high, and the number of progeny of each generation significant enough that selection pressures quickly lead to the dominance of resistant strains of the virus. Add to that the relatively high virus titers in infected individuals, and we find that HIV can respond to a therapeutic challenge with new strains resistant to the agent within a matter of weeks. Just as important is the antigenic variation of HIV, which has major implications for vaccine research. Unlike other viruses, such as measles, mumps and rubella (which don't mutate) or influenza viruses (which, while known for variable antigenicity, change slowly enough that an annual change in the vaccine is sufficient), HIV varies so extensively and unpredictably, both among a population and within an infected individual, that we have been unable to find a vaccine that can combat it effectively. Finding an effective vaccine assumes we could define what constitutes effective immunity, which we have not been able to do yet, either. Furthermore, successful therapeutic agents against AIDS will need to deal with these unpredictable properties of HIV without the drawbacks of toxicity. That has proven to be a tall order, despite dozens of research projects with various approaches to developing vaccines and inhibitors of reverse transcriptase, HIV-1 protease or the regulatory protein, Tat. --------- Sustained Incentives for Innovative R&D The United States leads the world in drug discovery because our research system is an effective partnership between government, academe and private industry, and because our free market economy has provided an environment that supports sustained innovation. Government excels at basic research, both in its own laboratories and through funding of academic science. Industry, which also does basic research, excels at developmental research and manufacturing, the most costly and time-consuming phases of the process. Government scientists facilitate clinical studies, but they do not generally conduct or pay for the clinical research, process R&D, quality control, regulatory development work and manufacturing investment required to bring new therapies to patients who need them. Vaccine development provides a good example of the complexity of the process and the institutional, economic and social pressures involved. "Merck's objectives are to develop the most effective therapies and vaccines for AIDS in the most efficient manner possible, and get them licensed and delivered as quickly as we can to patients whose lives depend on them." In 1983, there were 11 companies involved in the discovery, development and manufacture of vaccines in the United States: now there are only 4. Merck is one of only 2 U.S. -based firms still in the business, and only one other company manufactures vaccines in the U.S. If claims that vaccine profit margins are excessive were true, one would expect to see a reverse trend. Instead, company after company decided to leave the industry. In the 1970s and early 1980s, the key reasons were low profitability and increased liability. The National Vaccine Injury Compensation Program, created by Congress in 1986 and implemented in 1988, provided a measure of stability on the liability front. A few more pharmaceutical and biotechnology companies have entered the field since then, largely through mergers and strategic alliances designed to develop new pediatric combination vaccines. But the added stability on the liability issue has been offset by the troublesome threat of decreased revenues for vaccine developers from the Clinton Administration's original Vaccines for Children program. While we share the goal of assuring the availability of vaccines to children whose families cannot afford them, the Administration's policy supporting universal purchase of vaccines at discounted rates for distribution by government agencies is problematic on several counts. For instance, the U.S. General Accounting Office has stated that vaccine costs are not an obstacle to childhood immunization, and that the costly Vaccines for Children program will not result in more kids getting their shots. Indeed, it is clear that this initiative will not improve immunization rates~which depend crucially on the infrastructure for delivery and on effective communication with parents, not on the price of the vaccines~but it will have an impact on the profitability of vaccine manufacturers by eroding the returns on sales revenues, which balance the discounted prices for public-sector purchases and the prices available to children of insured and affluent families. (This erosion would result from shifting the 50-50 public/private market balance to a private market of less than 20%.) This situation, in turn, will force developers to reconsider their long-term commitment to investment in the discovery and development of new vaccines (including AIDS vaccines), if adequate returns are neither predictable nor certain. This includes continued industry research on new and improved vaccines, including combination vaccines and heat- stable, oral delivery and timed release forms, which public health officials agree is one certain way to address barriers to immunization. More than anything else, government should provide the stability to ensure a steady flow of research funding for the development of promising new vaccines. Recent claims that the U.S. federal government itself funds and conducts the majority of basic research leading to the development of new vaccines are simply incorrect, in part because they grossly underestimate the R&D spending of the vaccine industry. In fact, industry is the leading source of new funds for vaccine research and development of new vaccines. Most of the vaccines currently in use have come from the private sector; examples include vaccines to prevent measles, mumps, rubella, polio, pneumococcal pneumonia, hepatitis B, hepatitis A and Haemophilus influenzae type-b meningitis. Worldwide research spending for major vaccine companies is some $400 million, and Merck alone invested more than $100 million in vaccine research and development in 1992. Vaccine research and production are delicate, time-consuming and resource-intensive. The ability to maintain a flow of new capital and profits for re-investment in basic research and capital investment for manufacturing is critical to the development of new vaccines and other therapies. The threat of decreased revenues for vaccine products (a real possibility with the constraints of the Omnibus Budget Reconciliation Act of 1993 and the Administration's policy of encouraging universal purchase) will inevitably mean a decline in private-sector R&D investments in coming years and a slowdown in the discovery, development and introduction of new life-saving vaccines. --------- Overcoming Difficulties in Clinical Research and Regulatory Review It is becoming increasingly clear that the road to a safe, effective and successful AIDS vaccine is longer and more tortuous than we originally expected. Initially the scientific community had high expectations because we thought that basic virology and immunology would lead quickly to finding a simple component of HIV that would produce a vaccine. But this view has proven naive, and a moment's reflection from the viewpoint of vaccinology explains why: all effective vaccines involve the duplication of a naturally occurring protective immune response to the infective organism. But with HIV, we've found no evidence of this protective response among infected individuals, a factor that wasn't sufficiently appreciated earlier. Secondly, early efforts were focused on relatively simple proteins or glycoproteins of HIV, e.g., gp160 and gp120. Most effective vaccines involve whole viruses or whole bacteria, except where pathogenesis is known to involve only a single virulence factor, e.g., tetanus, diphtheria or Haemophilus influenzae type-b. Moreover, HIV has a unique capability of adapting to immune system responses. This aspect of AIDS is what makes our basic biological and clinical research so challenging. But once a viable vaccine candidate does emerge, a productive partnership between the public and private sectors will be absolutely essential. Early safety, tolerability and efficacy studies of an HIV vaccine will take place primarily in the United States and Europe, but large-scale efficacy trials will depend on populations in developing nations. Mastering the logistics alone (not to mention the intricacies of study design and analysis) will require close industry and government cooperation. Merck has the expertise to design efficient, scientifically rigorous and medically sound programs to achieve licensure. But we will need to work closely with the National Institutes of Health (NIH), the World Health Organization (WHO) and other government laboratories on studies to evaluate vaccines in special populations, to test alternate dosing regimens or formulations and to assess the impact of pre-existing disease conditions in patients receiving an HIV vaccine. Particularly important is the need to develop an international consensus on standards for demonstrating the safety, immunogenicity and protective efficacy of new vaccines. Such standards will provide advance guidelines to developers on criteria for eventual approval and adoption of vaccines in development, and will thus encourage the risk-taking and investment needed to complete the costly clinical development phase for new vaccines. --------- Distribution to People in Need Obviously, it's not enough to have an effective therapy; we must find ways to deliver it to patients in need. Gross inefficiencies exist in healthcare delivery systems for under- served populations, both in the United States and in the developing world. Without an infrastructure on which to build a distribution network, no amount of innovative resources, economic incentives or technology transfer will overcome these barriers and ensure access to populations at risk of HIV infection. Equally important will be a mechanism to pay for the vaccines and other new therapies, particularly in countries in the developing world. Policy-makers cannot rely solely on industry to solve these problems. Let's take an example to show the magnitude of the task. Since 1987, Merck has donated supplies of MECTIZAN (a human formulation of the antiparasitic ivermectin) to agencies and governments around the world to treat people infected with onchocerciasis, or "river blindness," a painful and disfiguring illness endemic to certain equatorial regions. This donation program has been enormously successful, having treated more than 6 million affected individuals. But even after working with the WHO's Onchocerciasis Control Programme and a variety of voluntary agencies, MECTIZAN has yet to reach all who need it, despite the geographical concentration of the disease in equatorial regions of Africa and Latin America. With an AIDS vaccine, even this solution is not possible because the populations at risk are too large to support a similar program. The only existing mechanism industry generally has to subsidize the cost of vaccine sales and distribution in the developing world would be the price differential between sales in the developed world and sales elsewhere. Political as well as financial considerations limit how large that differential can be. Thus the solution to finding efficient ways to ensure the availability of new vaccines to all those who need them around the world will necessarily involve complex considerations of technical feasibility, economic resources, public policy and political will. One novel response to this challenge is Merck's recent project to transfer the technology for manufacturing recombinant hepatitis B vaccine to China, where hepatitis B is a major public health problem affecting both children and adults. The magnitude of the challenge is daunting. There are 360 million children in China who are at risk. Some 150 million Chinese are carriers of hepatitis B and thus at increased risk to develop primary liver cancer. Of the 20 million children born in China each year, 1 in 10 acquires chronic hepatitis B from its mother. To combat the spread of hepatitis B, the Chinese government turned to Merck. Under a 1989 agreement, Merck sold to the Chinese the know- how to produce the vaccine and worked with Chinese engineers, quality control and production people, first in the United States, then at China's National Vaccine and Serum Institute, to design and then construct a plant in Beijing to manufacture 20 million pediatric doses of hepatitis B vaccine annually. The Beijing plant opened in October 1993; a second manufacturing plant, opened at Shenzhen in June 1994, has a similar capacity. China thus has found a mechanism to tackle a severe health crisis and to protect the lives of its 360 million children by developing indigenous expertise and manufacturing capabilities. This case illustrates dramatically the need for public and private sector cooperation to meet these challenges around the world and to move forward quickly to provide society with important new drugs and vaccines to conquer not just AIDS, but also the many other devastating diseases of our time. --------- What is Merck Doing About AIDS? Having reviewed the critical factors that will govern our success in developing new drug therapies and vaccines for AIDS, let me turn to what we have been doing at Merck. We have made a major commitment to AIDS research for nearly a decade: in fact, it is one of the largest research programs in our company's history. We are investigating the development of active preventive vaccines, antiretroviral drugs, passive immunoprophylaxis and agents to prevent and treat opportunistic infections. Several drug candidates have entered clinical trials to date. But the route to a successful therapy has not been easy. For a sense of just how complex and risky drug development is, let me describe in some detail our decision last year to terminate development of the pyridinone non-nucleoside reverse transcriptase inhibitor, L-697,661. Merck researchers had high hopes for this promising class of compounds when clinical development began in the fall of 1990. We conducted preliminary clinical trials of 4 reverse transcriptase inhibitors and, based on clinical and preclinical data, chose L-661 for further development. Monotherapy trials began in December 1990. In anticipation of the development of resistance, the Company began combination trials in the summer of 1991 in Germany. Clinical proof of the development of resistance to the monotherapy came in less than 12 months, but combination trials continued for a full year and a half, into 1993. We had hoped that by increasing the dosage and by combining L-661 with AZT (which inhibits reverse transcriptase through a different mechanism), we could slow down or prevent the resistance that we saw with L-661 alone. While it was safe and well-tolerated at the higher dosage~and did show significant dose-related activity against HIV-1~resistance still broke out rapidly and could not be suppressed. Moreover, this resistance problem made it likely that L-661 would not enhance AZT therapy; that is, the combination was no better at sustained viral suppression than AZT alone. On the basis of these disappointing results, Merck decided that we should not hold out false hope to patients about L-661. Accordingly, in early September 1993 we decided to stop development of this compound. As HIV mutated rapidly against the drug challenge, the early promise of L-661 as a possible combination therapy with AZT was dashed. As is so often the case in pharmaceutical R&D, the basic and clinical research failed to lead us to the discovery of a life-saving compound. Simultaneously, Merck had invested millions of dollars on a risk basis for parallel development of chemical processes to manufacture enough drug in the event of expanded trials. In the process, Merck researchers did gain valuable knowledge about the molecular biology of HIV (how specific strains of the virus developed resistance), and about the bioavailability and pharmacokinetics of L-661 (and, by extension, this class of compounds). But after years of research effort and millions of dollars invested, in a certain sense we were "back to square one." We are continuing our efforts to discover and develop inhibitors that act against other enzymes of HIV. One of those targets is the enzyme HIV protease. Merck research on this enzyme began in 1985. Early structure determinations were used to develop models for protease inhibitors that would work effectively in vitro and, hopefully, in vivo. Five years of dedicated, difficult research led to a product candidate, but it failed in animal safety assessment early in 1990. It took 3 more years before another suitable product candidate was found, and clinical trials of the HIV-1 protease inhibitor, L-735,524 began in February 1993. The goal was to assess safety and tolerability and to make a preliminary assessment of L-524's antiviral activity. The early results provided evidence that L-524 was generally safe and well-tolerated (although there was some concern about elevated liver enzymes in some of the patients in the earliest trials). A pilot antiviral activity study that began in June 1993 at the University of Alabama in Birmingham and at Thomas Jefferson Hospital in Philadelphia, Pennsylvania, showed sufficient evidence of antiviral effect to proceed with the clinical development program. Accordingly, a phase II clinical study was begun in October 1993 to test the antiviral effects of L-524 monotherapy (at 200 mg every 6 hours [q6h] and 400 mg q6h) in 60 HIVseropositive, p24-antigenemic patients with CD4 counts below 500 cells/mm3. Another small study was initiated to investigate the safety, tolerability and biological activity of L-524 at 600 mg q8h. These studies showed encouraging signs that L-524 has a significant antiviral effect, measured by decreases in p-24 antigen and plasma viral RNA. Patients on L-524 also exhibited improvements in CD4 counts, weight and hematological parameters. But after a number of weeks of treatment with L-524, the level of viral RNA in some patients began to rebound, and eventually returned to near-baseline levels. At the same time, the associated rise in CD4 counts also leveled and returned, in some cases, to near-baseline levels. This pattern could indicate the emergence of viral resistance. Our immediate response was to halt plans to expand the clinical program rapidly and to explore the causes of the viral rebound more fully. Merck's clinical scientists increased the dose of L-524 to 600 mg q6h for all patients in the trial that began in October, since in their judgment (and in consultation with outside investigators), this increased dose would be generally well-tolerated by most patients and might increase the antiviral effect. We also began small clinical studies to test the safety, tolerability and antiviral activity of L-524 in combination with AZT in AZT-naive patients with CD4 counts less than 500 (now underway), and L-524 together with AZT and ddI (set to begin in late August or September 1994), also in AZT-naive and ddI-naive patients with CD4 counts below 500. An additional 60- patient study (involving individuals with CD4 counts between 150 and 500 cells/mm3) will also be conducted this fall to optimize the dose of L-524. We will not know until early in 1995 whether the higher dose of L-524 or of L-524 combined with AZT and ddI is successful in overcoming viral resistance. As yet, the number of patients studied remains small and we are gaining clinical data daily. We are keenly aware that HIV is a wily opponent, and it's still early in the game. While the world anxiously awaits, progress has been slower than we hoped, and we have looked for other ways to speed up the development process. --------- The Inter-Company Collaboration for AIDS Drug Development The innovative solution to this concern was the Inter- Company Collaboration for AIDS Drug Development, a virtually unprecedented consortium of 15 leading pharmaceutical companies that have made a commitment to pool their efforts in order to identify the most effective AIDS therapies in the shortest possible time, and to deliver them to the patients whose lives depend on the success of our efforts. The AIDS Collaboration was announced in April 1993, with the specific goal of working together to facilitate early human effectiveness trials of combination drug therapies to fight AIDS and HIV infection. The objective is to expedite comparative studies of different investigational compounds by sharing scientific information and drug supplies, and by collaborating on certain aspects of drug development such as assay standardization. The movement to create the AIDS Collaboration was led by Merck Chairman Dr. P. Roy Vagelos and by Dr. Edward M. Scolnick, President of the Merck Research Laboratories. Dr. Vagelos and Dr. Scolnick along with other research leaders and scientists realized that, because of its unique adaptability, HIV was likely to develop resistance to every antiviral compound tested against it. At the same time, more and more compounds were becoming available for possible use in combination therapies that might mitigate the resistance problem. Discussions among leading companies took place for more than a year before the formation of the AIDS Collaboration to design a structure that would maintain competitiveness~to foster continued innovation~while catalyzing the sharing of data and compounds at an early stage in clinical development, where it might make a difference in the daunting odds against success. The Collaboration is not a "Manhattan Project" for AIDS: it is not a public-sector initiative, nor are the scientific processes of HIV infection as well understood as nuclear fission was when J. Robert Oppenheimer and General Leslie Groves began their work during World War II. But the Collaboration's ambitious focus is appropriate for the current state of knowledge, and together, perhaps we can speed the development of effective AIDS therapies. To date, the Collaboration's participants include: AB Astra, Aji Pharma, Boehringer Ingelheim, Bristol-Myers Squibb, Burroughs Wellcome, DuPont Merck, Glaxo, Hoechst AG, Hoffmann-La Roche, Merck, Pfizer, Miles (on behalf of its German parent company, Bayer), Sigma-Tau, SmithKline Beecham and Syntex. All pharmaceutical companies actively involved in HIV antiviral development are eligible to join the Collaboration, and researchers from universities and government, as well as representatives from the HIV community, are consulted and kept informed on a regular basis. In addition, Dr. Scolnick and Dr. Stephen Carter (Bristol-Myers Squibb) from the Inter-Company Collaboration have been appointed to the National Task Force on AIDS Drug Development (chaired by Dr. Philip R. Lee, Assistant Secretary for Health of the U.S. Department of Health and Human Services). The Collaboration meets periodically, and the exchange of basic scientific data on prospective antiviral agents is well under way, along with discussions on such issues as standardizing assay methodology and creating databases for antiviral resistance and historical controls. One of the most exciting results of the Collaboration's first year of activity, a consensus protocol for the rapid evaluation of triple-drug combinations for the treatment of AIDS, was announced at the inaugural meeting of the National Task Force on AIDS Drug Development in April 1994, by Dr. Juergen Drews of Hoffmann-La Roche, the Chair of the Collaboration's Scientific Panel. The consensus protocol, developed by the Collaboration's Clinical Trial Subcommittee (led by Dr. David Barry of Burroughs Wellcome), uses a continuous cohort variable regimen modeled after a strategy that has led successfully in the past to treatments for leprosy, tuberculosis and certain cancers. The selection of the triple combinations to be evaluated under the master protocol will be based on available clinical data generated by Collaboration members and scientific evidence of additive or synergistic effects of the combinations in cell culture, as determined by a standard laboratory protocol also developed by the Collaboration. The overall objective of the protocol is to identify those triple combinations of HIV antivirals that can produce significant decreases in plasma viral RNA and sustained increases in CD4 counts. Studies conducted under the master protocol are only pilot studies to identify truly effective triple combinations of HIV antiviral compounds. Additional studies will then be done to evaluate further the long-term safety and clinical benefit of triple combinations that look promising. The first combinations planned by the Collaboration will test various combinations of AZT, ddI, ddC, 3TC, saquinavir and nevirapine. The master protocol has been reviewed by the FDA, and the Collaboration's Clinical Trial Subcommittee is now revising the protocol and preparing to implement the trials this fall. Collaboration might seem antithetical in such a competitive environment as the pharmaceutical industry. But, as George W. Merck observed in 1950, "Medicine is for the people. It is not for the profits...." The critical need for effective AIDS therapies means we must make our best collective effort to surmount the problems faced. By pooling our knowledge about available drug candidates and cooperative clinical trials of these agents in combination, we are confident that we can develop new AIDS therapies more rapidly, thus benefiting the patients who need them and strengthening our own research efforts for new generations of therapy. --------- Conclusion The Inter-Company Collaboration for AIDS Drug Development is the most recent innovation on the AIDS research front. It offers our best hope to optimize the chance of discovery and development of medicines that work against this elusive enemy and to expand and expedite access to new AIDS drugs. But I don't want to minimize the inherent risks or the uncertainty of our efforts. For the Collaboration to succeed with an effective AIDS drug, establishing technical feasibility is not enough. In addition, we will need public and private sector cooperation to assure that the regulatory review process is quick and that delivery mechanisms don't impede our ability to reach patients in need. Most importantly, we must preserve a climate that encourages investment in innovation. That investment is our strongest guarantee that we will ultimately be able to stop the AIDS epidemic. ***** Update on the Merck Protease Inhibitor (L-524) Ronald Baker, PhD Background In early studies, the Merck protease inhibitor L-524 showed promising results, reducing substantially the amount of HIV in the blood plasma of study volunteers. However, HIV load in these individuals returned to near baseline levels within a few weeks, probably due to the ability of the virus to develop resistance to L-524. Ongoing Phase II studies are evaluating the safety and effectiveness of L-524 at varying doses as monotherapy, in a double combination with AZT and in a triple combination with AZT and ddI. Phase III trials, tentatively planned to start in the spring of 1995, may enroll up to 1,800 volunteers. In a meeting with treatment activists on August 22, Merck made a commitment to circulate for community input a draft concept sheet on the design of the Phase III trials. --------- L-524 Approval Timeline: 1997 According to Merck, FDA has informed the company that the agency will not consider surrogate marker data alone as sufficent evidence for accelerated approval of the protease inhibitor drugs. Merck says it intends to develop L-524 as fast as possible in Phase II and Phase III studies that will evaluate the drug using clinical endpoints (e.g., AIDS-defining illnesses). Merck does not plan to apply for accelerated approval of L- 524, nor will the company seek "expanded access" status for the drug. Expanded access is an FDA program that provides promising experimental drugs free to people who have failed on all approved anti-HIV therapies. "At this time we do not have enough data on the safety and efficacy of L-524 at its projected dose to begin large trials or to consider expanded access," said John Ryan, MD, Executive Director, Infectious Diseases, Merck Clinical Research. The decision not to establish an expanded access program for L- 524, says Merck, also is due to the company's current inability to manufacture an adequate drug supply for a program that might enroll up to 10,000 people. "L-524 is the most complex molecule Merck scientists have ever discovered," according to Paul Reider, PhD, Executive Director, Merck Process Research. In addition, Merck says, the high dose of L-524~potentially as high as 3 grams daily~presents an unprecedented manufacturing challenge. It will take about 3 years for L-524 to win FDA approval, assuming no major obstacles arise in the course of the Phase II and III studies. ***** HIV Disease: New Tools, New Understanding Mark B. Feinberg, MD, PhD Mark B. Feinberg is Director of the Virology Research Laboratory at San Francisco General Hospital and Associate Director of the Center for AIDS Research at the University of California at San Francisco. It has been approximately 10 years since the discovery of HIV and its identification as the cause of AIDS. Since then, tremendous progress has been made in understanding fundamental aspects of the biology of HIV. It is probably fair to say that we now know more about HIV than any other virus or infectious agent that causes disease in humans. Yet, all too obviously, we still do not have very effective antiviral treatments that limit the damage that HIV inflicts on the immune system and that clearly prolong the lives of infected people. Certainly, there have been obstacles to progress along the way including bureaucratic inefficiencies, adherence to procedures of bygone days, discrimination, alienation and unfortunate examples of corporate and personal self-interest. With hard work, advocacy and creativity, some of these obstacles have been overcome, while others need continuing attention. However, the biggest obstacle to progress in developing effective treatments for HIV infection has been the amazing and frustrating complexity of HIV itself. Nevertheless, research conducted over the past 10 years has provided a substantial foundation of basic knowledge about HIV, which now must be reinforced and expanded. This is a critical time in AIDS research and tremendous opportunities exist to now learn a great deal more about HIV. We must consider all we know about HIV, and carefully identify the most important and potentially fruitful new directions for future research efforts. If this is done aggressively and creatively, the results emerging from basic research hopefully will soon be increasingly translated into more effective therapies for HIV disease. Prior to the advent of HIV, the popular notion was that medical science had largely prevailed over infectious diseases. The expectation arose that, given an important problem, modern science could find a solution. This popular view was encouraged in part by scientists who were themselves impressed by the explosion of information and technology that has been taking place in the life sciences since the 1950s. But the HIV epidemic has taught all of us that this view is naive, and that we cannot simply solve a problem just because we want to do so. HIV has also taught us a number of other important lessons that, if heeded, may expedite its conquest. It is now clear that scientists, healthcare providers and advocates for HIV-infected people must continue listening to and learning from each other, in order to best identify effective treatments for HIV disease. It is also clear that we must confront the hard questions concerning the intricacies of HIV infection. Likewise, we must not expect that a cure be here next week or even next year. As has been demonstrated far too many times, raising false hopes diminishes everyone's motivation for continued effort, as the promise of the latest "breakthrough" fades. Progress will be made, but it will likely be incremental. It was tremendously disappointing to realize only recently, 6 years after the FDA approved zidovudine (AZT), that the drug does not work as well as was hoped. However, this realization does not return us back to where we started or anywhere near it. Although much of the recent pessimism about available HIV treatments is understandable, there is significant cause for optimism, as well. New information about HIV biology is accumulating at an impressive rate, and new research techniques that promise to teach us a great deal more have been developed recently. We now have the tools to determine why AZT and the other available antiviral drugs are incompletely active, to define how long they might be of benefit to individuals and to identify whether they are of benefit for some people but not others. With these tools, we hopefully will soon be able to use the drugs presently available in the most effective ways possible. Testing new drugs to treat HIV infection also now can be pursued more rigorously, definitively and quickly than ever before. In many ways, we are no longer in the dark about how HIV behaves in infected people. Calls for a renewed emphasis on so-called basic research have come in the wake of recent disappointments about the benefit of antiviral drugs such as AZT. Basic research can be defined as investigation into the fundamental aspects of the structure of HIV constituents, their mechanisms of action in promoting virus reproduction, and analyses of the sequential stages of HIV infection within individual cells and within the human host. In many ongoing discussions, it is often implied that progress in basic research has been neglected because of an early emphasis on clinical investigation, defined as the testing of drugs in HIV- infected people in the hopes of identifying useful therapies. There now seems to be general agreement that, in the absence of a better appreciation of why the currently available drugs do not work as well as had been hoped, conducting additional large-scale clinical trials of similar drugs is not likely to be very useful. One important basic research topic that has been identified as essential for more intensive study is that of HIV pathogenesis: how HIV is transmitted from one person to another, how it causes a chronic infection that cannot be cleared by the immune system, and how it irreversibly damages the immune system resulting in the development of AIDS. The importance of answering these fundamental questions, which have received far too little attention to date, cannot be over-emphasized. It is wrong to view the choice between clinical and basic research as a dichotomy, however. Certainly, in a world of limited resources, talent and energy, priorities must be established. Yet progress may be most effectively realized by an approach to AIDS research that emphasizes synthesis of the disciplines of basic and clinical investigation. Insights and questions emerging from basic research studies can and should greatly influence the design of more meaningful clinical trials. Likewise, basic scientists will need to better understand the clinical presentation of HIV disease in order to identify the most important questions for their studies. Neither clinical nor basic research should take place in a vacuum. In either realm, a good question for study and clear-cut methods and criteria for answering it are critical. The better we understand how HIV behaves in infected persons, the more effectively we will be able to intervene with antiviral drugs to protect their health. Similarly, if we pay careful attention to how anti-HIV drugs affect the replication of the virus in infected people, we may derive new insights into the basic mechanisms of HIV disease that might not have emerged from simple observational studies. In many ways the study of HIV infection represents the frontier of medical investigation, a hybrid of clinical and basic research. With the tools recently provided by basic HIV research efforts, we now have the opportunity to define new approaches to study a disease process as it is progressing in vivo (within an affected, living person). This new approach necessarily consists of a collaboration of clinicians, basic scientists and HIV- infected people. If we work together with imagination and commitment, it promises to be an extremely productive process. The perceptions of medical researchers about a disease process are greatly influenced by the nature of the tools with which they study it. The prevailing view about the pathogenesis of HIV disease evolved in this fashion, which also serves to highlight how basic insights can inspire better HIV treatments. Until relatively recently, the tools used to measure both the amount of HIV present in an infected person and how actively the virus was reproducing (collectively referred to as the "viral load" or "viral burden") were rather insensitive. As a result, scientists believed that very little viral replication was taking place during the asymptomatic phase of HIV infection. This perception made it difficult to understand how HIV infection resulted in the progressive depletion of CD4+ T cells (also known as T4 cells). Numerous hypotheses were proposed to explain how the virus, if it were not present at high levels, might damage the immune system. However, the recent development of sensitive methods to detect the relative amount of HIV present in an infected person, and to determine how actively the virus is replicating, have drastically changed this view. These new methods measure the amount of HIV RNA (the genetic material of HIV that is contained within viral particles) either in the blood or in the tissues of infected people. A variety of techniques based on either the polymerase chain reaction (PCR) method or so-called signal amplification strategies (known as branched DNA or bDNA) are now available to measure HIV RNA levels in the blood. These techniques currently seem to be the best way to monitor HIV activity (viral load) in infected people. With these techniques, it is now clear that significantly more HIV replication is taking place throughout the course of the disease process than was ever previously imagined. This new appreciation is incredibly important in terms of our basic understanding of HIV biology, as well as our clinical approach to treating HIV infection. From a basic science perspective, the fact that active viral replication takes place during the asymptomatic phase of the disease suggests that HIV is directly damaging the immune system. From a clinical perspective, this same information argues that, if effective drugs can be identified, they will probably be most effective if used early in the course of the disease, to preserve immune function when it is still largely intact. From both perspectives, we now have tools to study the disease process and to accurately monitor the impact of specific interventions on HIV replication in infected individuals. What can we now try to learn about the pathogenesis of HIV infection that might have important impact on designing better approaches to treat HIV infection? Previously we had the tools to measure the ability of a given antiviral drug (such as AZT) to inhibit HIV replication in vivo. However, we could not know whether the drugs were not doing what we thought they would (namely, decrease HIV replication in treated individuals) or were simply not doing it effectively. Recent studies indicate that drugs like AZT decrease HIV RNA levels in the blood, but by only about 1/3rd to 1/10th of their original levels. In some people (presumably those with drug-resistant viruses), the levels do not change at all with therapy. For the first time, we can see that these drugs do have some impact, but that they are not particularly potent inhibitors of HIV replication in vivo. The question that we must now answer is why this is the case. Are the drugs simply poor HIV inhibitors or is there something about the way that HIV behaves in people that limits the drug's effectiveness? This latter topic is a critical issue, but one that we presently know little about. It is essential that we determine the fundamental aspects of HIV replication in infected people if we are to design and use antiviral drugs most effectively. Where in the body, for instance, is the residual viral replication (seen after starting AZT) taking place? What allows this "reservoir" of HIV to escape the inhibitory effects of the drug? How long do HIV-infected cells live and how long can they continue to produce virus? As discussed below, the answers to these questions can now be productively pursued. The newly available methods to measure the levels of HIV replication taking place in infected individuals should also now facilitate the testing of new drugs in a much more rapid and definitive manner than previously possible. If an antiviral drug is to be useful in treating HIV infection, it is reasonable to expect that it will inhibit replication of the virus. Earlier clinical trials of anti-HIV drugs could not evaluate this important criterion directly, because they lacked sensitive measures. Instead, inferences were based on so-called surrogate markers or the occurrence of clinical endpoints (such as the development of an opportunistic infection) that might only occur after a long delay. Unfortunately, such trials necessarily involved large numbers of patients and could not readily identify subgroups of patients who might be benefitting from the treatment. Furthermore, they took a long time to produce answers. And all too often, when the results arrived, their meaning was unclear. These earlier trials were, I believe, pursued in good faith, but with more than a little wishful thinking. With the availability of more clear-cut measures to monitor the activity of antiviral drugs, a new paradigm for testing of antiviral drugs is emerging. Most new antiviral drugs will likely be tested first in small-scale intensive studies in a limited number of patients. Should a new drug effectively inhibit HIV replication in these study participants, it might then be evaluated in larger-scale studies for its ability to delay disease progression and prolong survival. In this way the community of HIV-infected individuals might be spared the expenses, toxicities and disappointments of relatively inactive drugs. Does this new approach actually work better? Results from some recent drug trials suggest that it does. The so-called non-nucleoside reverse transcriptase inhibitors (NNRTI) like L- 697,661 and nevirapine work very well at inhibiting the growth of HIV in a tissue-culture flask in the laboratory, and seem to be fairly nontoxic in people. Unfortunately, variants of HIV emerge shortly after initiation of treatment in infected people that are resistant to the antiviral action of the NNRTI. Using the older methods of clinical trials, it might have taken a fairly long time to realize that this class of drugs is unlikely to be useful when used alone for treating HIV infection. However, the newer approaches for monitoring the activity of antiviral drugs in people readily detected the appearance of drug-resistant virus variants and the loss of drug efficacy. In addition to helping validate the usefulness of the new generation of viral markers, the NNRTI saga is also an example of how "mistakes" or unanticipated results can present opportunities for greater learning. The rapidity with which viruses resistant to the NNRTI emerge after initiation of treatment demonstrated, for the first time, that there is a rapid turnover in the pool of HIV that is being expressed at any one time. This insight doesn't sound all that exciting, but it is. With this information, basic researchers should now be able to identify the reservoirs of HIV infection and measure the rates at which HIV replication is occurring. By defining these issues, we may be able to formulate entirely new treatment strategies to most effectively decrease HIV replication, and measure and augment the effectiveness of a person's immune response to help further decrease the resident viral burden. What needs to be done before we can apply these tools to improve the care of HIV-infected people? First of all, it is essential that studies be undertaken as soon as possible to prove that treating HIV-infected individuals based on the results of HIV RNA determinations actually does lead to better clinical success. Does making treatment decisions based on these tests help keep people healthier longer? As soon as possible, we also need to validate the utility of these tests in a clinical setting and answer important questions, including the following: * Which of the alternative approaches to measure HIV RNA levels are most accurate, most reliable and least expensive? How often should they be measured? * What is a significant enough increase in HIV RNA levels to warrant adding a new antiviral drug or switching to another drug? * What combinations of drugs work best in a given individual? * How much do we have to decrease viral burden in order to realize a meaningful clinical benefit? The challenge for scientists, healthcare providers and HIV- infected people is to work together to answer these questions as quickly and clearly as possible. ***** Food-Based Nutrients as Therapeutic Options in HIV Care Cade Fields-Gardner, MS, RD Cade Fields-Gardner is the Director of Services for The Cutting Edge. Nutritional recommendations for HIV-infected people abound. There seem to be as many strong opinions as there are healthcare professionals, product purveyors and patients. In spite of some uncertainties regarding what constitutes optimal nutritional therapy, nutrition clearly plays an important role in healthcare plans for all persons with HIV infection. Nutritional care can help prevent the general decline and progressive immune dysfunction seen in malnourished patients. In addition, because nutrients act as cofactors in chemical reactions that occur in the body, using nutrient supplements to emphasize certain physiological pathways may help prevent or reverse certain detrimental metabolic changes. How to accomplish nutritional goals simultaneously and safely can be challenging. Individuals should evaluate their particular circumstances in consultation with their healthcare teams to determine the most effective strategies. For some, the best approach will be a supplementation program. For others, it will mean modifying their diets~a challenge to their shopping and cooking talents. A combination of both strategies usually works best for most HIV positive people: a supplementation program that targets specific problem areas plus thoughtful food choices. In the process, it is important to be realistic and aware that "natural" [i.e., some nutritional] therapies can be as dangerous or, in some cases, even more of a gamble than the current standardized medical therapies. The purpose of this article is to explore a few ways in which an HIV positive person can meet many of the current therapeutic recommendations easily, safely and effectively. --------- Maintaining Nutritional Adequacy The fundamental goals of maintaining nutritional adequacy are the adequate intake of fluids, calories, protein and micronutrients. Accomplishing this creates a good foundation for all other therapies. In other words, without attention to these nutritional priorities, drugs, supplements, psychosocial and physical therapy will be ineffective. Though specific measurements should be made to determine individual needs, general guidelines recommend the daily intake of about 1 cup of fluid for each 15 pounds of body weight, and at least 16 calories and 1/2 gram of protein for each pound of normal body weight (baseline weight prior to infection or wasting). Although micronutrient requirements for persons with HIV are controversial and tentative, a number of different recommendations have been made. In general, the recommendation is to take 1-2 balanced multivitamin/mineral supplements daily, in addition to a sound diet based on the above recommendations for maintaining adequacy. Any other supplementation may interact with other therapies and normal body processes, and therefore should be plannned carefully with and monitored by the healthcare team. --------- Beyond Adequacy Many nutrition-related therapies are based on the potential that some single and/or multiple nutrients have to act as pharmaceuticals. Although the lack of research in this area prohibits firm, conclusive recommendations, anecdotal accounts have formed the basis for a number of published recommendations. Again, individual treatment plans should be based on the results of individual evaluations by the healthcare team. For example, antioxidant therapies are gaining attention as a potential treatment for people with HIV. The premise is that one of the body's cellular activities is the production of "pro- oxidant" molecules, such as oxygen radicals (superoxide anion and hydroxyl, alkyoxyl, and peroxyl radicals); reactive nonradical oxygen molecules (hydrogen peroxide and singlet oxygen) and; radicals of carbon, nitrogen and sulfur. A growing body of evidence shows that pro-oxidant production may be stimulated by a range of events, from immune dysfunction to oxidative challenges from environmental factors, and may contribute to disease progression. Normally the body would "detoxify" the destructive radical species of molecules formed during the pro-oxidant phases with its own supply of regenerating antioxidants. When the production of reactive radicals exceeds the body's supply or action of cellular antioxidants, an imbalance known as "oxidative stress" results. This state is characterized by cellular damage that interferes with normal body processes and, in severe cases, cellular death. Current investigations are exploring whether or not taking additional dietary antioxidants has a protective effect. In theory, antioxidant supplementation would bolster the body's ability to "detoxify" these destructive radical species of molecules and keep the overproduction of pro-oxidants in check. Moving from the cellular level into the real world of a patient, additional questions arise. Will dietary antioxidant supplementation significantly reduce the potential for damage from oxidative stress seen in HIV disease? Will dietary antioxidant supplementation bind or neutralize traditional HIV- related therapies including antibiotics? What antioxidants and what forms can be used? Where can antioxidants be obtained? How much is more beneficial than harmful? --------- Dietary Sources of Antioxidants The combined recommendations of the panelists of the April 1994 BETA LIVE! teleconference will serve as the guidelines for this discussion. The use of antioxidants was specifically addressed by panelist Howard Greenspan, MD, a researcher who was asked, "If you were HIV positive, what antioxidant regimen would you personally follow?" His answer was a daily range of specific antioxidant nutrients that included 50,000 IU beta carotene, 500 mg vitamin C, 1200 IU vitamin E, 1500 mg broad-based flavonoids, 3-6 mg quinones, 1-2 grams cysteine and 3-6 grams carnitine. Food should be regarded not only as a source of nutrients needed for normal body functioning but also as an important source of antioxidant-acting substances, which may be present in substantial amounts in selected foods. One example is beta carotene, a form of vitamin A with strong antioxidant properties. One-half (1/2) cup of cooked carrots (an obvious choice) has 11 milligrams of beta carotene, more than 1800 retinol equivalents (RE) or more than 18,000 IUs of beta carotene. [Note: Vitamin A activity in foods is expressed in "retinol equivalents," a representational standard unit. 1 RE = 1 mcg of all-trans- retinol or 6 mcg of all-trans-beta carotene or 12 mcg of other provitamin A carotenoids.] Carrots contain other antioxidant substances as well. Canthaxanthin is one such substance in the carrot. A pigment with as much antioxidant activity as beta carotene, canthaxanthin also may work synergistically with beta carotene to improve its overall effectiveness. Another good source of beta carotene is the sweet potato. Each 1/2 cup serving of sweet potatoes contains 32 mg beta carotene or more than 5000 RE, and more than 50,000 IU vitamin A activity from beta carotene. --------- Nutrient-Rich Menu Combining food-based antioxidant recommendations with other nutritional recommendations often given to HIV patients, a 3-day menu that met several criteria was developed. First, the menu incorporates as many of the antioxidant recommendations made during the BETA LIVE! teleconference as possible. Second, the menu is realistic and easy to prepare. Third, it includes various food groups important for maintaining good nutritional status in persons with HIV. The menu meets the tough recommendations made for a well-balanced, high-calorie, high- protein diet to replete and maintain nutritional stores. Additional emphasis was placed on such nutrients as bioflavonoids as additional antioxidant sources, fiber for bowel function and omega-3 fatty acids, which act as anti-inflammatory and anticytokine agents. (Certain cytokines including some of the interferons and interleukins have been implicated in a cascade of physiological events that lead to catabolism and wasting.) The best food sources of the antioxidant nutrients beta carotene, vitamin C and vitamin E are shown in Table 1. A computerized analysis of foods provided the best combination of nutrient antioxidants. Figure 1 presents an overview of each day of the menu. The actual guidelines used (a combination of Dr. Greenspan's recommendations and some general patient recommendations made in educational books~see references) and how the menu met specific goals are shown in Table 2. Top sources for calories in the menu are the meat, dairy and grain groups. High-protein guidelines are met by the meat and dairy groups. The best sources of beta carotene and vitamin C are the fruit and vegetable groups. Vitamin E is mostly contributed by the fat and vegetable groups. Finally, the menu went through a "reality check," guided by the question, "Could you eat like this?" The overarching goal was maximum contribution to clinical well-being as well as a positive effect on quality of life. --------- Summary Nutrition and nutrient-related therapies are unfolding as a new cornerstone of HIV therapies. Successful nutritional management contributes to success in other realms of health management. Since improving quality-of-life and maintaining nutritional adequacy are primary goals, nutritional regimens probably work best when they are relatively simple and practical. Effective guidelines to meet a patient's nutritional goals always need to be realistic. Most importantly, HIV positive persons and their healthcare teams need to keep the "big picture" clearly in sight. Therapeutic regimens should not heavily compromise overall physical and mental well-being, which are always fundamental goals. While it is up the the patient to make any ultimate decisions, it is up to the healthcare professional to explore, weigh and present options in the context of a complete and objectively evaluated picture, on which the patient can base his or her decisions. --------- References Salomon SB and others. Living well with HIV and AIDS: a guide to healthy eating. The American Dietetic Association. Chicago, IL. 1993. Wong G. HIV disease nutrition guidelines. Practical Steps for a Healthier Life. Stadtlanders Pharmacy. Pittsburgh, PA. 1993. Table 1. FOOD SOURCES OF ANTIOXIDANT NUTRIENTS BETA CAROTENE VITAMIN C VITAMIN E carrots melons seeds, nuts carrot juice citrus fruits mayonnaise, salad dressings sweet potatoes red and green peppers wheat germ yams leafy green vegetables fish pumpkins other fruits: avocados papaya, kiwi leafy greens mango, berries mangoes winter squashes cruciferous vegetables: whole grains apricots, mangoes broccoli, cauliflower fortified cereals broccoli brussel sprouts fortified cereals tomatoes sweet potatoes Figure 1. THREE-DAY MENU (*see recipe on page 47) Day 1 Day 2 Day 3 BREAKFAST 1 cup vegetable omelette* 3 pancakes 1 cup corn flakes 1 rye toast (1 tsp. margarine) 4 ounces vanilla yogurt 1 banana 3/4 cup apple sauce 4 ounces berries 1 cup 1% fat milk 1 cup 1% milk tea 1 can apricot nectar tea LUNCH 1 bean and cheese burrito* tuna fish sandwich on chicken/swiss cheese 1/4 cup avocado whole wheat bread* sandwich on pumpernickel* 1/2 cup tomato spinach, pepper and 1 can (12-oz) vegetable juice 2 ounces onions mushroom side dish* 1 cup carrot sticks 1/2 cup Spanish rice 1 cup 1% fat milk 1/2 cup cooked carrots tea DINNER 1 cup vegetable-beef stir-fry* 4-ounce pork chop 4 ounces rosemary salmon* 1 cup rice 1 artichoke with dressing 1/2 cup asparagus tips tea 1/2 cup sweet potato 1/2 cup mashed potatoes 1/2 cup carrot-raisin salad 1/2 cup applesauce tea 1 cup 1% fat milk SNACKS 6 ounces flavored yogurt 1 cup honeydew melon bagel and cream cheese 1/2 cup orange/grapefruit juice orange sections (1 orange) 1 cup cantaloupe 1/2 banana 1 (12-ounce) can of 1 slice angel-food cake with 1 slice pumpkin pie tomato juice berries 1 cup 1% fat milk rice cake with peanut butter frozen yogurt 4 square saltines wheat germ nectarine Table 2. Guidelines and Menu Comparison Guideline Menu Comparision Basic Composition: 50-55% carbohydrates 50% carbohydrates 15-20% protein 20% protein <30% fat 30% fat Servings by food group: Protein: 2-3 servings 2.5 servings Dairy: 2-3 servings 3+ servings Starch: 7-12 servings 7 servings Fruits/Vegetables: 6+ servings 9 servings Fats: in moderation 30% of calories as fat Antioxidant nutrients: Vitamin C 390mg Vitamin E 31 mg beta carotene approximately 15,000 RE or 150,000 IU beta carotene flavonoids high in flavonoid sources: fruits/vegetables and teas Other elements: omega-3 fatty acids approximately 8 grams fiber 40 g dietary fiber (emphasis on whole grains and fruit/vegetable groups) Recipes Vegetable Omelette 1/4 cup mushrooms 1/4 cup diced tomatoes 1/4 cup cooked spinach 2 eggs 2 ounces low-fat cheddar cheese Saute vegetables in non-stick pan until heated. Add beaten eggs and cover over low heat until firm. Top with cheese. Bean and Cheese Burrito 1 large flour tortilla 1/2 cup low-fat refried beans 1/4 cup low-fat cheese Spoon beans on top of tortilla and sprinkle with cheese. Roll tortilla burrito-style and place in microwave oven for 1 minute and 30 seconds at 80% power or wrap in foil and heat in oven for approximately 20 minutes, or until thoroughly heated. Vegetable-Beef Stir-Fry 1/4 cup tofu 1/4 cup diced bell peppers 1/3 cup chopped broccoli 1/4 cup snow peas 2 teaspoons sesame oil 2 teaspoons light soy sauce 3 ounces thinly sliced beef Stir-fry beef in non-stick pan. Add vegetables and stir-fry until thoroughly heated. Serve over rice. Tuna Fish Sandwich 1/2 cup tuna mix: 1 6-ounce can of tuna 2 tablespoons non-fat salad dressing or mayonnaise 1 teaspoon mustard 2 slices whole wheat bread Spread tuna mix onto bread. Chicken and Swiss Cheese Sandwich 4-5 ounces chicken breast 2 slices tomato or 1/4 cup drained canned diced tomatoes 2 ounces Swiss cheese 2 teaspoons fat-free salad dressing or mayonnaise 2 slices pumpernickel bread Spread dressing or mayonnaise on bread. Top with chicken breast, tomatoes and Swiss cheese. Serve as hot or cold open-faced sandwiches. Spinach, Pepper and Mushroom Side Dish 1/2 cup spinach 1/4 cup diced sweet red or green peppers 1/2 cup sliced mushrooms or canned mushrooms garlic powder or minced fresh garlic (to taste) Stir-fry in non-stick pan over medium heat or place in covered glass dish and microwave for 4 minutes on the high setting. Rosemary Salmon 5-ounce salmon filet or salmon steak 1 teaspoon rosemary (dried) 1 teaspoon canola oil lemon juice (to taste) Mix oil, lemon juice and rosemary together, and let stand. Dip salmon steak or filet in mixture and place on foil to broil in oven. Bake or broil until fish is thoroughly heated and flaky. ***** Research Notes Leslie Hanna Leslie Hanna is associate editor of BETA. This edition of Research Notes is organized under 7 categories: (1) Basic Science, (2) Treatment for HIV Infection, (3) Treatment for Opportunistic Infections, (4) Immunotherapy, (5) Nutrition and Weight Management, (6) Tuberculosis and (7) Miscellaneous. Basic Science --------- Viruses Evolve Ways to Outwit Immune System Cells HIV Immune system white blood cells called cytotoxic T- lymphocytes (CTL) normally respond to the presence of foreign proteins (antigens) by targeting, binding to and destroying them. CTL play a critical role in the immune system counterattack on HIV. However, variations of HIV proteins are capable of eliciting altered, ineffectual responses from CTL. The variant HIV proteins trigger an incomplete response from CTL, which recognize and target the proteins but fail, ultimately, to destroy them. Why this happens is unclear, but probably has to do with failure of the mechanisms that normally cause the foreign protein and immune system cell to bind together. Researchers who have seen this disruption in in vitro laboratory studies describe this inhibition of CTL-driven cell destruction as "antagonism" of CTL activity. The variant HIV proteins studied by the researchers are naturally occurring. The aberrant responses were observed in studies that used viruses and CTL isolated from the same people. If the same disruption occurs in vivo, these individuals' immune system cells' antigen-fighting capability may be effectively shut down. In vivo CTL antagonism, if it actually occurs, is a unique method devised by the virus to evade the immune system. --------- Hepatitis B Virus Another study examined the ability of the hepatitis B virus (HBV) to evade immune responses. In a manner similar to HIV, HBV may do so by altering or mutating proteins that are required for binding to CTL. Examination of the virus types and immune responses in 2 people chronically infected with HBV indicated that the viral protein variants were natural antagonists that inhibited the CTL antiviral response to the wild-type viral proteins. The cells that are infected by the variant virus survive and multiply. The researchers conclude that mutations of this type may be one cause of persistent HBV infection, and that other viruses known to be highly mutable, such as HIV and hepatitis C, may become persistent in the same manner. Additional studies of individuals who have recovered from hepatitis B may provide insights into the abnormal CTL responses in those chronically infected with hepatitis B and/or HIV. References Klenerman P and others. Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 gag variants. Nature 369: 403-407. June 2, 1994. Bertoletti A and others. Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells. Nature 369: 407-410. June 2, 1994. Allen PM and Zinkernagel RM. Promethean viruses? Nature 369: 411. June 2, 1994. --------- Studies Fail to Find Evidence for a TH1/TH2 Shift Cytokine dysregulation is common in people with HIV infection. Increased production of certain cytokines such as tumor necrosis factor may actually enhance disease progression. Recent research efforts inspired a pathogenic theory that describes discernible patterns of cytokine release that correspond to the earlier and the more advanced stages of HIV infection. According to the theory, there is a shift in 2 distinct patterns of cytokine release, TH1 and TH2, that indicates advancing disease and the immune system's ultimate failure to resist infection. Although the TH1 and TH2 patterns have opposing, cross-regulatory actions, the TH1 pattern tends to predominate earlier in HIV infection and the TH2, later. Early in HIV infection, a subset of CD4 of T-helper cells called TH1 cells, which release the cytokines IL-2 and interferon gamma, have the upper hand. TH1 cytokines, which dominate as long as the body resists infection, are associated with cell- mediated immune responses. During this phase, cytotoxic lymphocytes (CTL) and natural killer (NK) cells abound, destroying infected cells, and the individual is relatively healthy and asymptomatic. At some point (for reasons not fully elucidated by this theory), a shift occurs and a TH2 type of response begins to prevail. At this time, as levels of the cytokines IL-4, IL-5 and IL-10 increase and stimulate antibody production, an (ineffectual) humoral response begins to edge out the cell-mediated response. This theory derived in part from study of long-term nonprogressors, people infected with HIV who maintain "normal" CD4 cell levels (for at least 7 years) even without receiving antiviral treatment. Researchers found that these individuals tend to have strong cell-mediated responses as well as relatively high levels of the so-called TH1 cytokines. Now, results of 2 studies, both of which appear in the July 8, 1994 issue of Science, challenge the TH1/TH2-shift theory. The basic finding in common was that there was no evidence for a shift in dominant T-helper cell type nor in the cytokines associated with them. NIAID researchers analyzed the types of cytokines found in peripheral blood and lymph node cells taken from people with HIV, at various stages of infection. In brief, they detected little IL-2 and IL-4 expression from individuals at various stages of disease. They found that interferon gamma and IL-10 were expressed by CD8 cells, rather than by any type of CD4 (T-helper) cell, and that levels of these cytokines were basically the same, regardless of disease stage. They conclude that "these results indicate that a switch from the TH1 to the TH2 phenotype does not occur during the progression of HIV disease." The other study, conducted by an Italian team of researchers, found that levels of interferon gamma and of IL-4 were reduced in people with HIV. Studies with laboratory cell lines indicated that less IL-4 and IL-5 is produced in advanced HIV infection. Moreover, it looks as though, if any clear shift occurs, it may be from a TH1-type response to a TH0 response! TH0 cells produce both sorts of cytokines, i.e., those produced by both TH1 and TH2 cells. They also found that HIV replication is stronger in CD4 cells that produce TH2-associated cytokines (i.e., TH2 and TH0 cells). The full reports are cited below. References Graziosi C and others. Lack of evidence for the dichotomy of TH1 and TH2 predominance in HIV-infected individuals. Science 265(5169): 248-252. July 8, 1994. Maggi E and others. Ability of HIV to promote a TH1 to TH0 shift and to replicate preferentially in TH2 and TH0 cells. Science 265(5169): 244-248. July 8, 1994. Mosmann TR. Cytokine patterns during the progression to AIDS. Science 265(5169): 193-194. July 8, 1994. --------- HIV Replication in Non-Lymphoid Tissues A post-mortem examination of tissue samples from 8 HIV- infected persons found that the amount of HIV in non-lymphoid tissues differed greatly depending on disease stage (at time of death). The people whose tissues were studied were categorized as either pre-AIDS (Centers for Disease Control and Prevention [CDC] class II) or AIDS (CDC class IV). Three had presymptomatic HIV infection and died without HIV-related disease (e.g., drug overdose). Five died with CDC AIDS-defining illnesses (e.g., cerebral lymphoma). The researchers obtained blood, lymphoid (lymph node, spleen) and non-lymphoid (brain, spinal cord, lung, colon, kidney, liver) tissue samples. Using a quantitative polymerase chain reaction (PCR) technique, they determined viral load in all the tissue samples, and compared the incidence of significant versus non-significant infection between the 2 groups. Among immune system tissues, lymphoid tissues (lymph nodes and spleen) from all 8 individuals were significantly infected. An unexpected finding was that the HIV load in all white blood cells was lower in those with AIDS than in presymptomatic individuals. This finding may be due in part to the much lower CD4 cell counts in the group with AIDS. However, the viral load in CD4 cells, the main cellular target of HIV, was similar in both groups. No significant infection was found in organs outside the lymphoid system in tissues from presymptomatic individuals. On the other hand, significant infection was found in the brain, colon and lung tissues of several of the persons with AIDS, the lung being significantly infected in all 5. The abnormalities seen in non-lymphoid organs from the people with AIDS were associated with high levels of HIV. Researchers postulate that "although the immune system seems to be very effective in controlling the spread of HIV infection outside lymphoid tissue, it has no effect on the frequency of infection of lymphocytes and possibly other cell types in lymph nodes and spleen." The presence of lymphocytes in certain areas of the brain in presymptomatic individuals was unrelated to the presence of HIV. In AIDS patients, however, large amounts of provirus were associated with brain lesions and changes. Although previous studies have suggested that HIV infects the brain relatively early, these researchers found no evidence for an early spread of HIV into the brain or other areas of the CNS, such as the brain stem and spinal cord. They offer 2 explanations for the absence of significant HIV infection of the brain in the presymptomatic individuals: (1) their immune systems may have successfully prevented the spread of replicating HIV into the brain, and/or (2) cytotoxic lymphocytes (CTL) within the brain may suppress HIV replication by continually destroying HIV-infected cells. The investigators also suggest that the presence of HIV in the brain does not mean that fatal HIV-related CNS problems will automatically follow. Other factors may contribute to such complications. Researchers note that the highest HIV load was found in the tissues of the person with AIDS who, unlike the others in that group, had never taken either AZT or ddI. References Donaldson YK and others. Redistribution of HIV outside the lymphoid system with onset of AIDS. The Lancet 343: 382-85. February 12, 1994. --------- New Directions for U.S. AIDS Research Programs Dr. William Paul, coordinator of the Office of AIDS Research, stated at a news conference at the X International Conference on AIDS in Yokohama that federal monies allocated for AIDS research will be redirected from clinical trials of new drugs and toward basic research. Dr. Paul said that improving the efficiency of clinical trials of drugs would also save some money. Dissatisfaction with the mediocrity of the HIV/AIDS drugs and vaccines currently approved and/or in testing has reinforced the impetus to study the virus itself and the pathogenesis of HIV disease, or the way it causes disease in humans. The continuing release of information from studies of long-term survivors of HIV brings into view one potentially navigable bridge from basic science to treatment. That is, if researchers can understand better the nature of well-adapted immune responses to HIV infection, such as those observed in long-term survivors, they may be able to produce treatments designed to regulate the immune system that any infected individual could use as well as in conjunction with antiviral treatments. References Pollack A. U.S. official to shift funds toward basic AIDS research. The New York Times. A6. August 10, 1994. --------- Natural Human Cell Receptor Assists in Syncytia Formation In vitro studies show that the natural human protein and cell receptor CD7 participates in the enhancement of HIV infection. CD7 promotes both cell infection by free-floating HIV virions and syncytia formation. Membrane fusion via the cell receptor is an integral step in both processes. CD7 is found on various human cells including T-cells, natural killer cells and certain B-cells. It appears to be one of several necessary elements for membrane fusion to occur. In laboratory studies, blocking the CD7 receptor (by introducing antibodies to it) prevented cells from being infected by free virions and inhibited HIV-infected cells from fusing into syncytia. Syncytia are clumps of HIV-infected and healthy immune cells that the immune system targets for elimination from the bloodstream. Syncytia formation is associated with disease progression. References Sato AI and others. Identification of CD7 glycoprotein as an accessory molecule in HIV-1-mediated syncytium formation and cellfree infection. Journal of Immunology 152(10): 5142-5152. May 15, 1994. --------- Standard Antibody Tests Fail to Detect HIV Subtype Two separate reports appearing recently in Science and The Lancet discuss the failure of standard screening tests to detect a rare strain of HIV known as HIV-1 subtype O. To date there are no known cases in the U.S. and very few outside of the West African nations of Cameroon and Gabon. The reports are based on 11 cases of HIV-1 subtype O infection in France, which HIV tests there failed to detect but which subsequently came to the attention of public health authorities. The cases reported in France were primarily among immigrants from West Africa. In the immediate future, there is little likelihood that this subtype will threaten public health outside of that region, where, despite already being well established, it accounts for fewer than 10% of HIV infections. The World Health Organization (WHO) met to discuss subtype O and decided that testing procedures should be evaluated for appropriateness only in those regions where the subtype is found, rather than globally. One screening test has been pulled from the market in France for failing to detect the virus in multiple samples. A spokesperson for the U.S. Food and Drug Administration (FDA) stated that currently used tests could be modified to detect the new strain. However, the stories illustrate the limitations of tests that are highly specific. Although sensitive, the tests detect only what they are designed to detect, and therefore have the potential to fail to identify a viral variant. This scenario is similar to one in the past, when the FDA- licensed HIV ELISA antibody tests did not recognize the HIV-2 variant. The test kit manufacturers subsequently modified the test kits to the current form, which detects both HIV-1 and HIV- 2. References Russell S. Rare HIV strain eludes screening tests. San Francisco Chronicle. A2. June 8, 1994. French blood test misses some HIV. AIDSWeekly. 2. April 11, 1994. --------- Treatment for HIV Infection FDA Approves Zerit On June 27, 1994, Bristol-Myers Squibb received marketing clearance from the FDA for the antiretroviral Zerit (d4T). Reviewed and authorized under the accelerated approval mechanisms, Zerit was shown in clinical trials to affect surrogate endpoints (CD4 counts) and to satisfy an "unmet need." Zerit is the fourth anti-HIV compound to be approved by the FDA and the first to be brought to market since ddC in 1992. Like AZT, ddI and ddC, d4T is a nucleoside analog that inhibits the ability of HIV to replicate and to infect healthy cells. Zerit is indicated for adults with advanced HIV disease who are intolerant to or failing to benefit from other approved antiretroviral agents. Approval was largely based on data submitted from a study referred to as 019 and the parallel track study. Study 019 compared d4T to continued use of AZT in people with 50-500 CD4 cells who had used AZT in the past. The eligibility criterion specified at least 6 months on AZT but, in fact, the average length of prior AZT use was 18 months. In 019, those who were assigned to the Zerit arm took 40 mg twice daily if they weighed over 60 kg, or 30 mg if they weighed less than 60 kg. At 12 weeks, CD4 levels had risen by 22 in the Zerit group and had decreased by the same amount in the AZT group. p24 antigen levels also decreased in those taking Zerit, while they increased in those taking AZT. The parallel track study, which began in October 1992, involved 13,000 people. Data gathered from 10,000 people and presented at the FDA advisory committee meeting showed no difference in survival at 40 weeks between the 2 study groups (20 vs 40 mg twice daily). The principal side effect, peripheral neuropathy, is dose-related, and was considered by researchers to be the only dose-limiting adverse reaction. Across all trials, 15-21% of the participants experienced peripheral neuropathy. Stopping the drug usually resolves the symptoms. The accelerated approval mechanism requires applicants to continue to evaluate the drug even after approval. At this point, Bristol-Myers Squibb plans both to continue ongoing confirmatory studies and to begin new ones. Study 019, comparing Zerit and AZT, is ongoing but should be completed in December 1994. A European parallel track study that is looking at the dose effect of Zerit in "less advanced patients" has a May 1995 expected completion date. The company has additional plans for Phase IV studies to evaluate various drug interactions; pediatric use of Zerit; safety and prevention of perinatal transmission; and pharmacokinetic safety in women and minorities. On August 15, 1994, Bristol-Myers Squibb sent the final shipments of Zerit under the parallel track program, which was concluded the same day. Bristol-Myers Squibb has set up a phone line to answer any questions about the parallel track discontinuation; call 1-800-842-8036. For help finding sources of third-party reimbursement for patients who wish to continue taking Zerit, doctors may call the HIV Products Reimbursement HelpLine and Temporary Assistance Program at 1-800-788-0123. Patients who do not qualify for third-party reimbursement but are in need of financial assistance may be eligible for free drug through the Temporary Assistance Program. Zerit will be available in 40, 30, 20 and 15 mg capsules. References Hellman N. Director, Antiviral Clinical Research, Bristol-Myers Squibb. Personal Communication. June 27, 1994. HHS [U.S. Department of Health and Human Services] News. June 27, 1994. Yarin S. Public Affairs Manager, Bristol-Myers Squibb. Personal Communication. June 27, 1994. --------- ddC Approved for Monotherapy On August 8, 1994, the Food and Drug Administration (FDA) approved ddC (zalcitabine, HIVID) as a monotherapeutic (single- agent) treatment "for HIV infection in adults with advanced HIV disease who either have experienced disease progression while receiving zidovudine [AZT], or who are intolerant to zidovudine." Approval was based on a multicenter, open-label trial among 467 people with advanced HIV who were failing on AZT. Participants were randomized to either take ddI or ddC. The study concluded that ddC was "at least as efficacious" as ddI in treating HIV and in delaying death. For a review of this study, see the June 1994 issue of BETA, page 50. ddC will continue to be available in combination with AZT for people with fewer than 300 CD4 cells, under the FDA accelerated approval mechanism. The recommended dose for monotherapeutic ddC is one 0.750 mg tablet every 8 hours. For combination therapy with AZT, 200 mg of AZT every 8 hours are added to the ddC regimen just described. ddC is available in 0.375 mg and 0.750 mg tablets, in 100-tablet bottles. For information on ddC reimbursement, call ASSIST at 1-800-285-4484, Monday-Friday, 9 am to 5 pm, Eastern Standard Time. HIVID (zalcitabine) available as monotherapy for HIV infection. Roche News. August 8, 1994. --------- Thymomodulin for Treating HIV An article in the July 8, 1994 issue of AIDS Treatment News explores the idea of using thymomodulin, a thymus gland extract, as an anti-HIV treatment. Based on an extensive medical literature search as well as anecdotal reports, the report presents a compelling case for scientific study of thymomodulin. The premise is that this agent, which showed early promise in a small, European study in people with HIV, has been wrongfully neglected. Thymomodulin is made from animal (calf) thymus glands and is taken orally. Used in Europe as an immune treatment, it is an approved drug in Italy. Studies have shown it to be of benefit in treating a range of conditions related to immune dysfunction in humans, including hepatitis B, post-operative infections and allergies. Laboratory and animal studies have indicated that the agent has mechanisms of action that may improve certain aspects of immunity. One of the most important published studies of thymomodulin in people with HIV took place in 1987, in Italy. In that study, 15 people with HIV received 60 mg/day of a syrup formulation of the drug for approximately 2 months. Two participants with advanced AIDS apparently experienced no benefit. However, symptoms such as fever were alleviated in 12 of the 15 (80%); chronic lymphadenopathy (lymph node inflammation) resolved in 6; thrush (oral candidiasis) resolved in 6; and CD4 cell counts increased. Other white blood cell measurements had mixed results. There were no adverse reactions. An Argentinean study in 11 people with HIV reported that the use of thymomodulin in combination with AZT produced laboratory marker and clinical benefits in 9. The article also provides profiles of 3 people (noted as being well known by the authors) who have been using thymomodulin for approximately 2.5 years, and mentions other anecdotal accounts as well. A recurring theme is improvement in blood markers, particularly elevations in CD8 cells counts. A tentative proposal, prompted largely by anecdotal testimony, is to combine thymomodulin with an antiviral, to reduce the chances of CD4 cell (hyper-) activation. Nowhere in the literature was thymomodulation associated with any toxicity. Anecdotally, side effects were reported of "an aggravated, unpleasantly stimulated feeling~redness of the skin, and sometimes headache." Some people reported feeling "warmth in the chest, where the thymus is located, shortly after it is taken." The article closes by emphasizing the need for research to begin at once and proposing specific questions for study. The authors also provide an exhaustive "thymomodulin bibliography," consisting of all medical-journal articles they were able to find. Thymomodulin is available in the U.S. only for personal use and by prescription through some buyers' clubs. A follow-up note in the July 22 issue of AIDS Treatment News reports that the German Ministry of Health recently issued a warning against the use of "calf thymus or other organ extracts (widely used in Europe in cancer treatment) because of a theoretical risk of contamination with BSE (bovine spongiform encephalopathy)." BSE, also known as "mad cow disease," has caused the deaths of over 100,000 cattle in England. Although there are no reported cases of human infection with BSE, laboratory animals have been infected. Some suspect that BSE may be related to a rare but fatal human disease called Creutzfeldt- Jakob disease. Apparently, concern about BSE is nothing new in Europe. Manufacturers of calf thymus extracts have instituted previous precautions such as procuring animals from areas in which BSE is unknown. Nevertheless, people considering using thymomodulin or any thymus extract may want to consider the warning, which applies to natural thymic extracts only, not to synthetic forms. Natural thymic extracts include thymomodulin and thymostimulin. Synthetic compounds, exempt from the warning, include thymopentin (TP-5, Timunox), thymic humoral factor (THF) and thymosin-alpha- 1. References James JS and Getty J. Thymomodulin. AIDS Treatment News 202: 1-7. July 8, 1994. James JS. Thymomodulin warning. AIDS Treatment News 203: 4. July 22, 1994. --------- Acyclovir plus AZT: the Official Report Several studies have associated a survival benefit with acyclovir use in people with HIV. The June issue of BETA contains a report on the preliminary results of an analysis of data from the observational Multicenter AIDS Cohort Study (MACS). The full report on the survival benefit detected in MACS from combined use of AZT and acyclovir appears in the July 15, 1994 issue of Annals of Internal Medicine. In this latest published study of the effects of acyclovir on HIV disease, researchers sought to determine the effect of acyclovir on HIV disease progression and survival in people taking AZT. Researchers conducted an in-depth statistical analysis of data collected in the MACS, an ongoing prospective study of over 2,000 gay and bisexual men with HIV. There was complete data for 786 MACS participants who started taking AZT before receiving AIDS diagnoses, which were based on the 1987 CDC definition, which did not include having fewer than 200 CD4 cells as AIDS- defining. Among these 786, 515 also took acyclovir. Four hundred and eighty-eight (488) people took acyclovir as an antiherpes treatment and/or as an anti-HIV treatment. Two hundred and forty-two (242) reported using acyclovir solely for its anti-HIV potential. The available data indicated that the median dosage used for anti-HIV purposes was between 600-800 mg daily. Compared to people who took AZT alone, people who took both AZT and acyclovir were found to have a "clinically significant prolonged survival" period of about 1 year. In fact, using acyclovir for any reason and using acyclovir specifically for HIV "were each associated with a 44% decreased probability of death if the drug was used after AIDS developed...but not before." Taking the combination (AZT and acyclovir) was not associated with any change in time to AIDS diagnosis. Again, the 1987 CDC definition of AIDS was used in formulating study conclusions. Based on this study, the overwhelming evidence suggests that it is only after an AIDS diagnosis (or, perhaps, after CD4 cell levels fall below 150 or 200, based on an AIDS diagnosis) that any survival benefit is detected. The study could not measure any increase in lifespan that may take place before an AIDS diagnosis. The way the evidence was analyzed suggests only that it did not permit the detection of an effect in people who are HIV positive but pre- AIDS. Taking acyclovir consistently was more positively associated with prolonged survival. Increasing length of continuous use of acyclovir at doses required to suppress herpes was also associated with increased survival (i.e., 600-800 mg/day). The dose level appeared to have no influence on survival. There was no survival difference between people using high- vs low-dose acyclovir. Analysts focussed on acyclovir. Although everyone initially used AZT, some people switched from AZT to other antivirals such as ddI or ddC, or simply stopped taking any anti-HIV drug altogether. References Stein DS and others. The effect of the interaction of acyclovir with zidovudine on progression to AIDS and survival. Annals of Internal Medicine 121(2): 100-108. July 15, 1994. --------- ACTG Suspends Nevirapine Trials Accrual Concerned about the potential for nevirapine to cause liver toxicity, the ACTG, at the behest of the FDA, has temporarily ceased further enrollment of participants into ACTG trials involving nevirapine. Trials that are already closed to enrollment (i.e., fully enrolled) will continue unchanged. People already enrolled into affected trials, i.e., those not yet fully accrued, will continue on the existing protocol. In the meantime, the FDA is reviewing all nevirapine protocols to determine to what extent, if any, nevirapine may adversely affect the liver. The decision followed the release of information gathered in a trial conducted by Boehringer-Ingelheim, manufacturer of nevirapine. In this pharmacokinetic study, 3 HIV negative women developed reversible but significant liver toxicities. Apparently, no signs of unusual liver toxicity have emerged from ACTG nevirapine trials thus far, although scrutiny and careful analysis of data will continue. At this time, it is unclear what the next step will be. If the review proves satisfactory, it is possible that enrollment will soon resume and the trials will proceed unaltered. References Haas G. ACTG studies involving nevirapine temporarily closed. Critical Path AIDS Project 29: 41-42. Summer 1994. --------- Treatment for Opportunistic Infections TMP-SMX desensitization protocol Laboratory and clinical evidence indicate that TMP-SMX (Bactrim, Septra and generics) is an effective agent for preventing PCP as well as toxoplasmosis. However, an estimated 50% of individuals who attempt taking TMP-SMX are intolerant of it. Common adverse reactions include high fevers, rash, itchiness, and muscle aches and pains. Recent studies suggest that these are not allergic reactions, but occur because the drug is metabolized differently by people with HIV. Individuals intolerant of TMP-SMX may switch to another prophylactic agent such as dapsone or aerosolized pentamidine. Increasingly, however, people are considering another option: TMP-SMX desensitization. This allows an individual to begin taking the drug at very low doses, which are tolerable, and to gradually and steadily increase the tolerated amount until an effective dose level is reached (usually 1 double-strength tablet daily or 3 times a week). Several groups have developed or are developing TMP-SMX desensitization protocols. In San Francisco, California, the Conant Medical Group has developed one desensitization protocol that purportedly succeeds in 84% of people who complete it. Christopher King, former Associate Director of Research Activities for the Conant Medical Group, told BETA, "it is our intention to aggressively advocate that the standard of care be to offer to any individual with a history of hypersensitivity to TMP-SMX (or who develops hypersensitivity to the drug during prophylaxis or therapy) an effective standard desensitization before moving to a less effective agent." The protocol begins with a dose of pediatric-strength TMP- SMX oral suspension that has been heavily diluted (1,000,000 times) with sterile distilled water and administered 4 times over a 24-hour period. An outline of this protocol, presented at the X International Conference on AIDS in Yokohama and currently in use by the Conant Medical Group, follows: Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Dose 1 1 cc 1 cc 1 cc 1 cc 1 cc 1 cc 1 cc 5 cc Dose 2 2 cc 2 cc 2 cc 2 cc 2 cc 2 cc 2 cc 10 cc Dose 3 4 cc 4 cc 4 cc 4 cc 4 cc 4 cc 4 cc 20 cc Dose 4 8 cc 8 cc 8 cc 8 cc 8 cc 8 cc 8 cc DS tablet* *DS = double strength For more information on the desensitization protocol, call M. J. Norman at 415-923-0222. References King C and others. Survival, death, and desensitization to trimethoprim/sulfamethoxazole (TMP/SMX). X International Conference on AIDS. Yokohama, August 1994. 388B. King C. Associate Director of Research Activities, Conant Medical Group. Personal Communication. June 14, 1994. Conant M. Medical Director, Conant Medical Group. Personal Communication. August 3, 1994. --------- Mepron for Pneumocystis carinii Pneumonia (PCP) A study of people with HIV and mild-to-moderate PCP concluded that Mepron is as effective as intravenous (IV) pentamidine for treating the disease, and involves far less toxicity and fewer adverse reactions. Manufactured by Burroughs Wellcome, Mepron is the brand name for an oral formulation of atovaquone. Burroughs Wellcome is currently developing a suspension formulation of Mepron that is expected to produce higher, more therapeutically effective blood levels of the drug than do the tablets that were used in this study. The drug of choice for treating PCP is trimethoprim- sulfamethoxazole (TMP-SMX: Bactrim, Septra and generics). However, many people who begin taking the drug are forced to discontinue it because of the serious side effects it frequently causes. This study compared the efficacy and side effects of Mepron and IV pentamidine, alternatives to TMP-SMX, in people with AIDS and PCP. The multicenter trial randomized 56 people to take Mepron and 53 to take pentamidine for a 21-day period. All had histologically confirmed PCP. Laboratory and clinical tests were used to monitor participants for treatment success and adverse reactions, both during treatment and for 8 weeks afterward. Of participants whose treatment was considered successful, 57% received Mepron and 40%, pentamidine. More response failures occurred among people taking Mepron (29%) than pentamidine (17%). However, the incidence of "treatment-limiting" side effects that forced the discontinuation of therapy was much lower in the Mepron group (4%) than in the pentamidine group (36%). Significant adverse side effects in the pentamidine group were hypoglycemia, vomiting, nausea, elevated creatinine (a liver enzyme) and rash. The only significant adverse side effect for those in the Mepron group was rash. Dohn MN and others. Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Annals of Internal Medicine 121(3): 174- 180. August 1, 1994. --------- ACTG Study Results Support Use of Trimetrexate for Moderate-to- Severe PCP Results of ACTG 029/031 confirm that trimetrexate with concurrent leucovorin administration (brand name Neutrexin) can be used as an effective alternative treatment for moderate-to- severe PCP in people who are intolerant of or refractory to trimethoprim-sulfamethoxazole (TMP-SMX). This is the indication approved by the FDA in December 1993. Two hundred fifteen (215) people with HIV who were hospitalized for moderately severe PCP were randomly assigned to intravenously receive either trimetrexate or TMP-SMX. None had yet received any treatment for the current episode, and none had a history of hypersensitivity to TMP. The groups were similar in terms of disease severity, as determined by various laboratory and clinical markers. AZT was discontinued for the study period. Trimextrexate was taken at a dose level of 45 mg/m2 daily, with IV leucovorin at 5 mg/m2 every 6 hours (20 mg/kg/day). The TMP- SMX dose used was 20 mg/m2 every 6 hours. After 10 days, if the patient had improved, the study drug was unblinded and the patient was discharged, thereafter receiving medication once daily on an ambulatory outpatient basis. Patients too ill to leave the hospital continued to receive their treatment intravenously. Survival at day 21 was the primary endpoint. Secondary endpoints were therapeutic response at days 10 and 21, and side effects. Overall, the study indicated that TMP-SMX had superior efficacy. At day 10, 16% of those taking TMP-SMX had died or failed to respond, compared to 27% of those taking trimetrexate. By day 21, the cumulative number of failures were 20% in the TMP-SMX group and 38% in the trimetrexate group. At follow-up at day 49, a distinct survival advantage for those taking TMP-SMX was noted as well. Serious side effects were more frequent in the TMP-SMX group: fever, nausea, vomiting, abnormal liver and blood tests. Therapeutic success rates, roughly equal for both treatment groups, were 51% in the TMP-SMX group and 52% in the trimetrexate group. The trends were that people discontinued TMP-SMX because of intolerance (adverse reactions) and discontinued trimetrexate because of inefficacy. This observation in part allows researchers to conclude that "trimetrexate is an effective therapy for moderate-to-severe PCP, although inferior to TMP-SMX. " Since approval of this study protocol, evidence has emerged that indicates that concomitant use of corticosteroids may improve survival in people being treated for moderately severe PCP. Another change in the standard of care is that the dosage of TMP-SMX that is now commonly recommended is 15 mg/kg/day, rather than 20, as was used in the study. References Sattler FR and others. Trimetrexate with leucovorin versus trimethoprim-sulfamethoxazole for moderate-to-severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled multicenter investigation of the AIDS Clinical Trials Group protocol 029/031. The Journal of Infectious Diseases 170: 165-172. July 1994. --------- HPMPC for Treatment of Acyclovir- and Foscarnet-Resistant Herpes Simplex Virus Persistent and recurring mucocutaneous herpes simplex virus (HSV) types 1 and 2 are common in immunosuppressed people. Acyclovir is the drug of choice for anti-HSV therapy in people with HIV, but the same people not infrequently develop viral strains resistant to such treatment. Foscarnet is sometimes used for treating people with acyclovir-resistant herpes, yet the risk of toxic reactions (especially renal failure) is considerable. Many studies have shown the antiherpetic potential of HPMPC, a nucleoside analog under investigation for treating cytomegalovirus infection (CMV). Now, a report details the successful use of HPMPC in the topical treatment of herpes lesions in 2 immunosuppressed people infected with herpesviruses (simplex 1 and 2) who failed on either acyclovir and/or foscarnet. One HIV-infected patient had genital herpes that failed to respond to oral acyclovir; laboratory tests showed that his HSV-2 strain was acyclovir-resistant. Renal (kidney) insufficiency forced him to stop foscarnet, and ganciclovir produced unsatisfactorily transient relief. Following topical application of HPMPC, the lesions regressed. One week after ending HPMPC treatment, no virus was isolated. Virus isolated from subsequent recurrences had become sensitive to acyclovir, and the patient was successfully treated with it. The other patient studied was a bone marrow transplant recipient. After surgery, he developed neutropenia, fever and oral mucosal inflammation and lesions. Cultures of specimens from his mouth were positive for HSV-1, but subsequent tests (after failing treatment with acyclovir and foscarnet) revealed that he was infected with a strain of herpes simplex virus-1 that was resistant to acyclovir, foscarnet and ganciclovir. The oral lesions disappeared after topical treatment with HPMPC. However, after discontinuation, the patient developed lesions in different orofacial sites (chin, forehead and new places inside his mouth). Tests revealed that these most recent lesions were all HSV-1 positive, and that the HSV-1 was sensitive to acyclovir. Topical application of HPMPC caused resolution of the lesions on his chin and forehead but not in his mouth. Since tests had indicated that the strain was sensitive to acyclovir, acyclovir therapy was restarted. The oral lesions were completely resolved. The patient tapered off of acyclovir over a 1-month period, and thereafter remained lesion-free. Researchers conclude that topical HPMPC is a successful treatment for mucocutaneous herpes lesions that are resistant to acyclovir. Moreover, in this study, herpetic relapses following treatment with HPMPC had regained susceptibility to acyclovir. Alternating acyclovir and HPMPC may be an effective approach to treating herpes strains (especially those that are intermittently acyclovir-sensitive) in immunocompromised people, especially when foscarnet is of limited use. References Snoeck R and others. Successful treatment of progressive mucocutaneous infection due to acyclovir- and foscarnet-resistant herpes simplex virus with (s)-1-(3-hydroxy-2- phosphonylmethoxypropyl)cytosine (HPMPC). Clinical Infectious Diseases 18(4): 570-578. April 1994. --------- Clinical Trial: HPMPC for CMV Retinitis Ganciclovir (Cytovene) and foscarnet (Foscavir) are the 2 standard agents used to treat CMV retinitis, a condition that affects up to 25% of people with AIDS. CMV retinitis causes retinal lesions and, without treatment, can cause permanent vision damage. Individuals with strains of cytomegalovirus that are resistant to the standard drugs, however, face additional complications. On July 12, 1994, Gilead Sciences announced the beginning of an open-label study of their product HPMPC, or GS 504, for the treatment of refractory CMV retinitis in people with AIDS. About 100 people will be enrolled at 6 centers in the U.S. and 1 in the U. K. The study will be open to people with AIDS with ophthalmologist-diagnosed CMV retinitis who have unsuccessfully used the standard approved treatments, ganciclovir and/or foscarnet, for at least 4 weeks. Participants will be randomized to receive one of 2 dose levels of intravenous (IV) GS 504. For the 2-week induction phase, everyone will receive 5 mg/kg once per week. Then, once every other week, participants will receive either 5 mg/kg or 3 mg/kg. Participants may remain on the regimen until they experience treatment-limiting toxicity or sight-threatening retinitis. The clinical endpoint is "time to progression of retinal lesions measured by retinal photographs." Two other studies of GS 504 in previously untreated people with CMV retinitis are ongoing. In a small study, high-dose IV HPMPC (5 mg/kg weekly) caused CMV urine cultures to revert to negative in 4/6 people. Researchers are also studying the use of IV GS 504 to prevent CMV-related lung infection in immunosuppressed bone marrow-transplant patients. References AmFAR AIDS/HIV Treatment Directory 7(3): 76-79. June 10, 1994. --------- Gilead sciences commences open-label clinical trial of GS 504 for AIDS patients with relapsing CMV retinitis. Gilead Sciences press release. July 12, 1994. --------- New Drug Application Filed for Oral Ganciclovir Syntex Corporation, manufacturers of ganciclovir, submitted a new drug application (NDA) to the FDA on June 30, 1994. Syntex is seeking FDA approval to market oral ganciclovir for maintenance treatment of cytomegalovirus (CMV) retinitis in immunocompromised people, including people with AIDS. Intravenous (IV) ganciclovir (Cytovene) for CMV retinitis has been on the market since 1989 in the U.S. Compared with people who are untreated, people who receive maintenance treatment with IV ganciclovir have significantly prolonged periods of disease remission. Oral ganciclovir, studies have shown, can suppress viral replication. Encouraging results from 3 clinical trials of the efficacy of oral ganciclovir for maintenance treatment of CMV retinitis formed the basis of the Syntex NDA. (See Research Notes, BETA, 41, March 1994, which reported on data available at that time from 2 U.S. trials.) All 3 trials had similar, comparative designs. In the most recently completed, European trial, 159 participants with CMV retinitis first went through a 2-3 week induction phase that involved treatment with IV ganciclovir. Once the disease stabilized, participants were randomized in a 2:1 ratio to either take 3,000 mg/day of oral ganciclovir or to continue taking 5 mg/kg IV ganciclovir once daily. Researchers then looked at the different mean times to disease recurrence or progression, as revealed by retinal photos and fundoscopic evaluation (taken every 2 weeks during the study), as well as safety and tolerance of the oral regimen. Based on fundoscopic evaluation, the mean time to disease progression was 109 days for people taking IV ganciclovir and 86 days for those taking oral ganciclovir. (At press time, results of the retinal photographs had not yet been released.) People taking oral ganciclovir experienced more gastrointestinal upset; people taking the IV formulation experienced more neutropenia and leukopenia. References Syntex press information. Syntex submits oral ganciclovir NDA. June 30, 1994. Volker K and others. A randomized comparison of the efficacy and safety of maintenance treatment with oral and IV ganciclovir (GCV) in the prevention of recurrence of cytomegalovirus retinitis in AIDS patients. Fourth European Conference on Clinical Aspects and Treatment of HIV Infection. Milan. March 1994. Abstract #021. --------- New Drug Approved for Herpes Zoster (Shingles) On June 30, 1994, SmithKline Beecham received marketing approval from the FDA for its new drug famciclovir (Famvir). Famciclovir is indicated for the treatment of acute herpes zoster, or shingles. It is the first antiherpes drug to reach the market since 1982, when acyclovir was first introduced in ointment and intravenous formulations. (Zovirax brand acyclovir capsules were introduced in 1985 for the treatment and suppression of primary genital herpes and then, in 1990, approved for treating shingles.) Taken orally in 500 mg doses 3 times daily for 7 days, famciclovir is being marketed as an equally effective alternative to acyclovir, which needs to be taken at higher doses, more often (800 mg, 5 times daily). Once ingested, famciclovir is converted inside the body to penciclovir, the active ingredient that prevents herpesvirus replication. Penciclovir does this by selecting infected cells and inhibiting viral DNA replication. Famciclovir has 77% bioavailability. Oral administration of 800 mg of acyclovir, the only other drug currently available for treating shingles, results in 10% penciclovir bioavailability, according to SmithKline Beecham. In a study, the side effects of famciclovir, considered well tolerated, were similar to placebo (diarrhea, nausea and headache). Shingles is a viral disease caused by reactivation of the varicella-zoster virus, which also causes chickenpox. Shingles manifests as an outbreak of itchy, blister-like sores that are typically extremely painful and sensitive to most stimuli. About 600,000 people in the U.S. develop shingles each year; the elderly and other immunocompromised people are at increased risk. Famciclovir reduces the period known as postherpetic neuralgia, pain that persists after the blisters have healed, as well as the healing time of the blisters. Sharyn Arnold of SmithKline Beecham said that the wholesale cost for a course of therapy (500 mg 3 times daily for 7 days) is approximately $103, compared to $147 for a course of acyclovir therapy (800 mg 5 times daily). On July 26, the company announced that shipments were being made and that supplies should be available at once in local drugstores. Famvir, SmithKline Beecham's new treatment for shingles, cleared for marketing by FDA. News release. June 30, 1994. --------- Official Approval Sought for Valtrex (Valacyclovir) Wellcome plc filed an application for approval of its oral "next generation antiherpes" drug Valtrex (valacyclovir) with the FDA in the U.S., and with regulatory bodies in 18 other countries worldwide. Clinical studies of Valtrex have shown that it has greater bioavailability than acyclovir, which confers better clinical results. In other ways~mode of action, safety profile~Valtrex differs little from acyclovir. The application currently seeks approval of Valtrex as a treatment for herpes zoster, or shingles. Other studies are ongoing to determine its efficacy for treating genital herpes and cytomegalovirus (CMV). References Wellcome plc news release. Wellcome files for approval for new herpes product. July 8, 1994. --------- Immunotherapy NIAID Recommends No Expansion of gp120 Vaccine Trials In an atmosphere of general ambivalence about the HIV preventive vaccines now in development, the National Institute of Allergy and Infectious Diseases (NIAID) has made a procedural decision about its trial of the 2 gp120 HIV vaccines farthest along in development. After a full day of meetings on June 17, 1994, several key NIAID AIDS advisory committees submitted a unanimous recommendation to NIAID director Anthony Fauci, MD, who agreed to it. NIAID will proceed with the current clinical evaluation, but will not expand the trial(s) until new and compelling data from other studies arrives or until a new type of vaccine emerges. The 2 gp120 vaccines in the NIAID trial are made by Biocine Company in Emeryville, California, and by Genentech, Inc., in South San Francisco, California. Both are currently in a Phase II clinical trial which began in December 1992, among 300 individuals. NIAID plans to continue to evaluate data from various HIV vaccine studies in the hopes of identifying suitable candidate preventive vaccines for expanded trials. A large-scale HIV vaccine trial probably is still 1-3 years away. Other unsettling news about these 2 candidate vaccines was widely reported recently as well: 5 volunteers in the NIAID vaccine gp120 study became infected with HIV after receiving the vaccine. Two of the people who seroconverted were considered low-risk and 3, high-risk. One of the high-risk seroconverters has reportedly lost CD4 cells at a particularly high rate. Researchers note that the initial humoral immune responses of the individuals were normal post-vaccination~all developed expected levels of HIV antibodies. An article in the June 17, 1994 issue of Science reports that, among various combined HIV vaccine trials, a total of 10 people have become HIV-infected. Six of those had not yet received the total of 3 shots typically given to be considered fully vaccinated. The gp120 study, in which the 5 widely discussed seroconversions occurred, is designed to look at the safety of the vaccine and the immunologic responses of the participants. Therefore, in terms of the gp120 candidates' efficacy, it is not yet known what the seroconversions really mean. References NIAID News Release. June 17, 1994. Cohen J. Will media reports KO upcoming real-life trials? Science 264(5166): 1660. June 17, 1994. Crewdson J. AIDS vaccine future in doubt. The San Francisco Examiner. A7. May 29, 1994. --------- Flu Vaccines for HIV Positive Children and Adolescents Each year, influenza is a major cause of illness among all children. Studies have estimated that up to 30% of children develop symptoms that result in missed school and, for some, even hospitalization. Immunocompromised children have increased risk factors for developing serious influenza-related conditions such as anorexia, weight loss and malnutrition. Clearly, a successful prophylactic strategy would be valuable. Unfortunately, HIV- related impairment of the humoral immune response, the branch of the immune system that produces antibodies, causes diminished antibody response in infected children to various types of vaccines: tetanus, diphtheria, pneumococcal and others. Recently, however, a study of HIV positive children and adolescents concluded that HIV-infected children do have the ability to respond to influenza vaccinations, especially if they have not progressed to AIDS. Forty-six (46) HIV-infected children and 61 age-matched HIV negative controls between the ages of 6 months and 21 years completed the study. They were vaccinated before the beginning of the influenza season, according to the instructions on the package insert, against 3 strains (Taiwan, Shanghai and Yamagata). Blood samples were measured for levels of antibodies to influenza before and 1 month after each vaccination. CD4 cells were measured during the 3 months prior to vaccination. HIV positive children who received 2 injections had the greatest increases in antibody levels. Investigators suggest routinely using a 2-injection strategy for immunizing HIV positive children, and are currently conducting further studies to test that hypothesis. Another finding was that CD4 cell counts were not associated with responsiveness to the vaccine (serologic response to influenza A antigens), which is different from the pattern in adults. The child's clinical status, based on the CDC's case definition of AIDS, however, was correlated with immune response; children with CDC-defined clinical AIDS had much lower postimmunization influenza antibody levels than did children with earlier-stage HIV disease. References Chadwick EG and others. Serologic response to standard inactivated influenza vaccine in human immunodeficiency virus- infected children. Pediatric Infectious Disease Journal 13(3): 206-211. March 1994. --------- Promising Vaccine Being Developed for Genital Herpes Once infected with herpes simplex 2 (HSV-2), a person may experience either rare, isolated or frequent outbreaks of genital herpes. However, as with HIV, an infected individual carries the virus for life. One approach to treating such a chronic viral infection is through the use of an immunotherapeutic vaccine, although a successful one for any chronic viral infection has yet to be developed. Results of a study of an experimental treatment vaccine for genital herpes, published in the June 11, 1994 British medical journal The Lancet, constitute the first substantial evidence that "a vaccine can modify the course of a chronic viral infection in human beings." The randomized, double-blind study enrolled 86 healthy men and women with confirmed HSV-2 infection. Participants received an injection on the first day and then another, 2 months later, of either vaccine (recombinant glycoprotein D, or gD2) or placebo (alum). Thereafter, participants received periodic examinations and follow-up bloodwork for 1 year. Suspected recurrences were evaluated by standard cultures as well as clinical examinations. Episodic acyclovir use was permitted for confirmed recurrences, but long-term acyclovir use was disallowed during the study. The time to first recurrence was not statistically different for the vaccine vs the placebo group, but the frequency of outbreaks was less among the vaccine recipients. For the year overall as well as per month, the vaccine recipients had fewer post-vaccination outbreaks than did the placebo recipients. This trend or difference was most pronounced during the first 4 months following the vaccination: 34% less frequency for the first 4 months and 24% for the year overall. Side effects were common among both study groups but generally mild (headache, chills, transient pain at the injection site). After 2 injections, the vaccine recipients had substantial rises in levels of antibodies directed at the antigen (a protein fragment of HSV-2) and also in levels of neutralizing antibodies. Antibody levels were highest at day 84, but remained above baseline throughout the study year. The levels of antibodies in the placebo recipients did not change, despite recurrences. Outbreaks were not correlated with (high) antibody levels in either group. The reduced number of recurrences and the greater number of isolated prodromal symptom reports (tingling, etc. that failed to result in a blister or outbreak) among the vaccine recipients lead researchers to conclude that the vaccine successfully altered the recipients' immune responses. They note that daily use of acyclovir to suppress herpes resulted in fewer recurrences per month than did the vaccine, although episodic use of acyclovir did not change the frequency of outbreaks. Investigators are trying to identify additional HSV-2 proteins to use in the vaccine, to further boost the immunological response. Nonetheless, the results from this study alone indicate that vaccines can be effective treatments for chronic viral diseases. References Straus SE and others. Placebo-controlled trial of vaccination with recombinant glycoprotein D of herpes simplex virus type 2 for immunotherapy of genital herpes. The Lancet 343: 1460-1463. June 11, 1994. --------- Vaccines for Sexually Transmitted Diseases (STD)? In the U.S., rates of the sexually transmitted diseases syphilis, chlamydia and chancroid continue to climb. The bacteria that cause these diseases infect the genital tract and may provoke repeated infections. The infections, or STD, cause numerous adverse effects ranging from infertility to death. More recently, the role of STD in facilitating the sexual transmission of HIV has heightened interest in developing effective vaccines against them. An article in the March 1994 Proceedings of the National Academy of Sciences USA reviews the status of experimental vaccines for several common bacterial STD. The article, which evaluates research to date into vaccines for chancroid (genital ulcer syndrome, a significant cofactor in HIV transmission), syphilis, gonorrhea and chlamydia, finds that the greatest progress has been made toward vaccines for gonorrhea and chlamydia. Currently, researchers are trying to find which bacterial proteins trigger the most effective immunological responses, and thus would be the best targets for vaccines. References Sparling PF and others. Vaccines for bacterial sexually transmitted infections: a realistic goal? Proceedings of the National Academy of Sciences USA 91: 2456-2463. March 1994. --------- Nutrition and Weight Management Polyp Prevention Study Finds No Protective Effect from Antioxidants A large clinical trial that investigated the potential of the antioxidants beta carotene and vitamins C and E to prevent precolonic cancerous development concluded that the agents had no impact on the rate of polyp development among people who had already had 1 polyp removed. Previous studies have shown associations between diet and cancer. For example, diets high in vegetables and fruits are associated with reduced rates of colorectal cancer. Other studies have suggested that the antioxidant vitamins (A, C and E) may protect against cancer. With these precedents in mind, a team of researchers from several prominent clinics studied the efficacy of beta carotene and vitamins C and E to prevent the recurrence of colorectal polyps, precursors of colorectal cancer. While none of the 864 participants had a history of invasive colorectal cancer, all had at least one polyp removed from the bowel within 3 months prior to entering the study. At entry, all were judged to be free of polyps. Participants' diets were analyzed at study entry and exit (and deemed to have no significant changes). Essentially, researchers wanted to evaluate the separate effect of 2 treatments: beta carotene and a combination of vitamins C and E. The study endpoint was the development of new polyps. Participants were randomly assigned to receive 1 of 4 daily regimens: (1) placebo, (2) 25 mg of beta carotene, (3) 1 g of vitamin C plus 400 mg of vitamin E (d-alpha tocopherol, a form of vitamin E) or (4) beta carotene plus vitamins C and E. Two follow-up colonoscopic examinations were conducted at the end of the first and fourth years. During the examinations, the entire mucosa was viewed and any polyps or lesions detected were noted, measured and removed. Blood levels of beta carotene and vitamin E were measured at study entry and at the time of colonic examination. (Since blood levels of vitamin C do not reflect intake, they were not measured.) After the first year, serum beta carotene levels had doubled in the 2 groups receiving the agent. Blood levels of vitamin E increased by 40% among people receiving the agent. Based on data from 751 participants available for analysis at the end of the 4 years, the overwhelming finding was that "treatment for 4 years with either beta carotene or vitamins C and E did not affect the rate of occurrence of new adenomas in patients who had an adenoma removed before entering the study." The size of the detectable adenomas or polyps appeared equally unaffected by treatment modality. Equal proportions of people in the beta carotene and vitamin C/E groups developed new polyps (about 37%). Adjusting for variables like age, sex, number of prior polyps, study center, and so forth, did not affect the finding. People who took the vitamin C/E combination had a slightly higher incidence of right colonic polyps, a finding that was "unexpected and plausibly due to chance." The researchers posit 2 possible explanations for the failure of the study to demonstrate any benefit. First is that it may be that other substances, such as fiber and folate, in fruits and vegetables are what confer a protective benefit, rather than antioxidant vitamins. Second, the study may simply have been too short: it may be necessary to consume high levels of antioxidants for many years before gaining anticancer benefits. References Greenberg ER and others. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. The New England Journal of Medicine 331(3): 141-147. July 21, 1994. --------- Endocrine Function and HIV-Related Wasting HIV-related wasting and weight loss probably has multiple causes. Possible causes include metabolic disturbances caused by cytokine dysregulation or by infections, which increase the body's metabolic requirements; reduced food intake; malabsorption; and endocrine dysfunction. The endocrine system is collectively composed of various glands, distributed throughout the body, that produce hormones that regulate different body activities. Previous studies have indicated a possible link between endocrine dysfunction and HIV- related weight loss. Other studies have shown that levels of testosterone, a hormone produced by endocrine glands (gonads/testes), are reduced in advanced HIV disease. At Oregon Health Sciences University, researchers studied endocrine function in various people with HIV to determine if there were any associations with wasting. Sixty-six HIV positive people with a range of CD4 cell counts (both above and below 200) were followed for 2 years. None took any steroid or hormone medications. Fourteen people met the CDC criteria for wasting, which is greater than 10% loss of body weight without a clear cause other than HIV infection, such as an opportunistic illness. Levels of various hormones were measured and compared between the groups with and without wasting. People with wasting syndrome were found to have lower serum total and free testosterone levels than nonwasting people. Levels of the hormone prolactin were higher in wasting participants (compared to nonwasting participants with similar CD4 counts), and levels of the hormone cortisol were higher in wasting participants and in people with Mycobacterium avium complex (MAC). Thyroid function was essentially the same across all groups studied, and was normal even in those with significant wasting. Decreased testosterone was associated with wasting, although whether it was a cause or an effect (of wasting) remains unclear. These results suggest that testosterone replacement therapy in HIV positive people with abnormally low testosterone levels should be actively explored. This study concentrated on the role of endocrine function in wasting. Lean body mass, caloric intake and malabsorption were not examined. Other studies are needed to continue to define the causes of wasting. References Coodley GO and others. Endocrine function in the HIV wasting syndrome. Journal of Acquired Immune Deficiency Syndromes 7(1): 46-51. 1994. --------- Thalidomide Promotes Weight Gain French researchers reported the results of a small study of thalidomide at the Fourth European Conference on Clinical Aspects and Treatment of HIV Infection in Milan, Italy. Three people with advanced HIV disease (fewer than 50 CD4 cells), severe HIV- associated wasting, fever and myalgia took 100 mg of thalidomide daily. They also took AZT and PCP prophylaxis. After treatment, serum levels of tumor necrosis factor (TNF), a cytokine associated with wasting that previous studies had suggested might be suppressed by thalidomide, were unchanged. CD4 counts also remained unchanged. Other tests failed to detect any inhibition of HIV replication. However, after 2 weeks, the participants no longer experienced fever or myalgia and, after 3 weeks, all 3 gained weight. The median weight gain was 5 kg. While larger-scale testing will be necessary to substantiate the benefits reportedly observed in this study (and perhaps to give further information about the weight gains, such as whether there were increases in lean body mass or not), the authors imply that the benefits noted would be unlikely to occur in control patients. These study results do not address the type of weight gain; some researchers and clinicians consider lean body mass increases to be the most relevant concern for people with wasting. References Couderc L and others. Thalidomide in wasting syndrome of AIDS. Fourth European Conference on Clinical Aspects and Treatment of HIV Infection. Milan. March 1994. --------- Tuberculosis New Combination Drug for Tuberculosis A new drug has been approved by the Food and Drug Administration (FDA) for tuberculosis. Rifater, made by Marion Merrell Dow, Inc., combines 3 approved drugs commonly used to treat tuberculosis: rifampin, isoniazid and pyrazinamide. This new 3-in-1 product should increase compliance and decrease the chances for either under- or overdosing any of the 3 components, all of which reduce the likelihood of drug resistance. In the wake of increasingly common drug resistant strains of tuberculosis, the CDC has recommended the use of combination drugs. Poor patient compliance has been one factor contributing to the rise of multidrug resistant strains of tuberculosis. With assistance from the FDA, Marion Merrell Dow has worked for 2 years to bring this product to market. The specific indication for Rifater is "in the initial phase of the short-term treatment of pulmonary tuberculosis." Other drugs may be added when indicated. The initial phase of treatment is designed to last 2 months, after which the individual should take rifampin and isoniazid for a minimum of 4 months. References Nightingale SL. From the Food and Drug Administration. Journal of the American Medical Association 272(5): 344. August 3, 1994. --------- Tuberculosis in San Francisco San Francisco researchers used a DNA fingerprinting technique to study patterns of Mycobacterium tuberculosis (M. Tb) among cases reported in San Francisco from January 1991 through December 1992. Scientific and epidemiologic analysis of the results indicated that many more cases than expected resulted from new infection, rather than reactivation of the causative bacteria. Conventional methods of tracing contacts of people with Tb to try to uncover patterns identified clusters involving a total of 10% of the patients. Using the more innovative DNA fingerprinting method, 191 of 473 patients or 40% were found to be epidemiologically linked. Approximately one-third of the new cases seen in the 2-year study period resulted from recent infection. However, the actual incidence of tuberculosis due to recent infection is probably higher because only people with active disease, rather than latent infection, were considered by the study. Similar disease patterns or clusters indicated risk factors (combined epidemiologic and biologic risk factors). In people under 60, independent risk factors were associated with an AIDS diagnosis, and Hispanic and African-American ethnicity. Since HIV infection was not a risk factor, but AIDS was, the degree of immunosuppression appears related to the risk of developing active Tb. Birth in the U.S. was found to be a risk factor, even though many cases of Tb in San Francisco classically have been among immigrants. The explanation is that, at least among younger people, birth outside the U.S. and previous exposure probably protects against newly acquired Tb infection. Reactivation of latent infection is a likely cause of disease among the immigrant population. The CDC reports that 95% of patients treated in San Francisco during the study period completed their anti-Tb drug regimens. Yet the risk posed by noncompliant patients is best depicted by the finding that 1 unsuccessfully treated patient accounted for 6% or 29 of the 473 cases studied here. The study has "3 major implications for urban tuberculosis control." One is learning more about places where Tb is commonly transmitted, and taking active steps to improve conditions there, to decrease the risks. Two is emphasizing effective and timely treatment of people with Tb ("because a single infectious patient may have devastating effects on tuberculosis control.") And finally, researchers recommend increased use of newer methods such as those employed in the study for tracing contacts of people with Tb. References Small PM and others. The epidemiology of tuberculosis in San Francisco. The New England Journal of Medicine 330(24): 1703- 1709. June 16, 1994. --------- National Tuberculosis Center Opens in San Francisco On June 29, the National Tuberculosis Center opened in San Francisco's South of Market district. The center is charged with disseminating information about the most up-to-date as well as cost-effective methods for preventing Tb transmission, and with training healthcare workers to use the most current techniques for identifying and treating Tb patients. Today's anti-tuberculosis strategies emphasize using improved research and technological methods (DNA fingerprinting, directly observed therapy) over isolation and quarantine in sanatariums. New York City and Newark, New Jersey have the other 2 national tuberculosis centers funded by the CDC. References Coile Z. City organizes command post for the battle against Tb. San Francisco Examiner. A4. June 20, 1994. --------- Miscellaneous Inadequate Treatment of Pain in People with HIV Results of a self-administered survey given to patients at the infectious disease clinic at St. Paul's Hospital in Vancouver, British Columbia indicate that vast improvements are needed in the treatment of HIV disease-related pain. Faculty of Pharmaceutical Science at the University of British Columbia/Clinical Pharmacology modified the Wisconsin Brief Pain Questionnaire so as to evaluate the prevalence and effects of pain on patients' lives, treatments employed and the effectiveness of those treatments. One hundred forty-eight (148) ambulatory patients with HIV disease who visited the clinic between November 1991 and April 1992 voluntarily completed a survey on pain and pain management. The average age of the patients was 40.4 years, and the median CD4 cell count, 173. Ninety-one patients (61%) reported HIV disease-related pain at some point. Eighty-two (55%) had experienced such pain within the month prior to answering the survey; this is the group the researchers focused on. Those experiencing pain within the month prior reported, in order of decreasing frequency, pain in their legs, back, head, arms/hands, pelvic area and abdomen. Sixty (73%) reported pain in at least 2 locations. About half reported that pain was always present, and about 40% said they did not know the cause of their pain. Sixty percent (60%) said that pain interfered "moderately to extremely with their enjoyment of life," affecting their ability to work, mood, relationships, sleep and movement. Yet only 40% overall said they did not use any treatment for their pain. Many reported not doing so at some point out of concern that taking pain medication might worsen their medical condition. And, of those whose pain was treated, the average rate of relief was only 65%. The most common pain treatments used were acetaminophen, plain or with codeine, aspirin, morphine and other narcotics. Researchers concluded that pain is prevalent and has a significant impact on people with HIV, particularly on quality of life, and is currently inadequately managed. Clinicians "should realize that pain can be present regardless of the duration of the disease and its severity. Patients need to be educated about the proper use of pain medications and helped to understand that pain medications will not ~worsen their disease'." References McCormack JP and others. Inadequate treatment of pain in ambulatory HIV patients. The Clinical Journal of Pain 9(4): 279-283. 1993. --------- Seminar on Pain Management San Francisco Bay Area physicians, nurses and other AIDS patient care providers are invited to attend a dinner, followed by a seminar on pain management in HIV/AIDS. Sponsored by BETA, Roxanne Laboratories and Stadtlanders Pharmacy, the seminar will be held at the Hotel Nikko, 222 Mason Street, San Francisco, California on October 8, 1994. Guest presenters are Drs. Paul Volberding, William Breitbart and Matthew Lefkowitz. Please RSVP to Ellena Friedman at 1-202-333-7400. Participation will be limited to the first 150 people who register. ***** Results from the 1994 BETA Readership Survey Prepared by Communication Technologies Background and Methodology Since 1988, the San Francisco AIDS Foundation has published and distributed BETA (Bulletin of Experimental Treatments for AIDS), a quarterly magazine that focuses on experimental and approved treatments for HIV infection and AIDS-related illnesses. The average length of each issue of BETA is 72 pages. --------- BETA Online Over twenty million users worldwide can access BETA electronically and download its contents. INTERNET users can retrieve BETA through the HIVNET system in Amsterdam, Holland. BETA is also distributed in computer format through the OUTline San Francisco BBS and the AEGIS Network. AEGIS distributes BETA directly to numerous computer Bulletin Board Systems in the U.S., Canada, Europe and Australia. (For information about accessing AEGIS, call 714-248-5843.) The FidoNet FILEBONE hub in Virginia links BETA to approximately 20,000 active electronic bulletin boards. Once the file has been received by a local system, it can be displayed and downloaded by any user logging on to that system. PLANET CONNECT uplinks BETA to the Galaxy II satellite. Anyone with a C- or KU-band satellite disk and Planet Connect decoder can retrieve these files. HIVNET in Amsterdam, Holland, distributes BETA to all of its downlinks in Europe. In addition, it forwards BETA to APC/GreenNet, which distributes BETA to its downlinks in sub- Saharan Africa, India, Thailand and the Philippines. BETA in Print Format BETA is distributed quarterly in print format to over 19,000 readers, including to approximately 1,500 paid subscribers. Over 10,000 low-income, HIV positive individuals receive BETA free of charge through the BETA National Scholarship Program. Approximately 5,000 free copies of BETA are distributed quarterly to AIDS clinics and AIDS service organizations in San Francisco through the BETA San Francisco Bay Area Scholarship Program. In addition, each quarter over 4,000 copies of the Spanish edition of BETA (Bolet_n de Tratamientos Experimentales Para el SIDA) are distributed nationwide free to AIDS agencies that serve Spanish- speaking clients. About 1,000 copies of BETA are also distributed free quarterly to media, policymakers, researchers, community physicians, and other healthcare providers involved in AIDS work. Finally, over 600 copies of BETA are provided free to libraries and resource centers in correctional institutions nationwide, and AIDS service organizations in over 40 countries worldwide. The following report, prepared by the San Francisco marketing research firm Communication Technologies, summarizes the findings of a national survey of the BETA print readership, which includes the combined readership of the BETA National Scholarship Program, the Paid Subscription Program, and the BETA San Francisco Bay Area Scholarship Program. In order to evaluate the effectiveness of BETA as an educational resource for HIV/AIDS treatment information, and to learn the demographic profile of its readership, a four-page survey questionnaire was included in 4,897 randomly chosen copies of the March 1994 issue. Readers were asked to return their completed surveys by April 15, 1994, for analysis by Communication Technologies. Eleven hundred and sixty-eight questionnaires were returned by April 15th. These questionnaires were key-entered, and the results of this survey are discussed below. Since the cut-off date, just under 200 additional questionnaires have been received. These questionnaires have not been key-entered and are not included in the analysis. Counting the late questionnaires, this survey achieved a return rate of 28%~an unusually high rate of response. With a 1994 sample size of 1,168 respondents, the results reported here are accurate with q3.0% at the 95% level of confidence. This means that we can have 95% confidence that our results vary no more than plus/minus 3.0% from the results we would obtain if we interviewed every individual who receives BETA. In 1989, Communication Technologies conducted a similar study of the BETA readership, when the publication's total quarterly circulation was 5,000 and its average length was 20 pages. In the following report, comparisons are made between the results of the 1989 and the 1994 readership studies. Executive Summary HIV Profile of BETA Readership Three-quarters (75%) of BETA readers are HIV positive. One-fifth (21%) are HIV negative. Among those readers who are HIV positive, 32% have received a diagnosis of AIDS and 25% are HIV positive with no symptoms. Thirty-one percent (31%) of HIV positive readers are not pursuing any drug therapies for HIV. Sixty-nine percent (69%) of HIV positive readers are pursuing drug therapies for HIV. Thirty-six percent (36%) of readers are taking AZT. One-fifth (19%) are taking ddI, 16% are taking ddC, and 11% are taking d4T. (Responses add to more than 69% because some readers are taking more than one medication.) One-fifth (19%) of HIV positive readers do not have medical insurance. Demographic Profile of BETA Readership * One-fifth (19%) of readers are female, compared to the 1989 study in which 11% of readers were female. * One-fifth (19%) of 1994 BETA readers represent ethnicities other than Caucasian. In 1989, 11% of readers were not Caucasian. * One-fifth (20%) of readers identify themselves as heterosexual, compared to 1989 study results in which 14% identified themselves as heterosexual. * Four in ten (39%) readers are not employed or retired. In 1989, 23% were not employed or retired. * Four in ten (39%) readers report an annual income of $25,000 or less. These results are similar to those seen in 1989. * Two-thirds (67%) of readers have a college degree or higher. These results are similar to those seen in 1989. Mother-to-Child HIV Transmission Leslie Hanna Leslie Hanna is associate editor of BETA. According to the Global AIDS Policy Coalition, there are approximately 2,175,000 children worldwide who are living with HIV infection today. The majority became infected through vertical transmission, i.e., they acquired the virus from their HIV positive mothers. During this calendar year alone, the World Health Organization (WHO) estimates that 200,000 HIV-infected babies will be born. There are 3 main ways that mother-to-child infection occurs: an HIV positive woman may infect her child while carrying it (intrauterine), while giving birth (intrapartum) or after birth, primarily by breast-feeding (postpartum). As the fetus grows in utero, cells of the placenta, a combination of fetal and maternal tissues that act as the organ of exchange during pregnancy for mother and fetus, may become infected. Free virus or HIV- infected cells from the mother may enter the fetal circulation system. Although there are no documented cases of intrapartum infection, passage through the birth canal at the time of birth involves risk of infection to the infant through exposure to a large amount of infectious maternal blood and fluids. Like other retroviruses, HIV has been isolated in breast milk. Some pediatric AIDS cases have been reported in children whose mothers were infected by postpartum transfusions of HIV- infected blood, and who likely infected their infants by breast- feeding during primary (maternal) infection, when viral load is extremely high. A 1992 European Collaborative Study found that rates of vertical transmission among 721 children and 701 mothers were twice as high for mothers who breast-fed their children, compared to mothers who never breast-fed (median duration of breast-feeding was 4 weeks). There are no direct studies of breast-feeding and perinatal transmission, nor have prospective studies been well able to identify many exclusively breast- or bottle-fed infants from whom to gather data. Yet, the weight of evidence suggests that HIV is transmissible through breast milk, and thus is a mode of transmission of relevant concern even to women infected before pregnancy (in contrast to women infected after giving birth but while breast-feeding). Cumulative research suggests that pregnant women with HIV have a 10-40% risk of transmitting the infection to their infants. Vertical transmission rates appear to be higher~nearly twice as high~in developing countries than in developed countries. Reasons include possible differences in regional definitions of pediatric infection; design differences in studies of vertical transmission; and differences in the methods used to determine transmission. Research into the primary modes of transmission is ongoing. Risk factors associated with modes of transmission include maternal viral load, vaginal delivery and breast-feeding. However, other contributory risk factors as well as relative risk remain to be elucidated. Results of a groundbreaking study published in the June 25, 1994 issue of The Lancet offer important information about one possible factor in mother-to- infant HIV transmission, and suggest questions for further investigation. Another study recently published, in which researchers measured maternal viral load during pregnancy, at birth and afterward, presents the first conclusive data on the impact of viral load on mother-to-child transmission (Proceedings of the National Academy of Science USA, August 1994). Finally, based on the results of ACTG 076, FDA has approved the use of AZT during pregnancy as a strategy to prevent vertical transmission. The U.S. Public Health Service has published guidelines for that usage. Maternal Nutritional Deficiencies May Facilitate Perinatal HIV Transmission For this study, researchers wove together a few known facts about immunity and nutrition with speculation about perinatal transmission risks to arrive at a hypothetical question for scientific investigation: could poor maternal nutritional status increase the likelihood of vertical transmission? Specifically, could a maternal deficiency of vitamin A, known for playing a role in stimulating the immune response and protecting mucosal tissues, make it more likely that a baby will acquire HIV from its mother? Study Participants and Methods A team of U.S. and African researchers conducted the study in Malawi, in southeast Africa. The participants were HIV positive pregnant women who were patients at Queen Elizabeth Central Hospital in Blantyre, Malawi. Consenting women who visited the hospital's prenatal clinic between November 1989 and August 1991 were tested for HIV infection. Positive ELISA results were confirmed by Western blot. Three hundred and thirty-eight (338) HIV positive pregnant women from whom the researchers were able to gather complete data formed the core study group. During their first prenatal visit, healthcare workers recorded each woman's age, weight, height, length of pregnancy thus far, body mass index (equal to weight divided by height squared). Samples of blood serum were collected and stored at -70 C. Levels of vitamin A in serum were determined using a liquid chromatography technique, with standardized quality control monitoring (National Institute of Standards and Technology, USA). For a subset of women, flow cytometry was used to determine CD4 and CD8 counts at the first visit. (CD4 and CD8 counts were obtained from the other women after delivery.) Infants' weights were recorded at birth. Regular follow-up visits with both mothers and infants occurred every 3 months after birth for one year. During the follow-up visits, mothers reported if they were breast-feeding or not. [Note: a potential criticism of this study is that breast-feeding may have been a confounding factor. However, (1) over 99% of the 338 women for whom full data was collected and analyzed all breast-fed their children for at least 12 months, as is customary in Malawi, and (2) the study results do not purport to quantify vertical transmission rates due to vitamin A deficiency; rather, the study results show that, comparably, all other factors aside, vertical transmission rates were significantly higher among mothers who were vitamin A-deficient. In other words, study mothers who breast-fed their infants but had what nutritionists consider sufficient levels of vitamin A were less likely to transmit HIV to their infants than mothers who also breast-fed but were vitamin A-deficient.] When the babies were 1 year old, they were tested for HIV using ELISA with confirmatory Western blot. Follow-up tests at 18 months of age confirmed that all the babies had indeed lost maternal antibodies by 1 year of age. (Babies routinely acquire antibodies from their mothers, which are detectable by blood tests. This direct transfer of antibodies from mother to fetus across the placenta, or from mother to child through breast milk, is an important protective mechanism for the infant. However, children usually lose maternal antibodies by 1 year of age, when the (child's) immune system has become capable of actively producing its own antibodies. In fact, previous studies performed in Africa have shown that most infants lost maternal antibodies to HIV by 1 year of age.) Calculations and statistical analyses compared mothers of HIV positive babies to mothers of HIV negative babies, with emphasis on the vitamin A status of the mother. Because serum concentrations less than 1.05 micromoles/liter are associated with biological dysfunction, serum vitamin A sufficiency was defined as greater than 1.05 micromoles/liter. Results From November 1989 to August 1991, there were 567 births to HIV positive women. Of these, 146 mothers had infants who died before their first birthdays. Another 40 infants did not take further part in the study, because their mothers disagreed to testing them for HIV or for another reason. Three hundred eighty-one (381) infants were tested for HIV-1 infection when they reached 12 months of age. Fourteen (14) had indeterminate test results; 84 were HIV positive; 283 were HIV negative. Regardless of HIV status at 1 year, mean birthweight, proportions of low birthweight infants and mean gestational age were similar among all infants. The rate of perinatal HIV transmission among mothers whose infants survived to 1 year was 21.9% (84/381). Of the children whose HIV status was determined, data on the serum level of vitamin A was available for 338 mothers. Of these 338, mothers who transmitted HIV to their children and mothers who did not were similar in terms of the interval between prenatal screening and birth (105 vs 106 days), age and body-mass index. The mean serum vitamin A concentration for these 338 women was 1.02 micromoles/liter. However, the mean level for mothers of HIV-infected infants was 0.83 micromoles/liter compared to 1.07 for mothers of HIV negative infants. Overall, total lymphocyte count, maternal CD4 count, CD4% and CD4/CD8 ratios were lower "in mothers who transmitted HIV to their infants than in mothers who did not." The mean difference in CD4 percentage between transmitting and nontransmitting mothers was greater and more significant than CD4 cell count. Researchers examined history of sexually transmitted diseases and patterns of breast-feeding among the women as possible alternative explanations for the transmission rates seen in the study. However, neither sexually transmitted diseases nor length of breast-feeding were found to have had any impact on the rate of HIV transmission to infants. Again, lengthy breast- feeding is common in Malawi; more than 99% of all participants were still breast-feeding at 1 year. In summary, "maternal vitamin A and maternal CD4% were independently predictive of vertical transmission of HIV...and total lymphocytes, CD4 count and CD4/CD8 ratio were each highly correlated with CD4%." The latter 3 measures were not, compared to the CD4%, themselves significantly associated with vertical transmission. Vitamin A One hundred ninety-six (196) of the 338 mothers whose infants' HIV serostatus was known were found to be vitamin A- deficient (serum vitamin A levels below 1.05 micromoles/liter). The mean serum vitamin A level for all 338 women was 1.02 micromoles/liter. Mothers were grouped into 4 categories, based on their level of serum vitamin A: (1) 0.70 micromoles/liter or less, (2) 0.70-1.05 micromoles/liter, (3) 1.05-1.40 micromoles/liter and (4) greater than or equal to 1.40 micromoles/liter. The relative risk of transmitting HIV to their infant "increased with decreasing serum vitamin A" (see Figure 1). The transmission rates for groups 1-4, respectively, were 32%, 26%, 16% and 7%. Researchers also had data on serum vitamin A from 136 mothers whose infants died before 12 months. The mean serum vitamin A level for these women was 0.78 micromoles/liter, a figure that was not (statistically) significantly different from the mean for mothers of HIV-infected babies, which was 0.86 micromoles/liter. Again, however, both figures are significantly lower than the mean serum vitamin A level for mothers of HIV negative babies (1.07 micromoles/liter). Conclusion Overall, vitamin A deficiencies were "associated with a three-fold to four-fold increased risk of mother-to-child transmission of HIV. " This observation clearly suggests a relationship between nutritional status and vertical transmission of HIV. Vitamin A is known to play important immunological roles, disruption of which may increase the risk of vertical transmission. Vitamin A deficits are associated with impaired lymphocyte functioning, which may cause a higher viral burden in pregnant women. Similarly, impaired lymphocyte functioning could play a role in preventing protective maternal antibodies from crossing the placenta. Vitamin A deficiencies are also associated with mucosal impairment, involving the loss or destruction of mucus and certain cell types, which may damage the placenta. Mucosal surface damage could also mean that the birth canal is more susceptible to trauma, which could increase the amount of maternal blood the infant is exposed to during birth, in turn increasing the risk of HIV transmission. And, although this study did not show an association between vitamin A deficiency, breast-feeding and mother-to-infant HIV transmission, researchers suggest that vitamin A deficiency may permit the accumulation of higher levels of virus in breast milk, which may influence HIV transmission. Researchers note that "although our study showed that vitamin A deficiency was associated with increased mother-to- child transmission of HIV, we cannot attribute these findings to lack of vitamin A alone, since other micronutrient abnormalities may act as cofactors." HIV infection is associated with altered levels of other nutrients, such as vitamins E and B, copper and zinc. However, only vitamin A deficiencies "have been shown [elsewhere] to be risk factors [in HIV-infected individuals] for progression to AIDS, mortality, and increased perinatal and infant mortality." Sixty-five percent (65%) of the women in this study were found to be vitamin A-deficient. Vitamin A deficiencies are common in HIV-infected pregnant women in Africa and are probably attributable to a number of causes, including pregnancy itself. Other factors contributing to vitamin A deficiency include not taking in and/or absorbing enough foods containing vitamin A and opportunistic infection-related vitamin A depletion. Mothers whose children died before their first birthdays had the lowest average serum levels of vitamin A of any study subgroup. An earlier Rwandan study found an association between vitamin A deficiency and increased perinatal and infant morality. The mean CD4 cell count of the women in this study was 570 and the mean CD4 percentage, 29%, indicating that most were in the early stages of HIV infection. Because advancing HIV infection is associated with declines in serum vitamin A, researchers postulate that additional pregnancies in these women may be accompanied by greater deficits of vitamin A, and higher rates of vertical transmission and infant mortality. Finally, researchers emphasize that their study involved women in their second and third trimesters. Given the relationship between vitamin A deficiency and increased risk of transmission, they propose investigating repletion of vitamin A during pregnancy as a relatively inexpensive and simple strategy for reducing HIV-related infant risks. Regardless of its ultimate applicability, this study warrants further investigation of its central findings and implications. References Global AIDS Policy Coalition. AIDS In the World, Vol. II. Oxford University Press, forthcoming. Mok JY. Vertical transmission. In HIV Infection in Women. 191-211. Johnson MA and Johnson FD, editors. Edinburgh. Churchill Livingstone. 1993. Semba RD and others. Maternal vitamin A deficiency and mother- to-child transmission of HIV-1. The Lancet 343: 1593-1597. June 25, 1994. --------- Maternal Viral Load and Vertical Transmission Various groups are working to develop strategies to interrupt vertical transmission; the new U.S. Public Health Service guidelines, based on ACTG 076, represent the latest advancement in this area. One of the questions that guides current research efforts is, when is such transmission most likely to occur: in utero? during childbirth? A closely related question is, what are the determinants of vertical transmission? In other words, since in the U.S. the overall rate of perinatal transmission is about 25%, 3 of 4 pregnant women with HIV will not transmit the virus, while 1 will. What determines whether a mother will transmit infection to her child, or not? A precept of a study recently conducted by researchers in New York was that more definition is needed of the factors that determine whether vertical transmission will or will not occur, before developing strategies aimed at interrupting vertical transmission. Thus, investigators chose to quantify the impact of maternal viral burden on vertical transmission rates. They also evaluated how pregnancy itself affected viral burden. Nineteen mother/child pairs participated. The clinical and immunologic status of the mothers varied widely, but 12 had greater than 200 CD4 cells and were asymptomatic, and 7 had less than 200 CD4 cells. Of those 7, 3 had experienced serious opportunistic infections in the past. Nine took AZT (1 received AZT in ACTG 076). None of the mothers breast-fed their infants. Maternal viral load was determined at various points during pregnancy and after childbirth by endpoint dilution culture. Viral titers greater than 125 HIV-1 infectious units per 10 to the 6th peripheral blood mononuclear cells (IU/10 to the 6th PBMC) were considered high. CD4 and CD8 cell counts were also measured. Infants were followed prospectively after birth to determine their HIV status (for at least 6 months after their birthdays). Both viral culture and PCR were used to determine HIV status. Viral cultures using a special technique were performed in infants; HIV was detected in older children by using the same method as in mothers. Nested PCR was used to detect HIV in PBMC in infants and children. The overall rate of perinatal transmission in this study was 26%, consistent with the rate generally reported in the U.S. Of the 5 women who transmitted HIV to their infants, 4 had high viral loads (>125 HIV-1 IU/10 to the 6th PBMC). In the study overall, 6 women were deemed to have high viral loads; 4 of these 6 or 67% transmitted the infection to their infants. The other woman whose infant was infected did not have, within the study parameters, high viral load; she was the only 1 of 13 with lower viral loads to have an HIV-infected child. Therefore, 7.6% of study women with low viral burdens transmitted the infection. The relationship between maternal viral load and perinatal transmission was statistically significant. Maternal CD4 cell counts and viral burden were inversely correlated, as is frequently the case. Thus, a correlation was found between low CD4 cell count and vertical transmission in the study cohort. However, low CD4 cell count was not as strongly associated with transmission as was viral burden. Neither of 2 women in the study with fewer than 200 CD4 cells but relatively low viral titers (5 and 15 IU/10 to the 6th PBMC) transmitted the infection to her child. Since both viral load and CD4 counts were predictive of transmission, analysts stratified participants according to these 2 measures, in an attempt to identify women at greatest risk of transmitting HIV. Four of the 5 or 80% of the women with high viral load (>125) and low CD4 cell counts (<200) transmitted the virus to their children, compared to only 1 of the remaining 14 (7%). Researchers considered "this stratification ~highly effective in identifying HIV-1-infected women who are at very high risk for mother-to-child transmission." Another study finding was that viral load remained stable during pregnancy and after delivery. A subset of 12 women had from 3-8 viral load measurements determined "over periods ranging from 18-65 weeks. Viral titers varied greatly between the 12 women, but the viral load in each woman did not vary significantly over time." Thus, researchers conclude that "this systematic study identified maternal HIV-1 titer as a major determinant of mother-to-child transmission. These data help to elucidate the pathogenesis of HIV-1 mother-to-child transmission and are directly relevant to its prevention." This finding provides "the scientific rationale for implementing strategies to interrupt transmission by reducing viral titer." Larger studies will be needed to quantify the specific risk value associated with particular (ranges of) viral loads. References Weiser B and others. Quantitation of human immunodeficiency virus type 1 during pregnancy: relationship of viral titer to mother- to-child transmission and stability of viral load. Proceedings of the National Academy of Sciences USA 91: 8037-8041. August 1994. FDA Approves AZT for Pregnant Women and Infants Encouraging news about reducing the incidence of pediatric AIDS stems from a new strategy to prevent vertical transmission of HIV. On August 9, 1994, the Food and Drug Administration (FDA) approved marketing AZT as a treatment to prevent pregnant women with HIV from transmitting the virus to their babies. The FDA Antiviral Drugs Advisory Committee on July 28 had unanimously recommended approving the new indication for AZT, on the basis of the application submitted by Burroughs Wellcome, manufacturer of AZT. The application was based on data from ACTG 076, the study that demonstrated that HIV positive women could significantly reduce the risk of transmitting HIV to their infants by taking AZT during pregnancy. In fact, the study was stopped early based on "overwhelmingly positive findings:" women who took AZT during pregnancy and childbirth, and whose infants received AZT immediately after birth, reduced by two-thirds the likelihood of transmitting HIV. Overall, the risk of HIV transmission between women and infants who received AZT was 8.3%, compared to 25.5% for those who were not treated with AZT. Investigators were excited by the results of this study, stating that it is the rare single trial that so clearly demonstrates a positive effect. In ACTG 076, women were randomized to receive 500 mg/day of AZT during pregnancy (after completing the first trimester), and IV AZT during childbirth. Most began taking AZT between 14 and 34 weeks of gestation; most had never taken AZT before. Their infants also took AZT, beginning within 24 hours after birth, for 6 weeks. The only apparent side effect was transient anemia in some of the infants. No birth defects were attributed to AZT. While the safety data thus far is promising, the numbers of mother/infant pairs who have followed this regimen are small, so further information will need to be gathered. To this end, healthcare providers are encouraged to call the Antiretroviral Pregnancy Registry at 1-800-722-9292 extension 8465, or 919-315- 8465 if outside the U.S. The Registry, administered by Burroughs Wellcome together with Hoffman-La Roche Inc. and the Centers for Disease Prevention and Control (CDC), collects observational data on use of AZT (Retrovir) and ddC (HIVID) during pregnancy. A Burroughs Wellcome news release states that "the cost for the doses of Retrovir capsules, IV formulation and suspension called for in the new indication will vary depending on a number of factors such as the number of weeks a pregnant woman received Retrovir prior to the onset of labor." References FDA advisory committee recommends approval of Retrovir (AZT) for HIV-positive pregnant women and infants. Burroughs Wellcome News Release. July 28, 1994. Retrovir indicated to prevent transmission of HIV from pregnant women to their babies. Burroughs Wellcome News Release. August 9, 1994. --------- U.S. Public Health Service Task Force Recommendations for AZT Use in Pregnancy The results of ACTG 076, the government study that demonstrated that use of AZT by certain HIV positive women and their infants could reduce by 2/3 the risk for perinatal HIV transmission, quickly captured the attention of government officials and policymakers. Even before the August 9 FDA approval of AZT for use in treating HIV positive pregnant women, the U.S. Public Health Service held meetings to discuss the study. From June 6-7, the U.S. Public Health Service convened people from various communities (medical, scientific, legal, advocacy, etc.) who were interested in and affected by ACTG 076 results. The purpose of the workshop was to review study data, to formulate guidelines for the use of AZT by pregnant, HIV positive women, and to discuss the clinical implications for HIV testing and counseling. The official report was published in Morbidity and Mortality Weekly Report (MMWR) on August 5, 1994. It summarizes study results, discusses limitations of the applicability of the data and issues recommendations for treatment with AZT during pregnancy and monitoring. Immediate and ongoing concerns are noted, such as the unknown long-term risks of fetal and neonatal AZT use as well as the potential risk posed to the woman who uses AZT intermittently during pregnancies. A recurrent theme of the report is that interpretation and extrapolation of ACTG 076 results must be careful and individualized, since "the clinical status of many HIV-infected women may differ from that of women in this trial." ACTG 076: Summary of Study Participants, Regimen and Results The workshop panelists considered the ACTG 076 participant profile and exact drug regimen followed by mother/infant pairs to have great bearing on any possible extrapolation of results. Since these factors served as the framework for workshop discussions, a brief summary follows: Participants: ACTG 076 enrolled HIV pregnant women between 14 and 34 weeks of gestation who had greater than 200 CD4 cells, who had received no antiretroviral treatment during that (current) pregnancy, and who had no clinical indications for antiretroviral treatment. Participants who met these criteria were enrolled and randomized to receive either placebo or AZT. AZT regimen: (treatment arm) oral AZT beginning at 14-34 weeks of gestation and lasting for the length of the pregnancy; IV AZT during labor; oral AZT for the infant beginning within 24 hours after birth and lasting for 6 weeks. The placebo regimen was administered in exactly the same way(s). Results: Among 184 children in the placebo group, the estimated transmission rate was 25.5%. Among 180 in the AZT group, the transmission rate was 8.3%. Side effects were minimal among the women, and the only apparent side effect of AZT among infants was mild, reversible anemia. There were no differences observed in the pregnancies of women receiving AZT and placebo, as measured by sonography at 4- week intervals from study entry until delivery. Measurements of infants taken at birth~weight, gestational age, length, etc. ~were similar for both groups, as were congenital abnormalities. The National Institute of Allergy and Infectious Diseases (NIAID) ended the study early, based on the promising results of a preliminary data analysis, and women in the placebo group were offered AZT. Limitations There are several important limitations to consider when interpreting ACTG 076 results. * Taking the AZT regimen did not prevent perinatal HIV transmission 100% of the time. * It is unclear how effective the regimen may be in groups other than the study group(s), such as in women with advanced HIV disease, or who have used antiretroviral therapies in the past, or who have strains of HIV that show resistance to AZT. * The lack of AZT-related "serious short-term adverse side effects" observed in this study may or may not continue, or become a trend, as use for this new and related indications becomes more widespread and the number of users increases. * Long-term risks for children exposed in utero and neonatally have yet to be determined. * It is not yet known whether or not taking AZT during pregnancy will diminish the efficacy of the drug for the mother if and when she elects to take it later, when indicated for her health. Other potential problems for clinician and patient include lack of early prenatal care (e.g., women who do not receive medical attention until very late in pregnancy or even until delivery) and lack of awareness of HIV serostatus on the part of pregnant women, both of which obviously preclude use of the regimen as proscribed by ACTG 076. Summary of Workshop Recommendations The report outlines various clinical situations and corresponding recommendations about using AZT to reduce vertical transmission. Table 1 represents a summary of this part of the report, and is reprinted from MMWR. Authors note that the recommendations are designed to provide a basis for discussion between a woman and her healthcare provider(s) about the use of AZT during pregnancy. Providers should inform women about the benefits seen in ACTG 076 but should caution them that the long-term risks of treatment with AZT to both women and infants are unknown. After full discussion, whether or not to take AZT as a means for reducing the likelihood of vertical transmission is ultimately and finally the woman's choice. Future Investigations Several ACTG 076 results or occurrences warrant further investigation. For example, AZT reduced the incidence of mother-to-child HIV transmission, but did not completely prevent it. The reasons why some children become infected with HIV despite AZT treatment need to be elucidated. Children exposed in utero and neonatally need to be followed carefully in order to determine whether or not there are long- term adverse effects from such use of AZT. Laboratory and animal studies of AZT have led to theoretical concern about potential long-term effects of AZT. One concern is toxic effects on liver and heart tissues, although one prospective study of HIV positive children detected no effect from AZT on heart function. There also is concern over the carcinogenic (cancer-causing), mutagenic (birth-defect-causing) and teratogenic (causing malformations to occur in offspring) potential of AZT. Further data are needed to assess the efficacy of AZT use for preventing perinatal transmission in women whose clinical situations differ from those of the women who qualified for participation in ACTG 076, namely: women who are at >34 weeks pregnant (i.e., initiating AZT late in pregnancy); women with less than 200 CD4 cells; women who have used AZT in the past for more than 6 months; and antiretroviral-naive women in labor. Studies are also needed to determine whether or not giving AZT to newborns (beginning within 24 hours of life) who did not receive it antenatally can prevent HIV infection. Finally, the women who participated in ACTG 076 and others in similar situations will need to be followed carefully to determine the effects of using AZT intermittently during pregnancies. The authors note in the conclusion that these recommendations are designed for use in the U.S. and that other strategies may be more appropriate in other areas of the world. Relevant factors include access to AZT and treatment facilities (e.g., for administering IV AZT during delivery), and policies and interventions in local use. Single copies of the MMWR report can be obtained by calling the CDC National AIDS Hotline at 800-342-2437. References U.S. Department of Health and Human Services. Recommendations of the U.S. Public Health Service Task Force on the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus. Morbidity and Mortality Weekly Report 43(RR-11). August 5, 1994. Table 1. Summary of Clinical Situations and Recommendations for Use of Zidovudine* [AZT] to Reduce Perinatal HIV Transmission *These recommendations do not represent approval by the Food and Drug Administration (FDA) or approved labeling for the particular product or indications in question. I. Pregnant HIV-infected women with CD4+ T-lymphocyte counts > or = to 200 who are at 14-34 weeks of gestation and who have no clinical indications for ZDV and no history of extensive (> 6 months) prior antiretroviral therapy. Recommendation: The healthcare provider should recommend the full ACTG Protocol 076 regimen to all HIV-infected pregnant women in this category [women who meet the eligibility criteria for ACTG 076]. This recommendation should be presented to the pregnant woman in the context of a risk-benefit discussion: a reduced risk of transmission can be expected, but the long-term adverse consequences of the regimen are not known. The decision about this regimen should be made by the woman after discussion with her healthcare provider. [The following clinical situations II-VI concern women who do not meet the eligibility criteria for ACTG 076. The recommendations result from "consensus interpretation of available scientific data."] II. Pregnant HIV-infected women who are at >34 weeks of gestation, who have no history of extensive (>6 months) prior antiretroviral therapy, and who do not require ZDV for their own health. Recommendation: The healthcare provider should recommend the full ACTG Protocol 076 regimen in the context of a risk-benefit discussion with the pregnant woman. The woman should be informed that ZDV therapy may be less effective than that observed in ACTG Protocol 076, because the regimen is being initiated in the third trimester. III. Pregnant HIV-infected women with CD4+ T-lymphocyte counts <200 who are at 14-34 weeks of gestation, who have no other clinical indications for ZDV, and who have no history of extensive (>6 months) prior antiretroviral therapy. Recommendation: The healthcare provider should recommend initiation of antenatal ZDV therapy to the woman for her own health benefit. The intrapartum and neonatal components of the ACTG Protocol 076 regimen should be recommended until further information becomes available. This recommendation should be presented in the context of a risk-benefit discussion with the pregnant woman. IV. Pregnant HIV-infected women who have a history of extensive (>6 months) ZDV therapy and/or other antiretroviral therapy before pregnancy. Recommendation: Because data are insufficient to extrapolate the potential efficacy of the ACTG Protocol 076 regimen for this population of women, the healthcare provider should consider recommending the ACTG Protocol 076 regimen on a case-by-case basis after a discussion of the risks and benefits with the pregnant woman. Issues to be discussed include her clinical and immunologic stability on ZDV therapy, the likelihood she is infected with a ZDV-resistant HIV strain and, if relevant, the reasons for her current use of an alternative antiretroviral agent (e.g., lack of response to or intolerance of ZDV therapy). Consultation with experts in HIV infection may be warranted. The healthcare provider should make the ACTG Protocol 076 regimen available to the woman, although its effectiveness may vary depending on her clinical status. V. Pregnant HIV-infected women who have not received antepartum antiretroviral therapy and who are in labor. Recommendation: For women with HIV infection who are in labor and who have not received the antepartum component of the ACTG Protocol 076 regimen (either because of lack of prenatal care or because they did not wish to receive antepartum therapy), the healthcare provider should discuss the benefits and potential risks of the intrapartum and neonatal components of the ACTG Protocol 076 regimen and offer ZDV therapy when the clinical situation permits. VI. Infants who are born to HIV-infected women who have received no intrapartum ZDV therapy. Recommendation: If the clinical situation permits and if ZDV therapy can be initiated within 24 hours of birth, the healthcare provider should offer the ACTG Protocol 076 postpartum component of 6 weeks of neonatal ZDV therapy for the infant in the context of a risk-benefit discussion with the mother. Data from animal prophylaxis studies indicate that, if ZDV is administered, therapy should be initiated as soon as possible (within hours) after delivery. If therapy cannot begin until the infant is >24 hours of age and the mother did not receive therapy during labor, no data support offering therapy to the infant. Notes on Care for HIV Positive Women Leslie Hanna Are Pap Smears Sensitive in Women with HIV? Cervical dysplasia, which may develop as a result of infection with the human papillomavirus (HPV), is a frequent gynecological complication in women with HIV. Moderate or severe cervical dysplasia is a category B HIV-related condition, according to the Centers for Disease Control and Prevention (CDC), and invasive cervical cancer is an AIDS-defining condition. There have been reports that the technique most commonly used for routine screening, the Pap smear, is less sensitive in women with HIV. An ongoing challenge for caretakers is to determine the best way(s) for monitoring and detecting cervical abnormalities in their HIV-infected female patients. In San Francisco, a team of researchers decided to examine the sensitivity of the Pap smear in their HIV positive patients. HIV negative women referred to the colposcopy clinic for follow-up of abnormal Pap smears served as controls. The study involved 52 HIV positive women and 85 HIV negative women. All women had Pap smears and colposcopic examinations. Biopsies were performed where indicated. The pathologists who reviewed the specimens were unaware of serostatus and/or the study itself. The study and control groups were demographically compared, and the laboratory and clinical examination results were compared and statistically analyzed. Fifty percent (50%) of the HIV positive women had cervical dysplasia. Cervical dysplasia was detected by Pap smear/cytologic evaluation in 36%, and by colposcopic/biopsy/histological evaluation in 50%. This gave the Pap smear a sensitivity rating of 63% in HIV positive women, compared to 64% in the HIV negative control women. Pap smear specificity was 84% and 74% for HIV positive and negative women, respectively. Twenty-two of 28 HIV positive women with dysplasia on cytology had dysplasia on histology, for a positive predictive value of 79%. Of 45 HIV positive women with no dysplasia on cytology, 32 had none on histology, either, for a negative predictive value of 71%. In the control group, the corresponding values were 89% and 36%. Researchers gathered data from the control group in order to learn more about the sensitivity of routine Pap screening in the hospital clinic. They note that HIV seronegativity was self- reported, but feel that a higher seroprevalence would not affect their conclusions about sensitivity. Re-evaluating the cytologic slides from the controls (which they did not do), on the other hand, may have produced a higher sensitivity rating for this group. The investigators say that these results can be viewed 2 ways: the Pap smear sensitivity rating and negative predictive value can be used to "argue for cytologic screening alone for HIV-seropositive women" especially if they are able to have regular, repeated smears performed. However, higher prevalence rates of dysplasia are correlated with lower negative predictive values (of Pap smears). Since dysplasia was proved in 50% of the HIV positive women, and since that compares closely to that of all women for whom colposcopy is normally indicated (as standard procedure), HIV serostatus aside, one could also argue for routine colposcopic evaluation of HIV positive women. Colposcopy is also useful for detection of genital lesions (vulvar, vaginal, perianal), whereas Pap smears are not. Yet, colposcopic procedures are fairly involved and expensive. Thus, researchers offer a "reasonable alternative...colposcopic examination on diagnosis of HIV infection, with frequent cytologic follow-up if colposcopy is negative." They also state that further studies are needed to establish the best method for screening for dysplasia in HIV positive women. References Korn AP and others. Sensitivity of the Papanicolaou smear in human immunodeficiency virus-infected women. Obstetrics & Gynecology 83(3): 401-404. March 1994. Menstrual Symptoms in HIV-Infected Women There have been various anecdotal reports of HIV-related menstrual disturbances. In order to scientifically evaluate the impact of HIV infection on menstrual symptoms, British researchers conducted gynecological assessments of 55 HIV positive women and a matched control group of HIV negative women. This is the first controlled study of HIV-related effects on menstrual symptoms "in the absence of confounding variables such as substance misuse and methadone maintenance therapy." Previous studies that dealt with menstrual disturbances have found them in relation to substance abuse, which is known to affect the hypothalamus, a gland that controls the release of major hormones. Researchers postulated that any menstrual disturbances experienced may be caused by HIV-related endocrine dysfunction. Since gonadal failure has been reported in men with HIV, and although similar information for women does not exist, researchers considered that gonadal failure in women may present as menstrual disturbances. The hypothesis tested by the study was that HIV infection independently increases menstrual abnormalities such as dysmenorrhea (painful menstruation), and that this and other symptoms are related to the degree of immunosuppression. Subjects were recruited from medical clinics. Eligible HIV positive women were menstruating, non-pregnant, non-substance abusing, not receiving treatment for substance use, and not taking oral contraceptives. CDC-defined disease stage and most recent CD4 count were noted. A control group of HIV negative women were matched for age, parity and smoking. All were interviewed in great detail about gynecologic history and symptoms. The finding was that the symptoms of HIV positive women did not differ from those of HIV negative women. Women in both groups were roughly equivalent in terms of regularity and duration of cycles. Oligomenorrhea (scanty menstruation) occurred in 5.5% and 3.6% of study and control group women, respectively. Dysmenorrhea was reported by 58.2% of the subjects and by 61.9% of the controls. [Ed. note: the high numbers of both study and control women who reported dysmenorrhea may be an artifact of the study, particularly as self-reported pain is quantified with some difficulty.] Next, the researchers compared symptoms in asymptomatic to symptoms in symptomatic HIV positive women. No significant differences between the 2 groups were found here, either. References Shah PN and others. Menstrual symptoms in women infected by the human immunodeficiency virus. Obstetrics & Gynecology 83(3): 397-400. March 1994. ***** Colposcopy and Treatment for Abnormal Paps Joanne Genet, PA Reprinted with permission from WORLD, P. O. Box 115335, Oakland, CA, 94611. 510-658-6930. Colposcopies should be an important part of routine care for HIV positive women, especially women with histories of abnormal Pap smears. A Pap smear is a sample of cells that have been taken from a woman's cervix and spread onto a slide. This sample is evaluated by looking at the slide under a microscope. A colposcopy is a procedure in which the practitioner actually views the pattern of cells on the cervix rather than the random sample on the slide. To do this, she uses a colposcope~a kind of microscope with a strong light that magnifies the cells on the cervix. A colposcopy can be done in a medical office just like a Pap smear. A speculum is used to open the vagina, bringing the cervix into view. The practitioner can view the cervix from outside the vagina through the colposcope. During this exam, the cervix is washed with vinegar. This cleans the cervix and helps make some abnormalities more visible. The vinegar can sometimes cause slight burning, especially if you have been experiencing any signs of a vaginal infection. If this happens, ask your practitioner to wash your vagina with some water after the exam. This can be done using a giant Q-tip, called a scoppette, that has been dipped in water. The kinds of cervical changes that your practitioner is looking for are: 1. Lesions with increased or unusual patterns of blood vessels. These are called "punctation" or "mosaicism." 2. A change in color in any part of the cervix to a whitish color which may indicate the presence of human papillomavirus (HPV, which causes genital "warts") or some other abnormality. 3. Ulceration or other problems. If anything unusual is seen during this exam, a biopsy will be made. Tiny tissue samples are removed from the unusual area and other areas of the cervix, and then sent to a pathologist for evaluation. The biopsy procedure can cause some cramping similar to menstrual cramps. If, through the colposcope, abnormal areas are clearly present on your cervix, you and your practitioner may decide to treat them during the exam rather than wait several days for the results of the biopsy. The most common treatment, depending on the severity of the problem, is cryosurgery. During cryosurgery, the top layer of skin on the cervix is frozen, usually with liquid nitrogen. This may also cause cramping. The freezing kills the top layers of skin and causes it to slough off. New, hopefully healthy, skin then grows back. And, hopefully, this procedure also removes the HPV or whatever was causing the problem. Sometimes the problem is more extensive or persistent. If so, there are a variety of treatments including laser surgery, treatment-cautery (burning the skin), radiation, surgery (from removal of the cervix to removal of the uterus and ovaries) and chemotherapy. All of these treatments attempt to remove the area that is either pre-cancerous or cancerous. The type of treatment depends on the severity of the problem. As yet, the most effective treatment for HIV positive women with cervical abnormalities is unknown. If you have had an abnormal Pap smear and have been treated, then you should be followed closely afterwards to check for recurrence of the problem. This may mean more frequent Pap smears and colposcopies. Places to go for Pap smears and colposcopy (All practitioners seeing HIV positive women should be doing Pap smears routinely.) 1. San Francisco General Hospital, Gynecology/Dysplasia Clinic, 415-206-8833. 2. Lyon-Martin Women's Health Services, 415-565-7667. Pleasant, affirmative clinic that receives funding to see HIV positive women. 3. UCSF AIDS Clinic, Women's Clinic, 415-476-3226. Open Wednesdays from 9-12. Provides childcare. 4. Women's Needs Clinic, 415-487-5607. A supportive clinic; involved in Pap smear/colposcopy study of HIV positive women. Drug-Nutrient Interactions Edward Lor, PharmD Dr. Lor is an Assistant Clinical Professor of Clinical Pharmacy at San Francisco General Hospital/UC San Francisco. Reprinted with permission from AIDS File. The pharmacokinetic and pharmacodynamic efficacy of many commonly used medications in the treatment of HIV disease can be affected by diet. Conversely, nutritional status can be altered by various medications. The majority of AIDS patients take a number of medications, underscoring the need for awareness of drug-nutrient interactions. These interactions become clinically significant when they alter the intended response to a drug or impair the patient's nutritional status. The medications may exert a specific appetite-depressant effect, or they may cause side effects such as nausea, vomiting, diarrhea, alteration in taste, and anorexia, which in turn decrease appetite and nutrient intake. Some medications may have decreased or enhanced absorption with food. Although there are no data, patients with chronic diarrhea may have altered intestinal absorptive capacities, especially for those medications which need food for enhanced absorption. The increased transit time in patients with diarrhea may not allow sufficient time for the absorption of medication. Two drugs may increase appetite significantly enough to lead to weight gain: Megestrol acetate Megestrol acetate is a synthetic, orally active derivative of the naturally occurring steroid hormone progesterone. Investigators have reported that megestrol acetate enhances appetite and increases body weight in patients with AIDS and various advanced malignant diseases. The precise mechanism by which megestrol acetate stimulates appetite and weight gain in AIDS patients is unknown. Dronabinol The appetite-stimulating effects of marijuana have been well documented. There are anecdotal reports of marijuana-smoking cancer and AIDS patients who claim increased appetite and weight gain or stabilization. Dronabinol (Marinol, Delta-9) has been used as an antiemetic in cancer patients for many years. Studies of dronabinol in AIDS and cancer patients have shown not only antiemetic activity but also improved appetite, sense of well being (without euphoria), and weight gain. The weight gain was shown to have no clinical evidence of fluid retention contributing to water weight. Selected Open Clinical Trials for HIV/AIDS Treatments For further information, call the number provided with the individual listing or call the AIDS Clinical Trials Information Service (ACTIS), toll-free, at 1-800-874-2572 (1-800-TRIALS-A). This government-sponsored service can provide information about most of the following trials, but can only provide information about privately sponsored trials when the sponsor has elected to give that information to ACTIS. ***** Treatment for HIV Infection L-735,524 (Merck protease inhibitor), AZT and ddI This Phase II clinical trial will look at the safety and tolerability of a higher dose of the Merck protease inhibitor than previously studied, alone and in combination with other anti-HIV agents. Participants will be randomized to 1 of 3 treatment arms: (1) 600 mg L-524 plus AZT plus ddI, (2) 600 mg L-524 or (3) AZT plus ddI. The study lasts for 6 months. Entrance requirements include fewer than 500 CD4 (T-helper) cells and no less than 2 weeks of previous AZT and/or ddI use. ddC must be discontinued 2 weeks prior to study treatment, and d4T, 3TC or any other experimental agent, 30 days prior to treatment. There are multiple sites. saquinavir (Roche protease inhibitor) high-dose study This study will randomize 40 people to 2 treatment arms, and will take place at Stanford University in Palo Alto, CA. Participants in arm 1 will take 600 mg of Hoffman-La Roche (Roche) protease inhibitor, saquinavir, 6 times daily; those in arm 2 will take 1,200 mg 6 times daily. Entrance requirements include 200-500 CD4 cells, less than 3 months prior use of AZT and less than 2 weeks prior use of ddC or ddI. Participants may be p24 antigen positive or -negative. Call Jane Norris, PA, at 415-723-2805. saquinavir and ddC This 40-center Phase III study will involve 1,200 participants. The trial is open to people with HIV with 50-300 CD4 cells who have failed on AZT. Prior use of ddC, ddI or d4T must not be greater than 2 weeks. There are 4 treatment arms: saquinavir monotherapy, ddC monotherapy, ddC plus low-dose saquinavir and ddC plus high-dose saquinavir. For more information about the international and North American trials of saquinavir, call 1-800-526-6367. saquinavir and AZT This study compares saquinavir to AZT. Participants will be randomized to take protease alone, AZT alone or protease inhibitor in one of 2 doses with AZT. Some sites are still open. Call 1-800-526-6367. d4T (Zerit) plus ddI This double-blind, dose-ranging pilot study will evaluate the safety, efficacy and pharmacokinetics of combination therapy with d4T and ddI. Seventy-five (75) participants will be assigned to 1 of 5 combination-treatment arms; doses are based on body weight. The study is open to people who have never used AZT or ddI and who have no history of pancreatitis or peripheral neuropathy. Treatment lasts for 1 year. Study sites are New York, Los Angeles and San Francisco. sustained-release AZT Aztec is a sustained-release formulation of AZT, developed by Verex Laboratories. The study will evaluate the safety and effectiveness of the sustained-release product compared to the standard formulation of AZT. The 18-week, double-blinded study is open to people with HIV and 200-500 CD4 cells. Participants who complete the study will be eligible to enroll in a 3-year open-label study of Aztec. In the San Francisco Bay Area, call Brian Camp at the AIDS Community Research Consortium (ACRC) at 415-364-6563. OPC-8212 OPC-8212 is an oral medication used in Japan to treat congestive heart problems. This Phase I study evaluates the safety, tolerance and antiviral potential of 3 different doses of OPC. The study lasts for 12 weeks and is open to people with asymptomatic HIV infection. Call UCLA's Center for AIDS Research and Education (CARE) at 310-206-1960. In Atlanta, a similar Phase I study but with 4 different doses of OPC is enrolling people with 50-300 CD4 cells. Call the AIDS Research Consortium of Atlanta at 404-876-2317. SC-49483 vs AZT for inhibition of syncytia formation ACTG 259 is a Phase II multicenter study of SC-49483, a new drug that may help prevent the formation of syncytia, which are clumps of infected and healthy immune cells that the immune system targets for elimination from the bloodstream. Syncytia formation is associated with disease progression. Participants will be randomized to receive either (1) low-dose SC-49483 plus AZT, (2) high-dose SC-49483 plus AZT or (3) AZT plus placebo. Entrance requirements include 50-350 CD4 cells and less than 6 months prior use of monotherapeutic AZT. Treatment lasts 16-24 weeks. 935U83 This Phase I study of 935U83 (a nucleoside analog) will evaluate the safety, tolerance and pharmacokinetics of various oral doses of the drug. The study is open to people with 200-500 CD4 cells, not more than 1 month's prior use of nucleoside analogs (AZT, ddI, ddC, d4T) and no prior use of non-nucleoside reverse transcriptase inhibitors. delavirdine (DLV) and AZT A Phase II/III randomized, double-blind study of the BHAP compound delavirdine (DLV), a non-nucleoside reverse transcriptase inhibitor, will look at 3 fixed doses of DLV plus AZT vs AZT alone to examine safety, tolerance and preliminary efficacy of the combination. This 6-month study will enroll asymptomatic, HIV positive individuals with 200-500 CD4 cells. Exclusion criteria include prior use of AZT for longer than 4 months, AZT intolerance and prior use of ddI, ddC, d4T or 3TC. For information and study sites, call the Upjohn AIDS Hotline at 1-800-432-4702. delavirdine (DLV) and ddI This Phase II/III randomized, comparative trial will evaluate the safety, tolerance and efficacy of DLV in combination with ddI vs ddI alone. Participants have 300 or fewer CD4 cells and less than 4 months prior ddI experience (unlimited AZT experience is permitted). One arm will receive ddI and 400 mg DLV; the other arm will receive ddI and placebo. For study sites and more information, call 1-800-432-4702. Note: participants in both DLV studies described here who do not respond to the study treatment will be eligible for open-label, triple-drug therapy containing DLV. The Upjohn AIDS Hotline is 1-800-432- 4702. atevirdine atevirdine, another BHAP compound manufactured by Upjohn, is synergistic with AZT. This one-year, multicenter Phase II trial randomizes participants to one of 3 arms: atevirdine 600 mg/day + AZT vs atevirdine 200 mg/day + AZT vs placebo + AZT. Participants will have 50-350 CD4 cells, have had 1 or more opportunistic infection(s), and have been taking AZT for at least 3 months. For information about trial locations, call the Upjohn AIDS Hotline at 1-800-432-4702. GS-840 A Phase I study of an oral drug known as GS-840 (also called BIS-PON PMEA) is underway. Manufactured by Gilead Sciences, GS- 840 is a prodrug of another Gilead Sciences product, GS-393, or PMEA, which is in ongoing Phase I/II clinical trials. GS-840 is designed to be efficiently converted in the body into GS 393 and to achieve the highest possible bioavailability. Ongoing trials of GS 393 or PMEA have shown that taking the drug is associated with decreased levels of p24 and increases in CD4 cell counts. Call Dr. Paul Leitman at Johns Hopkins University at 410-955- 9707. PMEA plus AZT The National Cancer Institute (NCI) is conducting a Phase I/II dose-ranging study of the safety and efficacy of the combination of AZT and PMEA, a nucleoside analog like AZT, known to be active against herpesviruses and HIV. PMEA is given in IV form 3 times a week. Participants have less than 500 CD4 cells. Call Sergio Bauzo of NCI at 301-496-8959. PMEA for advanced HIV disease This Phase I/II study looks at the safety, tolerance, pharmacokinetics and anti-HIV effect of PMEA in people with advanced HIV disease. PMEA is administered daily by intravenous (IV) and/or subcutaneous (SC) injection. Twenty participants will receive a single IV or SC dose once a day for 4 weeks. Entry requirements include less than or equal to 100 CD4 cells and p24 antigen levels greater than 40. This study will take place at the University of Washington School of Medicine (in Seattle). Call Dr. John Nienow at 206-223-3184. oral hypericin (VIMRxyn) The NIH is sponsoring an open-label trial of oral hypericin, an antiviral compound made by VIMrx. The Phase I/II trial will evaluate the efficacy of a daily oral regimen. Eligibility requirements include being p24-positive and having less than 350 CD4 cells. Efficacy will be evaluated by measuring p24 antigen levels and viremia using cultures and PCR. Study sites still enrolling are New York University Medical Center/Bellevue Hospital and Johns Hopkins University in Baltimore, MD. short-term AZT for primary infection This NIAID trial, DATRI 002, will evaluate the effect of short-term daily doses of AZT in people recently infected by HIV. The p24 antigen test will be used to determine eligibility. Participants will be randomized to receive either 1,000 mg/day AZT or placebo for 24 weeks. CD4 cell counts will be measured during and after the 24-week period to determine whether or not taking AZT produced an increase in CD4 cells. BuCast in San Francisco BuCast is a compound closely related to a chemical (castanospermine) that is naturally found in a particular variety of chestnut trees. Laboratory studies have shown that castanospermine prevents HIV replication, and prevents HIV from binding to host cells. HIVCare is conducting a Phase I study to establish a maximum tolerated single dose and to evaluate safety and pharmacokinetics involved in using the agent over a period of 2 weeks. Participants have at least 500 CD4 cells. For more information call Mark Bowers at 415-353-6215. curcumin This Phase I/II study evaluates the safety, pharmocokinetics and antiviral effect of curcumin. A compound found in the cooking spice turmeric, curcumin has a long history of use in traditional Asian medicine. Forty (40) people with HIV but without active opportunistic illness(es) will be randomized to receive either 900 mg 3 times daily, or 1,200 mg 4 times daily. Call Mary Dugan, CRI of New England in Brookline, MA, at 617- 566-4004. Children AZT vs d4T ACTG 240 is a Phase III double-blind study that randomizes children to take either AZT or d4T. Children are 3 months to 18 years old and taking no antivirals immediately prior to study entry. Both drugs are taken orally. There are multiple sites nationwide. protease inhibitor The National Cancer Institute (NCI) is conducting a Phase I study of the safety, toxicity and antiviral potential of a new protease inhibitor, KNI-272, in HIV positive children aged 3 months to 18 years. Children with no prior antiretroviral treatment will comprise arm A, and children refractory or intolerant to antiretroviral therapy, arm B. The study will use 5 dose levels to establish maximal tolerated and minimally effective doses. Initial and final doses will be single IV or oral, with 12 weeks of oral administration falling in between. Call 310-402-1391 or 301-402-1387. recombinant human growth factor vs growth hormone This Phase I/II NCI study compares the safety and tolerance of recombinant human insulin-like growth factor (rhIGF-1) to recombinant human growth hormone (rhGH, Nutropin), in combination with antiretroviral therapy, in children with HIV and failure to thrive or grow. Investigators will also collect preliminary data on the effects of the growth factor and growth hormone on growth, immune function and viral burden. Eligible children are 6 months to 18 years old, have used antiretroviral therapy in the past, and have experienced growth failure. Exclusion criteria include diabetes and malnutrition. Initially, all children will receive AZT and ddI for 12 weeks. Then they will be randomized to receive either rhIGF-1 or rhGH for 12 weeks. Children who benefit from the regimen may continue for another 12 weeks (36 total). Call the NCI at 301-402-1391 or 301-402-1387. atovaquone for PCP prophylaxis ACTG 227 is a Phase I, open-label study of the safety, tolerance and pharmacokinetics of atovaquone (Mepron) for preventing pediatric PCP. Eligible children will be stratified according to age (open to children aged 1 month to 12 years). Within age groups, children will be randomized to receive low- or high-dose atovaqone for a period of 12 days. non-Hodgkin's lymphoma The NCI is conducting a pilot study of 2 drugs, systemic cyclophosphamide and methotrexate, for the treatment of HIV- related non-Hodgkin's lymphoma in children. The drugs under study are considered the 2 most effective drugs for treating childhood lymphomas. During the study, participants will continue to use antitretroviral therapy as well as IV gamma globulin, acyclovir and PCP prophylaxis to minimize the risk of complicating infection. The treatment period is 2 1/2 months. The age range is 3 months to 18 years. For more information, call the NCI at 301-496-2321. Immune Enhancement recombinant human interleukin-12 (rh-IL12) This Phase I study will evaluate the safety of single doses of rhIL-12, a natural protein involved in regulating the cell- mediated immune response. Participants have 100-500 CD4 cells, are currently taking an antiretroviral (for at least 6 weeks), and are asymptomatic or slightly symptomatic. In the San Francisco Bay Area, call UCSF at 415-476-9296, extension 84598. In southern California, call the UCLA CARE Center at 310-206- 6414. thymopentin (TP5) Thymopentin, or TP5, is derived from a natural hormone and stimulates the immune system. This Phase III double-blind, placebo-controlled trial will evaluate the safety and efficacy of thymopentin (Timunox) in HIV positive individuals taking an anti-HIV drug(s). Specifically, participants are randomized to receive thymopentin with AZT or ddI, or AZT combined with ddI, or AZT combined with ddC. A previous study indicated that the combination of thymopentin and AZT was more effective than AZT alone in slowing HIV disease progression. A related Phase II placebo-controlled trial will look at the impact of various doses of thymopentin on viral load; the study is open to people with less than 400 CD4 cells. HIVIG plus AZT vs IVIG plus AZT for pregnant women HIVIG, a solution of concentrated antibodies, is a type of passive immunotherapy. ACTG 185 is a Phase III trial that compares HIVIG to IVIG for efficacy in preventing transmission of HIV from mother to infant. Participants are randomized to take either HIVIG or IVIG; all participants take AZT. Mothers are given AZT intravenously during labor. Infants receive the same treatment as mothers. Newborns also receive either IV HIVIG or IVIG, within 12 hours of birth, and a syrup formulation of AZT for 6 weeks. There are numerous sites nationwide. vaccine for CMV A Phase I clinical trial has begun of a candidate vaccine against CMV. Sponsored by Biocine Company in a joint venture with Ciba-Geigy Ltd., the vaccine will be tested in seronegative healthy adults. The trial will evaluate safety, tolerability and impact on the immune system of the vaccine. Volunteers will be monitored through clinical evaluations and laboratory tests that will measure levels of CMV antibodies as well as CD4 cells and others. Treatment for Opportunistic Infections oral ganciclovir for maintenance treatment of CMV retinitis Syntex Research is sponsoring an open-label safety study of oral ganciclovir for maintenance treatment for CMV retinitis. Enrollment may be made through any licensed physician in the U.S. and Canada. Participants have stable CMV retinitis; treatment with IV gancicvlovir or foscarnet during at least 18 of the last 21 days prior to study enrollment; known difficulty tolerating the IV catheter; no known sensitivity to acyclovir or ganciclovir. HPMPC for refractory CMV retinitis Enrollment has begun for an open-label study of HPMPC or GS 504. The study is being conducted by the manufacturer, Gilead Sciences. Approximately 100 people will be enrolled at 6 sites in the U.S. and 1 in Great Britain. Entrance requirements include ophthalmologically proven CMV retinitis and unsuccessful ganciclovir and/or foscarnet treatment (for at least 4 weeks). During a 2-week induction phase, everyone will receive 5 mg/kg once weekly. After that, participants will take either 5 or 3 mg/kg once every other week. Retinal photographs will be used to evaluate efficacy. atovaquone (Mepron) vs aerosolized pentamidine for preventing PCP In an ongoing research effort to identify effective prophylactic strategies against PCP for people intolerant of TMP-SMX, Burroughs Wellcome is sponsoring a study of atovaquone (Mepron) vs aerosolized pentamidine (AP). The 18-month study will compare the efficacy of high- vs low-dose Mepron to AP. The study is open to 2 different groups of people with HIV: (1) people who have had 1 or more previous episodes of PCP and (2) people with HIV and less than 200 CD4 cells or thrush, or unexplained fever for more than 2 weeks. Other requirements include intolerance of TMP-SMX or some other trimethoprim or sulfa-containing compound. At study entry, chest x-rays must be normal or at least not indicative of active PCP. Exclusion criteria include active PCP, prior history of intolerance to either study agent and current use of rifampin and/or any other anti-PCP agent. In San Francisco, call Mark Bowers at HIVCare at 415-353-6215. azithromycin (Zithromax) for the prevention of MAC disease This study evaluates the safety and effectiveness of weekly azithromycin for the prevention of MAC disease in people with fewer than 100 CD4 cells. Participants take azithromycin or placebo. Criteria include not having had a positive MAC culture within 1 month of beginning the study, and no treatment with any anti-MAC drugs within the last 4 weeks. azithromycin (Zithromax), clarithromycin (Biaxin) plus ethambutol (Myambutol) for treating MAC This double-blind study compares 2 combinations of anti-MAC agents for the treatment of disseminated MAC. Participants will be randomized to take 250 or 650 mg azithromycin plus 800-1200 mg ethambutol daily (based on body weight) or clarithromycin 500 mg twice daily and 800-1200 mg ethambutol once a day. At the end of the regular 24-week study, participants may be evaluated for entry into an open-label maintenance protocol, with monitoring at trimonthly intervals. The study is open to people with HIV and a positive MAC blood culture performed within 2 months prior to study entry. Exclusion criteria include therapy for MAC after the positive culture that qualified for study entry, and known sensitivity to any of the macrolide antibiotics including erythromycin, azithromycin, clarithromycin or ethambutol, or concommitant therapy with another investigational drug starting within 1 week of study entry. A total of 300 people will be enrolled at 25-30 sites nationwide. In the San Francisco Bay Area, call the AIDS Community Research Consortium (ACRC) at 415- 364-6563. thalidomide (Synovir) for mycobacterial infections FDA 133A is a Phase I/II trial of the safety and efficacy of thalidomide in people with HIV and/or mycobacterial infections, including Mycobacterium avium complex and tuberculosis. Clinical examinations and laboratory tests will be used to evaluate the impact of thalidomide on reducing symptoms and improving immune responses in participants. The trial is open to people with proven mycobacterial infection (culture or smear), with or without documented HIV infection. HIV positive participants must have fewer than 500 CD4 cells and be taking an antiretroviral(s). Recent fever, weight loss and night sweats are also required. Participants will be randomized to receive oral thalidomide or placebo the night before beginning anti-tuberculosis treatment, to continue for 7 nights. Follow-up continues for a total of 28 days. thalidomide (Synovir) for aphthous ulcers ACTG 251 is a multicenter study of the safety and efficacy of thalidomide for the treatment of oral and esophageal aphthous ulcers and HIV viremia. Investigators will look at viral load and tumor necrosis factor (TNF) levels. To participate, people with HIV need to have had a biopsy within 8 weeks prior to study entry that documents the presence of aphthous ulcers lasting at least 2 weeks, as well as a negative culture for herpes (within the same period). Participants will be randomized to receive 4 weeks of either 200 mg oral thalidomide or placebo, once daily. foscarnet cream for herpes simplex This New York City pilot study will evaluate the efficacy of foscarnet in a cream form for herpes simplex lesions. HIV positive participants have virologically confirmed herpes simplex lesions of the skin or mucous membranes, within the past 60 days, and have unsuccessfully tried acyclovir treatment. Unacceptable benefit is defined as <25% decrease in herpes lesion size. All participants will receive topical treatment of lesions with a 1% foscarnet cream that is applied 5 times a day for "up to 6 weeks." Patients who show no improvement after 3 weeks will have the option of trying intravenous foscarnet. All patients will be followed until complete healing. For more information, call Arlene Hurley at New York University at 212-263-6411. amphotericin B, fluconazole and itraconazole to treat cryptococcal meningitis ACTG 159 is a multicenter, Phase I/II comparative trial. For the first 2 weeks of the study, participants will receive either amphotericin B alone or in combination with flucytosine. Then, for 8 weeks afterward, half will take fluconazole and half will take itraconazole. acitretin for severe psoriasis In New York, there is an open-label, dose-escalating trial of the efficacy of oral acitretin for the treatment of psoriasis in people with HIV. Acitretin is known to clear psoriasis and is considered an effective treatment in HIV negative people; this will be the first thorough study of its use in people with HIV. Eligible participants are 18-55 years of age with psoriasis that affects at least 10% of their bodies (as measured by the Psoriasis Area and Severity Index, or PASI). Initially, everyone will begin with a minimum dose of 25 mg/day. Every 4 weeks from then on, depending on PASI score, the dose will be increased up to a maximum of 100 mg/day. Various assessments will be performed at regular intervals during the 20-week study, including x-ray, skin biopsy, blood tests, PASI evaluations and photographic studies. For more information, contact Dr. Bradford Katchen at the Department of Dermatology, Beth Israel Medical Center, at 212-420-2184. Treatment for Malignancies and Cancers topical gel for Kaposi's sarcoma (KS) This Phase I/II study is looking at the efficacy of a topical medicine called LGD1057. People with KS can apply the medicine, which comes in gel form, to their lesions themselves. A natural retinoic hormone (9-cis-retinoic acid), LGD1057 is related to vitamin A, which plays various roles in immune system responses and in protecting body tissues. The study will last for 4 weeks. If appropriate, participants may be eligible to continue using the agent after the end of the study. Call the UCLA CARE Center at 310-206-6414. OPC-8212 for KS OPC-8212 is an oral medication being studied elsewhere for its antiviral properties. This study will evaluate the ability of 2 different doses of the agent to cause regression of KS tumors, and is open to people with HIV and KS, without other current opportunistic infection(s). Use of antivirals is disallowed during the study. Call the UCLA CARE Center at 310- 206-1960. interleukin 4 (IL-4) for Kaposi's sarcoma (KS) ACTG 224 is a Phase I/II open-label, dose-ranging study of IL-4 for treating KS. In Boston call Dr. Scadden at 617-632-8528 and in Los Angeles call Dr. Miles at 310-206-6414. For more information about a Phase II open-label trial of IL-4 for KS, call Dr. Gill in Los Angeles at 213-343-8275. photodynamic therapy for KS: tin ethyl etopurpin and lasers This Phase II trial looks at the safety and effectiveness of photodynamic therapy for cutaneous KS. The drug tin ethyl etopurpin is injected directly into lesions, followed by irradiation of the lesions with a laser. All participants receive treatment for a period of only a few days. Participants must have at least 3 measurable KS lesions that have been not been treated within the last 30 days. Contact Jorge Toro at the UCSF/SFGH Dermatology Department at 415-206-6099 or 415-206-8680. 5-FU for cervical dysplasia 5-FU is a cream that is applied intravaginally to prevent and treat cervical cancer. ACTG 200, a Phase II/III trial of safety and efficacy, compares the use of intravaginal 5-FU to observation for maintenance treatment of cervical dysplasia. After standard treatment for high-grade cervical dysplasia, women participants are randomized to receive treatment (topical vaginal administration of 5-FU) or to be observed. There are numerous sites nationwide. Treatment for Wasting Syndrome and Myopathy thalidomide (Synovir) for wasting syndrome FDA 230A is a Phase II placebo-controlled study of the safety and efficacy of thalidomide for treating HIV-related wasting syndrome. In particular, investigators will be examining the effect of thalidomide on "reducing weight loss," and on antiviral and anti-tumor necrosis factor-alpha potential. The study is open to people with HIV and wasting, or greater than 10% loss of normal/prewasting body weight in the absence of another infection that might account for such weight loss. Therefore, participants must be negative for acid-fast bacteria and active opportunistic illness(es) requiring systemic therapy. Participants will be randomized to receive low- or high-dose thalidomide (100 or 200 mg/day) or placebo for 8 weeks, and may continue for an additional 4. L-carnitine for myopathy (muscle weakness/degeneration) L-carnitine is a natural biochemical that stimulates the oxidation and synthesis of fatty acids. The NIH is conducting a Phase II placebo-controlled trial to evaluate L-carnitine as a treatment for myopathy, which at times is a side effect associated with use of AZT. Call Dr. Cupler at the National Institute of Neurological Disorders and Stroke (NIND), a division of NIH, at 301-402-4479. Miscellaneous acupuncture for chronic hepatitis This study examines the effectiveness of traditional Chinese acupuncture compared to traditional Korean acupuncture for treating chronic viral hepatitis. Participants with HIV and chronic viral hepatitis will be randomized to receive either Chinese or Korean acupuncture, or to a control group. Acupuncture is given twice a week for 4 months. For their participation, members of the control group will receive blood tests and also 2 free acupuncture visits and a bottle of Chinese herbs at the end of the study. The study will take place in San Francisco; call the Quan Yin Healing Arts Center at 415-861-4964. Clinical Trials Information by Region SAN FRANCISCO BAY AREA 415-476-9554 SOUTHERN CALIFORNIA HIV TREATMENT DIRECTORY 213-469-5888 AIDS/HIV TREATMENT DIRECTORY FOR NEW ENGLAND 617-424-1524 NEW YORK, CONNECTICUT, NEW JERSEY AND PHILADELPHIA 212-268-4196 AIDS Institute Experimental Treatment Infoline in New York state: 800-MEDS-4-HIV outside New York: 212-239-5523 DIRECTORY OF WISCONSIN HIV/AIDS CLINICAL TRIALS in Wisconsin: 800-359-9272 outside Wisconsin: 414-291-2799 NORTHERN GEORGIA & ALABAMA 404-874-7926 GULF COAST REGION 504-584-3605 HOUSTON CLINICAL TRIAL NETWORK 713-520-2083 CANADIAN HIV TRIAL NETWORK 604-631-5327 ACTIVELY RECRUITING U.S. TRIALS AmFAR Treatment Directory 212-682-7440 DISTRIBUTED FOR GENA by AEGIS/San Juan Capistrano -- 714.248.2836: Copyright (c) 1994 -- Bulletin of Experimental Treatments for AIDS (BETA), a quarterly publication of the San Francisco AIDS Foundation (SFAF). Reproduced with permission. Reproduction of this article (other than one copy for personal reference) requires written consent from the SFAF. For subscription information contact the BETA Subscription Office at 1.800.959.1059 or 1.510.549.4300, or via the internet at beta@sfsuvax1.sfsu.edu. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display