[Electronic distribution for GayCom by the Backroom 718 951-8256] Volume 7 no. 7 July/August, 1993 Gay Men's Health Crisis: Treatment Issues > Reports From Berlin: New Antiretroviral Agents > News from the Test Tube > HIV Immune Therapies > Treatment briefs >> Risky Drinking Water >> Self-Care Manual for HIV-Positive Inmates >> TAG Publishes Drug Company Report Card >> Parvovirus Linked To Anemia >> Severe Toxicities and Deaths in Hepatitis B Drug Trial >> Resistant Enterococci, New Threat in New York Hospitals > Drug Company Watch ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Reports From Berlin: New Antiretroviral Agents by Gabriel Torres, M.D. Several clinical studies of new antiretroviral drugs were presented at the Ninth International AIDS Conference in Berlin. Nevirapine Dr. Diane Havlir from the University of California at San Diego presented results from ACTG 164, an open-label study of nevirapine monotherapy in 38 HIV-positive patients with CD4 counts less than 400, no previous opportunistic infections, and p24 antigenemia. Participants had taken AZT for an average of 45 weeks, yet all had a 28-day washout period prior to starting 400mg/day of nevirapine. The most common side effect of nevirapine at this dose was a rash involving the trunk and extremities which occurred in 48 percent of patients after a median of thirteen days. Fever and muscle aches also occurred in many patients. The rash could be ameliorated by escalating the dose slowly from 12.5mg/day to 400mg/day over several weeks. Another common toxicity was elevated liver enzymes. Eight of ten evaluable patients who completed eight weeks of therapy showed a sustained 50 percent reduction in p24 antigenemia as well as a reduction in quantitative HIV RNA after four weeks. The CD4 counts showed a modest rise followed by a decline. There was a demonstrable relationship between higher plasma levels of nevirapine and p24 responses. Although study investigators had hoped that the 400mg dose of nevirapine would delay the onset of resistance to the drug, resistance still developed quickly. However, sustained antiviral activity, measured by p24 antigen suppression, was still demonstrable. A research group from the Netherlands presented a poster describing a trial which compared alternating and concurrent regimens of AZT and nevirapine.[1] Seventeen p24 antigenemic, AZT-naive patients with CD4 counts less than 500 were treated for a median duration of 50 weeks with combinations of alternating and concurrent nevirapine at 200mg/day and AZT at 600mg/day. After sixteen weeks of treatment, those receiving concurrent treatment had better and more sustained immunologic and virologic responses than those who received the alternating regimen. CD4 counts returned to baseline in both groups after one year of treatment. An Australian study also showed that alternating regimens of AZT and nevirapine were not effective in delaying the emergence of resistance against nevirapine.[2] Convergent Combination Therapy Convergent combination therapy, first proposed in February by Yang Kung-Chow, a doctoral student at Harvard Medical School, claimed that three-drug combinations, including AZT and ddI, with either nevirapine, Merck's L-drug, or foscarnet completely stopped HIV replication in test tubes. [See Treatment Issues March/April 1993 for coverage of convergent combination.] A press release issued by the Massachusetts General Hospital which described the discovery as the "Achilles heel of HIV" fueled a media frenzy. However, new information presented in Berlin by several research teams, including Chow's, show that the original report was inaccurate. Although the original report claimed three drug combinations rendered HIV incapable of replication, with multiple passages in the test tube, resistance developed to all three drugs and the virus remained viable. Despite this setback, convergent combination may still have a role. Firstly, test tube experiments used sequential drug treatment to select for resistance. The clinical study of three-drug combinations, ACTG 241, uses concurrent therapy. Secondly, although three-drug combinations do not eliminate HIV as originally hoped, convergent combination may still delay the onset of resistance or decrease viral burden more than other regimens, possibly extending or improving the clinical effect of the drugs. 3TC: The Next Nucleoside 3TC is a nucleoside analogue similar to AZT which is being developed by Glaxo, Inc. The drug is active against HIV-1, HIV-2, and AZT-resistant viruses. In vitro experiments have shown that 3TC is synergistic with AZT, non-nucleoside reverse transcriptase inhibitors, and with a protease inhibitor. Dr. Mark Wainberg of McGill University presented results from a phase I/II study of 3TC conducted at three sites in the US and Canada. In this open-label, non-randomized, dose-escalation study, 3TC was administered twice daily in escalating doses between 0.5 and 20mg/kg/day. Ninety- seven patients with AIDS or ARC, with a mean CD4 count of 142, and an average of twenty weeks of previous AZT therapy were enrolled. Four clinical events were found to be probably related to 3TC: insomnia, rashes, increased appetite, and increased energy. Three toxicities noted included vasculitis (inflammation of small blood vessels, usually causing a rash), upper extremity paresthesias (the sensation of "pins and needles"), and photophobia. The main laboratory toxicity was neutropenia which was dose-related and occurred more frequently in the 20mg/kg/day group. Weight stabilization or gain was noted at all dose levels. Nonsustained increases in CD4 counts were seen at dose levels of 4 to 20mg/kg/day and significant decreases in p24 antigen levels were seen at the highest dose level. Forty-two patients in the study were included in a resistance analysis. Twelve (25 percent) showed reduced sensitivity to 3TC indicating viral resistance, yet no clinical correlation was observed. Clinical progression of disease occurred in thirteen patients and death in eight patients. In vitro studies have shown that the mutation that causes resistance to 3TC may reverse the resistance to AZT. Future studies are planned using 3TC alone and in combination with AZT or AZT and DDC. In the United States, two 3TC studies are underway. One study compares 3TC with AZT or the combination of both in AZT-naive patients with CD4 counts between 200 to 500. The other trial includes patients with CD4 counts between 100 and 400 who have received AZT for six months or longer. This trial compares two doses of 3TC and AZT to AZT/ddC combination. In the New York area, the 3TC trials are enrolling at St. Luke's-Roosevelt Hospital (212/523-6743) and the Nassau County Medical Center (516/542- 5707). In the United Kingdom, a phase II study of AZT (200mg tid) versus AZT plus 3TC (300mg bid) in patients with 100 to 400 CD4 cells is ongoing. Tat Antagonist Disappointment Dr. Rich Haubrich of the University of California at San Diego presented results from the first human clinical trial of Hoffmann LaRoche's much-publicized tat antagonist.[3] This trial, designated ACTG 213, investigated the safety, tolerance, pharmacokinetics, and activity of oral R0 24-7429, the official name for the Roche drug. Tat, a crucial regulatory gene of HIV, leads to increased viral production. By blocking the function of the tat gene, researchers hoped to reduce HIV replication. The tat antagonist has been shown in test tube experiments to keep the virus in dormancy and to be active in chronically infected cell lines. In this clinical trial, 96 HIV-infected patients with CD4 cells between 50 and 500 were randomized to receive 75, 150 or 300mg/day of the tat antagonist or nucleoside analogue therapy (AZT or ddI) given orally for twelve weeks. Half of the patients in each group had detectable serum p24 antigen at baseline. Eighty- three percent of the patients completed eight weeks of therapy. The most common side effect was a rash which occurred in 24 percent of patients, usually within two weeks of starting therapy. A few patients also had elevations of liver function tests, headaches, fever, and an increase in the number of KS lesions. Compared with patients receiving AZT or ddI, those receiving the tat antagonist had declines in CD4 cell counts and rises in p24 antigen levels, indicating poor or no antiviral activity. Quantitative HIV RNA from this study was not available at the time of the presentation. In addition, no data were available on blood levels of the tat antagonist in order to ascertain if the drug was absorbed from the gastrointestinal tract. Needless to say, the data on the tat antagonist were a disappointment for those who hoped that this agent would open the gate to the next generation of antiretroviral agents. Protease Inhibitors: The Next, Best Hope Protease inhibitors inactivate protease, a viral enzyme responsible for cutting newly produced viral precursors into mature proteins and enzymes during viral assembly and maturation. Virions produced in vitro in the presence of a protease inhibitor are non-infectious in cultured cells. Protease inhibitors inhibit HIV production in chronically infected cells. A-77003: The Abbott Protease Inhibitor The results of the first clinical trial of the Abbott protease inhibitor, A-77003, were presented by a group of investigators from the Netherlands.[4] In this phase I/II trial, A-77003 was administered as an intravenous infusion over 24 hours, followed by a three- to six-day washout period, followed by a 28-day infusion. Patients received the infusions as outpatients through a central venous catheter with a portable infusion pump. Patients enrolled had CD4 counts between 200 and 500 and were asymptomatic or had previous histories of oral thrush, PCP, or limited KS. Women were excluded from the trial because of lack of data on teratogenicity. Twenty two males with an average CD4 count of 308 were enrolled and given infusions at doses of 0.035, 0.07, 0.14 and 0.28mg/kg/hour. The pharmacokinetics of the protease inhibitor showed that the drug is cleared quickly, with an average half-life of 30 minutes. The investigators conclude that A-77003 is metabolized rapidly, explaining the need for a rapid infusion rate. The most common adverse effect was phlebitis (inflammation of the vein) which occurred in eight patients receiving the higher dose. The occurrence of phlebitis in most of the patients receiving the higher doses limits continued use of the present formulation. Two patients developed infections related to the catheters and three had elevations in liver function tests. There were no significant changes in CD4 cell counts or p24 antigen levels, though two patients had negative plasma cultures for HIV after the 28-day infusion. However, since the protease inhibitor may lead to the production of inactive virions, the use of p24 antigen levels may not be suitable as a measure of this drug's antiretroviral activity. R0 31-8059: The Roche Protease Inhibitor Three trials using the Roche protease inhibitor (R0 31-8959) were presented by investigators from France, the United Kingdom, and Italy. The Roche protease inhibitor is active against HIV at nanomolar concentrations, while toxicity appears only at micromolar concentrations, thus affording a therapeutic index of at least 1000-fold in test tube experiments. In the French double-blind trial, 61 HIV-positive patients who had previously received AZT with CD4 counts between 50 and 250 were randomized to receive one of three doses of the protease inhibitor (75, 200, and 600mg given orally three times daily for sixteen weeks). Sixteen of the 61 participants were women. The drug was well tolerated with few to no adverse effects. A few patients experienced diarrhea, weight loss, and anal sphincter disorders. The highest dose group had the greatest elevations in CD4 counts and decreases in p24 antigen levels, indicating a clear dose response. The maximum increase in CD4 count (56 cells) occurred after four weeks of therapy with a median change of seventeen cells after sixteen weeks of therapy. Plasma levels of the protease inhibitor seemed to correlate with CD4 elevations but the elevations seemed to plateau at a dose of 600mg three times daily, suggesting that increasing the dose beyond this level may not affect CD4 counts. Decreases in plasma viral titers were demonstrated but were not maintained in the majority of patients. The British study was performed at St. Mary's Hospital in London and examined the effect of the Roche protease inhibitor in asymptomatic or mildly symptomatic HIV-positive patients without prior antiretroviral therapy and CD4 counts less than 500. Four doses were studied (25, 75, 200 and 600mg three times daily). Two patients experienced progression of disease. CD4 count changes tended to be dose-related with the largest increases occurring at the higher dose; the average increase from baseline was 106 cells which occurred after six weeks in the group receiving 600mg thrice daily. Dr. Stefano Vella from Italy presented the results of a trial comparing the protease inhibitor to AZT alone or the combination of both. Three groups received combination therapy with AZT and either 75, 200, or 600mg thrice daily of the Roche protease. Participants had no previous antiretroviral treatment and had CD4 counts less than 300. The best responses in CD4 counts occurred in the group receiving AZT and the highest dose of the protease inhibitor, with a maximum increase of 147 cells, which was sustained after sixteen weeks. The study concluded that synergy between AZT and the Roche protease inhibitor was present and accounted for the superior effect on the CD4 counts without additive toxicity. The data on the Roche protease inhibitor, though not spectacular, was perhaps the most encouraging antiretroviral news at the conference. Unfortunately, production of the Roche protease inhibitor requires multiple steps, and drug supply for clinical trials is extremely limited. Finally, ACTG 229, a study of the Roche protease inhibitor in combination with AZT or AZT and DDC, is fully enrolled and is expected to demonstrate whether these drug combinations produce a clinical benefit. 1 Lowenthal M, et al. Abstract PO-B26-2101. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 2 van der Ende ME, et al. Abstract PO-B26-2100. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 3 Haubrich RH, et al. Abstract WS-B26-5. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 4 Danner SA, et al. Abstract WS-B26-6. Ninth International AIDS Conference. Berlin. June 6-11, 1993. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ News from the Test Tube Other Protease Inhibitors: Several other companies have protease inhibitors in preclinical, or very early clinical studies. DuPont Merck, Vertex, and researchers from the University of California- San Diego each presented data on their protease inhibitor compounds. DuPont Merck's compound is in early human studies in Germany. GEM 91: GEM (gene expression modulation) 91 is an antisense oligonucleotide produced by Hybridon, Inc. of Worcester, Massachusetts. Antisense oligonucleotides inhibit genes which are necessary for viral replication. Hybridon has submitted an application to both the FDA and the Clinical Trial Committee in France to begin phase I clinical studies. Most analysts predict that clinical studies of the drug will first begin in France. Topotecan: Topotecan is an analog of camptothecin, a toxic anticancer drug made from the wood of the Chinese tree Camptotheca acuminata. Dr. Clyde Crumpacker from Boston's Beth Israel Hospital presented preliminary test tube data which shows that topotecan inhibited p24 antigen production and mRNA production in transfected human epithelial cells. Topotecan's mechanism of anti-HIV action is not yet known. SC-49483: SC-49483 is the prodrug of N-butyl DNJ, a glucosidase inhibitor. Glucosidase inhibitors block the addition of sugar molecules to HIV's outer envelope. Sugar molecules are a necessary component of HIV's structure; without them, the virus becomes noninfectious. An earlier clinical study of N-butyl DNJ demonstrated that the drug is toxic. It inhibited normal intestinal functioning, resulting in improper carbohydrate absorption and intense diarrhea. Scientists from Monsanto Searle, the drug's manufacturer, hope that SC-49483 will be converted into N-butyl DNJ after it passes through the intestines, avoiding the diarrhea. PIC 024-4 and PRO-189: Procepts, Inc, a Massachusetts company, presented preliminary data on their two lead anti-binding compounds PIC 024-4 and PRO-189. These compounds block the interaction of the CD4 receptor and HIV gp120, HIV's main gateway into human cells. Procept scientists hope that these compounds will prevent HIV from infecting new cells. Synthetic Humates: A research team from the Institute of Medical Microbiology in Freiburg, Germany presented data on the ability of synthetically produced humates to block the CD4-gp120 interaction. Humates come from the decaying organic matter found in coal, soil, and peat. Melanins, another proposed anti-HIV agent, are related compounds. Triterpine Derivatives: Rhone Poulenc Rorer, the French drugs giant, presented data on RPR 103611, a triterpine derivative. RPR 103611 does not inhibit integrase, protease, or reverse transcriptase, three common targets for new anti-HIV drugs. Although its exact mechanism of action is still unknown, Rhone Poulenc scientists believe that the compound inhibits HIV at an early point in its life cycle. Triterpines are a class of substances isolated from plants, particularly the root of Tripterygium wilfordii. New Reverse Transcriptase Inhibitors: Eli Lilly, an Indianapolis- based drug company, and Hoescht AG-Bayer, a collaboration of two German drug companies, each presented preliminary data on their new reverse transcriptase inhibitors. Lilly's drug LY73497 and Hoescht-Bayer's quinoxaline derivative both inhibit HIV reverse transcriptase in vitro, but are not nucleoside analogs like other RT inhibitors, such as AZT. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ HIV Immune Therapies by David Gold The Ninth International Conference, like other conferences in past years, saw a limited amount of clinical data about HIV immune therapies. However, there was a substantially greater discussion about HIV's interaction with the immune system. In particular, much emphasis was placed on the importance of certain immune reactions, such as cell-mediated responses and understanding the multitude of cytokines released by the body during HIV infection and how they affect disease progression. Salk Vaccine The Salk HIV-1 Vaccine Immunotherapy ( also known as the Salk Immunogen) received the most attention of any HIV immune therapy at the conference. Produced by a joint venture of Immune Response and Rhone-Poulenc Rorer, the vaccine is made from inactivated HIV- 1 (minus the gp120 envelope) with Incomplete Freund's Adjuvant (IFA), a mineral and oil emulsion used to increase the antigenicity of the vaccine. Jonas Salk, the polio vaccine pioneer, first proposed the idea of therapeutic vaccination for HIV-infected people in 1987 and has been involved in the development of this product. Dr. Alexandra Levine of the University of Southern California School of Medicine presented information on three trials of the Salk Immunogen. The first trial enrolled 23 gay men who were given eight 100ug doses of the Immunogen over three years. Participants were followed for a period of 4.3 years for clinical observation and 3.3 years for laboratory observations. No serious side effects were reported; 48 percent reported pain at the administration site and 22 percent reported fever or rash. Twelve of the 23 (52 percent) developed a delayed-type hypersensitivity (DTH) response to vaccine antigens. DTH is a skin test which measures certain aspects of the cellular immune system. (For a broader discussion of therapeutic vaccines, and the limitations of DTH responses, see Treatment Issues, June 1993). The investigators claim that those with a DTH response maintained greater CD4 cell levels (that is, the vaccine group did not lose as many cells as the placebo group) and had fewer opportunistic infections and deaths. Levine concluded from this study that there was a "correlation between DTH response and CD4 stability." The second study randomized 40 patients to receive 50, 100, 200, 400ug of the Salk Immunogen or placebo (in this case, IFA alone). Patients in the study entered with over 600 CD4 cells. The researchers claim that a dose of 100ug or more produced significantly greater humoral immune responses, as measured by anti-p24 antibodies, and cellular immune responses, as measured by DTH skin reactions. The third study was the most significant part of the presentation. This phase II/III randomized, double-blind study enrolled 103 asymptomatic HIV-positive patients with CD4 counts ranging from 233 to 1211, with a mean of 656. Participants were randomized to receive 100ug of Immunogen or IFA placebo at baseline, three, and six months. After the third dose, the study investigators report a significant increase in anti-p24 antibodies and DTH responses in those receiving the Immunogen. The vaccine group also showed a significant increase in body weight (2.3 kilograms for the vaccine group versus .5kg for the placebo group). Side effects were limited to injection site reactions. The greatest stir was created by Levine's report that the treatment arm had a significantly lower increase in the amount of HIV viral burden, as measured by DNA PCR. Using this measurement, viral burden increased 10 percent in vaccine group and 48 percent in placebo group over the course of one year. According to the researchers, this difference is statistically significant. However, there was no difference in the amount of HIV found by viral culture or by p24 antigen levels. In addition, no difference in CD4 levels was found, although this may have been expected in a short trial of relatively high CD4 cell individuals. Furthermore, researchers conclude that there was a "significant increase or stabilization" in cell-mediated immune responses as measured by DTH reactions. No data on cytotoxic lymphoproliferative responses, another measure of cellular immune response, were presented. Immediately after Levine's presentation, debate began over whether the reported effect on viral load was meaningful. In a press conference, Salk acknowledged that "these (results) are simply trends." Dr. David Ho of the Aaron Diamond AIDS Research Center in New York commented that the "very minor change in viral burden is within the variability of the assay." Dr. Anthony Fauci of the National Institute of Allergies and Infectious Diseases (NIAID) described the results as "statistically significant but not overly impressive." The high profile of financial analysts in the Salk Immunogen presentations must also be noted. Of course, the pharmaceutical industry is profit driven. However, the role of investors in this case appeared disproportionate. At the presentation, the first several rows of the auditorium were filled with investment analysts providing a slide-by-slide report of the data by cellular phone back to their headquarters. A strange and disconcerting sight, indeed. In any event, Wall Street seemed to concur with Salk's scientific critics; Immune Responses' stock dropped 26 percent after the presentation. New, More Powerful Adjuvants Dani Bolognesi of Duke University reported that antibody levels induced in seronegative volunteers by several new HIV preventive vaccines are approaching levels seen in HIV-infected individuals. In a plenary session devoted primarily to preventive vaccines, Bolognesi reported QS-21, a new adjuvant developed by Cambridge Biotech which is derived from Quillafa saponaria, a type of soapbark tree.[1] QS-21 produces "far higher neutralizing antibodies, and reasonably impressive CTL responses." QS-21 is in a Phase I trial with Genentech's gp120 vaccine in 80 seronegative volunteers which began in May 1993. Bolognesi did not indicate if QS-21 will be used in therapeutic vaccine preparations. Genentech gp120 J.D. Allan of Harvard Medical School reported an ongoing trial of Genentech's two gp120 vaccines (MN and IIIB strains). In the trial, 122 HIV-positive individuals are randomized to one of six arms (either MN vaccine, IIIB vaccine, combination of both MN and IIIB vaccines, alternating regimens of both vaccines, or a placebo). Both humoral and cellular immune responses were produced.[2] Immuno AG gp160 In a study of 21 HIV-positive individuals randomized to receive Immuno AG's gp160 vaccine, Hepatitis B vaccine, or placebo, gp160 vaccine was well tolerated and induced new lymphoproliferative responses.[3] Immuno AG announced that it will start a Phase I trial of gp160 with an MN strain in 20 asymptomatic HIV-positive adults with over 500 CD4 cells. In a trial of 55 HIV-negative individuals, gp160 (IIIB strain) induced new antibodies and a "vigorous lymphoproliferative response."[4] Chiron/Biocine gp120 James Kahn of the University of California at San Francisco reported a study of Biocine's gp120 vaccine (SF2 strain). Thirty HIV-negative volunteers received four injections of gp120 vaccine with MF-59 or MTP-PE (two adjuvants produced by Chiron) and twelve received either placebo or the just adjuvants. According to Kahn, antibodies in those who received gp120 vaccine with the new adjuvants persisted up to six months after the third injection. Interestingly, Kahn suggested that antibodies from the study volunteers might be collected and infused into HIV-infected people as an experiment in passive immunization.[5] Canary Pox Vectors In a French study, twenty HIV-negative adults were given gp160 vaccine in a live canary pox virus vector at baseline and one month, followed by gp160 boosters at three and six months. Immunizations were safe and well tolerated. Neutralizing antibodies and lymphoproliferative responses were reported.[6] MicroGeneSys gp160 In a Canadian study of MicroGeneSys' gp160 vaccine (also known as VaxSyn), 21 HIV-positive individuals with over 500 CD4 cells were given 160ug or 320ug of the vaccine six times the first year, three per year thereafter. After an average of three years follow-up, VaxSyn was safe and well-tolerated. A statistically significant increase in CD4 cells over baseline was observed during the first year, but by week 68 these increases were non-significant, and by week 84 a statistically non-significant decline was observed.[7] Viral Technologies HGP-30 Prem Sarin of Viral Technologies presented information on HGP-30, a vaccine based on the p17 core protein of HIV (most of the other vaccines currently in clinical trials are based on the envelope proteins, such as gp120 or gp160). In a study of 39 HIV-negative individuals, antibody responses and cytotoxic T-cell responses were found after administration of HGP-30.[8] Sarin also disclosed that the company has tested other adjuvants which may increase the immune reactions to the vaccine. A trial in HIV-positive volunteers will begin shortly. Pentoxifylline There were three reports on the use of pentoxifylline (PTX, and also known by its brand name Trental.) Two studies were reported by Dr. Bruce Dezube of the Beth Israel Hospital in Boston.[9] These studies indicate that PTX three times per day for eight to sixteen weeks decreases triglycerides (TG) and Tumor Necrosis Factor (TNF) levels. In a cohort of patients with advanced AIDS (median CD4 cells were 32) given PTX 400mg TID (three times daily), triglycerides dropped an average of 67mg/di and TNF levels dropped in ten of sixteen patients. HIV load dropped in four, remained even in ten, and increased in one. In the cohort given PTX 800mg TID, TNF fell in half the patients. HIV levels dropped in four, stayed the same in six and increased in one. The drug was well-tolerated. One patient in each cohort developed fevers probably from the drug. Dr. Joe Sonnabend of the Community Research Initiative on AIDS in New York City presented preliminary data on their community based PTX trial.[10, 11] Forty five patients were enrolled; 32 completed twelve weeks of therapy. The data presented are based on patients who completed eight weeks of therapy. Twelve patients discontinued study medication, four due to adverse experiences. Only one of these four were randomized to receive PTX. Sonnabend concludes "Ex vivo production of TNF by peripheral blood monocytes from HIV infected individuals with under 300 CD4 cells was significantly lower in patients after receiving PTX for eight weeks compared to patients receiving placebo." Cyclosporin In a wide-ranging plenary session devoted to the pathogenesis of HIV disease, Dr. Anthony Fauci asked whether some form of immune suppressive therapy may actually slow HIV disease progression. Some theories of HIV pathogenesis suggest that parts of the immune system in HIV-infected people appear hyperstimulated, even though AIDS is usually considered a syndrome of immune suppression. Fauci cites a German study which examined four patients who contracted HIV from kidney transplants in 1984.[12] All of these patients were given cyclosporin, an immune suppressive drug widely used in organ transplant surgery. Two died 66 and 74 months later, but not from HIV-related causes. The other two have not developed symptoms or infections typical of AIDS. Moreover, the authors claim that a review of case reports of 53 patients who developed HIV from transplants or transfusions found that the 40 patients who received an immune suppressive regimen, like cyclosporin, had a lower incidence of AIDS than the 13 who did not receive immunosuppressive therapy (five- year cumulative risk of AIDS 31 percent versus 90 percent). It should be noted that these are only retrospective case reports from a small number of patients and that cyclosporin can be a very toxic drug. Furthermore, several studies have examined the use of cyclosporin in HIV infected patients. While most are inconclusive, one study from Canada reported rapid clinical deterioration after cyclosporin use in patients with AIDS.[13] For this reason, cyclosporin is not recommended in HIV-infected patients at this time. Interestingly, Sandoz, the Swiss drugs giant which manufacturers cyclosporin, is reportedly working on cyclosporin analogs which inhibit specific T cell functions, without causing general immune suppression. Thymic Peptides Two abstracts reported studies about so-called "thymic hormone products." In an Italian study in which 147 HIV-positive individuals (less than 500 CD4) were randomized to either AZT or AZT and thymostimulin (TP1), the TP-1 arm had less toxic effects from AZT, including fewer blood transfusions and lower hepatic toxicities (SGPT).[14] A multi-site trial of 352 HIV-positive individuals (200 to 500 CD4) compared AZT to AZT plus Thymopentin (TP-5). The authors report that TP-5 with AZT reduces disease progression in asymptomatic HIV positive patients.[15] These two studies were both reported as posters so it was more difficult to discuss the details of these trials with the investigators. Alpha Interferon Alpha interferon (IFN-A) is a natural protein secreted by immune cells in response to viral infection. A manufactured version of IFN-A is approved to treatment Kaposi Sarcoma (KS), hepatitis B virus, and hepatitis C virus. Test tube studies have shown that IFN-A reacts synergistically with AZT against HIV. Therefore, some suggest that IFN-A be used in combination with AZT as an anti-HIV treatment. Clinical trials of this combination are ongoing and several abstracts were presented in Berlin. In a German study, asymptomatic or mildly symptomatic patients with rapidly declining CD4 levels were randomized to receive AZT and IFN-A 3 million international units (MIU) three times weekly or AZT alone. Ten patients on the IFN-A containing regimen and seven on the AZT control arm completed 24 weeks of treatment. No difference in CD4 counts was observed between the two arms.[16] Another German study raised concerns about IFN-A treatment for HIV.[17] In a two year double blind study, 36 patients (less than 350 CD4) were randomized to AZT, AZT plus IFN-A .75 MIU daily, or AZT plus Beta Interferon (IFN-B) .75 MIU daily. After 12 months, there was a marked CD4 cell decrease and five opportunistic infections in the IFN-A containing group compared to two opportunistic infections in the other groups. Furthermore, after 24 months, four patients in the IFN-A containing regimen developed pronounced neurological disorders. No patients in the other arms developed neurological disorders. Eight of twelve patients died in the IFN-A group compared with four and three deaths in other two treatment groups. "In this study," the investigators conclude, "we were unable to find an additional benefit in a ZDV therapy combined with IFN alpha or beta. It has to be discussed whether low dose IFN alpha may cause progression and neurologic complications in HIV disease." A Spanish study randomized 112 HIV-positive patients with less than 300 CD4 cells to receive either AZT 500mg/day or AZT 300mg plus IFN-A 5 MIU daily for the first month, reduced to three times per week thereafter.[18] A preliminary analysis of 62 patients who have completed six months of therapy "has not demonstrated significant differences in the groups." Finally, two other studies presented at the conference failed to demonstrate significant increases in CD4 cells from the use of IFN- A with AZT.[19, 20] One study showed a decrease in p24 antigen levels but no difference in CD4 counts.[21] A Belgian study reported a significant increase in the percent of CD4 cells among those given IFN-A plus AZT.[22] On the brighter side, a new form of IFN-A called N3-Alferon is being tested at the Walter Reed Army Hospital. Investigators report it to be ten to 1000 times more effective in vitro against HIV and to have dramatically lower symptoms.[23] Low Dose Oral Alpha Interferon: "Kemron" Kemron, an oral form of alpha interferon given in doses over 100,000 times lower than conventional subcutaneous doses, created an international stir a few years ago when Kenyan researchers reported dramatic improvements, including "HIV-seroreversions" (that is, HIV-positive to HIV-negative), with the drug. Since the original report, at least twelve different studies failed to replicate these results. At this year's conference, another study which failed to find any benefit to Kemron was reported. This Ugandan study, funded by the World Health Organization, followed 560 HIV-positive patients who were randomized and double blinded to either oral alpha interferon (Kemron, 150 international units per day) or placebo over 60 weeks. The researchers found no difference in mortality, progression of disease, body weight, and CD4 counts. None of the patients reverted to HIV-negative status. Despite the volume of data which now prove no benefit to Kemron, the National Institutes of Health has planned its own study and scurrilous individuals, including some physicians, have continued to sell Kemron (or other versions of oral interferon) at incredible mark-ups to people with HIV. Some reports indicate that Kemron may be selling for as much as $1000 per month. Interleukin-2 Fauci discussed a trial of Interleukin-2 conducted at the National Institutes of Health.[24] Interleukin-2 is a naturally occurring protein secreted by immune cells to stimulate other immune cells, particularly T cells. Like alpha interferon, IL-2 has been manufactured and is approved for kidney cancer in several countries. In addition, it is under development for other diseases, including AIDS. In the study, eight patients with less than 200 CD4 cells were given IL-2 18 MIU daily for five days every two months with AZT or ddI. Four of the eight patients had an average 100 percent increase in CD4 cells by six to ten months. However, five of the eight patients had to reduce IL-2 doses due to fever and "subjective toxicities." In addition, these were very small numbers of patients and there is no indication that these CD4 cell increases have clinical significance. IVIG Intravenous immune globulin (IVIG) is an approved treatment for immune deficiencies characterized by impaired antibody production. In a study at the Houston Immunological Institute, eighteen HIV- positive patients with less than 500 CD4 cells were randomized to receive IVIG six grams once a week or placebo for six weeks.[25] No difference was found in CD4 counts, p24 antigen levels, or DTH skin tests. In a German study, 35 patients (30 AIDS, five ARC) were treated with high dose IVIG (4g/kg twice a week every three weeks) and compared to a control group of 31 patients (24 AIDS, seven ARC).[26] After 26 weeks, there were fewer hospitalizations in the IVIG group. A National Institutes of Health (NIH) trial of 313 HIV- positive children suggests that IVIG may slow the decline of CD8 cells in children with AIDS.[27] Conclusion This year's conference saw a far greater discussion about basic science and immunology. There was a particular focus on the importance of cell-mediated responses and the different cytokines that are released during the course of HIV disease. A greater understanding of these two phenomenon will undoubtedly increase the likelihood of developing effective immune therapies for HIV. 1 Bolognesi DP. Abstract PS-05-1. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 2 Allan JD, et al. Abstract PO-B27-2137. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 3 Schwartz D, et al. Abstract PO-A28-0668. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 4 Gorse G, et al. Abstract WS-B27-4. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 5 Kahn J, et al. Abstract WS-B27-2. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 6 Pialoux G, et al. Abstract WS-B27-6. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 7 Tsoukas CM, et al. Abstract PO-B27-2134. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 8 Goldstein AL, et al. Abstract PO-B27-2139. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 9 Dezube BJ, et al. Abstract PO-B28-2142. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 10 Sonnabend JA, et al. Abstract PO-A28-0664. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 11 Sonnabend JA. Personal Communication. Data on file at GMHC. 12 Schwarz A, et al. Abstract PO-B28-2145. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 13 Phillips A, et al. Canadian Medical Association Journal. 1989; 140: 1456. 14 Palmisano L, et al. Abstract PO-B28-2147. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 15 Goldstein G, et al. Abstract PO-B28-2144. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 16 Jablonowski H, et al. Abstract PO-B28-2148. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 17 Brockmeyer NH, et al. Abstract PO-B26-1987. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 18 Clotet B, et al. Abstract PO-B26-1988. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 19 Carosi G, et al. Abstract PO-B26-2000. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 20 Villarreal RM, et al. Abstract PO-B26-2077. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 21 Barbarini G, et al. Abstract PO-B26-2027. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 22 Henrivaux PH, et al. Abstract PO-B26-2080. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 23 Skillman DR, et al. Abstract PO-B26-1998. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 24 Kovacs JA, et al. Abstract PO-B28-2155. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 25 Stroud S, et al. Abstract PO-B28-2157. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 26 Kiehl M, et al. Abstract PO-A28-0658. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 27 Mofensen L, et al. Abstract PO-B01-0877. Ninth International AIDS Conference. Berlin. June 6-11, 1993. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ treatment briefs by David Gold ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Risky Drinking Water Tap water in American cities may pose risks to PWAs, according to several recent reports. A study presented at the General Meeting of the American Society for Microbiology suggests that drinking water in Los Angeles may be a source of Mycobacterium avium intracellulare (MAI), as well as other mycobacteria. The study found non-tuberculous mycobacteria in all hospital water supplies sampled, 34 of 40 home water samples, and eleven of thirteen reservoir samples. MAI was found in nine of ten hospital water supplies, eleven of 40 home samples, and five of thirteen reservoir samples. The Report of the Expert Panel on New York City's Water Supply (1993) noted that potentially infectious levels of Cryptosporidium and Giardia, two serious intestinal parasites, were found in the city's water supply. Furthermore, the panel noted that measures to protect the city's water supply from these pathogens, such as an improved filtration system, were unlikely to be implemented within the next ten years. As many as 200,000 residents may have developed cryptosporidiosis in Milwaukee this spring due to contamination of that city's water supply. The contamination is believed to have been caused by drainage from cattle and dairy farms into the municipal water system. There is no effective treatment for cryptosporidiosis and in PWAs with low CD4 cells the disease can become chronic and life- threatening. The Milwaukee AIDS Coalition reports that 48 percent of 404 PWAs surveyed experienced symptoms suggestive of cryptosporidiosis during the period. In addition, twelve PWAs were admitted to hospital and three died from dehydration due to diarrhea, according to a report in The Lancet (4/24/93; 341:1084). As Treatment Issues goes to press, New York City officials reported July 27 that potentially infectious levels of E. coli bacteria were found in the water supplies of two neighborhoods: parts of the West Village and Chelsea and parts of the Lower East Side. They advise boiling water for cooking or drinking at least three minutes before use. They warn the elderly, young children, and people with HIV to exercise extra caution. Larry Waites, a San Francisco physician, recommended in his regular column in The Advocate, a national gay newsmagazine, that PWAs with CD4 counts under 100 or those with recurrrent bowel problems drink only bottled water. If bottled water is too expensive, he advises tap water be boiled and then stored in containers which have been washed with hot soapy water, rinsed, and allowed to dry completely. Correction In "HIV Therapeutic Vaccines: The Next Phase" (Treatment Issues, June 1993) the chart Therapeutic Vaccines in Clinical Trials incorrectly described the HGP-30 vaccine as derived from the LAI strain. HGP is derived from the SF2 strain of HIV. Self-Care Manual for HIV-Positive Inmates The Treatment Education Program of AIDS Project Los Angeles produced Be Good to Yourself, a self-care manual for inmates with living with HIV. Copies are available free of charge by calling Stephan Korsia at 213/962-1600 ext. 270. TAG Publishes Drug Company Report Card The Treatment Action Group (TAG) released its Annual Drug Company Report Card. Copies are available by sending a stamped self- addressed envelope to TAG, 147 Second Avenue, Suite 601, New York, NY 10003. Donations are welcome. Parvovirus Linked To Anemia A recent report from the University of Iowa (Journal of Infectious Diseases July, 1993. 101-105) further suggests that parvovirus B19 can persistently infect people with AIDS, resulting in bone marrow suppression and anemia. The researchers analyzed patients who entered the ddI expanded access due to AZT intolerance, particularly severe anemia. They found that four of five patients who entered the program with severe anemia while on AZT had persistent viremia. They suggest that parvovirus B19 infection, which can be treated with intravenous immunoglobulin, should be considered in people with AIDS, particularly when cytopenias occur. Severe Toxicities and Deaths in Hepatitis B Drug Trial A phase II clinical trial for fialuridine (FIAU), a nucleoside analog being studied for chronic, active hepatitis B, was halted due to severe liver or hepatic toxicities. Three patients required liver transplants, reportedly because of the drug's damage to the liver. Two of these subsequently died and one is still awaiting a transplant. The drug was under development by Eli Lilly. This episode points to the real risks that often accompany enrolling in clinical trials for unapproved therapies. PWAs must consider many complex factors when deciding whether to enroll in any study. The invaluable contribution so many have made by entering clinical trials for new therapies with unknown risks must be acknowledged and appreciated. Resistant Enterococci, New Threat in New York Hospitals Enterococci are bacteria which cause serious urinary or gastrointestinal infections, and in some cases death, if the bacteria enter the blood stream. Antibiotic use may predispose to enterococcal infections; antibiotics kill off "good" bacteria in the intestine which allows "bad" bacteria, like enterococci, to grow. Also, enterococci can be transmitted between patients in hospitals; enterococci account for 12 percent of hospital acquired infections. No curative therapy exists for enterococci. Vancomycin is the most widely used treatment for enterococci. A new study reported in The Lancet (July 10, 1993. 76-79) noted the wide-scale emerge of vancomycin-resistant enterococci in New York City hospitals. The first report of a vancomycin-resistant enterococcus isolated from a patient occurred in 1988. By October, 1991, 38 hospitals in New York had reported vancomycin-resistant enterococci. The authors suggest further surveillance of resistance patterns, contact isolation, strict hand washing for hospitals, and reduced use of vancomycin and cephalosporins. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Drug Company Watch by David Gold Famciclovir NDA By End of Year SmithKline Beecham, a Philadelphia-based drug company, plans to file a New Drug Application (NDA) for famciclovir, a new broad spectrum anti-herpes drug similar to acyclovir, by the end of the year. The NDA will probably be for herpes zoster ("shingles") with additional indications, including herpes simplex, and European filings to follow in 1994. SmithKline claims famciclovir is more bioavailable than acyclovir and has a greater intracellular half-life. SmithKline expects that famciclovir will require less frequent dosing than acyclovir. Dan Hoth Quits NIAID For Biotech Industry Dan Hoth, M.D., Director of the Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Disease, left his government position to become a Senior Vice President and Chief Medical Officer of Cell Genesys, a California biotechnology firm. Cell Genesys is developing universal killer T cells which target HIV antigens. Universal killer T cells are modified to function in all individuals. Currently, transplanted immune cells must be genetically matched between donor and recipient. Clinical trials are expected to begin by early 1994. Dr. Jack Killen has been appointed Acting Director of DAIDS until a replacement is found. The Director of DAIDS is a key figure in the government's AIDS research program; we will watch closely to see if Dr. Anthony Fauci, the Director of NIAID, appoints a well-respected, high quality scientist to the position. The Return of Thalidomide Celgene, a biotech company, filed a series of broad patents covering AIDS-related uses of thalidomide and its analogs. Celgene's patents are based largely on the work of Dr. Gilla Kaplan of Rockefeller University. Kaplan reported in The Proceedings of the National Academy of Science (July 1) that thalidomide can reduce tumor necrosis factor (TNF) production without affecting synthesis of other proteins. TNF is a protein produced by immune cells in response to infection and cancer. Elevated TNF levels have been connected to several disease processes, including increased HIV replication. Presently, thalidomide is used to treat an immunological condition which occurs in people with leprosy. Several small studies have suggested a role for thalidomide in the treatment of oral aphthous ulcers in people with AIDS. A 40-person study is underway at Rockefeller University to elucidate thalidomide's role in HIV treatment. Thalidomide is best remembered as the the drug first used as a treatment for morning sickness in pregnant women which caused severe birth defects in their offspring. The thalidomide controversy led to the drug's market withdrawal in the United States and Europe in the early 1960s and the creation of the present mandate of the Food and Drug Administration (FDA). Triple TB Treatment NDA Marion Merrel Dow, a Kansas City, Missouri-based drug company, filed a New Drug Application (NDA) for Rifater, a three-in-one combination of rifampin, isoniazid, and pyrazimamide, three widely- used tuberculosis treatments. The company already markets rifampin under the brand name Rifadin. The company hopes its three- in-one product will improve patient compliance by reducing the number of pills in a TB treatment regimen. HIVIG for Vertical Transmission Studies North American Biologics Supplies will provide HIVIG (HIV-specific immune globulins) to the National Heart, Lung and Blood Institute of the NIH for a phase II clinical trial in HIV-positive pregnant women. The study will the test the ability of HIVIG to prevent HIV transmission from mother to fetus. Four hundred women are expected to enroll in the study, which will begin in September. The company hopes this study will provide convincing evidence of HIVIG's efficacy.