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