Subject: Searchlight, Vol. 3, No. 3 Date: May/Jun 1993 (2063 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& && S E A R C H L I G H T && &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& A Publication of SEARCH Alliance, Southern California's Fast Track in AIDS Research Volume Three, Issue Three May/June 1993 SEARCH Alliance 7461 Beverly Blvd., Suite 304 Los Angeles, CA 90036 (213) 930-8820 1 800 64-SEARCH CONTENTS: [items are separated by "*****" for this display] SEARCH Alliance Launches Mural Project Study Of Identical Twins Yields Promising Results The Art Of Survival: A Six Year Odyssey The NIH And Pharmaceutical Companies: A Complex Relationship In Drug Development SEARCH Trials At A Glance SEARCH Alliance Funds Gene Therapy Research Common Drugs Used In HIV SEARCH Trials In Development AIDS in Women Continues to Increase -- May Pass Men Within the Decade Tuning In To Early Signs NOTES and EVENTS Free HIV Testing Program Launched By Womensearch With Personality, Humor, and Commitment, Volunteers Make A Difference The Strength Of A Symbol Marcia Smith Leaves SEARCH Alliance GLOSSARY TREATMENT BRIEFS SEARCH Alliance is looking for: CLINICAL TRIALS COORDINATOR *** In Memory of Lloyd Tittle December 5, 1951 - March 6, 1993 *** SEARCH Alliance extends grateful thanks to the Curtis W. McGraw Foundation for their continuing support of AIDS research. SEARCH Alliance thanks our physicians and their staffs for their invaluable assistance in the performance of clinical trials. *** EDITOR'S NOTE So much of the time it is the family and friends of the people living with HIV and AIDS who take on the burden of supporting not only their loved ones, but AIDS research as well. We all know the pain and sacrifice that people who live with the disease face, but sometimes I think we forget the efforts of people who happen to know someone with HIV/AIDS. This issue is dedicated to those who, while not carrying the virus themselves, make great emotional and financial contributions to AIDS research to help find the cure for someone they love. Thank you. Thank you also to Marcia Smith, the previous Executive Director of SEARCH Alliance, for being the kind of person I just described. (Marcia is leaving SEARCH Alliance--please see her articles which follow). I would also like to thank Henry Chang and Dr. Laurie Shaker Irwin. They put a great deal of time into writing and reviewing articles.for this newsletter. ***** SEARCH ALLIANCE LAUNCHES MURAL PROJECT by Susan Black, Assistant Editor In an effort to raise AIDS awareness, and to raise much- needed funds for research, SEARCH Alliance has commissioned noted public artist Russell John Carlton to design a mural which will span a 190 x 13-foot trapezoidal section of wall on the Santa Monica Freeway between Overland and National Boulevards. The project will raise funds for AIDS research through the sale of portions of the painting, from square inches selling for $1.00, to square yards or even special sections of the design. This arrangement allows for a wide variety of donations, so that even those with a limited income can participate in the effort. Large donations will be commemorated by placing donorsU names on a plaque next to the mural itself. This concept has been successful before, in a mural project that Carlton executed to benefit AIDS Project Los Angeles. The SEARCH Alliance mural will be a permanent Los Angeles landmark and, as Carlton puts it, "a standing affirmation of the courage and hope of the thousands of people united in the fight against AIDS." Construction on the site began March 13th with the erection of K-rails and fencing to protect the artist and his assistants as they embark on the huge task of translating his blueprint to the wall stretching alongside the freeway. The SEARCH Alliance AIDS mural will be seen by thousands of Los Angeles commuters every day, and watching its progress should prove to be a welcome distraction from the frustration of rush hour traffic. More importantly, though, it will raise awareness in the community of the need for constant vigilance in the fight against this devastating killer of men, women and children. In designing the expansive painting, Carlton has employed symbolism from a wide variety of ancient and present-day cultures depicting the quest for knowledge and the search for a cure. The mural is being dedicated to the memory of Dr. Paul Rothman, founder of SEARCH Alliance, who died on January 6, 1993 due to complications of AIDS. For further information on the mural or to make a donation to the project, please contact Jim Weinstein at SEARCH Alliance, (213) 930-8820. ***** STUDY OF IDENTICAL TWINS YIELDS PROMISING RESULTS by Laurie Shaker Irwin, Ph.D., Research Director and Raymond T. Borst, Editor Following a study begun at SEARCH Alliance last year, the National Institutes of Health recently received permission from its Recombinant DNA Advisory Committee (RAC) to conduct an extensive study of the effect of transferring lymphocytesQa type of white blood cell crucial to the immune system that is destroyed during the course of HIV diseaseQbetween identical twins where one is HIV negative and one is HIV positive. SEARCH Alliance believes this work may enhance the lives of the twins in the study, as well as provide evidence for expanding the study to include non-twin siblings. Eventually, there may even be evidence to support lymphocyte transfer between non-related donors and recipients, much like the process currently used for bone marrow transplantation. While SEARCH Alliance studied only one set of identical twins, the results have shown an encouraging increase in the overall health of the twin with AIDS, an increase in both CD4 counts and percentage, and an increase in immune system function. These results will be presented at the International AIDS Conference in Berlin this June. BACKGROUND The SEARCH Alliance lymphocyte transfer study was initiated by Dr. Paul Berry, who proposed that because identical (monozygotic) twins essentially have identical cells, an infusion of healthy cells from the donor-twin would not be rejected by the recipient-twin. Such therapy would theoretically boost the immune system in the recipient by increasing the number of white blood cells in general. However, it is clearly possible that the newly transferred cells could become infected by HIV. The patient therefore required antiviral therapy throughout the duration of the study in an attempt to prevent further infection. The process of removing the white blood cells or lymphocytes is done by a process called leukopheresis. A machine RspinsS the blood of the donor-twin to remove the required cells. Through centrifugal force, the machine is able to separate the required lymphocytes (along with smaller quantities of various other cells) from the rest of the blood. The remaining blood is subsequently returned to the donor-twin. (The leukopheresis process is also used for gathering other blood products, including plasma and CD8 cells; see "Ex Vivo Therapy in AIDS: CD8 Cell Expansion," Searchlight, March/April 1993.) THE FIRST PROTOCOL The goal of the first protocol conducted by SEARCH Alliance (with Dr. Berry serving as Principal Investigator) was to see whether or not the twin with AIDS was able to accept and tolerate the transfer of cells. The number of lymphocytes infused was based upon average estimates of total tissue and circulatory white blood cells in human beings (approximately 700 billion). Each infusion consisted of approximately ten billion white blood cells. The percentage of lymphocytes in the batch of infused white cells ranged from 60-68%, a figure which is determined by the donor- twinUs own lymphocyte count and the effective sorting of cells at the time of leukopheresis. The results demonstrated an increase in CD4 counts from 0 to 68, and an increase in CD4 percentage from 0% to 8%. THE SECOND PROTOCOL The goal of the second protocol (with Dr. Thomas Magee as Principal Investigator) was to determine whether or not the patient could reach and maintain 20% CD4 cells--essentially placing the patient out of the high risk range for acquiring opportunistic infections. The results show a decline in lymphocyte numbers and percentages over time during this study when the cells were infused every three weeks instead of every week as in the first study. In addition, the immune transfer therapy was not effective in achieving a CD4% of 20 as the clinical endpoint. The recipient was maintained on a course of antivirals and prophylactic medications during the study. Clinically, the patient developed recurrences of cytomegalovirus (CMV) of the stomach and pancreatitis during the course of these two protocols, but did not develop any new opportunistic infections. The patient also demonstrated an increase in well being during this same period, in spite of the pancreatitis which seemed to be related to high dose Dideoxyinosine (ddI). The donor-twin tolerated the removal of cells quite well during the first protocol. During the second protocol, the donor was not capable of donating during week 10 as scheduled, due to a low lymphocyte count, so the infusion was performed the following week. No medications were given to stimulate the proliferation of cells in the blood from the donor prior to removal. However, such medications are available and may significantly boost the transfer capacity of the donor. INCREASED IMMUNE FUNCTION Lymphocyte function studies were performed to test how well the lymphocytes are doing their job in the recipient. The results showed significant increases in lymphocyte function in the twin with AIDS. These tests use mitogens (substances that cause cell activation or cell division) to measure the stimulation levels of the lymphocytes. The mitogens that are utilized include phytohemagglutinin (PHA), concanavalin A (con A, and pokeweed mitogen (PWM). The reference range for lymphocyte function for all of these mitogens is >70%. The following chart shows the recipient's baseline and final percentages for these mitogen stimulation studies performed during the first protocol: Mitogen: Baseline %/Final % PHA: 22/67 Con A: 35/71 PWM: 38/45 The results represented here are preliminary evidence for the viability of transferring cells from one identical twin to another in a clinical trial protocol. Preliminary cell-typing studies must be performed before future studies involving sibling or non-sibling lymphocyte transfer can take place. SEARCH Alliance would like to emphasize that this was a small study performed under controlled conditions in a hospital environment. The next question to be answered in lymphocyte transfer studies is, RHow long do the transferred cells last in their new host?S The second protocol of the SEARCH Alliance study indicated that the lymphocytes were not living long enough to boost the recipient's counts above 20% based on a three week infusion cycle. However, further research is required to answer this question. For example, more frequent infusions with a higher number of cells might make it possible to reach such an endpoint. The answer may come from the second NIH study which proposes a three year Phase I/II protocol with several sets of identical twins. The first protocol to be implemented will test the ability of the recipient to tolerate transferred CD4 and CD8 cells. A second protocol calls for tagging the cells with a bacterial neomycin resistant gene; the tagged cells will then be infused into the HIV positive twin to track their length of survival. SEARCH Alliance has accrued anecdotal evidence that private physicians who specialize in the area of HIV hematology are conducting further studies on a limited basis in small numbers of patients. SEARCH Alliance may conduct its own further studies in this area. It is exciting that SEARCH Alliance has been on the cutting edge of this therapy; the organization will monitor the results of other studies in this challenging area of research. This clinical study was generously supported by a grant from the Curtis W. McGraw Foundation. The collaborators on the study were Dr. Paul Berry of Pacific Oaks Medical Group, Dr. Thomas Magee, an HIV specialist and SEARCH Alliance participating physician, and Dr. Joshua Levy of the HemaCare Corporation. We also wish to commend the participants in this study for their commitment to a very intensive and valuable research process. ***** THE ART OF SURVIVAL: A SIX YEAR ODYSSEY by Kenneth Thompson This is the fifth in a series on long term survivors of AIDS. No matter how one looks at it, living with AIDS is not an easy proposition. After six years, I am still amazed by the spectrum of feeling it evokesQat times I am immobilized with anxiety and alternately planning my demise or experiencing revelations of insight. My landscape is one of ever changing and unstable tableaux. It takes constant readjusting to function day to day. No, I'm not a total nut case, just a person striving to maintain a relative level of health and mental well-being. By trial and error I have created a system of physical and emotional supports that reinforce my life. MAINTAINING PHYSICAL AND EMOTIONAL BALANCE Because I am further along the spectrum of HIV, I cannot procrastinate when any symptom or condition appears. I have had numerous opportunistic infections and my T cell count fluctuates between 40 and 70. It is a real emotional challenge to be constantly vigilant without becoming fixated and a total hypochondriac. Maintenance takes many forms. For instance, tolerating toxic medications is a two-sided coin. Summoning the mental fortitude to ingest substances when I know they will make me feel RoffS is a real approach-avoid situation. There are times I must force myself to shove the stuff in my mouth, dreading the physical effects; other times I resort to all the tricks I've learned to get through the unpleasantness (fresh ginger, thinly sliced and sucked upon, will subdue any medication aftertaste, even lamprene and clarithromycin). Flushing out these life-saving drugs is nearly a full-time activity in itself. My kidneys at this point in time are in full rebellion and only fresh beets or cranberry concentrate keep them functioning at even a minimal level. Physical needs are the most immediate, but the psyche is a close second. For someone like myself, who must maintain a constant physical vigil, it can be emotionally taxing. I am constantly juggling variant levels of physical and emotional well-being, and only rarely are they in equal balance. The times when they are in balance is when I realize that it is great to be alive, and I take full advantage and spoil myself shamelessly. When all systems are "go," I perceive it as a window of opportunity to recharge my body and mind, and this re-energizing is critical to sustaining my life. FLEXIBILITY If anything has aided me in surviving these six years, it is the ability to "shift gears." With AIDS I cannot plan too far ahead, because I know that in any given moment I may be forced to compromise my desires because of physical ills. The need to see a doctor, for example, may preempt the pleasure of attending my Yoga class. However, I need to maintain goals and hopes and some sense of a future I can count on. It is not enough--in fact, I find it impossible--to live just in the moment. I find that philosophically to be like "the reed that bends with the wind" allows me to adjust to sudden changes and still maintain some degree of continuity in my life. It seems that many people with HIV and AIDS cling desperately to the idea of maintaining as much of a "normal" life as possible, and I support this concept. The reality as I perceive it, however, is that there is very little about my life that is normal. It is a futile and ultimately self-defeating quest to try to persuade myself otherwise. I realize that my life is charged with anxieties, unexpected turns of event, and vagueness at a level most humans don't experience. It is not a matter of "rising to the occasion"; rather, it is just striving for balance. BEING PASSIONATE A belief system is a very personal thing, and requires active involvement from the individual. This idea extends itself to the arenas of intimacy and passion. Passion in its larger definition means extreme involvement and dedication, and includes the physical expressions of who we are as human beings. If one is not passionate about life, the drudgery of medical regimens, fear, and self-doubt can subtly erode one's individual character. (Everyone has something about which they can feel passionate, even if it is as simple as moviegoing or cooking.) I therefore cultivate my areas of interest and things I love to do. Passion is expressed in many ways, and physical intimacy is among the most compelling. As human beings we are in great part motivated by the desire to touch and be touched, to caress, to alternately dominate and surrender and to ultimately cleave to one another for life-affirming energies. Presently, I have KS as well as a battery of other physical challenges, and I am no Robert Redford to begin with, and I still need, yes need, to be kissed and held and to experience an occasional orgasm (the forbidden word for persons with AIDS). Meeting others who are willing to suspend old standards of attractiveness, who are open to new ways of seeing and feeling, is another formidable challenge presented by this disease, though it is less often discussed. I have been to social events designed especially for people with HIV/AIDS, and seen the same old prejudices and narrowness at work so that many people leave dissatisfied and lonely. We must evolve our sensitivity and compassion for one another, or wither in isolation. THE WILLINGNESS TO STRUGGLE One of the most frustrating situations for me is the sudden interruption of progress on a project or on my physical recovery because of fatigue or a physical setback. I have found greater success in isolating each attack on my system as separate and repairable, instead of perceiving it as the overwhelming specter of AIDS. By dealing with each challenge individually the disease becomes more manageable, and I can muster the patience and the fortitude to overcome it. I am then able to continue, perhaps somewhat diminished but still triumphant. Each episode requires more recuperative time, and I must suspend old expectations of Rbouncing back.S To be gentle with oneself and to construct realistic expectations is an ongoing lesson. Life with HIV is one of almost constant struggle on one level or another. It is imperative to ask the question, RAm I willing to be in this situation, and to experience my life fully in spite of the difficulties and setbacks?S If one can answer YES, it is possible to discover joy and fulfillment no matter how reduced the circumstances. More than anything I have found strength and courage I never imagined I possessed. I liken myself to a pendulum that swings back and forth between hope and despair. I strive for the swings to be less extreme, and it is in this effort that my life gains true meaning. I believe that the power of the human spirit is immense, and that life's fulfillment comes through our struggle to prevail. My life is what I make of it. ***** Analysis: THE NIH AND PHARMACEUTICAL COMPANIES: A COMPLEX RELATIONSHIP IN DRUG DEVELOPMENT by Laurie Shaker Irwin, Ph.D., Research Director AIDS research was moving at a quicker pace at the National Institutes of Health (NIH) during the late 1980's then it is today. NIH research and productivity have lapsed while pharmaceutical companies attempt to bring new drugs to the market. Recently, both groups have come under fire. The NIH has come under scrutiny by Congress and AIDS activists who have noticed a wasteful duplication of research. Drug companies have experienced criticism in the wake of Clinton Administration censure blaming the children's immunization crisis on the high cost of vaccines. While the NIH is responsible for funding the majority of AIDS-related research in this country, pharmaceutical manufacturers are responsible to their shareholders who expect a high profit margin. These two groups and their agendas are at the center of the debate on AIDS research, and will be the focus of any attempt by the Clinton Administration to consolidate a national AIDS program. By examining the structure of the NIH and its relationship to the pharmaceutical industry, it is possible to illustrate why it continues to take so long to develop new AIDS drugs and why they are so expensive once they reach the marketplace. NO CENTRALIZED AIDS PLAN The National Institutes of Health is comprised of over 24 institutes and programs that are really individual kingdoms, each with its own director, research plan and budget. The interrelationships among the Institutes and their individual programs are complex, yet they remain ultimately isolated from one another. The irony is that many of them are conducting some form of AIDS research. The Institutes have been overseen by NIH Director Dr. Bernadine Healy, who recently announced her resignation. Recruitment for a new NIH Director must not involve the lengthy process that has characterized it in the past, since this country cannot afford to waste time in developing a national AIDS research plan to consolidate these disparate efforts. The two Institutes that have conducted the bulk of the research include the National Institute for Allergy and Infectious Diseases (NIAID) and the National Cancer Institute (NCI). Many of the Institutes have their own clinical trial study groups, the most familiar of which are the NIAID AIDS Clinical Trials Group (ACTG) and Community Programs for Clinical Research on AIDS (CPCRA). In addition to these two networks, there is (within NIAID) the Division of AIDS Treatment Research Initiative, which sees to it that fast, early phase studies and trials not of priority to the ACTG or CPCRA are funded. Other Institutes having their own clinical trial networks include the Studies of the Ocular Complications of AIDS (SOCA) at the National Eye Institute, the AIDS Lymphoma Network at the National Cancer Institute, and the pediatric ACTG at the National Institute of Child Health and Development. The Office of AIDS Research (OAR) at NIH is under the Directorship of Anthony Fauci, who is also the Director of NIAID and Chief of the Laboratory of Immunoregulation. The OAR is supposed to control all the AIDS research funding across the Institutes, however it is difficult for one office to be a centralized source of information regarding all the AIDS research that is being funded by the NIH. Because of this lack of a controlling organization, AIDS research at the NIH is basically an amorphous entity spread across multiple subprograms in each of the Institutes. Congress, the Institute of Medicine, and AIDS activists have encouraged the NIH to develop a comprehensive plan for its efforts, and in response, the NIH has developed a document which addresses these concerns. The "Strategic Plan for HIV-Related Research" is currently going through a complicated approval process by all the Institutes. There is considerable research overlap among these Institutes that needs to be consolidated. This includes basic science, epidemiology, vaccine, treatment and immune-based therapies. Other studies, although not directly related to HIV, have extreme relevance for HIV research. One example of the overlap is in the work many of the Institutes are doing on gene-based therapies for cancer, aging, neurological diseases and, of course, HIV. If the NIH could concentrate their efforts in this area, research productivity would markedly improve. Clearly, drastic reform that would lead to efficient collaboration among Institutes is called for, and the Clinton Administration has taken the initiative with the NIH Reauthorization Bill (S.1), which specifically addresses these issues. In addition, the Treatment Action Group of New York has presented a proposal for the revitalization of the NIH AIDS research effort through a restructuring plan which strengthens the NIH Office of AIDS Research and allocates increased resources and funding to the NIH AIDS research budget. DISSEMINATING NIH RESEARCH INFORMATION The process of data collection, analysis and publication of study results needs to be streamlined so that new information can be disseminated as quickly as possible. By the same token, time should not be wasted collecting data that is not directly relevant to clinical endpoints. In addition, long term data collection processes should be in place to follow individuals who have participated in AIDS trials, so as to determine factors that contribute to longevity. There should be a simple, straightforward and reliable follow-up process by which this information is collected and utilized. The ACTG has published a great number of valuable study results in various medical journals, but many studies, including those performed with regard to opportunistic infections, remain unpublished. The resultant gap in information available to patients and their primary care physicians has drastically slowed the implementation of new standards of care. There are sometimes unresolved problems between pharmaceutical companies and the researchers themselves with regard to the conduct and control of clinical trials, and this further complicates the process of information dissemination. Because of these "turf" conflicts, many pharmaceutical companies are no longer looking to the ACTG alone to conduct their studies. They may look abroad or to the community-based setting for their research. In addition to public relations problems, the ACTG is currently undergoing a major--and expensive--administrative overhaul which will remove certain sites from the group and fund new ones; but in the process, money is being drawn away from promising AIDS research projects. PLANNING THE BEST WAY TO MOVE FORWARD Commenting on the government's attempts to find a cure for AIDS, Martin Delaney of Project Inform has said, "There is little evidence that we have organized and structured our resources in an efficient manner capable of achieving this end." This is illustrated by the fact that, ten years into the epidemic, no fair, formal evaluation of AIDS research has been conducted. An evaluation plan to prioritize the problems associated with research and funding should be first on the NIH agenda, and this plan should serve as the basis for any restructuring that takes place. PHARMACEUTICAL POLITICS AND GOVERNMENT FUNDING AIDS activists have been after drug companies for years to cut or hold the prices on the limited number of FDA approved AIDS treatments. While there has been limited progress in this area, the Administration's pressure on companies to lower the price of vaccines was a welcome sign. In response to such criticism of drug companies, the Pharmaceutical Manufacturers Association and Merck & Co., Inc. have commenced a public relations campaign which includes full-page advertisements in major newspapers, and strives to shed light on their side of the controversy. According to the Bureau of Labor Statistics, prescription drug inflation was three times greater than overall consumer inflation in 1991. In the first 10 months of 1992, prescription drug inflation was 1.8 times the rate of inflation. Drug companies may not shoulder the entire blame for such inflationary prices, as pharmacies and drugstores also partake of the profit pie. The pharmaceutical industry prefaces all discussions of drug research and pricing with the adage that developing wonder drugs costs money; it can cost as much as $200 million to get a product to market. And then there is the other costly investment of marketing itselfQan investment the industry regards so highly that it spends approximately 22 cents of every prescription dollar on marketing and advertising, while only 16 cents of that dollar goes to research on new drugs. The industry's justification for this imbalance is: "What good does it do to discover a great drug and have no one know about it?" Companies further argue that the 17-year patents on their drugs force them to recoup their investments quickly. Since it can take an average of 12 years to develop new drugs and obtain approvals, only five years remain to make profits before the generic versions are authorized and introduced to the marketplace. But who is funding the research for drug development? Drug companies have been increasing their funding of research outside their own laboratories, often to universities and private research companies where scientists are already conducting basic research funded by the NIH. Scientists patent their research and sell it to drug companies, who in turn do testing and marketingQoften within the government networks of the ACTG. Therefore, the public pays for the same research at three different levels: initial development, clinical trials and again at the counter for what the pharmaceutical companies call "research and development.S Most drugs would not make it to the marketplace without government sponsored laboratory research. However, neither the government nor taxpayers ever realize the financial benefit one might anticipate from this sponsorship. Although AZT, ddC, and ddI were all developed with government support, they all have very high consumer price tags. Policies should be implemented in order to assure that federally-sponsored drugs are priced reasonably. PHARMACOECONOMICS Drug companies need to be held accountable and, like the NIH, should be subject to evaluation studies that are rightly being demanded by customers, HMOs and hospitals. Today, 40% of all prescriptions are paid for by third-parties such as managed care plans or Medicaid; according to one New York investment firm, that figure is expected to rise to 75% by 1996. When these third-party payers draw up pharmaceutical formularies (listing of drugs they will cover), direct cost should not be the only factor involved. There are indirect costs which affect the overall costs of medical care. (Direct costs are those actually being paid to receive the drug, while indirect costs may include other factors such as shorter hospital stays or less intensive regimens of medication. The latter also provides a measurable dollar value in terms of cost-effectiveness.) A whole field has been developed to address this area of concern: "pharmacoeconomics" has become the latest rage in the push for accountability and evaluation in the health care arena. Basically, it seeks to determine the most clinically effective drugs at the lowest direct and indirect costs. Should such studies be conducted by the HMOs, drug companies, or federal agencies? The Agency for Health Care Policy and Research in Rockville, Maryland has announced that pharmacoeconomics will be a primary focus in its clinical effectiveness trials commencing in 1994. It is important that drug companies consider cost- effectiveness in post-marketing studies (conducted after a drug has been approved for widespread sale) wherein the new drug has to prove as good or better than the currently accepted standard. Once considered worthy of competing, it must be "sold" to managed care and private physicians. Favorable outcomes are very difficult to predict, and therefore a pharmaceutical manufacturer has little information on which to base a decision to move forward with a particular drug. When a company has several drugs in development for a variety of disease conditions, it is likely that some will fail and some will be successful. To offset their risk, drug companies initiate cost-effectiveness analyses at the early stages of development and in clinical trials, and have now formally incorporated this research into their health economics departments. Ultimately, these studies can have a direct effect not only on drug development, but on the cost of those already in the marketplace. Overall, the public needs access to information on the best drug, not the least expensive one. The quality of the research matters far more than whether it is conducted privately or federally; the public ultimately picks up the tab and profits from the benefits of good medicine in either case. The real issue is how to produce sound scientific evidence while balancing the pharmaceutical's scientific and economic interests with those of the researcher. Toward this end, a 1991 article in The New England Journal of Medicine recommended that researchers should retain the right to their data for publication, whether the outcome is favorable or unfavorable to the sponsor of such research; that drugs should be tested against appropriate alternatives and not clearly inferior drugs; and that all financial relationships between researchers, the company, and consultants should be fully disclosed in the final reports. REGULATION ON DRUG PRICING The Clinton Administration has promised overall health care reform, and it is likely that prescription drug pricing will be included in any reform package. Negotiations are already underway between AIDS organizations such as The Physicians Association for AIDS Care (PAAC) and pharmaceutical companies in order to implement price freezes or price caps (annual or lifetime) on certain medications. Such negotiations, action, and reform are long overdue. An announcement resulting from one of these negotiations will be made on May 11, 1993 in Los Angeles, and it is anticipated that other companies are ready and willing to follow suit. Only time will tell the commitment of the Administration and the drug companies to good research and drug pricing regulation. Sources for this article are available from the author through SEARCH Alliance. ***** SEARCH TRIALS AT A GLANCE An Important Notice About SEARCH Alliance Research: SEARCH Alliance research usually differs from traditional research in many important ways. Traditional research, which is performed by government agencies, universities, and many community organizations, usually involves large numbers of patients, takes a long time, and costs a great deal of money. It is necessary that traditional research be done in this manner because the benefits of AIDS medications are often very subtle and might not be seen otherwise. SEARCH Alliance trials involve smaller numbers of patients and much shorter periods of examination than traditional research. We limit our research to drugs and treatments that may clearly and quickly show benefit. While we believe that both types of research are important, the people involved with SEARCH Alliance are looking to benefit those people who need help now. The decision to enroll in a specific research project should only be made after a detailed discussion with your personal physician. If you want to participate in any of these trials, you or your doctor are encouraged to call SEARCH Alliance for further information. SEARCH Project 92-2 Cimetidine (Tagamet() Purpose: To determine if cimetidine has an immune-stimulating effect through its proposed action of blocking histamine receptors on lymphocytes. Cimetidine is used most commonly to treat peptic ulcer disease, but is reported to boost immune function. In addition to monitoring CD4 and CD8 cell counts, the study is monitoring any immune status improvements through the use of delayed-type hypersensitivity skin testing. Preliminary Results: An interim analysis was conducted on the data collected from patients during the first three months of the study. (A six month assessment will be performed and reported after all patients have completed the study.) The initial results did not show any significant CD4 cell count improvements from baseline (the beginning of the study) among all patients, nor were there significant differences in the analysis that grouped baseline CD4 counts into three stratifications. These results are preliminary and the final results will provide the basis for the evaluation of the study overall. They will be presented in a future Searchlight. SEARCH Project 91-4 Human Growth Hormone BioTropinTM (hGH) Purpose: Synthetic human growth hormone is a recombinant DNA polypeptide, whose amino acid sequence is identical to that of human growth hormone from the pituitary gland. HGH has been shown to regenerate the atrophied thymus and subsequently the T cell populations in animal models. This new population of T cells is not only increased in number but in efficacy as well. HGH also increases the amount of interleukin-2 (IL2) and alpha interferon, two vital substances whose levels are below normal in HIV positive individuals. Status: This study has been completed and is being analyzed. The results will be presented in the next issue of Searchlight. ACCELERATED PILOT STUDIES Lymphocyte Transfer as Immune Therapy Purpose: To determine the potential therapeutic effects of transfusing lymphocytes from a monozygotic (identical) twin who is HIV negative to the other twin who meets the criteria of AIDS. This research holds promising implications for similar treatments with non-twin siblings. Status: Please see the related article above. Immunoglobulin to Alpha Fetoprotein Background: There are several functional similarities between the binding sites of human alpha fetoprotein (AFP) and HIV glycoproteins (the proteins that coat the virus). It has been demonstrated that immunoglobulin to AFP inhibits syncytial formation (cell clustering) and prevents HIV replication in cells in the laboratory. This immunoglobulin was administered to patients with advanced liver cancer during the early 1980s with no significant side effects. Status: The trial has been completed on two patients. The clinical results of the study demonstrated insignificant viral load changes with a single infusion. There were no significant changes in immunologic parameters, which included T-cell phenotyping. SEARCH Alliance is aware of a research study in the community, whereby multiple infusions are being performed and various laboratory assessments are being evaluated. SEARCH Alliance advocates that an individual be fully informed of the study protocol prior to participation. ***** SEARCH ALLIANCE FUNDS GENE THERAPY RESEARCH Two issues ago, Dr. Thomas J. Magee reported on current research being done in gene therapy to create an HIV construct (in essence, a synthetic, RdummyS virus) that may short-circuit the ability of HIV to replicate (RGene Therapy: A Potential Treatment for HIV,S Searchlight, January/February 1993). In recognition of the promise these investigations hold, and to ensure that the work continues uninterrupted, SEARCH Alliance has funded the project with $25,000. In addition, the Curtis W. McGraw Foundation is supporting this research through SEARCH Alliance with a generous $150,000 grant. We will follow Dr. Magee's progress closely, and will report the results in future issues. ***** COMMON DRUGS USED IN HIV The following table lists some of the most common medications currently used in treating HIV/AIDS, along with descriptions of their possible interactions with other drugs, and nutrition-related effects. This list is by no means exhaustive. It is presented here as a basic reference in hopes of stimulating readers to fully inform themselves on the drugs they are taking, Drugs which may interact with thge listed medication are followed by a description of the potential side effects in parentheses. For more information or clarification, please consult a physician. Information for this table was provided by Bob Meyer at Capitol Drugs, with substantial supplemental data provided by the Drug-Nutrient Interactions in AIDS Guidebook, by Cade Fields Newman and Bill Horn. This book lists many more references than are included here, and can be obtained by writing to The Cutting Edge, P.O. Box 392, Fremont, CA 94537-0392. (s) = serum labs; (u) urinary labs; WBC = white blood cells; RBC = red blood cells; CNS = central nervous system; Create = creatinine; BUN = blood urea nitrogen; glu = glucose; LFT = liver function test; ACYCLOVIR (Zovirax) Antiviral Drug Interactions: Amikacin, Amphotericin B, Capreomycin Sulfate, Kanamycin, Vancomycin, Probenecid (decreased renal clearance, increased acyclovir half life); Interferon, Methotrexate (neurologic abnormalities). Nutrition-related effects: Hypotension, headaches, sore throat, diarrhea, metallic taste, CNS effects; Rare effects: nausea/vomiting, abdominal pain, anorexia. How Taken: Ensure adequate hydration, avoid alcohol. AMPHOTERICIN B (Fungizone, Mysteclin-F) Antifungal Drug Interactions: Aminoglycosides, Cyclosporine (increased nephrotoxicity); Corticosteroids, K+ wasting diuretics (additive hypokalemic effect); Skeletal muscle relaxants (may potentiate relaxing effects); Flucytosine, Rifampin, Tetracycline (may increase therapeutic/toxic effect; acts synergistically); Antineoplastics, Nephrotoxic Antibiotics (do not administer concomitantly, or administer with great caution); Pentamidine (increased nephrotoxicity of amphotericin and pentamidine). Nutrition-related effects: Nausea/vomiting, hemorrhagic gastroenteritis (rare), fever, metallic taste, weight loss, dyspepsia, diarrhea, cramping, epigastric pain, renal dysfunction, muscle pain, anorexia, flu-like symptoms, chills, rigors. ANSAMYCIN (Rifabutin) Anti-infective Drug Interactions: None listed. Nutrition-related effects: nausea/vomiting, dyspepsia, hepatotoxic Labs: (s) anemias, increased LFTs (transient), creat, bone marrow dysfunction, seizure. AZYTHROMYCIN (Zithromax) Macrolide Drug Interactions: Terfenidine (increases half life of seldane). Nutrition-related effects: No data available. How Taken: Take on an empty stomach for maximum absorpsion. AZT - Azidothymidine (Retrovir, Zidovudine) Antiviral Drug Interactions: Dapsone, Pentamidine, Amphotericin B, Flucytosine, Vincristine, Vinblastine, Adriamycin and Interferon (may become nephrotoxic or cytotoxic and/or interfere with RBC/WBC function); Acetominophen, Aspirin, Indomethacin (increased risk of granulocytopenia); Acetominophen, Sulfonamides (may interfere with hepatic glucuronidation; use with caution); Acyclovir, Phosphonoformate, Castanospermine (may potentiate effect of AZT); DHPG (may cause additive bone marrow suppression); Indomethacin (may increase toxic effects of AZT); Pyrimethamine (decreased effect of pyrimethamine against Toxoplasmosis); Ribavirin (antagonizes antiviral effect of AZT); CD4 RcomplementaryS; attacks HIV differently, may reverse some anemia by boosting bone marrow function; AZT administered with G-CSF and EPO (decreased serum calcium, phosphorus in patients with poor nutritional status or diarrhea). Nutrition-related effects: Nausea/vomiting, increased/decreased appetite, diarrhea, dysgeusia, constipation, fatigue, insomnia, severe headaches, myalgia, neutropenia, thrombocytopenia, abdominal pain, dyspepsia, possible weight gain, severe polymyositis-like syndrome: weakness, tenderness, muscle atrophy (often in leg). Labs: Anemia, decreased hemaglobin, white blood cells. How Taken: May be taken without regard to food or milk. Take exactly as directed. Avoid fresh fruit/vegetables when WBCs are low. CLARITHROMYCIN (Biaxin) Macrolide Drug Interactions: Carbamazepine (may increase plasma levels); Terfenadine (increased plasma levels). Nutrition-related effects: No data listed. How Taken: May be taken without regard to food or milk. CLINDAMYCIN (Cleocin) Antibiotic Drug Interactions: Neuromuscular blocking agents (enhances blocker action); Kaolin, Antiperistaltic anti-diarrheals (reduces clindamycin absorption; may delay removal of toxins from colon and prolong or aggravate diarrhea; Antidiarrheals, Erythromycin, Chloramphenicol (may reduce effects of clindamycin). Nutrition-related effects: Nausea/vomiting, abdominal pain, esophagitis, diarrhea, psuedomembranous colitis, metallic taste (after phosphate form injection), thirst; Labs: (s) abnormal LFTs, increased alkaline phosphate; Note: combined with pyrimethamine or sulfadiazine in some treatments. CLOFAZIMINE (Lamprene) Leprostatic Drug Interactions: Dapsone (may inhibit anti-inflammatory action of lamprene). Nutrition-related effects: Abdominal and epigastric pain, nausea/vomiting, diarrhea, dyspepsia. Labs: (s) anemia, increased glucose. How Taken: Take with food to help absorption. CLOTRIAMAZOLE (Mycelex, Canestin, Gyne-Lotrimin, Lotrimin) Antifungal Drug Interactions: None listed. Nutrition-related effects: Troches: nausea/vomiting; elevated SGOT in about 15% of the patients using lozenge; elevated LFTs, GI distress, diarrhea (rare). Labs: (s) increased LFTs. How Taken: Troche is dissolved slowly in mouth. DAPSONE (Dapsone) Antibiotic, Antiparasitic Drug Interactions: Rifampin (decreased serum levels of dapsone, accelerates clearance); Trimethoprim (may inhibit metabolism of dapsone and increase serum dapsone levels, increasing dapsone efficacy and doxicity; Activated charcoal (may decrease GI absorption and enterohepatic recycling of dapsone); PABA (antigonizes effect of dapsone. Nutrition-related effects: Abdominal pains, anorexia (common), nephrotic syndrome, sore throat, fever, jaundice, peripheral neuropathy, nausea/vomiting (rare), hepatitis, hemolysis; Labs: (s) anemias, decreased RBCs, WBCs, albumin without proteinuria (u) albumin How Taken: Avoid alcohol. DIDANOSINE (Videx, ddI) Antiviral Drug Interactions: Nizoral and Zantac (absorption of these drugs is decreased due to high stomach pH). Nutrition-related effects: None listed. How Taken: Take on an empty stomach (take 1 hour before food or 1-1/2 hours after). ETHAMBUTOL HCl (Myambutol) Antituberculosis Drug Interactions: Aluminum salts (delay or reduce absorption of Myambutol); Ethionamide (may intensify effect and toxicity of ehtionamide). Nutrition-related effects: Nausea/vomiting, anorexia, GI upset, abdominal pain, dizziness, hepatitis, thyroid disorders (goiter), red-green color blindness may be due to changes in zinc metabolism. Labs: (s) increased uric acid, LFTs. How Taken: Take with food to avoid GI upset. FLUCONAZOLE (Diflucan, UK-49) Antifungal Drug Interactions: Dilantin (increased plasma concentrations); Warfarin (increased activity); Rifampin (increases metabolism of Diflucan). Nutrition-related effects: Nausea/vomiting, headache, abdominal pain; mild transient increase in transaminase, bone marrow suppression, hepatitis; increased activity of oral sulfanylurea; increased blood levels of dilantin. How Taken: May be taken without regard to food or milk. FOSCARNET SODIUM (Foscavir) Antiviral Drug Interactions: All nephrotoxic drugs inhibit elimination of Foscavir. Nutrition-related effects: None listed. How Taken: As directed. GANCICLOVIR (Cytovene) Antiviral Drug Interactions: Same as AZT. Nutrition-related effects: None listed. How Taken: As directed. ISONIAZID (Isoniazid, INH) Antituberculosis Drug Interactions: Alcohol (increases INH-related hepatitis; Anticoagulents (INH potentiates the affects); Benzodiazepines (INH decreases metabolism, which increases activity of the benzodiazepine); Aluminum-containing antacids (decreased INH absorption); Oral Antidiabetics, Antihypertensive, Atropine-like, Disulfiram, Sedatives/Narcotic, Stimulants (Isoniazid may increase effects of these drugs); Carbamazepine (increased effects and toxicity of carbamazepine and isoniazid); Corticosteroids (decreased isoniazid effects; increased isoniazid metabolism and excretion; Laxatives (decreased absorption of isoniazid); Keotconazole (may decrease absorption of isoniazid, which may also increase metabolism of ketoconazole; Phenytoin (Isoniazid may decrease metabolism and increase effects of phenytoin; Pyridoxine (high doses of pyridoxine may decrease isoniazid effectiveness; Rifampin (increased hepatoxicity of isoniazid). Nutrition-related effects: Hepatitis, acidosis, dry mouth, pellagram pyridoxine def, blood dyscrasias, fever, arthralgia, monitor diabetic, decreased B12, magnesium, calcium absorpsion; Infrequent effects: nausea/vomiting, epigastric distress, anorexia. May act as a monoamine oxidase inhibitor leading to severe hypertension (avoid foods high in tyramine). Labs: (s) anemias, increased LFTs, bilirubin, glucose; decreased folate; (u) increased B6 excretion. How Taken: May be taken without regard to food or milk. Increased need for folate, niacin, pyridoxine. Give 25-50 mg/d B6; take with 8 oz. water, avoid alcohol, foods high in pressor amines, monitor calcium, PO4. ITRACONAZOLE (Sporanox) Antifungal Drug Interactions: Terfenadine (may increase plasma levels) Nutrition-related effects: No side effects noted at 200-400 mg daily. How Taken: Take with food for maximum absorption. Not effective if achlorhdria is present because absorption enhanced in an acid environment; possible nausea, abdominal pain, diarrhea, vomiting, headache, rash, hypokalemia. KETOCONAZOLE (Nizoral) Antifungal Drug Interactions: Antacids (inhibit absorption of nizoral); Isoniazid (inhibits metabolism of nizoral); Anticoagulants (affects are potentiated by nizoral); Corticosteroids (affects are potentiated by nizoral); Cimetidine, Antacids, Anticholinergics (decreased GI abosorption of ketoconazole); Rifampin, Isoniazid (may increase metabolism of ketoconazole); Oral antidiabetics (severe hypoglycemia); Cyclosporin (decreased excretion of cyclosporin); Methylprednisolone (increased toxicity of methylprednisolone); Phenytoin (altered metabolism of ketoconazole). Nutrition-related effects: Nausea/vomiting (common), anorexia, abdominal pain, hepatitis, diarrhea, dizziness, adrenal insufficiency. Labs: (s) anemias (rare), increased LFTs. How Taken: Take with food to avoid GI upset. Avoid alcohol, antacids. METRONIDAZOLE (Flagyl) Ambecide Drug Interactions: Alcohol (can cause severe reactions such as nausea, vomiting, headaches, flushing, seizures); Warfarin, metronidazole, coumarin (effects of these are potentiated); Phenobarbitol and phenytoin (decreased effectiveness of all three); Disulfiram (severe emotional and behavioral disturbances); Oxytetracycline (decreased effects of flagyl); Cimetidine (inhibits metabolism of flagyl). Nutrition-related effects: Common effects include nausea/vomiting, diarrhea, epigastric distress, anorexia, metallic taste; Other effects include abdominal cramps, constipation, glossitis, stomatitis, associated with overgrowth of Candida during therapy, anemias, dry mouth, polyuria. Labs: (s) interferes with tests for LFTs, triglycerides, lactic dehydrogenase. How Taken: Avoid alcohol. Take with food to avoid GI upset. Avoid all items containing alcohol for at least 48 hours after discontinuing therapy. PAROMOMYCIN (Humatin) Aminoglycoside Drug Interactions: Anticoagulants (due to malabsorption of Vitamin K). Nutrition-related effects: None listed. How Taken: May be taken without regard to food or milk. PENTAMIDINE ISETHIONATE (Pentam-300) Anti-pneumocystis Drug Interactions: Diazoxide (may reduce hypoglycemic effect of pentamidine); Bronchodilators (bronchodilator pretreatment may decrease bronchospasm. Nutrition-related effects: IV: nausea/vomiting, diarrhea, sore throat, fruit-like breath, SIADH, metallic taste in mouth, anorixia, indigestion; Rare effects: acute renal failure; pancreatitis; Aerosol: dry throat, altered taste, nausea, fatigue, dizziness; Labs: (s) anemias, azotemia, increased LFTs, creat, glucose, and potassium (rare); decreased glucose (common in IV, rare in aerosol), calcium (rare). How Taken: Cleanse mouth before aerosol. PYRAZINAMIDE (Pyrazinamide) Antituberculosis Drug Interactions: None listed. Nutrition-related effects: Nausea/vomiting, anorexia, fever, arthralgia, hepatitis. Labs: (s) hemolytic anemia, increased uric acid. How Taken: Take as directed. Do not discontinue without consulting your physician. PYRIMETHAMINE (Daraprim) Anti-parasitic, including pneumocystis Drug Interactions: Paraaminobenzoic (PABA) (may decrease pyrimethamine effect on toxoplasmosis. Nutrition-related effects: Nausea/vomiting, anorexia, atrophic glossitis, bleeding, stomatitis, taste alterations, jaundice, blood dyscrasias, ARF Labs: (s) anemias How Taken: Take with food to minimize gastric irritation, vomiting, sore throat, dysphagia; requires folinic acid supplement. RIFAMPIN (Rimactane) Antituberculosis Drug Interactions: Ketoconazole (therapeutic failure of rifampin due to increased metabolism of ketoconazole); Aminosalicylic acid (PAS) (decreased absorption of rifampin); Oral anticoagulants (may change PTT, may decrease effects of oral anticoagulants); Dapsone, Trimethoprim (decreased effects of these); Oral contraceptives (decreased effects of contraceptives); Theophylline (decreased theophylline effects). Nutrition-related effects: Common effects include diarrhea, reddish urine and feces, stomach cramps; Rare effects include anorexia, vomiting, sore mouth and throat. Labs: (s) anemias, increased BUN, uric acid; decreased hemaglobin. How Taken: Take on empty stomach with 8 oz. water. Note: undernutrition may be a factor in triggering hepatitis. TRIMETHOPRIM/SULFAMETHOXAZOLE (Bactrim, Septra) Anti-infective Drug Interactions: Azathioprine (increased hemotoxicity of azathioprine); Phenytoin (increased serum level of phenytoin, decreased hepatic clearance; Sulfonylurea (may increase hypoglycemic response to sulfonylurea; Methotrexate (impaired renal excretion of methotrexate). Nutrition-related effects: Depression, neutropenia, anorexia, stomatitis, hepatitis, renal failure, pancreatitis, glossitis, decreased absorption folate, psuedomembranous enterocolitis; Infrequent: nausea/vomiting, diarrhea, abdominal/mouth pain; Rare: sore throat, fever; Labs: (s) anemia, increased BUN, creat, LFTs bilirubin; decreased potassium (with prolonged use), (u) increased vitamin C How Taken: Ensure adequate hydration, may require folic acid supplement. ZALCITABINE (Hivid, ddC) Antiviral Drug Interactions: Avoid drugs that may cause peripheral neuropathy. Hivid may potentiate the effects. Nutrition-related effects: None listed. How Taken: May be taken without regard to food or milk. ***** SEARCH TRIALS IN DEVELOPMENT In addition to the formal research projects described in "SEARCH Trials at a Glance," SEARCH Alliance physicians and the Medical Department have been busy examining the vast amounts of information on new therapeutics. The following treatments are being reviewed by SEARCH Alliance physicians and medical staff. If they pass the review process, they will become SEARCH trials. Check the next issue of this newsletter for an update. Convergent Combination Therapy: Background: Laboratory studies have demonstrated that a three drug combination of AZT, ddI, and nevirapine shows promise in eliminating replication of the virus in cell cultures through mutation of reverse transcriptase. Other nonnucleoside reverse transcriptase inhibitors, similar to nevirapine, are also being considered for trials. Numerous sites have been selected to begin a large scale, nationwide clinical trial this summer using nevirapine. However, it study will take six months to complete and another year to analyze the data. Currently, nine patients at the University of Alabama are on trial to test only the safety of this specific therapy, but not its effectiveness. Status: SEARCH Alliance is actively pursuing a trial that will test the safety and effectiveness of this therapy, and one that will produce results much more quickly than the national study. Work has already begun to organize the project so that we may move forward as quickly as possible when the drug becomes available. CMV Retinitis: Background: Cytomegalovirus (CMV) Retinitis is the most common opportunistic infection of the eye in patients with AIDS. Untreated, CMV retinitis typically will present itself unilaterally and spread to bilateral infection in approximately 81% of patients. Additionally, retinal damage occurs, eventually resulting in blindness once there is considerable optic nerve damage. Previous studies have demonstrated preliminary findings on the prevalence of CMV retinitis in small samples and have also proposed markers for screening AIDS patients with CMV. Status: SEARCH Alliance is investigating the logistics of a large community-based screening study to determine the prevalence of CMV retinitis and to develop an appropriate ophthalmologic profile for individuals with HIV/AIDS. Bitter Melon Extract MAP 30 : Background: Bitter melon (Momordica charantia) of the family Cucurbitaceae is a medicinal plant widely cultivated in many tropical and subtropical regions, and commonly available in the United States. The fruit and seed extracts of bitter melon have been reported to have antiviral, antitumor, and immunopotentiating properties. Status: Based upon information that has been received from the Division of AIDS at the National Institutes of Health, SEARCH Alliance will not be pursuing this therapy. The laboratory data was somewhat positive, however there are substantial problems with toxicity under prolonged use. Other Research under Review: SEARCH Alliance has been aggressively pursuing a variety of antivirals, immunomodulators, and other therapies in order to make a rapid assessment of them for their potential as clinical trials. In addition, we are examining Hyperbaric Oxygen Therapy, Swainsonine, and a drug that, once in the body, converts to glutathione. ***** AIDS in Women Continues to Increase -- May Pass Men Within the Decade By Laurie Shaker Irwin, Ph.D., Research Director New statistics on the incidence of AIDS in women confirms the growing number of cases in the United States, and predicts that by the year 2000 there will be more women than men infected with the disease. These statistics helped to define the discussion at the Third Quarterly WomenUs Medical Update held March 1st which focused on the urgency for prevention, protection from opportunistic infections, and access to medical care for women. However, the good news is that the death rate among both men and women is slowing down, indicating that people are living longer due to better treatment and prophylaxis. Although it is still unclear how many women have HIV because these statistics are not reportable to health authorities, women have become the fastest growing group of reported AIDS cases. According to the HIV/AIDS Surveillance Program (1/93), the number of women in Los Angeles who have been diagnosed with AIDS is 787, while the overall figure in the U.S. comes close to 25,000. THE STATISTICS ON WOMEN Dr. Sahdna Khalsa, of USC and the GLCSC HIV Health Care Center, pointed out that there is significant disparity between different ethnic groups and the rate of AIDS. Caucasian women, who make up 77% of the U.S. female population, constitute 24% of the AIDS diagnosed population. Among African American women, though, the ratio is dramatically different: they make up 12% of the U.S. female population, but represent 54% of women diagnosed with AIDS; the female Hispanic population represents 8% of the female population, and make up 21% of women with AIDS. Los Angeles offers an exception to these statistics: the number of AIDS cases in women is equal among Caucasian, African-American, and Hispanic women, with each group representing approximately 33%. The sources of infection for U.S. women varies among ethnic groups as well, as shown in the following chart. (Los Angeles statistics from January, 1993 are in italics.) %Caucasian %African-American %Hispanic Injection Drug Use45 (30) 50 (39) 46 (19) Heterosexual Contact 33 (31) 36 (34) 41 (36) Transfusion-Related 10 (22) 2 (7) 3 (20) There are approximately 1,500 women in the U.S. who fall under the category of RotherS in terms of source of infectionQmany women are likely to have contracted the disease through heterosexual contact, but are not able to define it as such when asked. To date, less than ten women nationwide are believed to have contracted the disease from other women, and though researchers have not noted a rise in cases in this category, it is important to point out that there is always a risk of transmission with intimate contact. The majority of the women represented here are in their 30s. Since there is a period of several years between contracting the virus and onset of opportunistic disease, it is likely that most became infected in their late teens or early 20s. These statistics are to be interpreted broadly, since a single episode of drug use could disqualify a woman from the category of heterosexual contact as the source of infection. This may produce misleading statistics and, in turn, skew priorities in the effort to prevent further infection. But even a conservative interpretation reveals that there is increased transmission through the Rreceptive intercourseS of heterosexual contact. It is therefore likely that in the AIDS infected community, women will outnumber men by the year 2000. OPPORTUNISTIC INFECTIONS Women are subject to many of the same diseases that strike men with AIDS (Although women are very unlikely to contract Kaposi's sarcoma). The percentages of the common opportunistic infections in women are as follows: Pneumocystis Carinii Pneumonia47.7% Esophageal Candidiasis 21.1% Wasting (Weight Loss) 21.0% Toxoplasmosis 6.1% HIV Encephalopathy5.8% Herpes Simplex 5.0% Cryptococcus4.1% Tuberculosis (Extrapulmonary) 3.9% Mycobacterium avium-intracellulare 3.7% CMV (cytomegalovirus) retinitis 2.6% There are a number of unique manifestations of HIV/AIDS in women. Vaginitis can be a chronic problem, as well as genital ulcers, which can be recurrent and severe, and must be monitored for care and potential infection. Pelvic Inflammatory Disease (PID) is also high in HIV infected women and may be a result of other infections or may occur as a serious unique complication of HIV. Some feel that endometriosis, a condition marked by the growth of tissue outside the uterus, may have more severe implications for women with HIVQbut there is no conclusive evidence to this effect. Endometriosis progresses very rapidly, and requires constant evaluation and monitoring. The relationship between HIV and breast cancer is still largely unknown, but it is strongly suggested that mammogram screening for breast cancer should start earlyQat the very least by age 35. By far the most serious manifestation of the disease in women is that of cervical cancer, which is related to the Human Papilloma Virus (HPV). This disease has only recently been added to the definition of AIDS, so no percentage figures are yet available. It is very important that a PAP smear (cells taken from the lining of the cervix) be done on a regular basisQpreferably every six months. It is also suggested that women with less than 200 CD4 cells should have regular colposcopy screenings and biopsies, because they are at a higher risk for pre-malignant changes. (Colposcopy is an examination used in conjunction with the PAP test to diagnose abnormalities of the cervix and vagina.) Khalsa added that GLCSC is conducting colposcopies every six months on their female patients. They will be looking at the data and coming up with new information and guidelines as trends emerge. The Centers for Disease Control (CDC), originally considered colposcopies to be cost-ineffective (a colposcopy costs $75- $150), but may reconsider their position on this issue. Because not all physicians are qualified to perform this office procedure, women are urged to inquire about the frequency with which their doctor performs the test, as well as the number of female patients that are seen in the office. This information can provide a good indication of the validity and reliability of colposcopies in a given office. FERTILITY AND CONTRACEPTION Fertility is not compromised in women with HIV, so some form of contraception is advised to guard against pregnancy as well as transmitting infection. Clearly, next to abstinence, condoms provide the best protection against both. Other forms of contraception include Norplant (an implant of progesterone that lasts 5 yrs.), Depo Provera (only recently approved as a method of birth control; this is an injection of progesterone that is effective for three months), oral contraceptives, and surgical sterilization. It is suspected that Depo Provera may compromise the immune system, although no formal studies have been conducted. Oral contraceptives are also an unknown in terms of their interaction with antivirals, but in any case they provide no protection against transmission of the disease. Use of the IUD is discouraged for women with HIV, because it is a conduit for ascending infection and an open invitation to PID infection. HIV does not appear to directly cause changes in the menstrual cycle itself, though disease manifestations of HIV including extreme weight loss can lead to amenorrhea (abnormal absence of menstruation). TRANSMISSION TO CHILDREN AND CHILDCARE ISSUES Many women are diagnosed during pregnancy, and their obstetricians are often the first to deal with them on the issues of HIV, and the particular concerns for the newborn. There is approximately a 30% risk of HIV transmission from mother to newborn; this risk factor may increase to 60% in women with less than 200 CD4 cells. Another consideration is the reality that the mother's own disease progression may lead to her death before her child grows up. In the U.S. alone, 50,000 children orphaned as a result of AIDS are anticipated by the mid-1990s, and 100,000 by the year 2000. These sobering projections indicate that a system receptive to the childcare concerns of parents and the needs of these children must be undertaken as soon as possible. This is another reason why early testing for the virus is strongly recommended, regardless of pregnancy. Free and anonymous testing at various Los Angeles County sites is being advocated by WomenSEARCH (please see article below). Special Thanks to Dr. Marki Knox, of the Women's Medical Group in Santa Monica; Dr. Sahdna Khalsa, of USC and the GLCSC HIV Health Care Center; Karyl Draper, R.N., M.S.W. of the GLCSC; and Christine Chandler, B.S.N, R.N.P. of the GLCSC and Planned Parenthood for their participation in this event, and to the Women's Advisory Board for its sponsorship. Thanks also to Dr. Stephen A. Schmones for valuable assistance with this article. Medical care for those women without insurance and whose CD4 count is above 200 is available at the West Hollywood HIV Clinic for Women, (310) 854-4301. Other articles recently published concerning women include the following: Proposed New AIDS Definition to Include Cervical CancerS by Henry Chang. SEARCHLIGHT, January/February, 1993; HIV in Women Increases While Services and Care Lag BehindS by Karyl Draper, Dina Rosen, and Constance Wynne. SEARCHLIGHT, January/February, 1993; HIV Disease in WomenS by Scott Wilson and Brenda Lein, Treatment Issues, Summer/Fall, 1992. ****** TUNING IN TO EARLY SIGNS With the availability of over the counter yeast treatments such as Monistat and Gyne-Lotrimin, many women may avoid the expense of an office visit when plagued by a recurring yeast infection. But according to Dr. Stephen Schmones, a Los Angeles OB-GYN in private practice, persistent yeast infections can be an early signal of HIV infection. Even if a woman does consult her physician with the problem, it may not be enough. RIf doctors were all alert to the symptoms of HIV in women, it would be okay to rely on an office visit,S he said. At times, the uninformed physician will only prescribe a stronger vaginal preparation or try an oral (systemic) treatment, and HIV infection may go undetected. RGet yourself an HIV antibody test,S he urged. RIf you find you are getting recurrent vaginal infections, see a doctor for a definitive microscopic diagnosis. The cause may be something other than yeastQfor example trichomonas, gardnerella, or chlamydiaQand an HIV blood test should be done to rule out that HIV is the underlying cause.S Schmones added that the problem may not be HIV, but it is better to know at the outset than later on down the line. With heightened awareness, he believes that it is okay to use over the counter products. RThe most important thing is to get tested,S Schmones advised, Rand take responsibility for your own health.S ***** NOTES AND EVENTS HIV Free Testing Centers for Women: Edelman Health Center (213) 464-7276 Roybal Comprehensive Health Clinic (213) 780-2288 Valley Community Clinic (818) 763-5963 South Bay Free Clinic (213) 376-3000 East Valley Community Health Clinic (818) 919-5724 Minority AIDS Project (213) 936-4949 Northeast Valley Health Corp. (818) 365-8086 Watts Health Foundation (213) 564-4331 The elegant Rex II Ristorante will host a cocktail reception for artist Stanley Weksler Casselman on May 16th from 6 to 9:00 pm, with a portion of the proceeds to be donated by the artist to SEARCH Alliance. Sixteen of Casselman's unique rear-illuminated paintings are on display in a private gallery at the restaurant, which is located at 617 South Olive Street in downtown Los Angeles. A $10.00 donation at the door is suggested. R.S.V.P. (213) 222-9650. The first international conference on HIV, AIDS and Chinese Medicine will take place at San Francisco State University on June 18-20 for practitioners of Traditional Chinese Medicine (TCM), Western physicians, nurses, persons with HIV, and caregivers from the AIDS community. The program features speakers, panels, round-tables and workshops led by leaders in the field. A special session will be held on Saturday evening, June 19th for the HIV community itself, to explain in nontechnical terms what TCM is, the state of the art in HIV treatment, and what TCM can do for them. A limited number of scholarships are available. For further information, call (415) 453-2130. The Sixth Annual conference on AIDS, Medicine & Miracles will spotlight RUnity in Diversity: Sharing Our Gifts,S and will be offered in Berkeley, California and Rhinebeck, New York. While the presenters at the two conferences differ, the spirit of Rbringing all we know to living long and living wellS will be the same. A wide array of panels, workshops and seminars are scheduled. The California conference is slated for July 8-11; the New York conference will take place September 23-26. A limited number of scholarships are available. For futher information, call (800) 875-8770. The newly opened Infectious Disease Care Center at the Country Villa South Nursing Center (CVSC) in Culver City is holding an open house on Thursday, May 13 from 4:00 to 7:00 pm. This new care center offers an alternative to acute care HIV/AIDS hospitalization, is staffed with skilled professionals and serves the Westside, South Bay, and greater Los Angeles area. For further information, call (310) 390-8049. The SEARCH Alliance Women and HIV survey, designed in cooperation with the Women's Advisory Board to build a profile of the fastest growing segment of the HIV-infected population, has been completed by over 60 participants. The results of the survey will be presented at the International AIDS Conference in Berlin this summer. If you are a woman living with HIV, or are involved with a group that would be interested in helping us collect this information, please contact Dr. Laurie Shaker Irwin at SEARCH Alliance, (213) 930-8820. This survey is also available in Spanish.. Safer Sex Workshops are offered by the West Hollywood HIV Clinic. A $5 donation is requested, however this may be waived for those who cannot afford it. Contact Karyl Draper at (310) 854-4301. The Women's Center also offers private and confidential group counseling on practices for Safer Sex. The four-hour session is $25. For further information, call (310) 246-0354. Searchlight is featured on the HIV/AIDS Info BBS, a free access, 24-hour electronic network for communication and exchange of HIV/AIDS information. The BBS number is (714) 248-2836. HIV Update is a cable television series produced by Physicians Association for AIDS Care (PAAC). In the metropolitan Los Angeles area, this community service broadcast is featured Saturdays at 1:00 p.m. on Century Cable Channel 3, and is coproduced by APLA. For further information and program schedules, call 1-800 243-3059. Please address submissions for this column to Susan Black at SEARCH Alliance, 7461 Beverly Blvd., Ste. 304, Los Angeles, CA 90036. FAX: (213) 934-3919. ***** FREE HIV TESTING PROGRAM LAUNCHED BY WOMENSEARCH by Susan Black, Assistant Editor In the six short months since its inception, WomenSEARCH has demonstrated its commitment to action with the realization of two significant projects. A free and anonymous HIV testing program for women has been implemented in Los Angeles, and three prime time network and cable television public service announcements (PSAs) that urge women to take advantage of this program have been produced. Hosting the PSAs is the acclaimed stage and film actress Elizabeth Perkins. From its inception, WomenSEARCH co-chairs Linda Berman and Stockton Briggle have emphasized women's awareness of HIV and the importance of getting tested as the first order of business. The promotion of the HIV testing program was kicked off at the first annual Women's Health Fair, held on March 27th in West Hollywood. Volunteers at the WomenSEARCH booth handed out information about testing, as well as a listing of test sites throughout the city. RIf we were able to convince even one woman to get tested, we will have succeeded,S said Berman of the day's event. (Please see RNotes and EventsS above for a listing of test sites.) A monumental accomplishment is the production and broadcast of the PSAs. Producer Mary Helfrich managed to arrange for all the film, post production, equipment, and editing facilities. A massive publicity effort has been organized by Catherine Olim and Susan Goldstein. The PSAs were premiered at the April 12th meeting of WomenSEARCH at Hollywood Community Hospital, 7:00 PM in the cafeteria. All future meetings will be held on the first Monday of every month in the 6th floor conference room. The April 12th meeting was one of WomenSEARCH's most important, according to Berman. RWomenSEARCH is now extremely active and moving quickly into many areas, and we need volunteers,S she said. The group will be organizing a movie benefit, and members are currently exploring several possible premiers. Also on the agenda is an educational program targeting highschools and colleges. RThe speakers we have encountered in the last six months have been very inspirational,S said Berman. RWe would like to find a way to implement their experiences into the school programs. Stockton Briggle pointed out that teenagers are one of the fastest growing groups of HIV infected patients. RThey need to hear the facts,S he said. RWe want to give them the information they need in a way in which they will listen and be responsive.S Anyone interested in joining WomenSEARCH and becoming a part of its fundraising and education efforts is strongly encouraged to attend the meeting. For further information, please contact Lynda Johnson (310) 282-0766 and Diane Robin (310) 657-7373. ***** SEARCH People With Personality, Humor, and Commitment, Volunteers Make A Difference by Susan Black, Assistant Editor This column continues to focus on the wide variety of people involved with SEARCH Alliance who contribute their time and energy and make an impact. The four people highlighted in this issue are only part of a core of volunteers that help keep the organization running. DUANE DOGGETT To say that Canadian born Duane Doggett has led a colorful life is an understatement. As a teacher of English to foreigners Duane spent a number of years abroad, living in places like London, Israel, Holland and Tokyo, and refining his own special teaching style. RI used to come to school in T-shirts and boxer shorts,S he said of his tenure in Tokyo. RI had to do something. Basically the class was full of bored housewives and businessmen.S Though his employers threatened to fire him on an almost daily basis, they couldn't ignore the fact that his classes were the most popular. Finally they lowered the dress code boom on our hero, who responded by accessorizing his requisite business suits with bright green high-top sneakers. Duane's dedication, along with his unique fashion sense, are valuable assets in the SEARCH Alliance office. Though the high-tops are long gone, he has proven to be an adept sprinter up and down the stairways of the city, helping to distribute Searchlight to its various destinations in town. When he's not lifting spirits in the office, Duane is putting pen to paper at homeQhe's in the process of writing not one but two books, both drawing on his experiences as a world traveller. No doubt, they will be next yearUs great summer read. DEANE LIND When Deane Lind says RSwartzwalde Kirschtorte!S he's not uttering expletives. It's his specialty, Black Forest Cherry Cake that he's talking about, and it's featured in a cookbook of family recipes he's compiling Rwith lots of dessertsQfor people who don't care about cholesterol.S Volunteers and staff at SEARCH Alliance can attest to the taste, having sampled a delicious array of Lind-style cookies and cinnamon rolls over the past year. Deane's contribution goes far beyond baked delicacies, though. He was initially attracted to SEARCH because of its small paid staff. RA lot of work was done by volunteers, so I felt my time would be well spent,S he said. He wasn't kidding. Deane's skills on the computer and his levelheaded sense of organization and persistent good humor have made him crucial to the office and a major asset to fundraising efforts and administration. Deane no doubt honed his stress-management skills in the ten years he spent as a buyer in the retail clothing business selling everything from menswear to surfwear. The cutthroat aspects of business helped Deane to clarify his priorities, and led him to community involvement and SEARCH Alliance. RThe people are the best part of SEARCH,S he said. RTheyUre here because they want to be, not because of a paycheck. It's a big switch from the regular nine-to-five.S JOSEPH VON TEICHERT Joseph von Teichert has worked everywhere, it seemsQfrom government jobs for the IRS and the Defense Logistics Agency, to the Pacific Design Center and the City of West Hollywood Department of Community Development. As a volunteer at SEARCH Alliance since its inception, he has discovered a passion for research that has changed the course of his life. He was initially attracted to SEARCH because he perceived a need in the HIV/AIDS community for a place where people share ideas, research, design protocols, and get things accomplished. Taking the fast track, cutting edge philosophy to heart, Joseph has spent much of his volunteer time in the medical library, unearthing the pros and cons of current experimental therapies as well as new information that he feels merits the attention of the Medical Department. His involvement with SEARCH Alliance has inspired him to go back to school and pursue a medical education. Last October, Joseph enrolled in the Institute of Computer Technology, where he is studying to become a lab assistant and EKG technician. It is yet another step in his continually evolving commitment to research. RThe community needs to stop waltzing around HIV and really support aggressive research,S he said. RWe have to beware of getting tied up in bureaucracy, and focus on getting things done.S TIM TRUEMAN Tim Trueman may consider himself Rjust your average, generic volunteer,S but he will have a hard time finding anyone at SEARCH Alliance to agree with that assessment. Few volunteers spend their time as Tim does travelling to various cities all over the United States, including Hawaii. A flight attendant for Continental Airlines for the past six years, Trueman devotes much of his off duty time to SEARCH Alliance answering phones and assisting on special projects such as the recent art auction. In addition to his regular job, Tim serves as the Los Angeles union representative for I.A.M. (International Association of Machinists and Aerospace Workers). With such a full load of responsibilities, there is little time left to pursue relaxing interests such as reading and throwing dinner parties for friendsQalthough working in the travel industry does allow him the opportunity to frequently visit favorite spots such as New England and the Bay Area, where he grew up. In the meantime, his work at SEARCH Alliance has become a fulfilling part of his busy life. RI feel a responsibility to give back to my community,S he said. RSEARCH Alliance is down-to-earth, not stuffy and regimented like other groups. The people who are involved in research are only as good as the people behind them, supporting themQand I want to help SEARCH fulfill its mission, which is to find a cure.S ***** FROM THE DESK OF THE EXECUTIVE DIRECTOR: THE STRENGTH OF A SYMBOL by Marcia R. Smith Since the beginning of time, man has identified himself through symbols of his tribe, religion, nationality, as well as those representing political and social beliefs. Most organizationsQfrom veteransU groups to childrenUs groupsQhave recognizable insignias. We identify our schools and teams by logos and colors all proudly worn in support. The symbols run the gamut from diamonds to paper poppies, tattoos, uniforms and bumper stickers, all displaying people's personal beliefs and loyalties. So why question the wearing of a red ribbon? I never heard an outcry against yellow ribbons to remember the hostages, or bracelets to show support of MIAs or POWs. Why then this recent rash of articles against red ribbons? Could it be that, once again, we are saying that AIDS is something to be ashamed of? That people who are HIV positive do not deserve our support? Criticism about the type of ribbonQjewelled or ceramic or whatever, seems entirely inappropriate. Do you really think that God cares if you wear a gold cross instead of a wooden one? Does Mary Smith's ruby ribbon make her more or less HIV positive than Mary JonesU satin one? The writers of recent articles challenge the wearing of ribbons as being trite and symbolic. Yes, they are symbolic: symbolic of the hundreds of thousands who have given their lives in the fight against AIDSQand symbolic of the millions more who are still waging the war. I, for one, will continue to wear my red ribbon, made of whatever, for as long as there is persecution of people living with HIV/AIDS, and until we find a cure. ***** Marcia Smith Leaves SEARCH Alliance Marcia R. Smith, who has served as Executive Director of SEARCH Alliance for the last two years, is leaving to take a new post as Development Director for the Shared Medical Research Foundation. During Smith's tenure at SEARCH Alliance, the organization evaluated many potential AIDS treatments, increased its fundraising ability, gained broad name recognition, expanded the number of local physicians involved in community based research, and began offering information on trials and treatment issues important to people with HIV by publishing Searchlight on a bimonthly basis. We at SEARCH Alliance thank Marcia for her significant contribution to our growth, and wish her the best of luck. SEARCH Alliance has begun an extensive search for a new Executive Director. SEARCH President Jim Weinstein will be running the day to day operations until a qualified candidate is found. ***** GLOSSARY BIOAVAILABILITY: measurable presence of a substance in its active form in the body. ENDPOINT: a research term used to indicate those clinical or laboratory assessments that will be used to evaluate the effectiveness of a drug or medication under study. GENOTYPE: the genetic constitution of an individual or group. immunopotentiating phenotype: the detectable expression of the interaction of genotype and environment constituting the visible characters of an organism. LIPOSOME: a spherical particle of fat or oil suspended inside a cell or in the bloodstream. NEPHROTOXICITY: toxic to the cells of the kidney. NUCLEOSIDE: combination of a sugar and a base (DNA and RNA are nucleosides). NUCLEOTIDE: combination of a sugar and a base, plus a phosphorous group. POLYPEPTIDE: a large number of amino acids (building blocks) linked together to form a protein. REVERSE TRANSCRIPTASE: an enzyme essential to retroviruses which copies the viral RNA into DNA. AZT and other nucleoside analogues apparently inhibit the reverse transcription process. VIRION: elementary virus particle. ***** TREATMENT BRIEFS By Henry E. Chang INTRAOCULAR ANTIVIRAL THERAPY FOR CMV RETINITIS Cytomegalovirus (CMV) retinitis is the most common opportunistic infection of the eye in individuals with AIDS. Current commercially available drugs for the treatment of CMV retinitis are ganciclovir (Cytovene), and foscarnet (Foscavir). While both drugs have been shown to be effective in delaying the progression of CMV retinitis following intravenous administration, nearly all patients experience progression of CMV retinitis while on a daily maintenance therapy. In addition, there are numerous problems associated with the use of ganciclovir and foscarnet, including the necessity of placing a central venous catheter in a person for long-term intravenous treatment. These drugs can be toxic and can cause side effects, including neutropenia (a decrease in a type of white blood cells) and nephrotoxicity (damage to the kidneys). Due to the problems associated with the intravenous administration of these medications, researchers have evaluated the safety and efficacy of intravitreal (directly into the eye) injections of ganciclovir. These studies indicate that intravitreal injections of ganciclovir are effective. At the 10th Annual AIDS Investigators' Meeting in March in San Francisco sponsored by the Universitywide AIDS Research Program, Dr. William R. Freeman of the University of California, San Diego, presented animal research data on the use of HPMPC as an antiviral agent against CMV retinitis (see RTreatment Briefs,SSearchlight, July/August 1992). In an animal model with viral retinitis of the eyes, HPMPC can be injected into the eye in high yet non-toxic doses. The half-life of HPMPC in the test tube when released from encapsulated liposomes is about 30 to 60 days. The data suggests that liposome encapsulated HPMPC may be used to control CMV retinitis with injections as infrequently as three times a year. The FDA has granted a physician-sponsored Investigational New Drug (IND) to Dr. Freeman for the local injection of HPMPC into the eyes of patients with CMV retinitis. For more information, call the UCSD Eye Clinic at (619) 543-5099. ANTISENSE OLIGONUCLEOTIDES Antisense oligonucleotides are synthetic fragments of genetic material that are designed to treat diseases by specifically inhibiting the production of proteins linked to a disease. Researchers at Hybridon, Inc. (Worcester, MA) working in conjunction with Dr. Robert Gallo, director of the National Cancer Institute Laboratory of Tumor Cell Biology, the Worcester Foundation for Experimental Biology, and the University of Massachusetts Medical Center, have developed an antisense oligonucleotide compound for the treatment of HIV infection called Gene Expression Modulation (GEM) 91. GEM 91 blocks the production of a viral protein that is necessary for HIV to replicate. According to Hybridon Vice President of Research A. Kirk Field, Ph.D., short-term cell culture data shows that GEM 91 can Rkeep the virus at bayIso that no infectious virus is being shed.S Given the high mutational rate of HIV, the company is exploring the use of GEM 91 in combination with other antiviral agents like AZT. Hybridon filed an investigational new drug application with the FDA in November 1992 and expects to begin clinical studies soon. Phase I trials will be conducted at the National Institutes of Allergy and Infectious Diseases to examine the safety and effectiveness of GEM 91 in individuals with AIDS. Another GEM 91 Phase I study sponsored by Hybridon will be conducted by a AIDS research group in France. BHAP COMPOUNDS Researchers at Upjohn Laboratories (Kalamazoo, Michigan) developed a number of non-nucleoside compounds (called BHA) with potent anti-HIV activities in the test tube. One of these compounds, U-90152, possesses excellent antiviral activity in HIV infected lymphocytes (white blood cells) grown in tissue culture. The inhibitory effect on viral growth by U-90152 is more dramatic than that of comparable non-nucleoside reverse transcriptase inhibitors (BI-RG-587, L-697, 661, and TIBO derivatives). Interestingly, the replication of AZT-resistant strains of HIV is also inhibited by U-90152, suggesting that U-90152 may be a good candidate for combination antiretroviral therapy. The safety and early efficacy profiles of U-90152 will be determined in two small Phase I studies. The Phase I study at the National Institutes of Health (NIH) will obtain safety data from 20 HIV-infected individuals with CD4 cell counts of 300 or less. Half of the study participants must be p24 antigen positive prior to study entry. Patients will be randomized into four treatment arms to receive: U-90152 alone; U-90152 plus AZT; U-90152 plus AZT plus ddI; or AZT plus ddI. The study is primarily aimed at defining the maximum tolerated dose of U- 90152. This study is expected to start in April 1993. Concurrently, Upjohn will conduct its own in-house Phase I safety study to compare U-90152 alone versus U-90152 in combination with AZT in HIV infected persons with CD4 cell counts of less than 500. PROTEASE INHIBITORS Protease is an enzyme essential to the replication of HIV. The function of protease is to cleave the gag/pol precursor proteins (part of the nuclear genetic material similar to tat) produced by HIV infected cells into essential viral components (such as p24 and reverse transcriptase). However, in the absence of protease function, the virus would essentially have a hollow core and the virions would be non-infectious. Researchers at Abbott Laboratories (Abbott Park, IL) and others designed a number of HIV protease inhibitors and studied these compounds both in vitro and in vivo. At a recent AIDS symposium sponsored by UCLA and UC Irvine in Palm Springs, California, Dr. David D. Ho of the Aaron Diamond AIDS Research Center in New York presented laboratory data on Abbott's protease inhibitor, A-77003. After treating HIV in the test tube (in the presence of increasing concentrations of A-77003) protease inhibitor resistant viruses were present. Given that A-77003 has resistance problems and poor absorption when taken orally, it is probably not going to go very far clinically. However, A-77003 serves as a template and will undergo chemical modification in order to increase its potency, enhance its bioavailability profile, and to avoid the resistance problem. To this end, a second generational compound (A-80987) has been synthesized by Abbott chemists and is more potent and easily absorbed when taken orally. A Phase I clinical study with A-80987 started in Amsterdam in February, 1993. A-80987 clinical trials are expected to start in the U. S. at the end of 1993. ***** SEARCH Alliance is looking for: CLINICAL TRIALS COORDINATOR (Nurse Practitioner or Physicians Assistant) To conduct clinical trials at SEARCH Alliance in our participation physiciansU offices. Research experience required. Please contact: Laurie Shaker Irwin, Ph.D. Research Director (213) 930-8820 FAX: (213) 934-3919 ***** SEARCH Alliance is always looking for volunteers to help in the office. If you can donate several hours a week on a consistant basis, please give us a call at (213) 930-8820. Searchlight is looking for a volunteer editorial assistant with writing/editing experience. If you are interested, please contact Susan Black at the above number. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display