gilbert@tcela.COM (Gilbert Cornilliet) (04/25/91)
Hi there! This is a selection of articles (mostly medical) from the April 1991 Being Alive Newsletter. I am one of the editors of this Newsletter. Comments, suggestions, critics, submission of articles, etc are welcome. My E-mail address is gilbert@tce.com. Please share this information with your friends. Take care. Gilbert. ======== TABLE OF CONTENTS ======== BEING ALIVE STATEMENT HOW TO SUBSCRIBE TO THE BEING ALIVE NEWSLETTER ABOUT THE BEING ALIVE NEWSLETTER A REPORT ON THE FEBRUARY FDA ANTIVIRAL ADVISORY COMMITTEE MEETING MEDICAL UPDATE - FEBRUARY 25, 1991 AZT RESISTANCE CHOOSING THE BEST HOSPITAL FOR PATIENTS WITH AIDS FREE PLANE TICKETS, ACTIVISTS' SUPPORT GROUP AND OTHER THINGS NUTRITION UPDATES AIDS AND CHEMICAL DEPENDENCY CLINICAL TRIALS AND YOUR PRIMARY HEALTH CARE PROVIDER COMPOUD Q: TRICHOSANTHIN AND ITS CLINICAL APPLICATIONS TEENS REACH TEENS WITH HIV/AIDS INFORMATION AIDS STORIES WANTED LOCAL RESOURCES ================================================================ BEING ALIVE STATEMENT Being Alive is an organization OF and FOR people with HIV/AIDS. We understand the pain and the fear; how easy it is to hide, how difficult it can be to come to terms with this disease and reach out. Being Alive is the means we have created to help us connect with each other, bring others like us out of isolation, and take charge of our lives, our care and our destiny. Being Alive provides the following services to its members and the community: Advocacy HIV Fight Back! Library Medical Update Neighborhood Networks Newsletter Peer Counseling Roommate Referral Social Events Speakers Bureau Support Groups Vital Information TOGETHER, WE ARE MAKING A DIFFERENCE. ================================================================ HOW TO SUBSCRIBE TO THE BEING ALIVE NEWSLETTER We are happy to provide the Being Alive Newsletter to people who cannot afford to purchase a subscription; however, we ask that anyone who can afford to subscribe, do so. |__| Enclosed is $12 for a six month subscription. |__| Enclosed is $20 for a one year subscription. |__| I cannot afford to pay for a subscription. Please enter my free subscription. |__| Here is an additional donation to support Being Alive. Name: Phone: Address: City: State: Zip: Please note that all names are kept confidential 4222 Santa Monica Blvd. Suite 105 - Los Angeles, California 90029 TOGETHER, WE ARE MAKING A DIFFERENCE. ================================================================ ABOUT THE BEING ALIVE NEWSLETTER The Being Alive Newsletter is produced and published by Being Alive, People with HIV/AIDS Action Coalition, which is solely responsible for its content. If you have articles you would like to submit to the Being Alive Newsletter or if you just want to help, please contact the Being Alive office during regular hours. Please note: Information and resources included with your Newsletter are for informational purposes only and do not constitute any endorsement or recommendation of, or for, any medical treatment or product by Being Alive, People with HIV/ AIDS Action Coalition. With regard to medical information, Being Alive recommends that any and all medical treatment you receive or engage in be discussed thoroughly and frankly with a competent, licensed, and fully AIDS-informed medical practitioner, preferably your personal physician. Being Alive and Being Alive Coping Skills Support Group are trademarks of Being Alive, People With HIV/AIDS Action Coalition, Los Angeles. Opinions expressed in various articles in the Being Alive Newsletter are not necessarily those of Being Alive's membership. Any individual's association with Being Alive or mention of an individual's name should not be, and is not, an indication of that person's health status. ================================================================ A REPORT ON THE FEBRUARY FDA ANTIVIRAL ADVISORY COMMITTEE MEETING by Jesse C. Dobson The FDA's Antiviral Advisory Committee met on February 13 and 14 in Rockville, MD. The agenda for the first day of the meeting was to review data on the correlation between CD4 cell counts and survival and progression to disease in patients with HIV infection. DAY ONE: CD4 CELL COUNTS AS SURROGATE MARKERS While not much is known about how HIV leads to the diseases commonly associated with AIDS, it is almost universally associated with a dramatic decline in numbers of CD4 cells. These cells play a pivotal role in the immune system. Healthy, uninfected individuals generally have counts between 750-1200/mm3 of peripheral blood. When the numbers of these cells get low enough, typically less than 200, the opportunistic infections (OI's) associated with AIDS often begin to appear. Historically, trials of anti-HIV drugs (like AZT, ddI, etc.) have used the occurrence and frequency of OI's or death as endpoints,or events indicating the drug's efficacy. Because HIV is a relatively slowly progressing disease, such events can take a long time to occur, especially in patients with high CD4 counts. This causes trials to necessarily be large (and therefore expensive) and slow, which results in both a long delay in finding desperately needed answers and a shifting of resources from other studies. Because of this, researchers and patients alike have wanted a surrogate marker for HIV disease progression. Such a marker would allow trials to be quicker and smaller since theoretical differences between the drug being tested and the control group would show up quickly. CD4 counts have seemed an obvious surrogate marker to most people working with HIV disease. Many HIV doctors have used it to guide their clinical response to HIV for many years, often allowing them to determine the best use of therapies like AZT long before traditional clinical trials do. For example, when the Antiviral Advisory Committee recommended reducing the dose of AZT from 1200 to 600 mg/day in February of 1990, this dose and even lower doses had been standard clinical practice for over 18 months for many doctors with large HIV practices. The FDA, however, has previously been unwilling to endorse this correlation between CD4 counts and disease progression as sufficient for approval of anti-HIV drugs. The meeting of the Antiviral Advisory Committee had the mandate for reviewing the data from several AZT trials to determine if such a correlation was scientifically justifiable, thereby allowing the agency to approve anti-HIV drugs on this basis. DATA PRESENTED The meeting began with a public forum, where several HIV community doctors and activists, including Dr. Marcus Conant of San Francisco and members of ACT UP/Golden Gate reminded the panel that such a recommendation was not purely scientific given the desperate need for better therapies. They argued that evidence of a correlation did not need to be ironclad to justify using CD4 counts and other markers like Beta 2-microglobulin, an indirect immune system measure, for drug approval, as they are the best markers we have. These were followed by data from large AZT studies, including those of the AIDS Clinical Trials Group (ACTG) and Burroughs Wellcome, the manufacturer of AZT. The data, which included some very sophisticated analyses by statisticians from Harvard, showed a strong relationship between CD4 counts and disease progression and survival. Particularly compelling were data from the National Cancer Institute (NCI) which showed that in a four year study of 55 patients with AIDS on AZT-based therapies only one death occurred in patients with over 50 T-cells. It is important to note, however, that this group of patients was receiving absolutely state-of-the-art medical care. The most important variable predicting health in all of the studies was the absolute CD4 count as opposed to the rate of CD4 change or the increase in CD4 due to the use of AZT. The bottom line was that increasing CD4 counts and keeping them high is the key to maintaining health. Another key variable in predicting progression was the age of the patient, with patients over 45 showing a significantly higher chance of progression. CONCERNS VOICED The main controversy of the day was a reluctance by some scientists to call CD4's a true surrogate marker. The strict definition of a surrogate marker requires that it be directly related biologically to the event that it replaces. Several scientists argued that CD4 count is only indirectly related to the occurrence of OI's. Also, it was observed in the analyses from Harvard that only about 30% of AZT's efficacy against disease progression could be accounted for by CD4 cell increases. This led to the concern that if studies become too dependent on looking for a rise in CD4, we miss real clinical benefits of drugs that don't give rise this rise but may reduce the risk of OI's anyway (DTC is such a drug). Dr.Larry Corey of the University of Washington at Seattle pointed out that any endpoint, including opportunistic infections and death are really a moving target, as improvements in treatments of OI's occur while trials are in progress and not uniformly at all centers. The panel agreed to call CD4 a partial surrogate marker and that clinical data needed to continue to be collected to prevent missing useful drugs. FDA GUIDELINES SLOW IN COMING Despite the unanimous support of CD4 for drug approval from the panel, until the FDA officially adopts guidelines on how to use them for drug approval the full benefit of such a marker cannot be realized. A key element of adopting this marker is that it could speed drug approval. This interests the pharmaceutical industry a great deal, as it would make drug development for AIDS cheaper and faster, which would allow them to recover their investment sooner (i.e., bigger profits). This may attract more drug companies to AIDS research, which would benefit everyone with HIV infection. Until the FDA gives definitive, quantitative guidelines on how to use these markers, the drug companies are left facing the discretion of an agency that is itself reeling from the changes that have been wrought by this awesome epidemic and the formidable political force formed by those affected by it. Clear signals would give the companies a known goal and relieve the agency of a dizzying set of conflicting responsibilities. Unfortunately, the ways of bureaucrats change slowly. In a meeting with ACT UP/Golden Gate after the committee meeting, Carl Peck, the acting head of the Antiviral Division of the FDA, was unwilling to say when such guidelines would be available, or how quantitative they would be. In a typical fashion, he has set up a task force to look into the issue. The task force hopes to have a draft of guidelines by April 1. Then after internal review, Peck is considering publishing the guidelines in the Federal Register for public comment. This would add about another six months to the process. The earliest anticipated completion would be October. This would be roughly equivalent to 25,000 U.S. AIDS deaths. Meanwhile, New Drug Applications for ddI and ddC are anticipated to arrive at the agency in the next few months. If these guidelines were in place, fast approval would be easy. Lacking them, the approval process will be subjected to bureaucratic equivocation and charges of political pollution. DAY 2: VETERANS ADMINISTRATION STUDY OF AZT The second day focused on the results of a very large, completed study of AZT use in Veterans Administration (VA) hospitals. The study raised questions about the efficacy of AZT in early HIV disease, especially in some minority populations. The findings contradict those of earlier studies conducted in clinical research settings. Experts were quick to point out that small numbers of patients involved and imperfections in study design make the new findings questionable and that AZT should still be considered an option for early HIV therapy. They also agreed, however, that the findings warranted new studies specifically designed to answer the questions of whether the effectiveness of early anti-HIV therapy may be affected by either race or socioeconomic conditions. The panel heard analyses of data from the VA study as well as from AIDS Clinical Trial Group (ACTG) studies and from Burroughs Wellcome, the manufacturer of AZT. None of the studies were designed specifically to look for the effects of race or socioeconomic conditions. The findings were based on retrospective analyses, which is considered to produce less reliable findings by most statisticians. FINDINGS ON BLACKS AND HISPANICS The VA study found that blacks and Hispanics, when lumped together to increase the number of events which improve statistical significance, were more likely to die from HIV-related causes when given AZT while their CD4 cells were greater than 200 than when they received therapy after falling below this number. They were also just as likely to progress to AIDS in both groups. This was in contrast to the non-Hispanic whites, who had significant benefit in progression to disease from early therapy and a small, but insignificant, improvement in survival. Data from other ACTG studies showed that all races benefitted from early therapy equally, although numbers for blacks and Hispanics were small. Experts on the panel were unable to find any overriding problem with the VA study, even though issues of compliance, drug use and consistency of medical care were considered. Most on the panel were genuinely surprised by the results, as they saw no biological reason for the difference. Some pharmacokinetic data, which looked at how long AZT stayed in the blood, did find that AZT is cleared about 25% more quickly from blacks than from whites, which also surprised scientists. Again, the numbers were small in a study not designed to answer this question. This finding was not considered the reason for the results of the VA study since patients were given 1500 mg AZT/day, well in excess of the therapeutic dose of 300-500 mg/day from other studies. No dose reductions were included in the study, unless a patient specifically showed toxicity to the drug. An ACTG study (016) showed that toxicity at 500 mg/day was not significantly less than the toxicity seen at the initial dose of 1500 mg/day. This goes against the conventional wisdom that lower doses of AZT are significantly less toxic. Overall toxicities in ACTG 016 were low, with no side effect seen in over 10% of the patients, including anemia. Other interesting findings from the VA study were that blacks and Hispanics did not show the typical rise in CD4 counts after initiation of therapy and that their decline in CD4 prior to therapy seemed to be slower than that found in whites. The minority patients also had a higher tendency to develop fatal opportunistic infections (OI's) with higher CD4 counts than whites. No cases of dementia were seen in the early treatment group, indicating AZT may help prevent dementia. COMMITTEE DELIBERATIONS ON AZT AND MINORITIES After reviewing all the data, the committee did not think that the data were strong enough to call for changing the recommended use of AZT for people with less than 500 CD4 cell/mm3. The doctors on the panel also generally agreed that they would not change their procedures in recommending the use of the drug, although most already caution their patients that the drug may not be a useful option for everyone. Most physicians said they would inform their patients of the VA results and let the patient decide.Dr. Howard Greaves, a consultant to and the only black on the panel, questioned the ethics of a large campaign promoting early intervention in light of the uncertainty raised by the study. When it was privately pointed out that the ads do not specifically recommend or even mention AZT, the panelists responded that in the information given when a person called the 800 number in the ad, AZT was specifically promoted. The results led some activists attending to question whether AZT was useful in early therapy at all, and that what led to longer survival was management and prevention of OI's. This conclusion was dismissed by most experts, as the data from other studies strongly indicate that the drug is beneficial. One attendee also made the interesting observation that the VA study is the first large study not financed either directly or indirectly by the drug company. An independent study in Europe (the Concorde study) of AZT versus placebo in early disease has also yet to find a significant difference. The panel then spent time deliberating on how to best evaluate the use of AZT and other HIV drugs in minorities. This led Alan Nowick, a member of the panel, to observe that all of those deliberating: the scientists, the regulators, the panel, the researchers, even the activists were all white, and that we all suffer for it. Indeed, there was one black doctor, especially invited to be on the panel instead of a regular member, and one other black and a few Hispanics and Asians in a audience of several hundred at a meeting about the effects of AZT in minorities. (Jesse C. Dobson is a medical consultant to the National Association of People With AIDS.) ================================================================ MEDICAL UPDATE - FEBRUARY 25, 1991 presented by Mark Katz, M.D., and reported by Jim Stoecker PCP IN HIV- ADULTS An article in a recent New England Journal of Medicine reported on five elderly patients in New York City. These patients, all HIV-, came down with PCP even though there was no predisposing illness. No prior weakening of the immune system was apparent. The authors of the article cannot fully explain why PCP was found in these particular patients and draw no conclusions. This information, however, is intriguing and warrants further study. MALE-TO-FEMALE SEXUAL TRANSMISSION OF HIV In Africa, HIV infection has been evenly distributed between men and women. Male/female sexual intercourse has been the main means of transmission of HIV. A recent study in the Journal of Infectious Diseases affirms that the cofactors for male-to-female transmission of HIV in Africa are the same as those in Europe and North America. (Some sought to explain the African situation by positing more anal intercourse or by pointing to native blood rituals.) The authors point to the presence of genital ulcers, to Chlamydia infection and to the use of oral contraceptives. There do not appear to be cofactors unique to Africa. RECOVERY OF HIV FROM SEMEN A recent study looked for HIV in the semen of thirty-four infected men. Virus was recoverable in about a third of the semen samples tested. The presence of HIV, however, did not correlate with the stage of HIV disease or to the use of AZT therapy. RHEUMATIC MANIFESTATIONS OF HIV INFECTION Another symptom of HIV infection is painful and/or swollen joints. Researchers estimate that about a third of HIV+ people experience such symptoms. Usually these symptoms are transient, although some people actually come down with arthritis. Most rheumatic manifestations of HIV can be treated with non-steroid anti-inflammatory drugs (ibuprofen) or aspirin, although injectable corticosteroids are sometimes called for. AZT CONSIDERATIONS Two recent studies, one from Australia and the other from England, again affirm that AZT prolongs survival. Both studies, however, look at the length of time people survive with AZT vs. data from 5-6 years ago when AZT was generally unavailable. The researchers assume that AZT is the factor which explains the differing survival rates. The open question is whether other factors need to be considered. Despite these and similar studies, some people resist taking AZT because they fear the drug's toxicity. What they need to keep in mind is that all AZT side effects are reversible. Once off the drug, side effects can be alleviated without, it appears, permanent damage. People also continue to question whether AZT will really work for them. We have all heard the stories about AZT-resistant virus. What such resistance really means, however, is still unclear. What seems to be clear at this point is that the average person who takes AZT will be healthier for a longer time than the average person who does not take AZT. DDI USE BY CHILDREN A recent New England Journal of Medicine study reported on the use of DDI by forty-three children with symptomatic HIV disease. The drug was well tolerated. No neuropathy was observed, although two children did develop pancreatitis. A rise in CD4 counts was seen and the rise appeared to be sustained over time. ROTATING ANTIVIRAL EXPERIMENT Search Alliance in Los Angeles has inaugurated a study called RAVE (Rotating Antiviral Experiment). This study will take a close look at combination antiviral therapy, an approach that has been much talked about lately. Study subjects are in the 200-500 T cell range. The protocol calls for a six week schedule: two weeks of AZT/DDI, then two weeks of DDI/DDC, then two weeks of AZT/DDC. The subjects then repeat this schedule for the length of the study. ================================================================ AZT RESISTANCE by Jeffrey M. Fricke, M.P.P. Most researchers were not at all surprised several years ago when the phenomenon of AZT resistance was first documented. In fact, several investigational teams had been searching for zidovudine-resistant strains of HIV for some time before Dr. Brendan Larder first published the influential article "HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy" in 1989. People with HIV infection, however, were understandably concerned. Dr. Larder detected a pattern in the measured sensitivity of viral isolates over time that suggested the development of AZT resistant strains of HIV. But he did not find this trend to be associated with a rise in viral p24 antigen concentration. Fortunately, he also did not find that patients with strains of resistant virus fared any worse than those without such strains. This important finding has been confirmed by many other studies. Furthermore, untreated patients have a poorer prognosis than those receiving zidovudine therapy, regardless of the presence of AZT-resistant strains of HIV. Last year, Dr. Charles Boucher reported to the Sixth International Conference on AIDS that high level drug resistance develops noticeably faster in people with symptomatic HIV infection than in asymptomatic individuals. Dr. Douglas Richman also presented data indicating that in vitro resistance may appear at six months in patients with advanced disease and less than 200 CD4 cells/mm3. However, in asymptomatic or mildly symptomatic patients with over 500 CD4 cells/mm3 treated for more than one year, only a small fraction showed any sign of resistant strains. Dr. Richman also reported in the August 1990 Journal of Acquired Immune Deficiency Syndromes that patients receiving lower doses of zidovudine at both early and late stages of disease did not develop resistance more readily than patients receiving higher doses of the drug. He further noted that the emergence of resistance results from both the mutation rate as well as the number of times the virus replicates. He concluded that "accumulating evidence indicates that virus replication progressively increases with disease progression as immunity diminishes." Dr. Richman's findings indicated that early initiation of AZT therapy could lead to a longer period of effective treatment than if treatment is delayed. It is now known that AZT resistance results from multiple mutations occurring at the site of the gene which encodes reverse transcriptase. But the clinical significance of AZT resistance is not understood. Again, it is important to note that patients who have been treated with AZT and who have been found to carry resistant HIV strains do not appear to have a clinically worse profile. Nonetheless, the existence of mutant, AZT-resistant HIV stains is a continuing cause of concern. Fortunately, cross resistance has not yet been demonstrated with the anti-retroviral drugs dideoxyinosine (ddI) and dideoxycytosine (ddC). This has led to speculation that combination and/or alternating therapy approaches may be effective in preventing the emergence of drug resistant HIV-1 mutant strains. There are many additional potential benefits associated with combination therapy approaches. For example, Dr. Tom Merrigan of Stanford University has reported that bone marrow toxicity was significantly reduced in alternating regimens with AZT and ddC than had been observed with continuous AZT therapy. The development of peripheral neuropathy remains a concern, however, and the optimal dosing schedules (including a drug-free period) have yet to be determined. Still other combination therapies, such as AZT, Recombinant Soluble CD4, and Recombinant Interferon-alpha A, have shown promise in the prevention of drug-resistant HIV-1 mutants. It is also important to remember that it is possible for a given individual to carry many different strains of HIV. Some of these strains may have developed through mutation, still others may represent re-infection. While some resistant strains may develop, other strains may well exist which are kept in check through zidovudine therapy. Because the clinical significance of AZT resistance is unknown, a state-of-the-art conference sponsored by the National Institute of Allergy and Infectious Diseases published a report last year recommending further research. The report also stated "therapy with zidovudine is recommended for both symptomatic and asymptomatic HIV-infected individuals whose CD4 cell counts are below 500." While AZT toxicities are well documented and many people require other anti-retroviral regimens, there is a general consensus that the known benefits of zidovudine therapy for most patients outweigh the theoretical concerns with AZT resistance. (Jeffrey M. Fricke is the Education Director at the UCLA AIDS Clinical Research Center. He can be reached at (213) 825-3594.Presentation of information here does not imply an endorsement of any action or treatment by the UCLA AIDS Clinical Research Center.) ================================================================ End of Being Alive Newsletter (April 1991 - part 1/2)