[Electronic distribution for GENA by AEGIS/San Juan 714.248.2836] Volume 8 no. 4 Gay Men's Health Crisis: Treatment Issues > Cover letter > The ICC's New Combo Trials > Commentary: Another Day, Another Trial > The Torturous Development Path of Alpha-Thymosin > Delavirdine Enters Efficacy Trials > Highlights from the Fourth European Conference on AIDS >> New Diagnostic Techniques for Cytomegalovirus Infections >> Oral Ganciclovir To Prevent Cmv Retinitis Recurrence >> Famciclovir for Herpes Zoster >> Toxoplasmosis Suppression >> European Tuberculosis Studies >> Visceral Leishmaniasis >> Terbinafine for Nail Fungal Infections >> Aspergillus Infections Associated with Hospital Renovation >> Vitamin B12 and Folate Supplements >> Zinc and Opportunistic Infections >> Clotting Disorders in HIV-Positive Patients > Drug company watch >> SmithKline Blocks Investigation of AIDS Drug >> First Human Data on Effectiveness of Antisense Drugs >> First U.S. HIV Antisense Trial Starts >> Bristol Meets with Activists on d4T >> Viagene Begins New Gene Therapy Trial >> Lilly Leaves HIV Research >> Price Competition for Acyclovir (Zovirax) > Treatment Briefs >> Oral Ganciclovir Access Plan (Sort of) >> Hyperthermia Trial to Start >> Pentoxifylline: Disappointing Data and a Warning >> Hydrogen Peroxide Therapy >> Poppers and the Immune System >> New Drug Tested for Genital Warts >> Depression and HIV >> Correction ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ [Cover letter] Dear readers: Your subscription payments, renewals and generous contributions have enabled us to provide vital treatment information to people all over the world. It has made possible our advocacy work aimed at creating a more proficient and productive HIV/AIDS research effort. If you have not yet renewed your subscription or are able to make another donation, please complete the form below and return it to us in the enclosed envelope. Your continuing support means a great deal to us. We would like to take this occasion to bring you up to date on Treatment Issues and the work of the new Treatment Education and Advocacy Department at Gay Men's Health Crisis: GMHC has reorganized its treatment education program. In January of this year, Jeff Richardson, the Executive Director of GMHC, created a new Department of Treatment Education and Advocacy (TEA) in order to expand GMHC's impact on national and corporate HIV/AIDS research policy. TEA also will broaden GMHC's treatment education programs to ensure that people with AIDS and their care providers have access to the best information possible when making difficult treatment decisions. The new department is headed by David Barr, formerly of the GMHC Policy Department. We are committed to providing objective HIV treatment information and making Treatment Issues available to whomever needs it. Treatment Issues remains the centerpiece of GMHC's treatment information program. The newsletter neither accepts nor solicits money from drug companies or government agencies. Since we began publishing in 1987, everyone who has requested a subscription to Treatment Issues has received one regardless of his or her ability to pay. Our monthly circulation of over 20,000 includes individuals and organizations from all over the world - North and South America, Europe, Asia, Africa and Australia. Our articles are reprinted in hundreds of other community publications. We are planning more special editions of Treatment Issues. We published a 32-page special edition of TI devoted to "Alternative Therapies for HIV" as well as a special edition on the Concorde Study results concerning early intervention with AZT. In the coming year, we are projecting special editions devoted to "Current Standards of Care for HIV," "Therapies for Advanced HIV Disease" and a complete glossary for TI readers. We also are expanding Treatment Issues. Treatment Issues has been expanded in both size and frequency. We now publish monthly instead of nine times per year. We often publish 16 page editions in order to provide more information to our readers. Last year such features as Washington Watch, Drug Company Watch, the TI Interview, editorials, and commentaries all began making regular appearances in TI. We now are considering adding other columns that would make TI a more accessible publication. We are introducing a series of Treatment Issues fact sheets. This month we will publish the first set in a series of "Basic Fact Sheets" on HIV-related opportunistic infections. They will appear in both English and Spanish These fact sheets will present information in a simple, easy-to-read format. We also will be offering "In-Depth Fact Sheets" that enable readers to obtain all the information ever published in Treatment Issues on any specific HIV-related therapy or condition. These fact sheets will significantly improve our ability to respond to requests for information from the public. Our "Treatment Forums" series is providing the community with a wide range of up-to-date information. Over the last year we have put together a regular series of community treatment forums to increase awareness of state-of-the-art medical therapy and focus attention on promising areas of AIDS research. These forums have covered such topics as long-term survival, future directions in the treatment of Kaposi's sarcoma, alternative therapies for HIV, risk of HIV transmission through oral sex, reports from the IX International Conference on AIDS, and prevention of opportunistic infections. We have initiated regular treatment forums in Spanish, too. Both the English and Spanish forums are presented in collaboration with many other AIDS organizations, including the Community Research Initiative on AIDS, Treatment Action Group, Latino AIDS Treatment Issues Group, Latino Commission on AIDS, Elmhurst Hospital and Columbia University. Tapes and summaries of many of these forums are available to TI readers. Our Treatment Library continues to grow. The GMHC AIDS Treatment Library has enlarged its size and scope. It is now open to the public four days a week from 10 a.m. to 1 p.m. and provides Medline and AIDSline computer services, the latest medical journals, newsletters, reference materials and our comprehensive files on all medical aspects of HIV/AIDS. The library has received substantial donations from a number of publishing companies and has become a member of the prestigious METRO Medical Network made up of New York area hospital and university medical libraries. In an effort to use our resources even more effectively, we have reduced our printing and mailing costs substantially in the course of the past year. Nevertheless, your continuing support is essential to our expanding effort. Please take a moment of your time to send us a renewal or contribution with the form below. Note that, as always, all Treatment Issues subscription lists are kept strictly confidential. We do not even allow them to be part of the general GMHC mailing lists. Thank you in advance for your assistance. We would appreciate any comments you might have as to how we could better fulfill our goals. A business reply envelope is enclosed for your convenience. David Gold, Executive Editor ; Dave Gilden, Editor; Gabriel Torres, M.D., Medical Consultant; Paul Warren, Technical Coordinator [GMHC 129 W. 20th Street New York, NY 10011] ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The ICC's New Combo Trials by Derek Link The Inter-Company Collaboration for AIDS Drug Development (popularly known as the ICC), a private consortium that includes sixteen major drug companies involved in AIDS research, announced its "master protocol" for triple-drug combination therapy to a meeting of activists in New York on April 26. According to its chief architect and proponent, Dr. David Barry of the Burroughs Wellcome Company, the master protocol is designed to find a "home-run" triple drug combination that for 52 weeks restores CD4 cell levels back to an immunologically normal state (above 800 cells/mm3 of blood) and eliminates detectable viral replication. The study's sponsors do not plan to collect clinical data (such as symptoms and disease progression) on study participants. The plans for the trial were greeted with substantial criticism by the activists in New York, many of whom regarded the potential for finding a "home-run" treatment from any of the proposed combinations as negligible. The critics questioned whether the trials would produce meaningful data to clearly determine whether any of these combinations have a more modest benefit in treating HIV infection. Trial Design The protocol, designed as a pilot study, will enroll 100 asymptomatic patients with 200 to 500 CD4 cells and no prior HIV treatment in each study arm. The study will sequentially enroll patients. The first 100 patients will receive the first combination regimen, the next 100 patients will receive the second regimen, and so forth. The ICC initially will use two approved drugs and one unapproved drug to create the three-drug combinations. The ICC will begin with four triple-drug regimens, enrolling patients at "10 to 20" sites nationwide. Sites have not yet been selected, but accrual could begin sometime this summer. The four regimens selected for earliest evaluation are: Arm 1: AZT + ddC + Saquinavir (the Roche protease inhibitor) Arm 2: AZT + ddI + Nevirapine Arm 3: AZT + ddI + 3TC Arm 4: AZT + ddC + Nevirapine All drugs will be used at standard monotherapy doses. Dr. Barry anticipates that accrual into each regimen will take two to three months. If a "home-run" effect occurs, it could be noted as early as 26 weeks into the study because regular interim analyses are planned. Although the ICC hopes to score a home-run with this strategy, it recognizes that a less dramatic therapeutic effect may also occur. Thus a graded scale has been developed to record a range of therapeutic responses that fall short of a home run. Four types of response will be examined: immunological markers, HIV levels, adverse effects and emergence of drug-resistant HIV strains. Each of these areas will be graded. For immunological markers, a "Grade A" response is CD4 cells returning to normal (above 800) in 90 percent of patients. A "Grade D" response is no CD4 effect at all. Criticisms of the Trial Design The first criticism of this trial design concerns randomization, the process by which patients in a clinical trial are "randomly" assigned to different treatments. Randomization minimizes the differences among groups by equally distributing people with particular characteristics among all the arms. It also allows for certain statistical methods to be applied to the data. But the ICC master protocol is not randomized. The failure to randomize the study means that the data generated by it will lack both confidence and sophistication. It may be open to substantial bias if the different groups do not have equivalent characteristics that affect their response to therapy. Then too, the study has no "control arm" (e.g. a placebo or even a standard therapy regimen) against which the effect of triple-drug combination is compared. Instead, the master protocol will compare triple-drug combination to an historical control - i.e., surrogate marker data from similar patients in previous studies. Historical controls do have some advantages. Fewer patients are required for a study, resulting in easier recruitment. The trials also are much cheaper and simpler to conduct. Historical controls have some significant disadvantages, though. In the specific case of anti-HIV therapies, little is known about two-drug combination therapy in patients who have never before taken anti-HIV drugs. It is hard to imagine how the ICC can arbitrarily establish standard comparison data for this patient group. Not only are immunological markers, such as CD4 cell counts, open to considerable uncertainty for these people, but the effect of antiviral drugs on newer virological markers (like PCR or branched-chain DNA assay) has not been established. In general, trials utilizing historical controls tend to over-estimate the therapeutic effect of treatment. Uncontrolled studies generally yield a much higher percentage of positive results than controlled studies.[1,2] All criticisms of the trial are not scientific. Only "nucleoside analog naive" volunteers (no history of taking AZT, ddI, ddC, etc.) are eligible for the study, which raises a difficult issue. People who have faithfully followed government, industry and (in some cases) community recommendations that "it's never too early" to start nucleoside analog treatment now find that the presumed cutting edge of research is unavailable to them. Is this anyway to treat one's best customers? The most significant criticism of the trial is the drugs themselves. Three of the four regimens selected for initial investigation include only reverse transcriptase inhibitors, with the combination of AZT, ddI and 3TC being particularly dubious. Few virologists believe that a "home-run" is possible with a regimen that includes just reverse transcriptase inhibitors or even any of the drugs currently available. The trial appears in some respects to be a renamed repeat of the notorious "convergent combination therapy." The obvious, sad reality is that there are few new drugs to plug into the master protocol. This situation underscores the desperate need for new agents. Accordingly, the ICC must open up membership to the biotechnology industry, which is at the cutting-edge of drug discovery. Strengths of the Trial The master protocol has some important strengths that should not be overlooked. For treatment-naive asymptomatic patients, this trial represents a new option that some may find highly desirable. Despite the study design's scientific weaknesses, the protocol is probably adequate to detect a "home-run" treatment. A dramatic "cure," a treatment that brings patients back to normal and eliminates viral replication, is not difficult to observe. The problem, of course, is that treatments up to now have not shown such a dramatic, overwhelming effect. The ICC protocol is a good sign that the drug industry is serious about cooperation. By explicitly going after a home- run strategy, the industry also has taken an important step toward defining its role in clinical research of HIV disease. Up to this point, no research group (government, industry or academic) has so clearly defined its mission. One hopes that other organizations, particularly those that are publicly funded, will follow the ICC's example and clarify their own missions. And here's a final point not to be dismissed lightly: ICC members are spending their own money on these trials. 1 Sacks H, et al. American Journal of Medicine, 1982; 72(2):233-40. 2 Sacks H, et al. Archives of Internal Medicine, 1983; 143(4):753-5. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Commentary: Another Day, Another Trial by Dave Gilden and David Gold Low dose oral alpha interferon (LDAI) - including Kemron and similar products - attracted a great deal of attention almost five years ago when Davy Koech, M.D., of Kenya announced a stunning reversal of the AIDS disease process in patients who let lozenges containing the substance dissolve in their mouths. Dr. Koech also claimed a series of controversial "serodeconversions," in which HIV-positive patients became HIV antibody-negative after Kemron therapy. Not surprisingly, these results received widespread publicity, creating significant demand for oral alpha interferon at AIDS buyers clubs, and even a number of physicians began selling various oral alpha interferon products. In 1992, the National Institute of Allergy and Infectious Diseases (NIAID) reviewed thirteen different LDAI studies here and abroad. The Institute concluded, "The initial claims which have been made on behalf of Kemron ... have not been confirmed.... People with HIV infection will be best served if they receive treatments which have been shown efficacious in well controlled studies."[1] At the 1993 International Conference on AIDS, Elly Katabira, M.D., of Uganda announced the results of a 560-person placebo-controlled trial.[2] The study, which was sponsored by the World Health Organization, found no difference between Kemron and the placebo. There was no evidence of any effect on CD4 cells, viral load, disease progression, survival or "quality-of-life" indicators. Nevertheless, officials at NIAID, the division of the National Institutes of Health (NIH) that receives almost half of all U.S. government AIDS research dollars, are proceeding with plans for another large oral alpha interferon trial. Taking the lead in planning and funding the study is the Community Programs for Clinical Research on AIDS (CPCRA), a unit of NIAID. Why Another Trial? Even those planning the study do not believe that oral alpha interferon works. Dr. Lawrence Deyton, Director of the CPCRA, readily admits that "scientific evidence proves [the LDAI] products give no benefit in fighting HIV or in improving the immune system of persons with HIV infection."[3] Why then proceed with an expensive new test that only prolongs uncertainty over the substance? Dr. Deyton argues that continued community use of LDAI, particularly in the African- American community, requires yet more definitive testing of the substance. Why not just publicize the results of the WHO/Ugandan study then? "We accept the immunological and virological data from the WHO/Ugandan study," Deyton told Treatment Issues, "but the quality of life issues are clouded. The Ugandan people were very sick to start with." Additionally, deficient care may have obscured the results. The new LDAI trial will primarily investigate whether the therapy causes any reduction in clinical symptoms related to the HIV-associated decline in immunity. Small trials in Los Angeles and New York did find some slight symptomatic relief, mainly in terms of restored energy and weight. But with enough studies, some positive data will always appear, just from random variation. These results are specifically countered not by just the WHO/Ugandan study, but by a trial conducted through the Community Research Initiative of Toronto in 149 HIV-positive individuals,[4] in addition to all the other oral alpha interferon studies that found no significant effect from the drug. Most researchers do not believe that oral alpha interferon can have any effect because the interferon protein is broken down and rendered useless by fluids in the stomach. That is why all interferons approved for therapeutic use are injected subcutaneously (into the skin). The conjecture that alpha interferon directly affects immune cells in the mouth and sparks an improvement in immune system responsiveness remains highly speculative with no supporting data. Wasting Precious Dollars and Goodwill The new trial, which will enroll 800 people and compare three versions of LDAI, is to begin later this year. The cost of the study may be in the millions (not including the cost of NIAID staff time in planning and overseeing the trial). Dr. Deyton claims the cost will be less, but refused to be quoted on a specific figure. In addition, the smaller and more difficult a drug's benefit is to measure, the larger and more extensive a clinical trial must be to document that benefit. There is no reasonable assurance that this trial will prove large enough to show any quality-of-life benefits from the drug. Failure of this trial to document an effect from LDAI may only elicit calls for another, still larger trial. Besides consuming valuable research funds and staff time, the proposed trial will waste human resources. People who enroll in a clinical trial are contributing the most valuable thing they have - their bodies. It is unconscionable to enroll people in a clinical trial, particularly one sponsored by the U.S. government, when there is no reasonable evidence that the therapy being tested is of benefit. Individuals participating in this study may forego other therapeutic options, or render themselves ineligible for more appropriate clinical trials. They also may become further disenchanted with the clinical trial system when the false hopes played upon to draw them into the trial are dashed. Rather than improve relations between the scientific and African-American communities through this trial, as has been hoped, the gap between the two may only grow more insurmountable. Making Sense of Research Priorities Many observers, including The New York Times, report that LDAI is being kept alive by political pressure, especially from medical clinics connected with the Nation of Islam, which has helped popularize LDAI in the African-American community.[5] But LDAI has also received support from the National Medical Association, the well-established organization of African-American physicians in the United States. The chair of the LDAI protocol team, Lawrence Brown, M.D., of Brooklyn argues, "Things are not driven by pure science, there's politics on all sides: Who believes in what data? Look at all the effort put into AZT, and with such little yield." Dr. Brown is exactly right. Too much government funding has gone towards studying AZT and its sister drugs, ddI and ddC (although these drugs at least can reduce viral load and provide modest increases in CD4 levels - oral alpha interferon does neither). Let's not do the same with LDAI, while leaving promising experimental therapies and areas of basic virological and immunological research starved for funds. LDAI keeps reappearing precisely because the medical establishment has nothing really effective to offer people with HIV - especially those in disenfranchised and poor communities, who have the least access to care and promising therapies. The LDAI saga sums up much of what is wrong at NIAID: endless trials of mediocre drugs without any clear insight into what strategies could yield effective therapies and an all too pervasive acceptance of wasteful and redundant clinical studies. Let people take Kemron - if they want it. NIAID resources should be used for more productive lines of research. This is the first in a series of commentaries that will appear in Treatment Issues on AIDS research at the NIH. 1 National Institutes of Health. Interim Report: Low-dose oral interferon alpha as a therapy for human immunodeficiency virus infection (HIV-1): completed and on-going clinical trials. April 1992. 2 Katabira E, et al. IX International Conference on AIDS, 1993; abstract PO-B26-2056. 3 Deyton L. Letter to CPCRA Steering Committee. October 5, 1993. 4 Hulton, MR et al. Journal of Acquired Immune Deficiency Syndromes, 1992; 5(11):1084-90. 5 The New York Times. March 4, 1994. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The Torturous Development Path of Alpha-Thymosin by Dave Gilden and Jay Levin One of the great hurdles that any anti-HIV drug must overcome is the lack of a persistent immune response that combats HIV. A successful antiviral treatment will have to clear the virus from the body in the face of an increasingly dysfunctional immune system. A number of immune modulators have been tested in conjunction with anti-HIV drugs in an attempt to improve the immune response. Yet, results have been inconclusive and the side effects often severe. Recently, a small, unblinded Italian study reported that a substance known as alpha-thymosin (thymosin), when used in combination with alpha-interferon and AZT, provided more sustained increases in CD4 cells than AZT alone. Just announced results from another, larger study of thymosin suggest that the drug is not effective as a treatment for chronic hepatitis B, however. The question now is whether Alpha 1 Biomedicals, the small, underfunded biotech firm developing thymosin, has the resources to mount new, redesigned trials. Natural Thymic Hormones The thymus gland has been identified as a key immune system organ. It is thought to be responsible for the development and regulation of the immune system cells that mature in that organ (such "T-cells" as CD4 helper cells and CD8 cytotoxic cells). The thymus seems to exert its regulatory functions through the secretion of various hormone-like products called thymic peptides. Although the importance of thymic peptides remains in dispute, several investigators have reported that thymic peptide products can assist development of immature, precursor cells into fully competent T-cells. They also regulate the functioning of T-cells once they have matured. Alpha-thymosin is a thymic peptide that adjusts an individual's immune responsiveness when aberrations occur. Thymosin boosts the number of receptors on T-cells, especially for alpha-interferon and IL-2. It also increases the efficiency of T-cells' response to signaling agents and causes cells to produce more of them.[1] Intercellular signaling molecules ("cytokines") like alpha- interferon and IL-2 commonly have severe adverse effects. These agents are released during disease to help bolster the inflammatory response, which causes a variety of flu-like symptoms. Thymosin, in contrast, circulates in the blood at comparatively constant levels. In a series of clinical trials involving a total of nearly 1,000 people, no serious side effects have been noted.[1] Since thymosin promotes the action of alpha-interferon and IL-2, combining it with these products could allow lower dosages to be used, resulting in both greater safety and more efficacy. Thymosin in HIV This year, an Italian research group led by Enrico Garaci published encouraging results from a small trial comparing various combinations of thymosin, alpha-interferon and AZT in people with HIV.[2] The trial enrolled 40 HIV-positive men and women with CD4 cell counts of 200 to 500 per cubic milliliter of blood and without previous treatment for HIV infection. (The trial was randomized, but unblinded - everybody involved knew who was receiving which treatment.) Unfortunately, the dropout rate in this already small trial was high: by the end of twelve months, only 28 patients were available for evaluation, and by eighteen months only 23 remained. Trial volunteers were assigned to one of four groups. The first received 500mg of AZT twice daily. The second group received AZT plus two million units of natural human alpha- interferon twice weekly, and the third group received AZT plus 1mg thymosin subcutaneously twice weekly. The fourth group had the complete combination - AZT, thymosin and alpha-interferon. Over the first ten months, CD4 counts rose by an equivalent amount in the AZT plus interferon group and in the triple combination group. In the AZT only group and the AZT plus thymosin group, CD4 counts fell or were stable, respectively. But then CD4 counts in the AZT plus interferon group on average dropped back to baseline whereas the triple-drug people saw their CD4 counts continue to rise. At twelve months, the average increase amounted to 187 CD4 cells per cubic millimeter of blood. At eighteen months, the average increase was 237 CD4 cells while the counts for the other three treatment groups were close to the original, baseline averages. The small size and high drop-out rate of this trial make it difficult to have confidence in these results. Those who discontinued were not followed, and without this data, it is difficult to draw even tentative conclusions. Be that as it may, the Italian government subsequently funded a much larger, more definitive trial of the thymosin-interferon-AZT regimen. This 100-person study is now two-thirds enrolled. Investigators will present an update on this trial at the "Fourth International Conference on Combined Therapies," to take place next month in Sardinia, Italy. No confirmed data is available at present from this trial. The investigators hope to release preliminary data on the first six months of treatment by the end of the year. Measurements will include assays of CD4 and CD8 counts, HIV p24 antigen, beta2 microglobulin (an index of immune activation), HIV levels in the blood, and a lab test for immune cell proliferation response. Crucial clinical data on the rate of opportunistic infections also will be available. (A reduced rate of opportunistic infections would confirm that the improvements seen in laboratory tests, if any, actually have functional value in improving people's health.) A Disappointing U.S. Trial for HIV Thomas Merigan, M.D., the director of the Center for AIDS Research at Stanford University, has been conducting an initial study of thymosin combined with PEG IL-2 (IL-2 joined to polyethylene glycol for increased stability) and AZT. Dr. Merigan, who has studied IL-2 for some years with disappointing results, says, "Thymosin has had some interesting results in Italy and with hepatitis [see below]. The point of this trial is to see how thymosin boosts the effect of IL-2 in patients with 50 to 200 CD4 counts, where IL-2 just starts to have an effect." Merigan is following changes in trial participants' CD4 counts and HIV levels. The fourteen volunteers for this study started out on AZT alone (500mg per day) for eight weeks. Then they went on AZT plus IL-2 (one million units per square meter of body surface every other week) for another eight weeks. In the final twelve weeks, an escalating dose of thymosin was added. Merigan will not yet comment on the results of this trial, which enrolled its first volunteer a year ago. (The final analysis of the data will not be available until late summer, he says.) Several informed sources have told Treatment Issues, though, that the trial has not found any benefits from the triple combination regimen. Some suggest that the participants were not receiving thymosin long enough to make a difference or that, alternatively, since patients in the U.S. trial, who had more advanced disease than those in the Italian trial, may have been too sick for thymosin to have an effect. A final possibility is that thymosin plus IL-2 is just the wrong combination for fighting HIV. Discouraging Results with Hepatitis B In the United States, Alpha 1 Biomedicals has concentrated on developing the product for chronic hepatitis B, which affects at least 300 million people worldwide. Chronic hepatitis C is also under study. Of course, a safe treatment for chronic hepatitis would be of great interest to people with HIV, many of whom are co- infected with hepatitis B or hepatitis C. Progression of hepatitis disease may trigger progression of HIV or vice versa. Alpha-interferon, the only approved treatment for chronic hepatitis B, induces sustained disease remission in only 25 to 30 percent of those treated, and side effects often dictate stopping treatment. Data from a phase II study of chronic hepatitis B suggested that thymosin might be a significant advance.[3] Nine of the twelve of the "thymosin treated" volunteers responded favorably to treatment, and seven (58 percent) had a sustained remission with normal liver tests and negative hepatitis B antigen status after four years. However, recently announced results of a phase III, placebo controlled study indicate that thymosin was no better than placebo as a treatment for chronic hepatitis B. The 99 patients in the study received either thymosin or placebo for six months, with another six months of follow-up. After one year, eleven of the 49 people in the thymosin arm tested negative for hepatitis B virus DNA, compared to twelve of 50 people in the placebo arm. Unraveling the Contradictions The hepatitis B trial is extremely disappointing. The Italian group, meanwhile, is conducting a combined alpha-interferon plus thymosin study for hepatitis B and C in 30 people. Researchers are reporting high rates of remission, even in people who previously had not responded to interferon alone. Thymosin's main hope is now likely to be new trials using interferon and thymosin together. But Alpha 1 may not be financially able to mount more trials, let alone large, definitive ones. The day the recent hepatitis B results were announced, Alpha 1 Biomedicals' stock fell by two-thirds. The company has been further weakened by a dispute with the company's marketing licensee for outside North America and Europe, which is now before an arbitrator. That licensee, SciClone Pharmaceuticals, is demanding and may well get damages and greater rights to alpha-thymosin because Alpha 1 has not been able to provide the drug due to a breakdown in the manufacturing agreement with a Belgian company. The damage award alone could bankrupt cash-starved Alpha 1. SciClone is moving aggressively to sell thymosin in Asia, which has an enormous population of hepatitis B carriers. (Thymosin is already approved in Singapore.) The day Alpha 1's stock price fell, SciClone bought 15 percent of the shares, making it Alpha 1's largest shareholder. This only adds to the uncertainty concerning alpha-thymosin's future development. Meanwhile, Alpha 1's Italian licensee, Sclavo, has been caught up in Italy's general financial scandal, and progress in bringing thymosin to market in Italy (where it is approved as a vaccine additive) has been retarded. Because of these difficulties, thymosin is not available outside of clinical trials anywhere in the world, although Italian supplies are expected to exist eventually. Thymosin may soon appear in the U.S. underground market, too, but wide availability awaits future positive trial data. Lacking quick, convincing results from the Italian HIV trials, funding will be a serious problem. Despite the problematic aspects of past thymosin trials, some believe that the drug merits further scientific attention. The Los Angeles-based Search Alliance wants to conduct a rigorous study combining AZT, alpha-interferon and alpha- thymosin in HIV-positive individuals. Chuck Chesson, Search Alliance's clinical trial coordinator, says, "Thymosin results have been interesting. The question has to be answered - people need to know whether thymosin works or not." Although Search Alliance is a community organization, the total cost of this medium-size trial still will amount to $200,000, not counting the cost of the medicine. Encouraging findings from this economical option (or the current Italian government funded HIV study) may offer thymosin its only chance for garnering the grassroots and financial support. Without that support, its continued development is questionable, regardless of the compound's value. 1 Goldstein, A. personal communication, April 24, 1994. 2 Garaci E, et al. International Journal of Clinical and Laboratory Research, 1994; 24(1):23-8. 3 Mutchnick MG, et al. In: Graci E and Goldstein AL. Combined Therapy: Biological Response Modifiers in the Treatment of Cancer and Infectious Diseases, 1992; Plenum Press. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Delavirdine Enters Efficacy Trials by Gabriel Torres, M.D. Delavirdine (also known as U-90152) is a new anti-HIV drug manufactured by Upjohn Company. It belongs to the class of compounds called non-nucleoside reverse transcriptase inhibitors (NNRTIs). These compounds block HIV replication by inhibiting the same enzyme, reverse transcriptase, that is blocked by nucleoside analogs like AZT, ddI, ddC and d4T. NNRTIs strongly protect uninfected cells from HIV, but they have been plagued by HIV's ability to rapidly develop resistance to them. It is hoped that delavirdine, when combined with other drugs such as AZT, ddI, other NNRTIs, or protease inhibitors, can slow down emergence of viral resistance. Precisely because of this resistance, delavirdine is unlikely to be effective as a single agent. Combining the drug with additional antiviral agents, though, might so reduce HIV replication that resistance to any of the components in the combined regimen will take much longer to evolve. Also, the development of resistance to delavirdine seems to increase HIV's sensitivity to other NNRTIs. Delavirdine's long-term side effects still need to be evaluated, as does its activity during pregnancy. The influence of the drug on fetal development and its ability to reduce mother-to-child HIV transmission remain unknown. Laboratory Studies In the test tube, very low concentrations of delavirdine can totally stop HIV-1 from infecting new cells and causing cell death. It is also more potent than AZT and is effective against AZT- and ddI-resistant strains of HIV in the laboratory.[1] In AZT- or ddI-sensitive strains, delavirdine has been found to be synergistic with AZT or ddI (the effect of the combined treatment is greater than the sum of the individual drugs' effects).[2] The compound is synergistic with the first version (now canceled) of Upjohn's protease inhibitor, too.[3] Delavirdine can also reduce the formation of syncytia (clumping of cells which leads to rapid T cell destruction).[1] Unfortunately, when delavirdine is introduced to HIV-infected cell cultures, viral strains that are ten- to 100-fold less sensitive to the drug emerge. This drug resistance is triggered by single changes (or point mutations) in the amino acid sequence of the reverse transcriptase enzyme. One such mutation (at amino acid number 236) causes high-level resistance to delavirdine but sensitizes the virus to other NNRTIs such as nevirapine, TIBO compounds and Merck & Co.'s L-drug (L-697). Yet, it does not change sensitivity to nucleoside analogs such as AZT and ddC.[4] Animal Studies Animal studies using delavirdine have focused on determining its toxicities and adverse effects. The lowest dose in animals in which notable toxicity has been observed is 50mg per kilogram of body weight per day. This dose produced inflammation of blood vessels (vasculitis) in dogs over a two week period. Higher doses caused gastrointestinal ulcerations, bone marrow toxicity and lung inflammation. The drug also led to birth defects in pregnant rats at extremely high doses. Since the drug is so potent, there is a wide margin of safety - low doses can be effective in achieving levels in the body that inhibit the virus. Phase I Human Studies Two clinical studies in normal healthy male volunteers have been completed. These placebo-controlled studies showed that the drug was tolerated in single doses of up to 300mg and multiple doses of up to 100mg four times daily without side effects; headache occurred frequently in both the delavirdine and placebo groups. Two multiple-dose safety, tolerance, and pharmacokinetic studies in 87 HIV-positive volunteers have been completed. It appears that the drug is well tolerated when given orally in amounts up to 400mg three times daily in combination with AZT and up to 300mg four times daily in combination with AZT and ddI. The most frequent side effect is a rash that appears after one week on the drug. The rash occurred in 27 percent of patients who took delavirdine in combination with AZT and in 38 percent of those who took it in combination with AZT and ddI. Most patients were subsequently rechallenged with a lower dose once the rash had resolved. They were able to tolerate their original assigned doses after two weeks on the lower dose. Increases in liver function tests occurred in two patients and resolved after all antiretroviral agents were discontinued. A new crystal form of delavirdine has also been developed by Upjohn that seems to be more heat-stable. The new form is being used for the large scale clinical trials initiated this spring. New Delavirdine Clinical Trials Upjohn is launching three new clinical trials of delavirdine in multiple centers throughout the United States. The first trial is a double-blind randomized study of three doses of delavirdine in combination with AZT versus AZT alone. The trial will measure delavirdine's efficacy based on changes in HIV viral load, CD4 cell counts, and disease progression. HIV-positive persons with CD4 cell counts of 200 to 500 who have had less than six months of prior AZT therapy are eligible for this two-year trial. According to trial plans, 1,200 to 1,500 participants will be enrolled. It is hoped that women will make up 20 percent of the participants. The delavirdine doses used will be 200, 300 or 400mg three times daily in combination with AZT at 200mg three times daily. The addition of ddI will be allowed in all treatment groups if a study participant experiences a fall in CD4 count to below 50 percent of baseline on two consecutive occasions or develops an AIDS-defining illness. The study will exclude persons with previous ddI, ddC, 3TC or d4T therapy, patients unable to take AZT, and those who have received therapeutic vaccines. The use of drugs that can interact with delavirdine and lower its blood levels will not be allowed within 21 days of study entry. These include a large number of drugs used to treat opportunistic infections and other conditions, including ketoconazole, fluconazole and itraconazole for fungi; isoniazid and rifampin for tuberculosis, rifabutin for mycobacterium avium complex (MAC); and astemizole and loratadine, which are anti- histamines. A second parallel study will compare delavirdine in combination with didanosine (ddI) versus ddI alone. This trial will follow people with HIV who have CD4 counts less than 300 and previous experience on AZT but less than four months on ddI. Plans are to enroll between 800 and 950 patients for a two-year time period. This study, too, will exclude patients with prior ddC, d4T or NNRTI therapy. There is some concern that such people will develop HIV strains resistant to ddI in addition to ddC. This will be a problem for those in the ddI-only arm. The trial also will exclude patients requiring therapy with rifampin, rifabutin or the anti-histamine terfenadine (seldane). Both studies will compare the emergence of drug-resistant HIV in patients on the delavirdine combinations versus those on nucleoside analog monotherapy. One interesting aspect of these studies is that they will also measure the cost- effectiveness and quality of life effects of adding delavirdine to AZT or ddI monotherapy. Finally, a third study is being conducted by Upjohn for patients who have participated in previous delavirdine studies. It will evaluate and compare the use of delavirdine in triple combination with ddI and AZT or ddC and AZT. This third trial is expected to enroll over 4,000 people. For information on the delavirdine trials contact 800/TRIALS- A. A number of trial sites will be located in the New York area at various sites, including the Community Research Initiative on AIDS (contact Bette Smith at 212/924-3934), St. Vincent's Hospital (contact Daisy Soto, R.N., 212/604-8920), Beth Israel Medical Center (contact Carsandra Sanders, P.A., at 212/420-4519), Mt. Sinai Medical Center (contact Eileen Chusid, Ph.D., at 212/241-3933). 1 Dueweke TJ, et al. Antimicrobial Agents and Chemotherapy, 1993; 37(5): 1127-31. 2 Chong KT, et al. Ninth International Conference on AIDS, 1993; abstract PO-A25-0606. 3 Chong KT, et al. Ninth International Conference on AIDS, 1993; abstract PO-A25-0557. 4 Dueweke TJ, et al. Proceedings of the National Academy of Science USA, 1993; 90(10):4713-7. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Highlights from the Fourth European Conference on AIDS by Gabriel Torres, M.D. The Fourth European Conference on Clinical Aspects and Treatment of HIV Infection was held in Milan, Italy on March 16-18, 1994 and was attended by over 2,000 delegates from Europe and the United States. The conference focused on clinical issues in the management of HIV infection and its complications rather than on basic or social sciences or epidemiology. Last month we highlighted conference reports on anti-HIV therapy. This month we give an account of the presentations concerning AIDS-related opportunistic infections. New Diagnostic Techniques for Cytomegalovirus Infections Various studies presented new methods for diagnosing CMV infections, especially those of the central nervous system. In one Swedish study,[1] 148 patients with encephalopathy had their cerebrospinal fluid examined with PCR for detection of viral genome (DNA). Diagnoses of herpes simplex, varicella zoster, Epstein Barr virus, JC virus (which causes PML) and CMV were made using this PCR technique in 39 to 42 percent of patients. One presentation[2] showed how CMV encephalitis could be diagnosed by detection of CMV DNA by in-situ hybridization from cerebrospinal fluid and cells. Another technique used by an Italian group[3] utilized a CMV pp65 antigen test as a blood or cerebrospinal fluid marker of active CMV infection in HIV- positive patients with painful peripheral neuropathy. The development of these new diagnostic tests for CMV is crucial in making a prompt diagnosis of CMV encephalitis or neuropathy, which would otherwise require a brain or nerve biopsy. Oral Ganciclovir To Prevent Cmv Retinitis Recurrence A multicenter European-Australian study reported data comparing the use of oral and intravenous ganciclovir in preventing the recurrence of CMV retinitis.[4] Following induction with intravenous ganciclovir for two to three weeks, 159 patients were randomized to receive either oral ganciclovir (3 grams per day) or intravenous ganciclovir (5mg per kilogram of body weight once daily). Using photographic (fundoscopic) evaluation, the mean time to progression was 109 days for the intravenous group and 86 days for the oral group. These results are not too different from those of the trials in the United States and confirm that the oral drug is almost as effective in delaying disease progression as the intravenous drug. It is certainly less toxic. Famciclovir for Herpes Zoster A randomized placebo-controlled study found that famciclovir,[5] a new potent oral anti-herpes drug, was effective in the treatment of herpes zoster (shingles). Two doses of famciclovir (500 and 750mg) showed comparable efficacy and superiority over placebo in reducing the duration of virus recovery from zoster lesions as well as time to healing of lesions. A significant decrease in the duration of pain was detected for famciclovir-treated patients with severe rashes. The drug was well tolerated and had minimal side effects. A poster presentation reported that famciclovir also reduced the duration of post-herpetic neuralgia (pain which develops after the shingles have healed) from 128 days to 55 to 62 days.[6] Toxoplasmosis Suppression A randomized trial conducted by the ENTA Toxoplasmosis study group in France and Belgium[7] showed that the combination of pyrimethamine and clindamycin is clearly less effective for long term suppression of toxoplasmosis than the combination of sulfadiazine and pyrimethamine. Of 175 patients who had completed acute therapy for toxoplasmic encephalitis and who were randomized to one of the two suppressive regimens, 28 percent relapsed on the clindamycin group compared to 7 percent in the sulfadiazine group. A quarter of patients in each group had to discontinue therapy because of adverse effects, most commonly rashes in the sulfadiazine group and diarrhea in the clindamycin group. Other options for suppressive therapy of toxoplasmosis include atovaquone alone or in combination with pyrimethamine, azithromycin or rifabutin. European Tuberculosis Studies A multicenter European study[8] testing a three-drug against a four-drug regimen for the treatment of tuberculosis in HIV- infected patients was reported by a large consortium of researchers. The treatment regimen included isoniazid, rifampin, pyrazinamide with or without ethambutol. Of the 611 patients under study, 475 had TB confirmed by culture. The treatment failure rate was similar in both groups, as was overall mortality. The level of TB resistance to more than one drug was low (6 percent). In this population of TB patients with low levels of drug resistance, the addition of ethambutol did not seem to be justified. A Spanish tuberculosis study[9] described an outbreak of hospital acquired, multidrug resistant tuberculosis (MDRTB) at a facility in Madrid. Twenty cases of MDRTB were diagnosed between December 1992 and October 1993. The majority (85 percent) of the patients died, 53 percent within the first month of diagnosis. In a Rome hospital, 31 percent of the cases of TB were resistant to at least one drug.[10] Drug resistance was more common among patients with TB who had received previous anti- TB therapy and had been noncompliant. A blood test measuring adenosine deaminase (ADA) is being studied in Spain[11] for rapid diagnosis of tuberculosis and may prove useful in cases where there is a need to make an immediate treatment decision. Other rapid TB tests include PCR, the tuberculostearic acid assay and the luciferase gene detection method. Visceral Leishmaniasis A relatively uncommon opportunistic infection in the United States was described by groups from three European countries (France, Spain and Italy). The disease, visceral leishmaniasis,[12] is caused by the Leishmania infantum protozoan which disseminates throughout the body and leads to high fever, liver and spleen enlargement and bone marrow disorders (leading to low red blood cell, neutrophil and platelet counts). The disease responds poorly to amphotericin, pentamidine or antimony drugs such as meglumine. Patients often relapse and the average survival is only 10.6 months. Resistance to meglumine was reported by one group of researchers in patients who had received several courses of the drug.[13] Immigrants from these European countries, as well as from Asia and South America who present with these symptoms should be evaluated for visceral leishmaniasis since it can be rapidly fatal if untreated. Terbinafine for Nail Fungal Infections Toe nail fungal infections are very common in HIV-positive persons and may be the first sign of an impaired immune system. A British group reported that five of fifteen HIV- positive patients with nail fungal infections caused by Tinea rubrum were successfully treated with a new antifungal drug called terbinafine.[14] Terbinafine is an allylamine antifungal agent that in the trial was given once daily at a dose of 250mg for twelve weeks. The five patients who were cured did not relapse after 48 weeks of follow-up. But terbinafine was not effective in the treatment of oral thrush in another study reported at the conference.[15] Aspergillus Infections Associated with Hospital Renovation A cluster of thirteen cases of an invasive fungal infection called aspergillosis was reported by a group of Italian investigators.[16] The cases were associated with exposure of patients to the fungal spores in a hospital ward undergoing reconstruction. The cluster confirms the dangers of hospital acquired infections for AIDS patients during construction or renovation, which may release fungi such as Aspergillus fumigatus into the air. Vitamin B12 and Folate Supplements A group from Spain studied 75 patients with CD4 cell counts under 500 who were randomized to receive AZT (500mg per day) alone or in combination with folate (15mg per day) and vitamin B12 (1,000 micrograms per month, injected intramuscularly).[17] The study attempted to determine whether the vitamin supplements prevented AZT-related suppression of blood cell production in the bone marrow. After one year of follow-up, there were no differences in the hemoglobin, hematocrit, white blood cell, neutrophil or platelet counts between the two groups. The researchers concluded that these vitamins were not effective in preventing AZT-related hematological effects. Other studies have reported a beneficial effect of vitamin B12 in HIV-related peripheral neuropathy. Zinc and Opportunistic Infections A poster presentation reported on the use of zinc sulfate supplementation as preventive of opportunistic infections.[18] Thirty volunteers received 200mg of the supplement a day in combination with AZT and were compared to a group of eleven patients who received AZT alone. The frequency of opportunistic infections in the next two years was reduced in the group who received the zinc supplementation (nine infections versus 26 in the control group). The opportunistic infections in which zinc may have played a role included PCP, toxoplasmosis, cryptococcus, salmonella and tuberculosis; no effects were seen for CMV and esophageal candidiasis. Clotting Disorders in HIV-Positive Patients A French group reported 35 episodes of unprovoked thromboses (clots) among twenty patients in three hospitals.[19] Nineteen of the clots were in the deep leg veins, fourteen in the pulmonary vessels and two in cerebral vessels, leading to strokes. A deficiency of free protein S had been noted in a previous study of HIV-positive patients, and was recorded in six of eight of the patients who developed clots and had levels of Protein S measured. Protein S is involved in preventing spontaneous formation of clots, and a deficiency predisposes to thrombotic (clotting) episodes. It is unclear why some HIV-positive persons have protein S deficiency and are consequently at higher risk of unprovoked thrombotic episodes. 1 Cinque P, et al. abstract O20. Fourth European Conference on Clinical Aspects and Treatment of HIV Infecton, 1994. 2 Manicardi G, et al. abstract P138. 3 Volpi A, et al. abstract P137. 4 Knopse V, et al. abstract O21. 5 Tyring S, et al. abstract O24. 6 Tyring S, et al. abstract P159. 7 de Wit S, et al.; abstract P192. 8 European Tuberculosis Study Group. abstract O54. 9 Moreno V, et al. abstract 355. 10 Palmieri F, et al. abstract 356. 11 Fern ndez-Gonz lez F, et al. abstract 360. 12 Rosenthal E, et al. abstract O27. 13 Gambarelli F, et al. abstract O28. 14 Nandwani R, et al. abstract P233. 15 Cartledge JD, et al. abstract O31. 16 Libanore M, et al. abstract P234. 17 Falguera M, et al. abstract P264. 18 Mocchegiani E, et al. abstract 306. 19 Pulik M, et al. abstract O62. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Drug company watch by David Gold and Dave Gilden SmithKline Blocks Investigation of AIDS Drug Alan Pardee, M.D., and his group at Harvard University's Dana-Farber Institute has found that the experimental anticancer drug topotecan is also a potent inhibitor in the test tube of HIV replication. General rights to topotecan are owned by its manufacturer, SmithKline Beecham, but Dana- Farber proceeded to file a use patent for HIV applications. SmithKline in response has stopped supplying topotecan for any HIV experimentation and refuses to negotiate any payment to Dana-Farber. One prominent researcher is said to have been ready to begin a trial using topotecan in HIV-positive people with lymphoma, but SmithKline delayed it at the last moment. The company reportedly now insists that all future topotecan trials for whatever purpose exclude anyone who tests HIV- positive. First Human Data on Effectiveness of Antisense Drugs Isis Pharmaceuticals of San Diego is reporting encouraging preliminary data on its antisense compound aimed at CMV, blocking a gene necessary for the virus's reproduction. The drug, ISIS 2922, is injected weekly into the patients' eyes to arrest CMV retinitis. CMV-associated retinal lesions resolved (leaving inactive patches) in all five members of the ISIS 2922 trial's high-dose arm. The same happened to two of three volunteers receiving the medium dose. There have been no relapses so far in up to four months of treatment. All these patients had failed or become intolerant of the standard CMV therapies, ganciclovir and foscarnet. Despite these positive results (which were publicized by the company's PR department), Isis insists that it is premature to begin a compassionate use program for people outside of the Isis trials who are doing poorly on the approved CMV retinitis medications. First U.S. HIV Antisense Trial Starts Hybridon, a Worcester, Massachusetts based biotechnology company, received FDA approval to test its antisense product, GEM-91, which disrupts a sequence on the HIV gag gene essential for constructing the core of new virus particles. Trials are to begin by the end of April at the University of Alabama and will include six HIV-positive patients. Michael Saag is the principal investigator. GEM-91 is administered intravenously. The drug has been studied in 23 patients in France without side effects. However, in primates, serious cardiovascular side effects were seen. In test tubes, GEM-91 inhibits HIV replication. Bristol Meets with Activists on d4T Officials from Bristol-Myers Squibb met with activists to discuss the company's new drug application for d4T. Bristol officials suggested that the company's AIDS drug development program would be negatively affected if community representatives did not support FDA approval of the drug. By the end of the year, the company will release results from a trial comparing d4T and AZT in 813 patients with at least six months of previous AZT therapy. Bristol also is commencing a d4T/ddI combination trial, even though the combination enhances the risk of peripheral neuropathy. Viagene Begins New Gene Therapy Trial A 20-person trial of Viagene's HIV gene therapy product has begun in HIV-infected individuals with CD4 counts between 200 and 500 at the University of California San Diego. Participants will receive three injections over six weeks. The injections contain the participants' own cells genetically altered to express HIV protein on their surfaces. It is hoped these cells will stimulate immune system cytotoxic "killer cells" to attack HIV-containing cells. An ongoing study is following the therapy in HIV-positive patients with over 500 CD4 cells. Green Cross, a Japanese company has agreed to continue funding development of this immune therapy through 1996. Lilly Leaves HIV Research The Eli Lilly Corporation has announced that it is discontinuing its HIV research. The company is in the midst of restructuring its clinical program. Lilly had worked with Agouron in developing the company's protease inhibitor. Price Competition for Acyclovir (Zovirax) SmithKline's famciclovir received approval as a treatment for shingles (herpes zoster) in England. The drug is priced about eight percent less than acyclovir. Most people expect that the U.S. will approve famciclovir in the near future. Approval will mean greater price competition for zovirax, it is hoped. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Treatment Briefs by David Gold Oral Ganciclovir Access Plan (Sort of) The Syntex Corp. of Palo Alto, California has announced a program to make oral ganciclovir available to PWAs with CMV who are unable to receive ganciclovir through central catheter due to catheter infections or thrombosis (clotting of veins). Physicians should call 800/569-4630. Activists criticized the open label program because of the amount of time it took to develop and, more importantly, because it requires that patients must have a history of having a catheter removed two or more times due to catheter infection or thrombosis within the six months prior to enrollment. Kevin Frost of ACT UP and TAG called the program "laughable." Syntex plans to meet with community representatives to "discuss these issues." Hyperthermia Trial to Start The FDA has allowed a six-patient trial of hyperthermia as a treatment for Kaposi's sarcoma in people with AIDS. Dr. Kenneth Alonso, who conducted hyperthermia on a number of patients, will be overseeing the trial. Dr. Alonso's hyperthermia procedure involves withdrawing blood from the patient, then heating it to 110 degrees Fahrenheit and returning the blood to the patient. Hyperthermia attracted widespread attention in 1990 when a few patients with AIDS claimed a "remission" after undergoing the procedure. Some individuals were reportedly charged upwards of $30,000 for the treatment. At the time, the National Institutes of Health stated that it found no benefit to hyperthermia therapy. Concerns about hyperthermia include the fact that a significant number of patients died from the procedure (seven percent in one trial) as well as the procedure's high price. In addition, it is unlikely that removing blood and "treating" it will affect the lymph system, where much of the early HIV replication occurs. Nevertheless, Biocontrol, a Pittsburgh-based company, is developing the hyperthermia procedure. The company claims that "favorable results" were seen from the hyperthermia procedure on KS patients. In what is no doubt a bit of an understatement, Senator Frank Lautenberg (D-New Jersey), who pushed the FDA to allow the trial to proceed, suggested "we are far from announcing a cure for AIDS." Pentoxifylline: Disappointing Data and a Warning Pentoxifylline (also called trental) is an approved treatment for a circulation disorder caused by a narrowing of the arteries. The drug is also being used by HIV-infected people based on preliminary data that suggests it reduces tumor necrosis factor (TNF), an immune system protein that may increase HIV replication and contribute to wasting syndrome. However, a three week study by researchers from the Veteran's Administration Medical Center in Palo Alto, California reported that pentoxifylline produced no immediate benefits in terms of CD4 counts, viral load or clinical status (May 1994; Journal of AIDS; 7:5(5)19-20). In addition, significant side effects were seen at the dose given (2,400mg per day). Of nine HIV-positive patients (CD4 count less than 400) given the drug, one patient had to be reduced to 1,200mg per day and three others could not tolerate the drug at either dose. Reported side effects included fevers, gastrointestinal upset, headaches, and nausea. No antiretroviral therapy (AZT, ddI or ddC) was given. The six remaining patients were followed for three weeks of therapy. Viral load (as measured by HIV plasma RNA and p24 antigen) did not change in five of six patients. In addition, no overall effects on TNF levels were seen. In a reply to the published results, Dr. Bruce Dezube, a researcher from Beth Israel Hospital in Boston who has done extensive studies of pentoxifylline, noted that antiretroviral therapy such as AZT was not included in the study regimen. Dr. Dezube believes that if pentoxifylline is to play a role in the overall treatment of HIV disease, it will be in combination with an antiretroviral agent. The VA study comes on the heels of a request by the BGA, Germany's drug regulatory agency, that doctors report any changes in the retina in patients treated with pentoxifylline. According to Scrip, a drug industry newsletter, the advisory was issued because a patient on pentoxifylline developed retina bleeding and detachment. The BGA emphasized that no causal relationship has been established between the drug and retinal disorders. Pentoxifylline is known to cause bleeding of the skin, mucosal areas and stomach. Hydrogen Peroxide Therapy Treatment Issues has received a number of questions regarding the use of hydrogen peroxide as a therapy for HIV. There is no evidence that injecting hydrogen peroxide will provide any benefit for HIV disease and there is some evidence that it is quite dangerous. A recent letter in the Annals of Internal Medicine (April 15, 1994;120: 694) reported the death of a PWA who injected hydrogen peroxide into his catheter. He subsequently developed nausea, dark urine, and a rapid heart beat. Kidney problems soon developed and the patient died five days after injecting the hydrogen peroxide. Poppers and the Immune System Isobutyl nitrite inhalers or "poppers" can reduce the functional ability of T-cells in mice, according to a researcher from the University of Arkansas (Toxicology Letters, February 15, 1994; 70:319-29). Mice in the study were exposed to three doses of isobutyl nitrite (900 parts per million, 600 ppm and 300 ppm) for 45 minutes a day for fourteen days. By comparison, one of the leading "popper" products, "Probe," releases over 1,500 ppm of isobutyl nitrate. The study found that mice given the two higher doses had T- cell mediated responses that were reduced by 37 percent. However, three days after the last exposure to isobutyl nitrate, T-cell functions returned to normal. In a conversation with Treatment Issues, the lead investigator of the study, Dr. Lee Soderberg, concluded that the reduction in T-cell functioning in mice after exposure to isobutyl nitrate was statistically significant, but reversible. He also noted that the mice exposed to isobutyl nitrate showed reduced tumor killing capabilities which returned to normal levels more slowly than T-cell functioning. New Drug Tested for Genital Warts A topical formulation of HPMPC, an anti-CMV drug being developed by Gilead Sciences, is now being studied as a treatment for anal and genital warts in HIV-infected patients. The trial is ongoing at three sites: the Conant Medical Group, the University of Washington at Seattle, and the Houston Clinical Research Network. An intravenous (IV) version of HPMPC is now in phase II/III trials for CMV. The drug is believed to work against strains of human papilloma virus (HPV) which are associated with genital warts. HPV has been linked to increased rates of cervical cancer in HIV-positive women and anal cancer in gay and bisexual HIV-positive men. The topical formulation of HPMPC is being administered once a day. It is also being studied in acyclovir-resistant herpes. According to Dr. Conant's office, early indications from the study for genital warts are "promising." In the first three patients treated (all with anal warts), one patient had a complete clearing, one had "extensive reduction," and one had a self-described 50 percent reduction in warts per day. It should be noted, however, that genital warts clear spontaneously in about 25 percent of cases when a placebo is given. Nevertheless, HPMPC is the first therapy tested against HPV that attacks the virus itself and, according to the company, protects uninfected cells against HPV. Depression and HIV Two studies on depression and disease progression among HIV- positive individuals were recently published in The Journal of the American Medical Association (JAMA, 1993; 270: 2563- 74). One group of researchers, Lyketsos, et al. from the Multicenter AIDS Cohort Study (MACS), found that depression was not associated with increased disease progression or death. However, another study, published in the same edition, by Burack, et al. from San Francisco General Hospital, concluded that "depression predicted a more rapid decline" in CD4 counts. The first study, which did not find an association, was significantly larger than the second. It measured not only CD4 counts but "at least five assessments" of disease progression. An editorial entitled "Depression and HIV: How Does One Affect the Other?" accompanied the two reports. It noted, "We are reminded by both studies that most HIV-infected subjects are not depressed." The editorial continued, "We continue to urge clinicians to view depression in this population as a psychopathological condition warranting treatment to reduce suffering and to improve functioning. But we also recommend that clinicians be cautious in suggesting that HIV-infected patients should reduce their depression because of its direct effects on their T-cells. Such a stance is not well substantiated and may foster self-accusation when disease progression occurs." Correction March's edition of Treatment Issues incorrectly stated that the on-going trial of Abbott Laboratories lead protease inhibitor, A-84538, required participants to visit the clinic every day for their daily dose. Actually, trial participants will receive a cooler to transport their supply of the drug, which comes in pill form and has to be stored at temperatures below freezing. Other conditions for entering the trial remain restrictive: Participants must have no opportunistic infections and forego all other medications except for prophylaxis for pneumocystis carinii pneumonia. They also must have a CD4 count of more than 50. These criteria exclude most people at the low end of the CD4 range. Volunteers also must have substantial HIV levels in their blood, as measured by the branched-chain DNA assay. This requirement excludes many people with higher CD4 counts - a CD4 count of up to 500 is allowable in the trial.