Subject: GMHC Treatment Issues Vol. 6 No. 8 Date: Sep 1992 (1105 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& && T R E A T M E N T I S S U E S && &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& TREATMENT ISSUES The Gay Men's Health Crisis Newsletter of Experimental Therapies Volume 6, Number 8 -- September, 1992 CONTENTS: [items are separated by "*****" for this display] VIII International Conference on AIDS: Antiretroviral Update HIV Negative AIDS? Vaccine Developments Treatment Briefs Events ***** VIII International Conference on AIDS: Antiretroviral Update by Gabriel Torres, M. D. While sensational stories such as HlV-negative AIDS (see side bar, page 5) stole media attention at the Netherlands-hosted International Conference on AIDS, science did manage to make an appearance at the conference. Treatment Issues will publish several reports in the upcoming editions on new data about antivirals, vaccines, opportunistic infections, immune therapies women and HIV, and AIDS pathogenesis. This article covers much of the new research about anti-HIV therapies. AZT Monotherapy Dr. David Cooper of Australia presented data from a Burroughs Wellcome long-term study of AZT (1000 mg/day) versus placebo in asymptomatic HIV-positive patients with more than 400 T4 cells. The treatment lasted an average of 93 weeks, making it the longest of any placebo-controlled trial using the drug. The study enrolled 993 patients from both Europe and Australia. Results showed that 22 patients (5%) progressed to AIDS or ARC in the placebo group compared to 11 (2%) in the AZT group. Progression to early HIV disease (which included one episode of oral thrush or herpes zoster) occurred in 13% of the placebo group compared to 7% of the AZT group. In addition, 25% of participants receiving placebo had declines in T4 cell counts to less than 350, compared to 15% of patients receiving AZT. The most common side effects in the AZT arm were nausea, headache, weakness and loss of appetite. There were no differences in survival between the groups, but slowed disease progression was seen in all subsets of patients taking the drug, including those with entry T4 cell counts between 500-750. In the 500-750 T4 cell count group, 7% of the placebo recipients progressed to AIDS/ ARC, compared to only 3% of the AZT recipients. In addition, 13% of those taking placebo with T4 counts between 500-750 progressed to clinical HIV disease compared to 7% of the AZT recipients. The authors conclude from this study that AZT therapy offers a small but definite benefit for preventing disease progression, even in people with T4 cell counts between 500-750. Dr. Paul Volberding reported that the subset of patients in the U. S. study of AZT monotherapy (ACTG trial 019) with T4 cell counts greater than 500 are still in the double-blind phase of the trial. No results are yet available about whether the drug will be beneficial to this group. High-level AZT resistance has not been seen yet among the patients in ACTG 019, despite the two years of therapy with this drug. Additionally, Dr. John Hamilton presented some follow-up data on the Veterans' Administration study of "early" (when T4 cells drop to 500) versus "late" (when T4 cells drop to 200) treatment with AZT. Progression to AIDS has been reduced in the early treatment group, but no survival benefit has been noted. More anemia, nausea, decrease in white blood cell units, diarrhea and headaches occurred in the early treatment group. The average survival after AIDS diagnosis was longer (17.3 months) in the group that started AZT later than in the group that started the drug early (13.7 months). The overall percentage of patients surviving after two years remains similar for both groups. Dr. Samuel Broder, Director of the National Cancer Institute (NCI), who first tested the use of AZT as a treatment for HIV, raised a question about whether asymptomatic HIV-positive people benefit from early use of AZT. Dr. Broder urged researchers to focus on answering this question. DDI Monotherapy The crucial questions regarding ddI monotherapy are still unanswered and little new information was presented in Amsterdam. Dr. James Kahn presented the final results of a large phase II/III U. S. study (ACTG 116B/117) that compares ddI (500 or 750 mg/ day) to AZT (600 mg/day). Participants had AIDS or ARC and less than 300 T4 cells or were asymptomatic with less than 200 T4 cells and had received AZT for greater than 4 months. The study enrolled 913 patients between November 1989 and March 1991. Among the asymptomatic and ARC patients, fewer participants who switched to 500 mg of ddI progressed to AIDS or died than those who remained on AZT. No difference was noted between those who switched to 750 mg of ddI and those who remained on AZT. T4 cell count elevations were higher for those on either dose of ddI than those on AZT. No overall differences in survival between the groups were observed. An Italian study (ISS901) presented by Dr. Marco Floridia and colleagues corroborated the results of ACTG 116B/117. In a group of 160 patients with AIDS and previous AZT therapy for six months, a trend of improved survival and lower incidence of opportunistic infections and malignancies was seen in participants who switched to ddI, compared to those who remained on AZT. In another randomized multicenter Italian study (ISS902) comparing AZT to ddI in previously untreated ARC patients, no differences in clinical endpoints after six months were seen. However, those who received ddI seemed to have greater T4 cell responses than those who received AZT. These Italian studies are important because the participants were mostly injection drug users and women, unlike most of the U. S. study participants who are largely gay men. Antiretroviral research on women and IDUs is scant and greatly needed. The overall conclusion that can be made from these ddI studies is that the drug appears to be beneficial in patients with AIDS or ARC who have received 4-6 months of AZT therapy. Clinical effects and responses in T4 cell counts have been demonstrated in asymptomatic patients and patients with ARC with T4 cells less than 200. Only a T4 cell benefit has been demonstrated in patients with AIDS. In patients with ARC and T4 cells between 200-500 the data suggest a benefit for ddI but are not entirely conclusive. Why the clinical benefit seems to be more evident in those with earlier HIV disease is unclear but may be related to a greater degree of AZT resistance in more advanced patients, predisposing them to ddI resistance. The question of whether ddI should be added to, or substituted for, AZT after six months of AZT therapy is still unanswered, as is the question about which drug is preferable for initial therapy. DDC Monotherapy Relatively few presentations addressed the use of ddC as monotherapy in patients with advanced HIV disease. The "expanded access" ddC program which enrolled nearly 3500 patients in the U. S. A. was presented by Dr. Judith Lieberman of Hoffmann-La Roche which compared the toxicity of ddC in the high dose (0.75 mg every 8 hours) versus low dose (0.375 mg every 8 hours) groups.[1] Peripheral neuropathy occurred twice as commonly (15% vs. 8%) in the high versus low dose group. Rare toxicities included inflammation of the pancreas (less than 1%), ulcers in the esophagus (less than 1%) and in one patient, seizures. Half of those who developed pancreatitis had previous history of the condition. Many who had ddI-induced pancreatitis were able to tolerate ddC without recurrences of pancreatitis. No difference in survival has been seen between the high and low dose groups. A Canadian group also presented the experience of the open label use of ddC in patients intolerant to AZT or ddI.[2] Of 425 patients enrolled in January, 1991, only 152 (36%) remained on therapy. Thirteen percent discontinued therapy and 6% died while on therapy. Side effects included peripheral neuropathy in 38 patients and mouth ulcers in 15 patients. Another poster from New York by Barr et al compared AZT, ddI, and ddC to no anti- retroviral therapy in patients with late stage disease.[3] While all the nucleoside analogues were superior to no therapy in terms of the development of opportunistic infections, ddC seemed to provide a survival benefit to those who switched from AZT to ddC over those who switched to ddI or remained on AZT. D4T (STAVUDINE) Various presentations on the use of this new nucleoside analogue, manufactured by Bristol-Myers Squibb, showed that it improved T4 cell counts and decreased HIV replication in human subjects. The largest study presented by Dr. Lisa Dunkle combined the data from six phase I and phase II trials that together enrolled 264 patients in d4T studies at 10 sites in the U. S.[4] Improvements in T4 cells of 50% or greater were seen in some patients and were sustained for a year. Other beneficial effects included declines in p24 antigen levels, weight gain and improvement in senses of well-being. Side effects were seen mostly at high doses and included peripheral neuropathy and elevated liver enzymes. The doses that were tolerated best were less than 2 mg/kg/day. Side effects were usually reversible when the dose was reduced to 1 mg/kg/day. In another d4T study with 38 HIV-positive patients who had less than 500 T4 cells at entry, the drug reduced HIV in peripheral mononuclear blood cells and acid-dissociated p24 antigen levels at a dose of 2 mg/kg/day but not at lower doses after ten weeks of therapy.[5] Another study showed that d4T had similar cognitive enhancing effects as AZT as measured by neuropsychological tests.[6] A phase II/III study being conducted at many sites in New York and Philadelphia comparing d4T to AZT is up and running for people with under 500 T4 cells. For more information about trials in your area call Bristol-Myers Squibb at 1-800-662-7999. Rumor had it that phase I trials by the company continue to require that women entering d4T studies be sterilized. However, the company denied the rumor, but women are still required to use approved forms of birth control in larger trials of the drug. 3TC A new reverse transcriptase inhibitor, 3TC, under development by Glaxo, is under study in phase I/II trials. Preliminary data were presented by researchers describing more than 170 patients who have received doses between 0.5 mg/kg and 12 mg/kg per day. The drug was well tolerated in asymptomatic patients as well as ARC and AIDS patients, and the changes in T4 cell counts and p24 antigen levels seem to suggest that the drug has antiviral activity. Isolated cases of bone marrow damage, elevated amylase levels or peripheral neuropathy have occurred. Further studies will try to evaluate which is the best dose to be used in phase II trials. Trials for children who have received little or no antiretroviral therapy are being conducted by the NIH. For more information call (301) 402-1387. ACYCLOVIR Several studies presented at the Amsterdam conference suggest that the use of acyclovir may be beneficial in patients with HIV infection. Dr. Michael Saag of the University of Alabama at Birmingham presented a poster with the results of a large trial comparing AZT (600 mg/day) to AZT (600 mg/day) plus high dose acyclovir (4800 mg/day). The 677 participants had ARC and T4 cell counts between 200-800. After more than 18 months of follow-up, a significant improvement in T4 cell response (an average of 25 cell difference) and less frequent herpes infections were noted in participants taking the combination therapy. No other significant clinical differences were seen.in the two arms. Dr. Michael Youle from the U. K. presented the final results of the European-Australian Acyclovir Study which had been reported in the London Times and in Treatment Issues several months ago. The original goal of this study was to determine if high dose acyclovir (800 mg four times daily) could prevent CMV in HIV-positive patients with T4 cells under 150. Three- hundred-two HIV-positive patients with evidence of CMV infection but no active disease were randomized to receive acyclovir or a matching placebo in 19 centers. The effect of acyclovir on survival was most evident in, but not limited to, patients receiving AZT therapy and those with T4 cell counts less than 50. Acyclovir seemed to reduce the risk of dying by 50%. The explanation for the improvement in survival is unknown, though it is speculated that high dose acyclovir could be inhibiting a cofactor (such as CMV or human herpes virus-6). AZT/INTERFERON-ALPHA Studies suggest that the combination of AZT and interferon may enhance T4 cell responses and reduce levels that mark HIV activity. Interestingly, though, none showed a definitive clinical benefit. Dr. Clifford Lane from the National Institute of Health (NIH) presented an update on the large trial comparing AZT (600 mg/ day) alone, alpha-interferon (5 million units/day) alone, or the combination in asymptomatic patients with T4 cell counts greater than 500. The study started with 60 patients in each group; however, after 16 months more than 25% of the patients had to be withdrawn from the study. Toxicities included muscle wasting (AZT alone), headache and depression (Interferon alone) and hepatitis, weight loss, nausea, and vomiting (combination arm). A slight improvement in T4% was seen in the combination arm, leveling off by 24 weeks. The reduction in p24 antigen levels was more pronounced in the combination arm compared to the other two arms, and there was a delay in the emergence of AZT-resistant virus in the combination arm. NEVIRAPINE Dr. Sarah Cheeseman from the University of Massachusetts presented early data from ACTG studies 164/168 comparing AZT (600 mg/day) in combination with one of four doses (12.5, 50, 200 and 400 mg/day) of nevirapine. This drug is a non-nucleoside reverse transcriptase inhibitor, made by Boehringer Ingelhelm, which had been shown in early experiments to lead to resistance within several weeks. In the nevirapine alone arms, p24 antigen levels declined within the first few weeks and then rose again, indicating the onset of viral resistance to nevirapine. A dose- response relationship was noted with increasing doses of nevirapine in terms of p24 antigen reduction. A trend for more profound suppression of p24 antigen levels in the combination arm (especially with the 400 mg dose of nevirapine) was noted, compared to the nevirapine alone arms. No consistent effects on T4 cell counts were observed that could be attributed to nevirapine. However, in a poster presentation, Dr. Douglas Richman presented data from the same study which showed an initial boost in T4 cells that correlated with a p24 antigen reduction and disappeared by week 4 when resistance had developed.[7] Side effects of nevirapine included sleepiness, fevers, and rashes occurring mostly with the 400 mg dose. AZT/DDI A study which was initially reported in the May/June 1992 Treatment Issues demonstrated significant T4 cell increases with the use of AZT and ddI together, compared to monotherapy with either agent. Dr. Robert Yarchoan studies 164/168 comparing AZT of the National Cancer Institute presented a study comparing an alternating regimen of ddI (500 mg/day) and AZT (600 mg/day) to a regimen where both drugs are taken together (AZT 300 mg/ day and ddI 250 mg/day). Patients enrolled had AIDS and entry T4 cell counts between 200-350 and less than three months of previous antiretroviral therapy. Patients in the alternating arm switched from AZT to ddI every three weeks. After a follow-up period of 63 weeks, a statistically significant benefit in T4 cell counts was noted in the patients taking the two drugs together. Superior weight gain and reduction in p24 antigen levels were also more sustained in participants taking the drugs together. New opportunistic infections occurred in two patients in the simultaneous arm and five patients in the alternating arm. Toxicities in participants on either regimen were similar. In general, therapy with the lower dose combination of AZT and ddI was well-tolerated and associated with more sustained T4 cell elevations than the drugs taken in an alternating fashion. Dr. Ann Collier presented follow-up data on 69 patients enrolled in a six-arm study of AZT / ddI combinations compared to AZT alone. All groups had rises in T4 cells, but data showed that patients on the combinations using 600 mg of AZT and either 334 or 500 mg of ddI did better. Reductions in HIV, as tested by PCR, were demonstrated in 78% of patients on combination compared to 14% of patients on AZT alone. Patients on combination therapy also gained more weight and developed less anemia than patients on AZT alone. AZT/DDC Relatively little new information was presented in Amsterdam about the use of AZT and ddC in combination. At a symposium sponsored by Burroughs Wellcome Company, Dr. Robert Schooley of the University of Colorado, reviewed the data from the studies that led to the approval of the combination of ddC and AZT in patients with T4 counts less 300. In one study, participants receiving AZT alone had an average increase of 50 T4 cells compared to a 100 cell increase among those on the combination.[8] These increases were sustained for six months. Two studies conducted by community researchers in San Francisco showed that AZT/ddC combination therapy was well tolerated and associated with rises in T4 cells.[9] A final study described 51 patients who took ddC, obtained through buyer's clubs, and experienced average rises in T4 cells of 47 cells after six months of therapy.[10] PENTOXIFYLLINE Pentoxifylline (brand name Trental) is a drug which reduces levels of tumor necrosis factor (TNF), a cytokine which enhances HIV replication and contributes to the development of wasting syndrome in AIDS. The first phase I trial, conducted through the AIDS Clinical Trials Group (ACTG), was presented in Amsterdam by Dr. Bruce Dezube from Boston. Twenty five AIDS patients with T4 cell counts under 300 who had been on AZT or ddI for at least two months were treated for 16 weeks with pentoxifylline (400 mg three times daily). Most patients had T4 cell counts of under 100. Seventeen patients completed eight weeks of therapy. Eight had to discontinue because of noncompliance (2), chemotherapy (2), PCP (2), cryptococcal meningitis (1) and fever (1). In 11 of 13 patients studied, levels of TNF dropped. A slowing down of weight loss was also noted, though it was not statistically significant. Decreases in levels of triglycerides, a surrogate marker of cytokine activation, were also noted. However, no changes in neoptrin (a marker of macrophage activation) were found. In four of seven patients T4 cell counts rose. These preliminary results are very encouraging given the relatively low cost and toxicities associated with pentoxifylline. Future trials are planned which will use higher doses of the drug. Pentoxifylline is FDA-approved for treatment of leg cramps and poor circulation. TAT ANTAGONIST (24 -- 7 4 2 9) The TAT antagonist is a drug found to inhibit a gene product of HIV, called TAT, that is responsible for regulating transcription of the virus. Test tube experiments have demonstrated that it decreases cell-associated viral codes in acutely and chronically infected cells. It also seems to be active against HIV-2 and strains of HIV-1 which are resistant to non-reverse transcriptase inhibitors such as nevirapine. A study to determine how well the body absorbs the drug was presented by Dr. Paul Lietman from John Hopkins University. Three cohorts of HIV-infected volunteers received doses of 60 mg, 200 mg, or 600 mg of the drug, or a placebo. Accumulation of the drug over time was noted at the dose of 600 mg/day. Mild side effects were noted in 16 of 18 patients, the most common were headache, discoloration of urine, and drowsiness. The latter was not unexpected since the drug is chemically very similar to diazepam (Valium). Notably, activists were able to convince Hoffmann-La Roche to drop the criterion requiring women to be sterilized in order to participate in TAT trials. N-ACETYLCYSTEINE (NAC) Robert Walker from the NIH presented the results of a phase I study of NAC, an amino acid precursor which has been shown in test tube studies to inhibit HIV transcription and replication. Twenty-three patients with T4 cell counts under 500 were enrolled in the study and assigned to different doses of intravenous NAC three times a week for six weeks followed by daily oral NAC. Most of the patients had been or still were receiving AZT, ddI or ddC. Side effects seemed to occur more often with the intravenous drug including allergic reactions, fatigue, flushing, and gastrointestinal symptoms. The highest tolerated dose was 100 mg/kg and the bio-availability of the drug was found to be less than 5%. There were no changes in T4 cells, p24 antigen levels or plasma viremia during the first 12 weeks of therapy. Another study of NAC was presented as a poster by Dr. Bonaventura Clotet from Barcelona, Spain. In this study, 32 patients received either NAC (3000 mg intravenously) or placebo.[11] All patients were also receiving AZT and PCP prophylaxis. In the NAC group levels of p24 antigen fell from 171 pg/ml to 75 pg/ml after 14 days of therapy. No other changes in surrogate markers occurred. Three patients developed a rash during the last few days of the infusions. Further studies of NAC will use higher doses to determine if the drug truly has an antiviral effect in humans. GLQ223 (COMPOUND Q) The results of a phase 1B study of GLQ233 (trichosanthin) were presented by Dr. Ken Gorelick from Gene Labs Technologies, sponsor of the drug. Data demonstrated that intravenous infusions of the drug were associated with dose-related increases in total number of T-cells and beta-2 microglobulin levels in patients with AIDS or ARC.[12] Side effects included muscle pain, headache, and fever, most of which were controlled by over-the-counter medicines. Dr. Larry Waites of Project Inform also presented data on a long term tolerance community study of GLQ2333. He showed that the drug was relatively well-tolerated in combination with other treatment, such as AZT, ddI, ddC and PCP prophylaxis. A phase II trial is currently underway comparing GLQ223, AZT and the combination of both drugs in participants with T4 cell counts between 200-500 and at least 9 months of AZT treatment. In New York, the trial is enrolling at St. Vincent's Hospital. For more information, contact Kerry McIntyre or Noel George at (212) 790-8605. In San Francisco, contact Carol Arri at (415) 476-4082, extension 84094. PROTEASE INHIBITORS Researchers from five different pharmaceutical companies reported on compounds that are able to inhibit the HIV protease enzyme. The protease enzyme is responsible for cutting large precursor proteins into smaller peptides that eventually form the mature virus parts. The main problem in the development of protease inhibitors has been that the candidate compounds are poorly absorbed into the body. Dr. Daniel Norbeck of Abbott Laboratories demonstrated that an oral form of the compound named A-80987, achieved good plasma levels in rats, dogs and monkeys in an oral form of the drug and was able to significantly inhibit HIV activity in the test tube. Significantly, Dr. Norbeck stated that A-80987 should enter phase I trials "soon after the conclusion" of the conference. Another researcher, Dr. Michael Otto, of DuPont showed that HIV strains resistant to protease inhibitors can occur in the laboratory. This seems to be caused by a single mutation. Another investigator from Upjohn showed that the Upjohn version of the protease inhibitor (U-75875) was able to shut off HIV replication in chronically infected macrophages. Despite these advances, the research on protease inhibitors continues at a slow pace, and there were no data released on the ongoing studies of these compounds being conducted by Hoffmann-La Roche. CONCLUSION Reports about antiretroviral drugs confirmed some preliminary reports from earlier studies. Clinicians and community members disagree about what is the most optimum time to start AZT or combination regimens in people with asymptomatic disease. Information concerning antiretroviral drugs and women and the effect of these drugs on menstruation and the female hormonal system was notably lacking from most reports. Additionally, some of the hopeful drugs of the 90s are turning out to have many more resistance problems than projected. On the positive side, however, data from the few studies of combination regimens offer some new proposals to doctors and people living with HIV. FOOTNOTES 1. VIII Int'l Conf on AIDS. #Po. B. 3004, Amsterdam, July, 1992. 2. VIII Int'l Conf on AIDS. #Po. B. 3006, Amsterdam, July, 1992. 3. VIII Int'l Conf on AIDS. #Po. B. 3001, Amsterdam, July, 1992. 4. VIII Int'l Conf on AIDS. #WeB. 1011, Amsterdam, July, 1992. 5. VIII Int'l Conf on AIDS. #WeB. 1010, Amsterdam, July, 1992. 6. VIII Int'l Conf on AIDS. #PoB. 3033, Amsterdam, July, 1992. 7. VIII Int's Conf on AIDS. #PoB. 3576, Amsterdam, July, 1992. 8. VIII Int'l Conf on AIDS. #PoB. 3592, Amsterdam, July, 1992. 9. VIII Int'l Conf on AIDS. #PoB. 3006, Amsterdam, July, 1992. 10. VIII Int'l Conf on AIDS. #PoB. 3005, Amsterdam, July, 1992. 11. VIII Int'l Conf on AIDS. #PoB. 3013, Amsterdam, July, 1992. 12. VIII Int'l Conf on AIDS. #PoB. 3442, Amsterdam, July, 1992. ***** VACCINE DEVELOPMENTS by Gabriel Torres, M. D. There are two types of HIV vaccines: therapeutic vaccines are designed to provoke an immune response in antibodies and cells in order to suppress HIV infection and halt disease progression; and preventive vaccines are meant to protect HIV- negative people from HIV infection. Dr. Dan Hoth of the National Institutes of Allergy and Infectious Diseases (NIAID), gave an overview of both types of HIV vaccines that have advanced into human trials. Notably, some progress has been made in this area since the last international conference. So far, the three strains of HIV used for vaccine development have been LA1 (IIIB), SF2 and MN. The IIIB strain is the most widely used in candidate vaccine trials, though the MN strain is more prevalent in people in the U. S. Envelope proteins, which are particles from the outer part of the HIV coat, such as gp160 and gp120, comprise the most well-known human HIV vaccines. Inner core HIV proteins which have been widely used in vaccine work are p24 and p27. In addition, whole inactivated virus (WIV), stripped of its envelope, has been used in some vaccine trials. Candidate vaccines have taken various forms including recombinant (manufactured) HIV proteins, synthetic peptides, whole virus particles and vector vaccines, which use another virus to carry the vaccine into the body. Some new approaches include the use of pseudo-viruses and various adjuvants that are added to assist in the development of an immune response. Phase I trials have demonstrated that most candidate vaccines are well-tolerated and that few side effects result from their administration. Minor side effects include fever, malaise, mild pain and erythema at the injection site. Many of these vaccines have induced humoral responses (antibody activation) including binding antibodies in nearly 100% of immunized subjects followed by a decrease in antibody titers over subsequent weeks, as well as neutralizing antibodies in a majority of cases. In trials of recombinant gp160, cellular responses have also been noted which represent the generation of lymphocytes and T killer cells. When blood from vaccinated patients was injected into laboratory mice, the mice were protected from HIV infection. THERAPEUTIC VACCINES Various presentations in Amsterdam focused on the use of vaccines as immunotherapy, which means that they enhance the immune response in HIV-positive people and hopefully prevent disease progression. The only human vaccine which is known to be effective in preventing disease progression is the rabies virus vaccine. It has the expectation of eliciting an immune response that will counteract the effect of the rabies virus prior to the onset of symptoms. Among the hopeful HIV candidate drugs are gp160 and gp 120. Descriptions of each of these therapies follow. GP 160 Various presenters from different parts of the world presented encouraging data about the use of recombinant gp160. Dr. Christos Tsoukos from Canada presented the results of a small phase I trial using 21 asymptomatic HIV-positive participants with less than 500 T4 cells at entry.[1] Ten patients received 160 ug of gp160 and 11 receive 320 ug of the vaccine injections on days 0, 30, 60, 90 and 180. There was no evidence of toxicity after one year. Ninety percent developed either new or augmented antibody responses to specific gp160 epitopes. These patients have also had significant increases in absolute T4 cell counts (mean increase is 117) and the percentage of T4 cells (mean increase 2%). There were no significant differences in absolute T4 cells between the different dose groups. Dr. Fred Valentine of New York University presented data on 52 asymptomatic HIV and Hepatitis B virus (HBV) antibody positive patients with T4 cell counts over 400 who received one of four doses of gp160 or recombinant hepatitis B vaccine.[2] Patients receiving gp160 developed substantial lymphocyte responses as well as antibodies directed at gp160. Lymphocytes recovered from immunized patients also released interleukin-2, a virus-killing substance, when stimulated by gp160 in the test tube and directly attacked gp160 envelope proteins. The immune responses demonstrated by the patients in Dr. Valentine's trials occurred only in participants who received the gp160 vaccine and not in those who received the Hepatitis B vaccine, suggesting that they were caused by the vaccine and not by a general response of the immune system related to stimulation with a nonspecific antigen. Dr. Gary Blick, a community physician from Greenwich, Connecticut, investigated the combination of gp160 and p24 vaccines.[3] Participants were enrolled to receive 320 ug of gp160 vaccine and 640 ug of p24 vaccine on days 0 and 7, and months 1, 2, 4 and 6, and then at three month intervals thereafter for 24-months. Thirty patients were enrolled with different levels of entry T4 counts. There was no evidence of toxicity other than a red inflamed reaction at the injection site. All of those with greater than 200 T4 cells at entry had new or augmented antibody responses against HIV's gp160 protein. Levels of Beta-2 microglobulin, p24 antigens, and p24 antibodies have remained stable. No patient with entry T4 cells between 200 and 500 has developed AIDS or ARC or has died. Mean changes in T4 cell counts ranged from 42-108, but could not be ascribed solely to the vaccine, since patients were also on antiretroviral therapies. Dr. Robert Redfield from the Walter Reed Army Institute of Research in Rockville, Maryland presented data concerning 30 patients who had received recombinant gp160 in the original trial of the vaccine [See Treatment Issues, Vol 5, No 6].[4] Dr. Redfield reported that after increasing the vaccination schedule from three to six injections, 29 of the 30 patients mounted an immune response. Perhaps most significantly, by using polymerase chain reaction (PCR), he was able to demonstrate reductions in viral load 18 to 24 months after vaccination. Toxicities remain limited to local reactions. A large multicenter, placebo-controlled trial is underway to assess the efficacy of this vaccine in HIV-positive participants with more than 400 T4 cells. In a poster presentation, Redfield and colleagues reported an increase in the absolute number and percentage of T4 cells in the majority of patients vaccinated with gp160.[5] In a controlled study comparing AZT to placebo among gp160 recipients, the researchers were able to demonstrate that the T4 cell elevations were not related to AZT. A poster presentation by a Stanford group headed by Dr. Smriti Kundu showed that gp160 injections were able to induce a type of lymphocyte cell able to kill HIV-infected cells. Another Stanford researcher, Dr. David Katzsenstein reported on the use of a skin test, namely a gp160 protein injected under the skin directly after six gp160 injections.[6] This test is used to detect whether the gp160 vaccine is working to boost the immune response, as measured by cytotoxic T-lymphocyte activity and lymphocyte proliferation. Forty-eight hours after the injection, swelling around the site of injection correlates with a positive response to the vaccine. The skin test will be used to monitor patients in vaccine trials. GP 120 Dr. Deborah Birx of Walter Reed Army Hospital, in cooperation with researchers from Genentech, Inc., demonstrated that in 45 asymptomatic HIV-positive patients, recombinant IIIB gp120 is well-tolerated.[7] The vaccine induced new cellular and humoral responses to HIV. Responses were dose-related and the only toxicities reported were mild headaches in 9 out of 45 participants and one case of increased liver enzymes. PREVENTIVE VACCINES Various investigators reported on initial results of candidate vaccines used in HIV-negative individuals to prevent HIV infection. Dr. Hoth projects that a candidate vaccine with a 60% efficacy made available in 1988 to 1 million persons at risk of infection, could prevent 145,000 infections. On the other hand, if we wait for a vaccine to be 90% effective, which would take until 2004, only 87,000 infections of the same would be prevented. This analysis suggests that candidate vaccines should be made widely available as early as possible, despite the possibility of not being maximally effective. IIIB RGP 120/HIV-1 Vaccine Investigators from the federally-funded AIDS Vaccine Clinical Trials Network also reported on the safety and immunogenicity of the rgp 120 described above.[8] This vaccine given with an alum adjuvant had been shown to elicit type- specific neutralizing antibodies in chimpanzees and protect them from when HIV is intravenously introduced into the body. Two years later, the chimpanzees still have no sign of HIV infection. In a double-blind, dose-escalation phase I trial, 25 HIV- negative volunteers at low risk for HIV infection were randomized to receive either 100 or 300 mcg of the vaccine or the alum adjuvant (a vehicle that helps the body have a bigger immune response to the vaccine) injection at 0, 4 and 32 weeks. Few side effects were reported. They included pain and redness at the injection site, malaise, headache, nausea, and one case of elevation in liver enzymes. Antibody responses directed against he V3 loop (a specific inner region of HIV) and blocking antibodies against T4 were elicited in those receiving the 300 mg dose. Nine of ten developed neutralizing antibodies at the highest titer seen with a IIIB envelope vaccine. In addition, a lymphocyte-inducing response was elicited in nine of ten participants receiving the higher dose. IMMUNO RGP 160 Investigators from the AIDS Vaccine Evaluation Group presented the results an Immuno rgp 160 phase I safety study using 60 HIV-negative volunteers. Immuno rgp 160 is different from other gp160 vaccines because it is produced in mammal cells rather than insect cells, and is coated with a sugar-like substances. This version therefore more closely resembles the gp160 protein made by natural HIV. Volunteers received 12.5 or 50 mcgs of Immuno rgp 160 or an adjuvant control by injections given at 0,1, 6 and 12 months. After three injections, more than 90% of the volunteers had developed antibodies which bind rgp160 and lymphocyte-inducing responses. In the extension studies with this vaccine doses of 200 mcgs will be used to see if the vaccine induces neutralizing antibodies. GP120 VACCINE Dr. James Kahn from the University of San Francisco presented the initial results of a phase I study using a recombinant gp120 vaccine developed by Chiron Corporation.[9] The vaccine was made using recombinant gp120 from the SF2 strain of HIV, taken from the ovary cell of a Chinese hamster. It is fully glycosylated (coated with sugar molecules) as well, therefore mimicking the native conformation of an HIV surface protein, and it can bind to the CD4 receptor of HIV. In the study 42 HIV-negative participants received gp120 and an adjuvant oil emulsion (MF59) alone or with increasing doses of a potent immunomodulator called muramyl tripeptide (MTP-PE). All volunteers who received the three injections of gp120 and MTP-PE developed neutralizing antibodies, and two thirds developed cross-neutralizing antibodies directed against another HIV strain called MN. Volunteers who received gp120/MF59 had no serious side effects; those who received MTP-PE had more adverse effects including muscle aches, headache and fever. Another vaccine being developed by Chiron Corporation is the Env 2-3 antigen, a recombinant gp120 from the SF2 strain of HIV which is produced in yeast. In an initial trial of 62 subjects, 75% developed neutralizing antibodies to HIV's SF2. Trials are planned combining this vaccine with the MF59 adjuvant and MTP-PE. SALK THEORY Dr. Jonas Salk, the developer of the polio vaccine, introduced a new vaccine theory at the Amsterdam international conference which generated much controversy. He postulates that two types of immune responses account for containment of HIV infection: the first is the cellular response called the "TH1 response"' and the second is a humoral response, called the "TH2 response" and characterized by the production of antibodies. Dr. Salk suggests that an effective vaccine should arrest the immune system so that only the TH1 response occurs, but not the TH2 response. This theory supported the work of Dr. Gene Shearer of the NIH who reported HIV-specific cellular responses in HIV- negative repeated exposure through high-risk individuals who have remained free of HIV infection (as measured by PCR) despite high risk behaviors. Dr. Salk suggests that minuscule amounts of the virus may be able to elicit cellular responses without eliciting antibodies. This theory was challenged at the conference by other vaccine researchers such as Robert Redfield and Emilio Emini, who feel that both antibody and cellular responses are important in preventing initial infection because they can neutralize virus much quicker than memory cells. CONCLUSION The debate and the research move vaccine progress forward, making it perhaps one of the most exciting areas of HIV medical science. Unfortunately, trials of therapeutic vaccines presently enrolling human participants, are difficult to access. It is essential for pharmaceutical companies and government research officials to work together to expand access to these therapies. An expanded access program on a true parallel track with clinical trials would be ideal. Treatment Issues will continue to report on all HIV vaccine research as it unfolds. FOOTNOTES 1. Int'l Conf on AIDS. Abst.# Tu.B. 0560, Amsterdam, July 1992. 2. Int'l Conf on AIDS. Abst.# Tu.B. 0561, Amsterdam, July 1992. 3. Int'l Conf on AIDS. Abst.# Tu.B. 0562, Amsterdam, July 1992. 4. Int'l Conf on AIDS. Abst.# Tu.B. 0563, Amsterdam, July 1992. 5. Int'l Conf on AIDS. Abst.# Po.B. 3040, Amsterdam, July 1992. 6. Int'l Conf on AIDS. Abst.# Po.A. 2192, Amsterdam, July 1992. 7. Int'l Conf on AIDS. Abst.# Tu.B. 0564, Amsterdam, July 1992. 8. Int'l Conf on AIDS. Abst.# Mo.B. 0026, Amsterdam, July 1992. 9. Int'l Conf on AIDS. Abst.# Mo.B. 0025, Amsterdam, July 1992. ***** HIV-NEGATIVE AIDS? The report which received most attention at the VIII International Conference on AIDS was a presentation describing several cases of severe immuno-deficiency in persons without detectable HIV at a "Recent Reports" session at the conference, Dr. Jeffrey Laurence of Cornell Medical Center reported five cases of immune suppression characterized by low T4 cell counts, opportunistic infections, like CMV colitis, PCP and KS. Some patients had risk factors for HIV-1 infection yet none had any evidence of HIV-1 or HIV-2. Dr. James Curran, Director of AIDS at the Centers for Disease Control (CDC), reported six additional cases which had been reported to the CDC in the past years. The agency chose not to report these cases and received severe criticism by many researchers for that decision. Other researchers reported similar HlV-negative cases of immune- suppression, including Dr. David Ho with 11 cases of patients. These were mostly gay men with low T4 cell counts, three of whom had OIs. In addition, Luc Montagnier, the co-discover of HIV-1, reported experience with a similar case. He claimed to have found HIV in the urine of a patient whose blood had no traces of the virus after PCR analysis. Another researcher, Dr. Sudhir Gupta from the University of California at Irvine reported evidence of a new virus in a 66 year old woman who had developed severe immunodeficiency and OIs many years after receiving blood transfusions. Dr. Gupta described the virus as a "human intracisternal retroviral particle" or "HICVR" because it was found in closed spaces called cisterns in the cytoplasm of cells. Other researchers countered that these particles represented lab contaminants and not viruses. Dr. Max Essex of Harvard's School of Public Health argued that this virus-like particle was probably a "retroid" -- a fragment of the normal human gene that resembles a virus, yet which have no pathogenic potential. In this case, as in four of Dr. Ho's cases, reverse transcriptase (the enzyme that copies HIV inside infected cells) was present. However, this is a non- specific finding that occurs during Hepatitis C, Grave's disease, and Kawasaki's disease. Other researchers from New York reported cases of Kaposi's sarcoma (KS) in gay men who were not infected with HIV. Most of these cases were relatively mild (non-extensive, less than 10 lesions and without oral involvement) and their meant T4 cell count was 768. Tumor samples failed to show HIV-1 OI HIV-2, but one patient's tumor revealed evidence of HTLV-1. It has been postulated that an undetermined sexually transmitted agent may be responsible for the development of KS in these men. Officials from the World Health Organization and the CDC plan to organize an international meeting to investigate all these cases of HIV negative AIDS from both a basic science and an epidemiological perspective. In the meantime, The New York City Department of Health is gathering information about any immune suppressed illness that may be related to these cases. Doctors, health care providers, people with HIV and others are encouraged to contact Allen Greenberg at (212) 566-5062, who is conducting investigations. ***** Treatment Briefs by David Gold ASTRA BOYCOTT The boycott of Astra Pharmaceutical's widely used drug Xylocaine is in full swing with much publicity generated from the Amsterdam Conference. Many organizations and health care professionals have already signed on to the boycott, including Project Inform, Lamda Legal Defense, AIDS Project/LA, and the Swedish Lesbian and Gay Alliance. Let's hope Astra and its PR firm, Hill and Knowlton, come to their senses and reduce the $25,000 per year price of foscarnet, so that we all can get on to working on other issues. Call David Rephun at (212) 929-6143 to sign on to the boycott. TAG REPORT ON AIDS RESEARCH AT THE NIH Gregg Gonsalvez and Mark Harrington of the Treatment Action Group (TAG) have written an incredibly insightful and comprehensive report entitled "AIDS Research at the NIH: A Critical Review." Part I is a summary and Part II "A User's Guide to the NIH. " For copies of both reports send a $15 check or money order (made out to TAG) to 239 7th St., #3, N. Y., N. Y. 10009. NONOXYNOL 9 A study recently published in JAMA (July 22/29, 1992) raised concerns that nonoxynol-9 may not be as effective in preventing transmission of HIV and other sexually transmitted diseases as had been hoped. In the study, the use of a nonoxynol-9 contraceptive sponge among women in Nairobi, Kenya, was associated with an increased frequency of genital ulcers and vulvitis. In addition, there was a small, but statistically insignificant, higher rate of HIV seroconversion among women using the nonoxynol-9 sponges as compared to those using placebo over a 24-month period. However, the nonoxynol sponge was associated with a 60% lower frequency of gonorrhea. The nonoxynol-9 gel has been shown in the test tube to be active against a variety of sexually transmitted bacteria and viruses, including HIV. Given the widespread use of nonoxynol-9, more research to determine its effectiveness in preventing HIV transmission is clearly needed. DAIICHI KS DRUG On August 7,1992, activists from GMHC, ACT UP/ NY, ACT UP/Golden Gate and WHAM met with representatives from Daiichi Pharmaceuticals to discuss plans for SP-PG (now known as DS- 4152), a compound which has shown promising results against Kaposi's sarcoma-like and solid tumor diseases in animals. Company officials disclosed plans to seek FDA approval for phase I trials in October 1992. These dose-escalating trials are planned for San Antonio and Los Angeles. Activists demanded that the company meet with the FDA before October so that the trials can be approved and initiated as quickly as possible. On August 11, 1992, Daiichi informed activists that it had already begun initial discussions with the FDA and that submission of documents would begin shortly. It is hoped that this is the beginning of a more cooperative effort by Daiichi to work with activists for the rapid testing and development of this promising compound. Reports indicate that another promising drug for KS, AGM-1470, which is believed to work in a manner similar to SP-PG, is about to begin clinical trials at the National Cancer Institute. TAT DRUG PLANS Hoffmann-La Roche unveiled its plans for the TAT inhibitor drug, a long-awaited anti-HIV agent. Phase I trials showed the drug to be safe for at least five days. The multi-site trial (ACTG 213) will be a six month dose-ranging trial in people with "early stage" HIV disease. It will be located at ACTG sites in Baltimore, Boston, San Diego and Cleveland. A second Roche- sponsored trial will enroll people with "late stage" HIV-disease and a third ACTG (217) trial is planned for testing the drug in combo with AZT. ACT UP/NY'S T&D DIGEST George Carter and Theo Smart of the Treatment & Data Committee of ACT UP/NY have been publishing extremely useful, informative and well-written issues of the "T&D Digest." Call (212) 564-AIDS for subscription information. HANDS AROUND THE WHITE HOUSE ACT UP/DC is organizing an action immediately following the display of the NAMES Project's AIDS Memorial Quilt on October 12,1992, in which thousands of people will link hands around the White House to symbolize the desperate need for Presidential leadership to end the AIDS crisis. Call (202) 328-2437 for more information. NEW TREATMENTS INFO-LINE The NYS AIDS Institute's Experimental Treatments Info-line is now up and running. Using a touch tone telephone, you can access information on all expanded access programs and clinical trials in the New York area. When you call, you can enter a condition, such as PCP (727) or HIV (448), and hear a recording of all the treatments currently available. People with HIV can even enter their T4 cell count to access only the trials for which they qualify. Call 1-800 MEDS 4 HIV (in NYS only) or 212- 613-4348 for access instructions. Congratulations to Mark Milano for getting this project going. LAUGHTER IS THE BEST IMMUNOMODULATOR In February, 1991 researchers from the Loma Linda University School of Medicine reported that individuals who viewed a 60 minute humor video showed "a significant increase" in T4 and T8 cells, natural killer cell activity, and interferon alpha, as compared to a control group who did not view the video. The researchers called for further research on the potential immunomodulating effect of humor-associated laughter, but we have heard no word on whether any large simple trials will soon be launched. BULK COPIES OF WOMEN'S TREATMENT ISSUES Bulk copies of the special edition of Treatment Issues devoted to Women and HIV treatment are available to all not for profit organizations. This 28-page issue, edited by Mary Beth Caschetta and Garance Franke-Ruta, is considered by many to be one of the most comprehensive reviews of issues relating to women and HIV treatment ever done. Call (212) 337-3505 for more information. ***** TREATMENT ISSUES EXECUTIVE EDITOR David Gold EDITOR Mary Beth Caschetta MEDICAL CONSULTANT Gabriel Torres, M. D. TECHNICAL COORDINATOR Paul Warren COPY EDITOR Gary Schmidgall MEDICAL CONSULTANT Gabriel Torres, M. D. David Gold Mary Beth Caschetta DESIGNER Stephen de Francesco PRODUCTION MANAGER Bill Boedeker PROOFREADER Steven Humes OFFICE VOLUNTEERS Barclay Dunn Joseph Evans Edward Friedel Eric Goldsborough Bradley Nance Gary Schmidgall Frank Schramm STUDENT INTERN Julie Francis Treatment Issues is GMHC's newsletter devoted to providing reliable information on experimental therapies. Describing an experimental therapy should not be construed as recommending it. All new treatments should be conducted under a physician's care. Treatment issues is published ten times yearly. All rights reserved. Non-commercial reproduction is encouraged. Subscription lists are kept confidential. Treatment Issues is supported in part by contributions made to the Richard Dunne Memorial Fund. Medical Information 129 West 20th Street New York, NY 10011 Copyright (c) 1992 Gay Men's Health Crisis, Inc. We Need Your Support Your contribution will help GMHC continue to publish Treatment Issues. All donations are tax-deductible. Mail to: GMHC Medical Information 129 West 20th Street New York, NY 10011 I want to help GMHC continue its vital medical information and treatment advocacy work. I have included a tax-deductible contribution. Suggested amount: * $30 Individuals * $50 Physicians/lnstitutions * $60 Foreign Sliding Scale PWA/HlV+/Low Income Please check one: [ ] New Subscription [ ] Renewal Subscription [ ] I am unable to contribute at this time, but please send me a complimentary subscription to Treatment Issues. [ ] Please send a compilation of back issues (we suggest a donation of $12 for those who can afford to pay.) All contributions of $50 or more will receive a copy of the Treatment Issues Compilation. Please make your checks payable to GMHC. If you cannot afford to contribute at this time, and you are a PWA, or are HIV-positive, a copy will be sent free of charge. ORGANIZATION STATEMENT A copy of GMHC's latest financial report filed with the Department of State may be obtained by writing to: NYS Department of State, Office of Charities Registration, Albany, NY 12231, or to GMHC. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display