Subject: Treatment Issues Vol. 5 No. 4 Date: May 15 1991 (1128 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& && T R E A T M E N T I S S U E S && &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Gay Men's Health Crisis: Treatment Issues Volume 5 no. 4, May 15, 1991 Contents: [items are separated by "*****" for this display] New Antiviral Research Acupuncture Interview with Dr. David Ho Hepatitis B and HIV In Brief New Studies ***** A New Tide in Antiviral Research Garance Franke-Ruta Most of us have had our fill with AZT-related stories. For a long time AZT, ddI, and ddC research data were all that was available for the headlines, since anti-HIV strategies have historically been focused on such drugs. But recently, HIV research has offered more understanding of how the virus works, and a number of new compounds have moved from the realm of the theoretical into clinical trials. New Approaches Several new and exciting approaches to inhibiting HIV are now under observation. For example, drugs called protease inhibitors are in development by a number of firms, including Hoffmann-La Roche, Smith-Kline Beecham, Upjohn, Abbott, Lilly Research Labs, and Merck, Sharpe and Dohme. Roche Products has begun the first human trial of a protease inhibitor in England in order to examine the pharmacology of the drug. Protease inhibitors have a different target on HIV during the HIV-replication cycle, than other antiviral drugs. Nucleoside Analogues (AZT, ddI and ddC) function by stopping HIV from copying its genetic information onto that of the cell it has infected. This action then stops the virus from reproducing within the new cells it has infected. Protease inhibitors -- instead of interrupting HIV when it first invades a healthy cell -- interrupt a later stage of the HIV production cycle. More specifically, protease inhibitors interefere with certain natural cell substances, called enzymes, which tailor-make the precursor virus particles that form new HIV. Other drugs aim at specific genes of HIV. These genes have a variety of functions. One, called the tat gene, plays an important role in controlling reproduction of HIV (1). New drugs that inhibit tat are under investigation by Hoffman-La Roche and competitor company, Smith Kline and French. The Hoffmann-La Roche tat inhibitor recently completed a phase I nine-person, single-dose safety study at Johns Hopkins University in Baltimore, Maryland. Further trials have been "put on hold," while Hoffmann-La Roche "aggressively seeks a partner company" to co-sponsor further multiple dose studies, said Paul Oestreicher, a company representative. The decision is financial and not based on scientific data. In the meantime, Hoffmann-La Roche is committed and moving ahead on ddC and protease inhibitor development, he said. Other novel approaches to treating HIV have also caught fire recently. Drugs, prescribed for distinct medical conditions, such as N-acetylcysteine (NAC), an inexpensive, relatively non- toxic medication routinely used to treat bronchitis, and pentoxifylline, prescribed for people with poor blood circulation to the legs, are finally receiving serious consideration. Both these agents work by mediating the effects of a protein, called tumor necrosis factor (TNF). This particular protein is elevated in many people with HIV. TNF is believed to increase production of HIV, antagonize the affects of AZT and may be linked to wasting syndrome by stimulating the breakdown of fat. What's in a Name? Two new drugs which inhibit HIV at the same stage, but in a different manner as AZT, have entered Phase I testing. These drugs block the action of an enzyme called reverse transcriptase (RT) which helps the virus copy its own genetic material into the mechanism of the cell it has infected, in order to make more virus. Infected cells are transformed into virtual "virus factories." Without the RT enzyme, HIV cannot infect new cells. These new reverse transcriptase inhibitors agents are BIRG (made by Boehringer Ingelheim) and the so-called "L" drugs -- L-679,639 and L-679,661 (made by Merck, Sharpe and Dohme). The rest of this article will focus on these drugs. The "Boehringer Drug" BIRG inhibits HIV in the test tube, and shows little toxicity against uninfected human cells at up to 8,000 times the dose necessary to inhibit HIV (2). The majority of BIRG's antiviral activity appears to be dependent on its ability to inhibit RT. BIRG shows activity against HIV-1 only, but not against HIV-2. BIRG also does not appear to have activity against SIV or FeLV, two viruses found in monkeys and felines, respectively, which are often used as models for HIV. Several other human, viral, and animal enzymes are also unaffected by the drug. In the test tube, Dr. Douglas Richman has found that BIRG has anti-HIV activity in blood taken from patients who have developed resistance to AZT. In addition, there appears to be a synergistic effect in the test tube when AZT and BIRG are used together. In other words, AZT and BIRG have a stronger anti-HIV effect together than each drug has when used singly. In monkeys and chimpanzees, an oral form of the drug was well absorbed. BIRG has a half-life in animals of over 24 hours (it takes more that 24 hours for half of the drug administered to clear from the bloodstream). Its long half-life means that frequent dosing will probably not be necessary. Other animal studies using oral administration indicate that the drug can effectively reach the brain, an important consideration in patient's with HIV dementia. BIRG is a derivative from a class of drugs called benzodiazepines, drugs used to treat anxiety, like Valium. Studies in mice have shown that BIRG does increase sleeping. Because of these promising test tube and animal studies, BIRG received a disproportionate amount of media attention in the fall of 1990. The excitement can be attributed in part to the fact that the drug appears to be relatively specific, as compared to nucleoside analogues, like AZT, ddI and ddC. This fact means that BIRG could be less toxic. Now, five months later, the phase I single-dose study has been completed, and the phase II protocols are under review. BIRG will have to be studied in a phase I trial that looks at longer-term dosing before it can be moved into the comparative or pediatric study trials planned through the ACTG. Plans for future trials of BIRG include two studies through the AIDS Clincial Trials Group (ACTG). ACTG trial 164 will be an open-label (participants will know what and how much drug they are recieving), dose-escalating study of BIRG alone, or in combination with AZT. The trial is for HIV-infected people with T4 counts under 400, and will seek to enroll 72 people. Trial 164 will determine the safety and tolerance of BIRG, as well as the compound's antiviral activity. A pediatric study is also planned for BIRG. ACTG trial 165 will be an open-label study of single, increasing doses of the compound in children with symptomatic HIV infection. Boehringer Ingelheim has made a commitment to develop the drug in children and adults at the same time. Usually adult studies are completed before the initiation of pediatric trials. Late-breaking reports reveal that no more than twelve people have yet received BIRG in single doses. A comparison study with AZT has not yet been started, because a safety study is needed first, and development seems to be going slowly. For more information see AIDS Treatment News Issue 125. History of the Drugs Called "L" Merck took the AIDS communities by surprise with the initiation of trials in the U. S. of the so-called "L" drugs. As it turns out, Merck had been working on AIDS research since 1986. The company has focused on the development of antiviral agents, as well as a vaccine to prevent HIV infection, in collaboration with a company called Repligen. In 1989, Merck researchers noted that one of the compounds from their laboratory had significant activity against the RT enzyme of HIV-1. This discovery came after two years of screening approximately 23,000 compounds. Versions of the anti- HIV compound which would make the best drug candidates were then synthesized. Two promising compounds, L-697,639 and L-697,661, were synthesized in April 1990. The compounds were tested against multiple T-cell lines and human peripheral blood lymphocytes. According to the "informed consent" for one of the phase I studies (a document which explains the pros and cons of the trial to participants), "Animal testing (primarily in rats and monkeys) with L-697,639 has revealed that the drug appears to be generally well tolerated and safe over a broad range of dosing, although certain mild toxicities have been identified." The toxicities are mild elevations of certain liver enzymes and injury to some cells of the liver (3). No other serious toxicities have yet been identified during extensive testing with this drug. The data from animal and test tube studies has been submitted for publication. Later in 1990, Merck conducted phase I safety trials at undisclosed sites in Europe whcich enrolled approximately 40 HIV-negative, paid volunteers. Some of these volunteers were on drug for as long as ten days. According to the pharmaceutical company, the preliminary studies indicated that the two "L" drugs were well-tolerated over this short period of time. Long-term toxicities are still unknown. In December of 1990, Merck opened a phase I study of L- 697,639 at the National Institutes of Health (NIH) in Bethesda, Maryland. This trial examined absorption of the drug in the body and side effects in 24 asymptomatic people with T4 counts over 500. It looked at the absorption of single-doses of oral drug. However, L-697,639 had poor absorption and distribution of the drug to body tissue. Further study of this particular compound is not anticipated. Phase I testing of another L drug, "L-679,661", began in February to examine the saftey and absorption of single-doses of the drug. Sixteen asymptomatic HIV-positive people with T4 counts over 500 were enrolled. Doses ranged from 25 mg to 500 mg. Preliminary results of these studies showed no significant toxicities. The drug was well absorbed. L-679,661 was selected as a candidate for further studies. Phase II, double-blind, placebo-control trials are already underway. These phase II trials are being conducted at two sites -- the National Institute of Allergy and infectious Disease (NIAID) at the NIH in Maryland and the University of Alabama at Birmingham (UAB). The trials will seek to collect initial information on how well the drug works. The NIAID study at the NIH is for people with T4 counts over 200. Thirteen patients have already enrolled, and the study plans to recruit a total of 75 participants. The trial consists of five arms: one group of participants will receive 25 mg of drug twice a day; another will receive 100 mg of drug three times a day; the third group will receive 500 mg of drug twice a day. The fourth group will receive 500 mg of AZT alone, and the last group of participants will receive only placebo. After 12 weeks of the trial, those participants receiving AZt alone or placebo will be randomized to receive one of the doses of the "L"-drug. Participants are being informed in the informed consent that they may receive placebo for twelve weeks, which is sub-standard treatment. The UAB study contains an arm for people with T4 counts under 200, and no placebo will be used. Discussions among Merck, the NIH, and the AIDS Clinical Trials Group have been initiated regarding pediatric trial. It is hoped that such trials will begin this summer, when further information about the drug is available. Also on the discussion table is larger-scale adult trial. For more information about the NIAID trial call 1-800-772- 5464. The contacts are Donna O'Neill at ext. 312, Susan Haneiwich at ext. 403, and Marilyn Decker at ext. 306. Due to a large number of interested parties, enrollment into the UAB trial will be prioritized according to previous involvement in other UAB trials and regional proximity. For more information call (205) 934-9999. Conclusion If history is any indication, these drugs have a long journey ahead of them. But there are indications that at least Merck is moving full speed ahead. People anxiously await trial results and, ultimately, access to these drugs, if they prove efficacious. At this point, the only way to try these drugs is by enrolling in a clinical trial. Treatment Issues has heard reports that efforts are being made to create bootleg copies of the new RT inhibitors. Potential users of these products should bear in mind that there is no solid information about their efficacy, long-term safety, or interactions other drugs often used by PWAs. ***** Acupuncture Priscilla Scherer, R. N. Acupuncture is an ancient technique of Traditional Chinese Medicine (TCM) which stimulates or disperses the natural flow of energy within the body. It is used both to prevent disease and to maintain health by restoring and/or sustaining the body's optimal balance. The therapy involves the insertion of thin needles into specifically prescribed points in the skin, but it may also include the application of heat (moxibustion), pressure (acupressure), massage, or a combination of these techniques. The History The first known writings on acupuncture were in the Nei Ching (also called The Yellow Emperor's Classic of Internal Medicine; a translation is available at bookstores in New York). This early textbook is believed to have been written between 2697 and 2596 B. C., but the elaborate system of therapy outlined in the ancient textbook is based on several thousands of years of study before it. Acupuncture is believed to have its beginnings on primitive battlefields, where weapons included arrows and stones (4). Apparently, Chinese soldiers and their local internists noticed that after suffering certain war wounds, other chronic, pre-war complaints disappeared. As patterns of healing emerged, physicians began to map them out and a science was born. Acupuncture has had a slow start in the United States. Currently, it is used primarily as a last resort for the treatment of intractable pain, and for dieting and smoking cessation. Other countries have been much quicker to accept the technique as an alternative and even a partner to Western medicine (standard U. S. care). Additionally, acupuncture has had recent well-publicized successes in treating drug abuse (5) and less well-known successes with AIDS-associated symptoms such as diarrhea, painful neuropathies, and even Kaposi's sarcoma (KS). Most importantly; however, is that acupuncture is not a treatment for specific, divided conditions. Instead, it depends on the status of the patient as a whole (6). It is often difficult for Western thinkers to grasp this concept of medicine, but it is vitally important to understanding acupuncture. At Lincoln Hospital in New York, and at centers in Chicago, Boston, San Francisco and Austin, acupuncture for HIV-related treatment is gaining in popularity and acceptance. It is worth noting that many of programs and clinics offer free acupuncture therapy. The Principles of Acupuncture The science of acupuncture is based on Chinese medicine principles. In TCM, the entire universe is in a dynamic (as opposed to static) state of equilibrium. Integral to this dynamic equilibrium is energy (Qi). In such a schema, each person also has ultimate power over his or her own body's equilibrium -- and acupuncture is meant to stimulate that natural power. Thus, the intensity of energy or the relative lack thereof can be said to sustain our health or to detract from it. According to Taoist thought, perfect harmony of the energies within us and of our energies with those of the universe, is health. An imbalance of energy -- either because of an excess or insufficiency -- results in disease. A variety of external as well as internal factors could affect a person's energy balance. These include viruses and bacteria, traumatic injuries, depression, vitamin and sleep deficiencies, environmental toxins, and drug-related side effects. There is also a physiologic basis for some of the success of acupuncture in symptom relief. Experiments conducted with rats and rabbits showed that when needles were inserted into specific points on the neck and chest (perhaps stimulating the vagus nerve), the animals' blood vessels dilated, and remained dilated as long as the needles were in place (7). Needles inserted into specific points along the spinal column resulted in narrowing of the blood vessels of the brain. These phenomena have implications for treating high blood pressure, headaches, digestive problems, and for promoting wound healing. In another experiment, acupuncture produced higher levels of white blood cells, and certain clotting factors (8). For pain control, needles inserted into a point that affects a sensory nerve might either block the pain impulse before it reaches awareness in the brain or preoccupy the brain with another sensation, and thus override the sensation of pain. Finally, piercing skin and muscle tissue with needle points could stimulate the production of natural steroids and endorphins, and produce pain-relief as well as reduce inflammation. To confirm that the effects observed were, indeed, due to acupuncture, scientists in Minneapolis compared acupuncture to placebo in 80 participants from a substance abuse program (9). Since acupuncture had previously improved compliance and reduced relapses in drug treatment programs (10), these were considered the end points of the study. In the study, 40 participants received acupuncture in prescribed acupuncture points (treatment group) and 40 participants received acupuncture in nonspecific points (placebo group). Twenty-one of the treatment patients completed the program compared to one of the placebo group. Improved compliance and reduced relapse had persisted after six months of follow-up. The Technique Acupuncture is based on the understanding that just as energy can be disrupted or depleted, so also can it be rechanneled and replenished. Thus, the acupuncture needles may stimulate the body's own energy reserves or they may transmit energy from the environment into the body. Because each individual will have a unique interplay of energies, organs, and elements, as well as a unique character, the treatment is, theoretically, individualized. A complex network of pathways, called the twelve meridians, conducts and circulates energy from one part of the body to another. These meridians are connected to various organ systems through the skin. The connections have been carefully mapped out to correspond with specific organs in the body. It is important to find a licensed acupuncturist who is experienced in treating people with HIV. Local AIDS hotlines and community-based organizations may be helpful in offering referrals. After finding a qualified acupuncturist, the first step in treatment is accurate diagnosis. The practitioner uses several traditional diagnostic techniques to determine whether treatment should be aimed at stimulating or dispersing energy. Needles are then inserted at specific points along the appropriate meridian. Depending on the treatment indication and the location, needles may be placed slowly, in stages, and left for up to twenty minutes, or they may be placed deeply and withdrawn quickly with a twisting motion. The angle of the needle depends on the location of treatment. Acupuncture in HIV Infection and AIDS Initially, practitioners used acupuncture to provide symptom-relief for persons with AIDS. Michael Smith, M. D., D. Ac., of Lincoln Hospital in the Bronx has noted that after the first four or five treatments, most patients begin to experience a decrease in abnormal sweating, diarrhea, and skin rashes (11). Patients have also reported higher energy levels and many have gained substaintial amounts of weight. Patients on chemotherapy have noted a reduction in side effects such as nausea, fatigue, and weakness. "Acupuncture helps the body help itelf," claims Dr. Smith, who emphasizes that the affects of the treatment on the overall health of a person is the key to understanding acupuncture (12). The Somerville Acupuncture Center in Boston, The AIDS Alternative Health Project in Chicago, and Quan Yin herbal support program in San Francisco have reported similar symptomatic relief and overall improvement. Magnolia Goh, C. M. D., L. Ac, reports a study of 31 patients with painful peripheral neuropathy (nerve damage in the extremities), acupuncture alleviated pain or tingling in 12 (38.7%) of the patients (13). Another 11 patients from this study noted relief of most symptoms, with the exception of one or two, who were only partially relieved. Five others had a reduction in pain with occasional recurrences. Three patients who received only one treatment did not respond. In this series, patients received one to three treatments per week; they began to see results within three to five treatments. During the treatment period, 23 of the patients were taking medications such as AZT, acyclovir, ddI, Septra, and Bactrim. Eight patients were taking no medication. Unfortunately, the response to acupuncture was not examined independently of the effect of medications in the study. In the last several years, practitioners have begun to look at the direct effects of acupuncture on the immune system and more specifically at its effect on HIV disease and AIDS. Reports from China of a small 20-patient study claim that acupuncture stimulated rises in white blood cell (WBC) counts in previously neutropenic patients and normalization of hemoglobin counts in patients with low red blood cell counts (14). Research from Japan reports rises in WBC counts, improvement of WBC function, and increased interferon production in response to acupuncture (15). In the Japanese study, a control group received acupuncture stimulation at points which were non- specific to treatment, and demonstrated no change in blood cell counts or interferon levels. Specific acupuncture points, according to some small studies, are believed to strengthen the immune system, induce interferon production, raise the energy level, improve and stimulate digestion, strengthen blood, increase body fluids and improve dry skin (16). As with other treatment regimens, acupuncture seems to be more successful in individuals with healthier immune systems. In one study, fourteen ARC patients and six AIDS patients received acupuncture for at least three months, along with a regimen of Chinese herbs (17). Nine of the ARC patients improved and four remained stable (by T4 counts and T-cell ratio). Two of AIDS patients improved and two remained stable. One patient with ARC deteriorated, and one patients with AIDS worsened as well. One patient with AIDS died. In the ARC patients, T4 counts rose by an average of 154; they rose an average of 35 in AIDS patients. Symptomatic relief was also greater in ARC compared to AIDS patients. Again, little information is given regarding other medications in the two groups of patients during the study period. Transmission of HIV Some people have raised the fear of contracting HIV through acupuncture. Because the needles used are either sterilized or disposable, risk of transmission is believed to be extremely low. One case of acute HIV infection after acupuncture was reported in a letter to the British medical journal, The Lancet in 1989 (18). Exposure to HIV was thought to stem from the use of unsterilized needles. The simplest and most effective method of sterilization for acupuncture needles is through physical cleaning followed by autoclaving at 121 degrees celsius (250 degrees Fahrenheit) for at least 15 minutes (19). Dr. Smith asserts that procedures are no different for acupuncturists than they are for surgeons. "A piece of metal under the skin may seem like a new idea in people's minds," said Smith, "but it is not a new mechanical practice (20)." Some acupuncturists use disposable needles to eliminate the fear of transmission for their patients altogether. Woodson Merrill, M. D. uses disposable needles in his practice and says that transmission is "near impossible (21)." Western Views on Acupuncture Recently, at a local conference on AIDS, Dr. Merrill presented a compelling view regarding acupuncture and HIV- infected individuals (22). Dr. Merrill stated that he would not recommend alternative therapies as a sole treatment for HIV, but that acupuncture may add significantly to an overall improvement in the sense of well being of HIV-infected patients. Additionally, while Merrill believes acupuncture may not cure infections or increase T4 cells, it does provide subtle enhancing properties, like increasing endorphins and possibly reducing stress and pain. Merrill also stated that acupuncture may be helpful in reducing spasms in gastrointestinal conditions, common drug-induced nausea, and some neurologic problems. Michael Smith, M. D., D. Ac., has a very different way of talking about acupuncture. He indicates acupuncture is not for specific conditions, but instead for overall vitality and immune capability. Treatment indications depend entirely on the status of the person as a whole. Magnolia Goh, CM. D., L. Ac. of Queens Hospital asserts that a balance between Western medicine and acupuncture, Chinese herbs, nutrition, meditation, visualization and other holistic treatments may offer more complete care. The combination of Western medicine and acupuncture is working for thousands of HIV patients (23). Conclusion The validity of acupuncture and TCM remains controversial in the Western culture. There is no claim that acupuncture has direct antiviral effect on HIV. But many professionals trained in both Western and Chinese medicine, have found that acupuncture offers many benefits to the overall health of a person with HIV. In fact, more and more people with HIV are using acupuncture to reduce stress, pain, and tension, among other conditions. Insurance coverage is erratic for treatments, and therapy, when it is not free, may cost from $35-$75 per acupuncture session (24). In all likelihood, acupuncture will continue to gain attention and offer alternative views of illness, health, and treatment in HIV disease and other areas. ***** Interview with David Ho Kevin Armington Dr. David Ho is the director of the recently unveiled Aaron Diamond AIDS Research Center located on the east side of Manhattan. He was wooed to New York from UCLA where his lab generated intriguing data about the body's initial reaction to HIV infection and about new drug development. Treatment Issues had a chance to talk with Dr. Ho about the current direction of AIDS research. KA: Your research has shown that people have extremely high levels of virus in their blood soon after infection, but that those levels drop after the body mounts an immune response. Any theories as to why the immune system is able to control HIV early on? DH: First of all, we should not be surprised that the immune system is able to reponse like that. With every viral infection that has been studied in detail, for example, CMV (cytomegalovirus) and influenza virus, there is a burst of virus replication and a rapid control by the immune system after initial infection. We have not formally documented the immune parameter responsible for this, but we suspect that it is likely to involve a combination of killer T cells and antibodies. What is different with HIV is that this virus, in time, escapes from the immune response, and we don't understand why. Perhaps it is because of HIV's rapid production and variance. KA: Do you think in general there has been too much emphasis on drugs like AZT, ddI and ddC (nucleoside-analogue reverse transcriptase (RT) inhibitors)? DH: Well, that's all we had to talk about for a while. But now I think a lot of people are focusing on non-nucleoside anti- HIV drugs. Now, there are several non-nucleoside reverse transcriptase inhibitors like BIRG, TIBO derivatives, etc. And you also know there are several candidate drugs that inhibit other HIV enzymes, like protease. These things are all non- nucloesides. KA: But it seems that these drugs entered clinical trials only recently and anti-HIV research has been going on for seven or eight years now. DH: But the technology for some of those approaches was rather limited. If you consider protease (an enzyme on HIV), the crystal structure only became available about two years ago. So the technology was limited until 1987 or 1988. Now they can move ahead quickly. Lots of attention was focused on RT early on because it was the only enzyme we could test for. The RT test was available back when HIV was known as HTLV, or even before. KA: What do you think are some of the most hopeful targets? DH: Tat (a gene on HIV) and protease. I still think you need to combine them with drugs that target RT. They are different from the RT inhibitors in that they can have an effect on infected cells. AZT is not going to do anything to chronically-infected cells; those cells will make copies of HIV happily even in the presence of antibodies or AZT. Protease and tat inhbitors, however, could have an antiviral effect on these cells. That's their conceptual advantage. Also, the technology around protease inhibitors is fairly advanced because the protease for HIV belongs to a family which includes enzymes that control blood pressure -- renins, specifically. Research has been done for many years with renin inhibitors to treat hypertension and that research will be somewhat applicable to the development of protease inhibitors for HIV. And there are lots of candidate drugs to take off the shelf to screen for anti-HIV activity. I think people are going to be coming out with more and more protease inhibitors. KA: Work done in your lab has shown some important shortcomings with the antiviral drug CD4. Do you think further research with this drug is warranted? DH: CD4 looked very exciting in the beginning but we quickly realized that it wasn't working as well as we thought it would. Now we have the opposite situation; people have abandoned the drug. CD4 will never be a cure, but it still may be an important adjunct. In its current form, however, it won't go very far. KA: Do you think your talk in San Francisco at the Sixth International AIDS Conference dampened enthusiasm for CD4? DH: I believe so. Unfortunately, the pendulum has swung to the other extreme. We've always been "middle of the road" with CD4. I don't think we should abandon the concept of blocking entry of the virus into cells. But I would focus on the second generation of CD4 drugs rather than the original formulation. KA: Do you think that one of the reasons interest is being kept alive in CD4 is its potential role in protecting health care workers exposed to HIV through needle sticks? DH: That is one setting where the drug might be useful. But I know the producers (Genentech) of the drug and they're not really targeting that population. If they think there's a place for CD4 it is in preventing transmission from mother to fetus. KA: Do you see a role for immunomodulatory therapy? DH: I have mixed feelings about that. I certainly would be in favor of rejuvenating the immune system but not at the risk of turning on the virus even more. We know that many of the immunoenhancing agents also stimulate HIV in the test tube. There's no question that IL-2 does; we use it in the lab to grow HIV efficiently. There's some debate about tumor necrosis factor: some say it stimulates HIV; some say it doesn't. KA: Some of the community-based groups are looking at drugs that might have an immunomodulatory effect. What do you think of this? DH: I think I would caution against haphazard studies. I think immunomodulators are worth looking at, but you should look at them in a setting where you can get some meaningful information about them by careful monitoring of patients who go on them. KA: There's not much out there for people who've developed AZT resistance, and who can't or won't take ddI or ddC. Unless they want to go into a trial of some new antiviral (and they happen to fit the eligibility criteria), their options are limited. A lot of people in that situation are willing to experiment with various drugs available through the underground network. What do you think of that sort of experimentation outside of clinical trials? DH: Well, I think once you get to a more desperate situation, logic and rational approaches don't hold much water. You try whatever you can get your hands on. A last attempt to take something may be useful -- who knows? I certainly understand that. The patients I cared for in Los Angeles all did that when they ran out of options. I don't have any specifics to recommend. Some would try meditation, various herbs, acupuncture. I would keep an open mind. We have screened some herbs in the lab and some of them have pretty good anti-HIV activity. We need to systematically characterize these compounds and their mechanisms. Some useful agents may come out of this approach. KA: Will some of these alternative compounds be screened at this lab? DH: We're already doing it. We're taking natural products from Asia and screening them the way many scientists would study a compound off the shelf. So we want to do it in a way that will convince other investigators in this country. KA: What about trichosanthin (Compound Q)? Are you working with that drug at all? DH: We have in the past. It's not one of the natural products we have found to have good activity against HIV. We have not looked at the preparation that Geneslab is producing; we used trichonsanthin from China. It was not one of the compounds we selected. KA: What do you think about using unproven approaches to prevent opportunistic infections (OIs), like MAI or CMV? DH: There are already some trials for prevention of various OIs like toxoplasmosis. There's talk of using high-dose acyclovir for CMV. These things should be addressed; especially within the AIDS Clinical Trials Group (ACTG) system. The ACTG network is massive and consumes so much federal money, yet how many new anti-HIV drugs do we have to look at? If the ACTG is going to continue to be supported, at least for the short run, more attention should be focused on OIs. It might be different three years down the line when there are more anti-HIV drugs to be tested, but right now there are only a handful. Why aren't people working harder to look at OIs? I think, to a large extent, those studies are not as sexy. Investigators are all human beings; they all want to do the most exciting studies. But they're using massive amounts of federal funds and they must do what is in the patients' best interests. To some extent, Dr. Fauci and others are trying to get the system to be more responsive in those areas. KA: Do you think it makes sense for clinicians to experiment with prophylaxis before trials are done? DH: Once again, I think any time a practitioner wants to experiment, it should be done in a way that useful information can come out of it. Otherwise, I'm not sure the whole thing is worth it. KA: What do you think about the role of underground buyers' clubs that help people import drugs approved abroad but not available here, for example, clarithromycin? DH: I think if you know a drug is of a specific use, and it's not available it seems very reasonable to go through whatever channels necessary to get it. Now what I sometimes fail to understand is why a lot of people go through these clubs to buy things that have no proven efficacy. KA: For example? DH: Well, Compound Q, for one. Many people have made lots of efforts to obtain this drug. KA: What do think about the potential role of co-factors in the development of HIV disease? Specifically, do you have any comments about Dr. Montagnier's claims that mycoplasma is an important co-factor? DH: I'm a strong believer in co-factors. Based on everything we know about the virus, co-factors could play an important role in HIV pathogenesis. But I'm sure I'm not prepared to say that mycoplasma is the co-factor. It may be one important co-factor, but there are probably many others. I'm not sure Montagnier is saying that, but because it's Luc Montagnier making the statement, it's being portrayed as the major development in the field of co-factors. I think it is just one aspect. I'm not sure it is justified to make a big deal out of it; mycoplasma is everywhere. It is a common contaminant in laboratories, particularly AIDS laboratories. KA: Some clinicians are treating mycoplasma in their patients with HIV infection, using antibiotics such as doxycycline. Do you think it is too early to do that? DH: Not if mycoplasma is found. But if there's no documentation, it might not be justified to treat it. KA: But the more sensitive tests are not easily available to clinicians, so cases of mycoplasma might be missed. DH: Right, so many clinicians must rely on the routine clinical lab. But the more obvious cases of mycoplasma won't be missed. I don't know about treating mycoplasma without looking for it. Clinicians who are doing that should keep track of their data and write it up so people can learn about their experience. If people are going to be subjected to novel approaches, the data should be gathered in a useful way. KA: Unfortunately, most clinicians who are trying novel approaches have extremely busy practices and they don't have much time to write up results. So there are obstacles to compiling these data. DH: I don't know if these clinicians need to do everything themselves, but if they are going to build novel approaches into their practice, they almost owe it to their patients to get useful information out of new treatment approaches. They may be able to get some assistance from nurses, for instance, to compile the data in a simple way. I'm not talking about constructing a complex clinical trial; just compare treated versus untreated patients. KA: Do you expect any big stories to emerge from Florence? DH: Perhaps, but I'm not expecting half a dozen major breakthroughs. I am expecting significant developments on selected topics. If you ask me how many of those will translate into direct patient care in 1991, I'd say ...maybe one? But usually if there's a major breakthrough in someone's lab, word gets around, and we haven't heard anything yet. ***** Hepatitis B & HIV Infection Gabriel Torres, M. D. Hepatitis B is a virus which can cause serious disease, leading to liver failure, cirrhosis and liver cancer. The usual symptoms of hepatitis B, include a flu-like illness, fatigue, a lightening of the stool, occasional yellowing of the skin or eyes, and a darkening of urine color (jaundice). However, many persons who carry the hepatitis B virus (HBV) show no symptoms. In such cases, infection is usually detected by a blood test of antibodies developed against the virus, similar to HIV-antibody testing. Since immunization is available with successful, safe and relatively effective vaccines, screening for HBV is urged. Transmission Approximately 300,000 new cases of hepatitis B are diagnosed per year (25). Ten thousand of those cases require hospitalization. Six to ten percent of infected persons become chronic carriers and may infect others despite showing no signs of illness themselves. These numbers are unconscionably large given that HBV can be fairly easily prevented. HBV can be transmitted through contact with blood, semen, and saliva. Following the safer sex guidelines to prevent HIV transmission will help in avoiding HBV transmission as well, but those guidelines are not enough. It is important to note that because hepatitis B virus is more contagious than HIV, oral sex and deep kissing are much higher risk activities for the transmission of HBV. While, historically, homosexual men have had a higher prevalence of HBV infection than any other single group (26), the advent of safer sex practices among gay men has decreased the number of new cases among gay and bisexual men in this group. On the contrary cases attributable to heterosexual activity have increased 77% between 1982 and 1988 (27). Protection by Vaccine The best protection from Hepatitis B is by vaccination, which may be effective in 85-95% of cases. Two types of vaccines have been developed which have been shown to protect uninfected individuals. Heptavax-B is a vaccine derived from the plasma of HBV-infected persons. Recombivax is another vaccine, which is artificially produced from yeast through genetic engineering. One study shows that the plasma-derived vaccine may be superior in building antibodies against HBV in uninfected persons (28). Though the vaccine is prepared from human blood, the method used to purify the product, kills all types of viruses found in blood, including HIV. No case of HIV infection from the vaccine has been reported. The Hepatitis B vaccines are administered as injections. Usually three injections are given over a six-month period, followed by a yearly booster shot. The most common side effect of the vaccine is soreness in the arm, at the site of injection. The Centers for Disease Control (CDC) is urging vaccination of the millions of people at risk for HBV infection. According to the CDC, these include infants, heterosexual men and women with multiple sex partners, health care workers, gay and bisexual men, intravenous drug users, and persons with occupations which put them in contact with blood and body fluids (i.e. firefighters, emergency personnel, and morticians. HBV Infection in HIV Hepatitis B has been shown to be a more severe disease in HIV-positive persons than in HIV-negative persons. HIV-infected persons may have the virus for a longer period of time, including more prolonged liver function test abnormalities and clinical illness. Additionally, HIV-positive people may be more likely to become HBV-carriers (29). The duration of protection from the vaccine seems to also be shorter in HIV-seropositive people. In one study of hemophiliacs, all of the 67 HIV-negative, hemophiliac patients who were vaccinated, developed and maintained antibodies after 4 years. But five of 11 HIV-positive hemophiliac patients did not retain antibodies, when tested 4 years later (30). Though the vaccine may be less effective in HIV seropositive persons, it is still advisable because such vaccination may result in protection from a severe and debilitating disease. It is unclear whether HIV-positive persons should receive extra boosters at yearly intervals to maintain the adequate antibody amounts for protection. However, levels of antibodies, should be checked routinely as part of regular health maintenance. For antibody testing and immunization in New York contact Community Health Project at (212) 675-3559. The total cost of screening for Hepatitis B antibodies is $21.00. The cost the vaccine is free. ***** In Brief Pentoxifylline To Be Tested: A drug, originally approved by the FDA to treat leg cramps from circulatory problems, has been shown to have anti-HIV activity in test tube and in other preclinical trials. Pentoxifylline, manufactured by Hoechst- Roussel Pharmaceuticals, Inc., under the name Trental, was found to lower levels of a natural body protein, called Tumor Necrosis Factor (TNF). TNF is thought to contribute to fever and wasting in cancer patients and may help fight similar TNF-related symptoms in patients with AIDS. TNF is also known to increase reproduction of HIV, and recent test tube studies show that pentoxyfilline may also slow HIV in the human body. Researchers at the Community Research Initiative (CRI) in New York plan to begin human trials "starting anyday" with a 16-week, controlled study to determine safety and efficacy data of pentoxifylline. For more information, call (212) 481-1050. In the meantime, Hoffman-La Roche is sponsoring a trial to determine the effect of pentoxifylline and antiviral drugs, AZT or ddC. The trial is being conducted at Beth Israel Hospital in Newark, New Jersey. Twenty-four male HIV- positive volunteers or non-pregnant, non-nursing female volunteers are being recruited. The trial offers a compensation of $1,500.00 at the completion of the study and includes some brief hospital stays. A non-Burroughs AZT? Barr Laboratories, Inc. submitted an abbreviated New Drug Application (or an ANDA) to the FDA on March 19, 1991 for zidovudine (AZT) capsules, 100mg. The company, located in Pomona, New York, reported in a letter that the FDA acknowledged receipt of the ANDA and "made a threshold determination that "the application "is sufficiently complete to permit a substantive review." Generic drug products, like Barr's version of AZT may foster public policy by making affordable AZT available to the AIDS community. The legislation defines approval time as 180 days. Mark your calendars. Clarification: Colposcopy and anascopy are reimbursable by medicaid in New York and New Jersey when used as diagnostic procedures (i.e., when smears indicate that abnormal or cancerous growths are present). They not reimbursable when used as screening procedures, which some professionals recommend and, as recent studies indicate, may detect abnormal growths in HIV- infected individuals much more acurately. New Studies Treatment for Psoriasis: The New York University Department of Dermatology is beginning a study of treatment for HIV- associated psoriasis. Psoriasis is a skin condition, consisting of a rash of raised bumps and sometimes a thick silvery scale, which can be partiuclarly severe in people with HIV illness (See Treatment Issues Vol. 4, No. 8.) Trial participants will be required to have a physical examination by a physician at Bellevue Hospital, Tisch Hospital, or Manhattan VA Medical Center with skin biopsies and blood tests. During the first seven weeks of the study, participants will be treated with Ultra Violet B (UVB) phototherapy three times a week. UVB is a concentration of sunlight, similar to that used in tanning salons, but much stronger. For more information contact Janet A. Moy, M. D. or Miguel Sanchez, M. D. at (212) 263-6484 or (212) 561-3115. Clindamycin Dropped from Toxo Trial. The Toxoplasmosis Prophylaxis Study sponsored by the Community Programs for Clinical Research on AIDS (CPCRA) reported in Treatment Issues Vol. 5, No. 3 has been changed. The clindamycin arm has been dropped from the trial because the drug has been causing rashes and diarrhea. The trial is continuing with pyrimethamine vs. placebo. For more information contact the Newark Community Health Centers in New Jersey at (201) 565-0355 or (201) 483-1300. 566c80 at Harlem Hospital. The Harlem AIDS Treatment Group at Harlem Hospital Center is conducting a trial with the drug 566c80 for people with toxoplasmosis, who are either failing or intolerant to standard therapy. For more information call Andrew Masterson at (212) 694-4033. CD4 Trial Still Recruiting. Columbia Presbyterian Medical Center is running a trial for HIV-positive patients with T cell counts under 300, on AZT (500 or 600 mg per day) to receive soluble CD4 for six months. CD4 is thought to block HIV from infecting cells (see Treatment Issues Vol 4 No. 5). Participants will learn to give themselves injections three times a day. Phase I studies have shown no toxicity and minimal side effects. For additional information call Dr. Jay Dobkin at (212) 305-8507. ***** Treatment Issues is GMHC's newsletter devoted to providing reliable information on experimental AIDS therapies. Describing an experimental therapy should not be construed as recommending it. All new treatments should be done under a physician's care. Treatment Issues is published ten times yearly. Copyright 1991 Gay Men's Health Crisis, Inc. All rights reserved. Non- commercial reproduction is encouraged. Subscription lists are kept confidential. Editor: Kevin Armington Associate Editor: Mary Beth Cashetta Medical Consultant: Gabriel Torres, M. D. Technical Assistance: Wayne Kawadler Writers: Garance Franke-Ruta Priscilla Scherer, R. N. Gabriel Torres, M. D. GMHC, Department of Medical Information, 129 West 20th Street, New York, NY 10011 Treatment Issues is supported in part by contributions made to the Richard Dunne Memorial Fund. References: 1. Rosen CA et al. Tat and Rev: positive regulators of HIV gene expression. AIDS 4(6):499-509, 1990. 2. Merluzzi VJ et al. Inhibition by a non-nucleoside reverse transcriptase inhibitor. Science 250:1411-1413, 1990. 3. L-drug Informed Consent Form, 1991. 4. Chang ST. The Complete Book of Acupuncture, Celestial Arts, Berkeley, 1976. 5. Smith, MO. Testimony presented to the select committee on Narcotics of the U. S. House of Representatives. The Lincoln Hospital Drug Abuse Program, July 25, 1989. 6. Smith M. Personal communication. 7. Smith, MO. Testimony presented to the select committee on Narcotics of the U. S. House of Representatives. The Lincoln Hospital Drug Abuse Program, July 25, 1989. 8. Chang ST. The Complete Book of Acupuncture, Celestial Arts, Berkeley, 1976. 9. Bullock M et al. Lancet 1(8652):1435-9, 1989. 10. Smith MO. Testimony presented to the select committee on Narcotics of the U. S. House of Representatives. The Lincoln Hospital Drug Abuse Program, July 25, 1989. 11. Smith MO. Results of chinese medical treatment show frequent symptom relief and some apparent long-term remissions. Presented to the World Congress of Acupuncture and Natural Medicine, Beijing, November, 1987. 12. Smith MO. Personal Communication. 13. Goh M. Acupuncture treatment for neuropathy -- patients with HIV infection. Unpublished paper. 14. ibid. 15. Wang JL, Chinese herbs and acupuncture to treat ARC and AIDS. Unpublished report from the Oriental Medical Center, 1987. 16. ibid. 17. ibid. 18. Vittecoq D et al. Acute HIV infection after acupuncture treatments. Lancet 320 (4); 259-251,1989 19. Favero MS. Sterilization, disinfection and antisepsis in the hospital. In: Lenette EH et al. Manual of clinical microbiology. 4th ed. Washington, D. C. American Society for Microbiology; 129-37, 1985. 20. Smith MO. Personal communication. 21. Merril W. Personal communication 22. Merrill W. Acupuncture and holistic therapies in AIDS, PWA Education Lecture Series and Workshop, NMC homecare, April, 1991. 23. Goh, M. Acupuncture and HIV, unpublished overview, 1990. 24. ibid. 25. NIAID. National forum addresses AIDS and hepatitis B. The Double Helix 13:Spec Conf issue, January 1989. 26. Ma P et al. AIDS and Infection of Homosexual Men: Second Edition. Buttersworth Publishers, 1989. 27. Hadler SC et al. Outcome of Hepatitis B virus infection in homosexual men and its relation to prior HIV infection. J Infect Dis 163:454-459, 1991. 28. Odaka N et al. Comparative Immunogenicity of Plasma and Recombinant Hepatitis B virus vaccines in homosexual men. JAMA 260:3635-3637, 1988. 29. Alter MJ et al. The changing epidemiology of Hepatitis in the United States. JAMA 9:1218-1222, 1990. 30. Mannucci PM et al. Longterm immunogenicity of a Plasma- derived Hepatitis B vaccine in HIV seropositive and HIV seronegative hemophiliacs. Arch Intern Med 149:1333-1337, 1989. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display