[Electronic distribution for GayCom by the Backroom 718 951-8256] Volume 7 no. 5 May, 1993 Gay Men's Health Crisis: Treatment Issues > HIV Therapeutic Vaccines: The Next Phase > Cooperative Vaccine Development Groups for AIDS > Vaccine Vocabulary > Lymphoma Treatment Update > Treatment Briefs >> Foscarnet/Ganciclovir Combo for CMV >> New Study Results: Smoking Is Still Bad for You >> Gynecological Care Manual for HIV-Positive Women >> Merck Protease Trial Begins >> Dr. Lew Katoff, Pioneer AIDS Activist, Dies >> "Sperm Cleaners" > Drug company watch ================================= ================================= HIV Therapeutic Vaccines: The Next Phase by Mike Barr Dr. Jonas Salk, the famous polio researcher, was the first to suggest vaccination of HIV-infected people with HIV vaccine products. This month, at the Berlin AIDS Conference, the company he helped start is expected to release the first clinical efficacy data to support his theory. Additionally, the federal government and several private companies plan their own large efficacy studies of therapeutic vaccines. In total, ten therapeutic vaccines are in trials. Despite the appearance of growing momentum, major scientific obstacles remain. This backgrounder reviews the known data on all the vaccines and helps explain an emerging debate among clinical researchers. Some may find the information in this article complex; the data on all the therapeutic vaccines consist solely of detailed tests of immunologic function. However, there are no other data for an individual to use when considering participation in a vaccine study. Although therapeutic vaccination seems a new concept to many, it is actually a well-known medical technique first introduced a century ago for the treatment of chronic staphylococcal infections, syphilis, and tuberculosis. These early efforts with therapeutic vaccination were only marginally successful; they almost faded from use when antibiotics were introduced in the 1940s. However, therapeutic vaccination today remains the standard of care for babies born to mothers infected with hepatitis B virus and those believed infected with rabies. There are many theories to explain how an HIV therapeutic vaccine might boost the weakening immune response to HIV and, perhaps, slow the course of disease.[1] However, the exact way a vaccine could help the immune system is still unclear. Furthermore, in cases where therapeutic vaccination does work, like hepatitis B and rabies, the vaccine prevents early infection before the development of a natural immune response. In HIV, therapeutic vaccines would be used after a natural immune response has been elicited and disease is already in progress. Interestingly, therapeutic vaccination is also under investigation for several herpes viruses, another form of chronic viral infection.[2] Human Studies The clinical studies of the therapeutic vaccines are summarized on page three. Each therapeutic vaccine is made by a different manufacturing process and includes different parts of HIV, different strains of the virus, and different adjuvants. Some of these differences may be significant. (See Table II, below.) However, at this point in the process, no objectively reviewed information suggests one vaccine product is superior to any other. Claims about the advantages or disadvantages of a particular vaccine or vaccine manufacturing technique come exclusively from its producer. Since studies which will answer these questions have just started, we will publish a detailed article describing the best approach when data emerge. [Editor's Note: See Bulletin of Experimental AIDS Treatments 3/93 for a review of different vaccine manufacturing techniques.] All studies summarized are phase I/II safety studies. All show that the vaccines are safe and well-tolerated over the course of the study period. One study, though, followed the trial volunteers for over four years and found no evidence of increased viral replication or exacerbated CD4 cell loss. The therapeutic vaccines induce both humoral and cellular immune responses in the study participants. The humoral arm of the immune system is controlled by B cells and responds to infection by producing antibodies. The vaccines stimulate antibodies to new parts of HIV's envelope, including increased binding antibody in nearly all subjects at titers which usually decreased over time. Neutralizing antibodies were also seen; however, these antibodies were directed at the vaccine itself, not HIV. The cellular arm of the immune response is controlled by T cells and responds to infection by activating other immune cells to kill diseased or infected cells directly. Components of the cellular arm of the immune system include the familiar CD4 and CD8 cells, as well as natural killer cells, macrophages, and various other monocytes. Cellular responses to the vaccines include improved lymphoproliferative responses, such as delayed hypersensitivity reactions (a skin test of cellular immune response) and T cell proliferation to foreign antigens in nearly all subjects. Increases in cytotoxic T lymphocytes (immune cells which kill viral infected cells) were observed in only a few subjects. While some studies suggest increases and/or stabilization of CD4 cell counts, these results remain inconclusive and controversial. Some initial reports claimed an observed decrease of HIV in the blood; however, these claims were found to be inaccurate and have been retracted. The Role of Cellular Immunity A major problem vaccine researchers face is knowing which aspects of the immune response should be stimulated to improve the course of disease. Recent work by Ronald Desrosiers with an SIV vaccine (Simian Immunodeficiency Virus is a monkey virus similar to HIV which is used as an animal model for human disease) may provide a clue. Desrosiers notes that monkeys immunized with a vaccine which induces high levels of neutralizing antibodies were not protected from infection. However, when the same vaccine was used to induce less robust antibody responses, all animals were protected. "Either the nature of the neutralizing antibodies being elicited is different with the different approaches," Desrosiers concludes, "or the key protective component is something other than neutralizing antibodies." [3, 4] Accordingly, Gene Shearer of the National Cancer Institute proposes that the same may be true for humans. He notes that HIV-infected individuals continue to produce HIV antibodies, but have a progressive loss of cellular immunity. In the progression towards AIDS, production of interferon-gamma and interleukin-2 (cytokines associated with cellular immunity) falls while production of interleukin-4 (a cytokine associated with humoral immunity) increases. As evidence to support his theory, Shearer cites cases of seronegative individuals at high risk for HIV infection (such as gay men and injecting drug users) who have been exposed to HIV and demonstrate HIV-specific cellular immunity, but no HIV antibodies. Similarly, cell-mediated immunity specific to HIV has been seen in infants who remain seronegative despite being born to seropositive mothers. "These babies were effectively immunized in utero," Shearer explains.[5] Shearer suggests these people were infected with "defective" HIV or such a small volume of virus that they became "exposed" without productive infection. Under the right conditions, a certain degree of cellular immunity or protection might be achieved without the production of HIV-specific antibodies. An inoculum of 40 to 80 micrograms, Shearer reasons, is enough to induce strong cellular immunity but a weak or no antibody response. In experiments with macaque monkeys infected rectally with live SIV, Shearer shows that while a high volume of inoculum produced a vigorous antibody response in three out of three monkeys, only one mounted a detectable cell-mediated response to the infection. Perhaps most interesting of all, two monkeys with high antibody levels but little or no cellular immunity have progressed to symptomatic disease. The monkey with strong cellular immunity has not. Seven additional monkeys inoculated with tiny volumes of SIV produced no antibodies and all remain symptom-free more than 75 weeks later. Salk also now believes that cellular responses are critical. He proposes that antibody responses will not protect against HIV; rather, the antibody arm of the immune system needs to be shut off entirely and the cellular portion stimulated in isolation.[6] Salk cites a study of two groups of monkeys immunized with two SIV vaccines.[7] The monkeys immunized with the vaccine which induced the most robust humoral (including neutralizing antibodies) and cellular immune responses developed infection -- as did both of the controls. This, Salk explained, represents an unexpected and paradoxical outcome and raises the question as to whether or not immunization might -- under any circumstances -- induce a protective effect. (He fails to explain, however, why the experiment was not conducted to induce a principally cellular immune response in one group and a predominantly humoral response in the other -- in order to directly compare the utility of each in isolation.) As further evidence, Salk points to a study performed in mice with Leishmaniasis.[8] In that experiment, resistance to disease was associated with cellular immunity and the absence of antibody responsiveness. Also, in work with leprosy patients, resistance to disease is associated with predominance of a cell-mediated immune response while susceptibility to disease is associated with a predominance of an antibody response. Surrogate Markers If a consensus has begun to emerge that increased cellular responses are critical to the success of a therapeutic vaccine, there is still no agreement on which cellular responses to measure. As described above, three tests of cellular immunity have been used in therapeutic vaccine studies. However, no data yet exist to support using any one of these measures as markers of efficacy. Margaret Johnston, Acting Deputy Director, Division of AIDS, NIAID commented "The biggest problem with the vaccines is surrogate markers." Increased cytotoxic T lymphocytes (CTLs) have been observed in a few vaccine study patients. This may be a good sign; Bruce Walker of Harvard University has observed HIV-specific CTLs in four out of five long-term survivors he studied.[9] Walker hopes to characterize further these CTL responses by learning how they might improve prognosis and survival. However, it is technically difficult to measure CTL responses. It is unlikely they will be used widely in the near future. T cell proliferation to foreign antigens, a measure of the immune system's ability to respond quickly to infection, has also been seen in vaccine study subjects. However, like CTL tests, these tests are difficult to perform and will likely not be used widely. Delayed type hypersensitivity reaction (DTH) measures the immune system's ability to remember previous infection and its response time to infection. Unlike the other tests, DTH is widely available. It is a simple skin test well known to most researchers. A DTH test injects antigens under the skin. Within a few days, the skin becomes indurated (a red, hardened bump) if the immune system has responded to the vaccine. Since the level of induration can be measured (i.e. by measuring how wide the area of hardening is), scientists hope to use the size and length of the DTH reaction to predict ultimate clinical outcome. Salk and his colleagues have attempted to make the case that improved DTH responses correlate to clinical outcome.[10] Salk reports on a study he began in 1987 with 107 HIV-infected people. The therapeutic vaccine induced both new humoral and cellular immune responses. After six months of follow-up, HIV-infected individuals had significantly improved anti-HIV DTH responses. In a slide presented to several vaccine conferences over the past year, the Salk team grouped responders and non-responders to the vaccine by the strength of their DTH reaction. Among the twelve "responders" there were no deaths, no new opportunistic infections, and only two new cases of Kaposi's sarcoma; while among the twelve "non- responders" four new opportunistic infections, three new cases of Kaposi's sarcoma, and three deaths were observed. Ostensibly, the responders were the ones who had exhibited the strongest DTH response while non-responders had a weaker DTH reaction. Yet this conclusion was not easy to glean from the bar chart which illustrated the magnitude of DTH responses. Rather, some claim the two groups had different baseline CD4 cell counts. They argue that these baseline differences, not the magnitude of DTH response, account for the difference in outcome. Conclusion Small phase I studies of several HIV therapeutic vaccines show that they are safe and induce new cellular and humoral immune responses. No vaccine has conclusively demonstrated a positive effective on CD4 cell levels. No vaccine has demonstrated that it can reduce HIV levels in the body, either. As phase III studies begin, new surrogate markers are needed to measure the treatment effect of the therapeutic vaccines. In particular, research is needed to clarify what role, if any, DTH responses may have in gauging treatment effect. 1. Salk J. Nature 1987; 327:473-76. 2. Straus S, et al. Journal of Infectious Disease 1993; 164:1045-52. 3. Cohen J. Science 1992; 258:1880-1. 4. Daniel M, Kirchhoff F, et al. Science 1992; 258:1938-41. 5. Shearer G. Oral Presentation. 2nd Annual GMHC/CRIA Forum on HIV Vaccines. New York. 11-12 February, 1993. 6. Salk J. Reconceptualization of Requirements For Induction of HIV Immunity By Vaccination. Salk Institute, La Jolla, CA. Presented at VIII International AIDS Conference, Amsterdam. 20 July, 1992. 7. Vaslin B, et al. Abstract PoA 2239. VIII International AIDS Conference, Amsterdam. 8. Bretscher PA, Wei G, Menon JN et al. Science 1992; 257:539-42. 9. Walker B. Oral Presentation. 2nd Annual GMHC/CRIA Forum on HIV Vaccines. February 11-12, 1993. 10. Salk J. Oral Presentation. 5th Annual Meeting of the National ================================= ================================= Cooperative Vaccine Development Groups for AIDS. Chantilly, VA. 30 August to 3 September, 1992. Vaccine Politics After nearly a year of turmoil, the Department of Defense (DOD) agreed to transfer a controversial $20 million Congressional appropriation for HIV vaccine therapy research to the Department of Health & Human Services (HHS). The Congressional set-aside was initially made to the DOD to study only one vaccine product, Vaxsyn, MicroGeneSys's gp160 product. However, critics argued that VaxSyn was no more worthy of targeted funding than other vaccine products, including those manufactured by Genentech, Immuno AG, Immune Response Corp., and Chiron. Also, critics charged that scientists, not Congress, should set scientific priorities. In January 1993, a blue-ribbon panel of leading scientists and patient advocates appointed by Dr. Bernadine Healy, Director of the National Institutes of Health (NIH) recommended that the funds be used to evaluate the clinical usefulness of several vaccine products. The trial could include 6,000 to 12,000 participants. While no protocol has yet been released, it is expected that the final study will comply with these recommendations. The DOD, heavily lobbied by MicroGeneSys's President, Frank Volvowitz, initially opposed the comparative study, and announced that it would test only VaxSyn against placebo. However, the DOD finally accepted the NIH position. A statement released by the DOD says "Transfer of the funds will permit rapid initiation of studies through NIH's large, established AIDS Clinical Trials Group (ACTG) network of civilian medical research units throughout the United States." As Treatment Issues goes to press, a new complication has emerged. Rumors abound that MicroGeneSys has refused to provide Vaxsyn to the NIH for the comparative study. Volvowitz refused to comment to Treatment Issues on the rumors. By threatening to charge the NIH to study Vaxsyn, MicroGeneSys may hope to scuttle the comparative study. The $20 million allocation is insufficient to fund the large, comparative trial if the cost of drug is included. ================================= ================================= Vaccine Vocabulary Adjuvant: a substance, usually mineral oils and/or killed mycobacteria, added to a vaccine preparation to increase the immune response to it. Antibody Dependent Cellular Cytotoxicity: direct killing of an infected cell by lymphocytes when it is coated with antibodies. Binding Antibodies: proteins produced by B cells which bind antigens and form immune complexes. Chimpanzees: an endangered ape native to Africa used in HIV research. Extremely limited supplies, and their high cost, limit their use in research. Chimps are the only other mammal, besides humans, that can be infected by HIV. Dendritic cells: Immune cells with long, tentacle like branches called dendrites. Four types of dendritic cells are recognized: follicular dendritic cells, lymphoid dendritic cells, interdigitating cells, and Langerhans' cells. Their exact function is still unknown, although it appears to be antigen presentation to lymphocytes. Follicular dendritic cells: a dendritic cell found in lymphoid follicles. (see dendritic cells) Langerhans cells: a dendritic cell found in the skin. (see dendritic cells) Live-attenuated vaccine: a vaccine composed of a live virus chemically or procedurally weakened so that it is incapable of causing disease. Macaques: any monkey of the genus Macacca, including rhesus monkeys. Natural Killer Cells (also called NK cells): Immune cells which kill infected cells directly within four hours of contact. NK cells differ from other killer cells, such as cytotoxic T lymphocytes, in that they do not require contact with antigen before they are activated. Neutralizing Antibodies: proteins produced by B cells which can directly inactivate an invading microorganism, such as a virus or bacterium. Nef-deleted vaccine: a live-attenuated HIV vaccine composed of HIV with nef, a key component of the virus, deleted to lessen its ability to replicate or reproduce. Post-infection immunization: see therapeutic vaccines Prophylactic vaccine (also called preventive vaccine): a vaccine administered prior to infection with a disease causing microorganism to create an immune response which prevents infection. Proteins: substances which form the major component of cells, involved in all essential life functions. Rhesus monkeys: (Macacca mulatta). A small monkey native to India used frequently for research purposes, especially testing the safety and efficacy of vaccines. Subunit vaccine: a vaccine composed solely of a synthetically produced piece of the virus, usually by recombinant DNA technology. Therapeutic vaccine: a vaccine administered after infection with a disease causing microorganism to modify the immune response to cure or improve the course of disease. Vaccine: A substance, usually derived from a microorganism, which can induce immunity to disease. Whole-killed virus vaccine: a vaccine composed of an intact, but killed, virus. ================================= ================================= Lymphoma Treatment Update by Gabriel Torres, M.D. and David Straus, M.D. Hodgkin's Disease and non-Hodgkin's Lymphoma (hereafter HD and NHL respectively) are both lymphomas, cancer of the lymphatic system.[1] NHL is the most common lymphoma in PWAs. Central Nervous System lymphoma is the most common manifestation of NHL; it is lymphoma localized in the brain or spinal cord. Lymphomas can also present with systemic disease involving the bone marrow, liver, spleen, lung, and gut (see Treatment Issues Vol. 5, No. 7 for a comprehensive review of lymphomas). Pluda and colleagues form the National Cancer Institute report an increased incidence of NHL among AIDS patients treated with zidovudine (AZT) for over two years. They speculate the increase is related to prolonged survival despite profound immunosuppression.[2] The expanded use of combination antiretroviral therapies and prophylaxis for multiple opportunistic infections are expected to increase survival and, therefore, may lead to an increase number of cases of lymphoma in people with AIDS in the next several years, making the search for new treatments more critical. HD has also been reported with increased incidence in HIV-infected people, yet is associated with a better outcome than NHL.[3, 4] The prognosis for a PWA with NHL is poor; median survival is only six months in most cases.[5, 6] Death is directly related to the lymphoma in approximately 50 percent of patients and to infections, probably aggravated by side effects of chemotherapy, in the rest.[7] In some cases, however, prolonged, complete remissions with disease- free survival for more than one year have been attained with combination chemotherapy. One research team reports that a CD4 count greater than 100 predicts long term survival for patients with NHL.[8] Other predictors include no other concurrent AIDS-defining illnesses and absence of disease outside of the lymphatic system. In patients with good prognostic factors who are treated with AZT and prophylaxis, low-dose chemotherapy achieves a median survival of five to six months.[9] In those with poor prognostic factors, chemotherapy does not affect the rate of complete remission and survival is 3.5 months.[10] Monoclonal Antibodies A new experimental approach to treating HL and NHL is monoclonal antibody therapy. Antibodies are proteins produced by immune cells to respond to infection or cancer. Monoclonal antibodies are produced in laboratories using clones of a single immune cell. Monoclonal antibody technology can produce large quantities of one antibody. Monoclonal antibodies have two properties which lead scientists to believe they may be used therapeutically. In some cases, they are directly cytotoxic; monoclonal antibodies, on their own, may destroy unwanted cells. In other cases, the monoclonal antibodies have no destructive effects themselves but can carry toxins or radioactive particles directly to target cells or tissues. Lymphoma patients considering monoclonal antibody therapy must have a biopsy of their tumor to ensure it reacts to the monoclonal antibody under investigation. A short initial hospitalization is usually required to observe the effects of the monoclonal antibody therapy. In addition, a catheter may be required to administer safely the experimental agents and to obtain frequent blood samples. Patients must be strong enough to live at home and take care of most of their personal needs. Three monoclonal antibodies are being studied at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, two for the treatment of NHL and one for HD. For NHL patients, OK B7, a monoclonal antibody attached to radioactive iodine, is under investigation. A phase I trial of the OK B7 monoclonal antibody among eighteen patients with relapsed NHL showed that the therapy was nontoxic and well-tolerated at six dose levels ranging from 0.1 to 40mg.[11] The investigation was able to show that the tumor cells which expressed the OK B7 antigen had uptake of the radioactive monoclonal antibody compared with tumor cells which did not express the antigen. No lymphoma regression could be attributed to the OK B7 infusions; altogether three patients had complete remission for eleven to twelve months; these three had the highest percentage of uptake of OK B7 per dose in their mode. Little is known about the side effects of radioactive monoclonal antibodies; some potential side effects may include allergic reactions, fevers, chills, low blood pressure, and liver and kidney problems. Possible side effects of radiation include low blood counts, infections, bleeding, and the development of other cancers. For NHL patients ineligible for the OK B7 protocol, monoclonal antibody anti-B4 is under investigation. Anti-B4 is linked to ricin, a potent immunotoxin derived from the castor bean. Anti-B4 blocked ricin will attach to most lymphoma cells but not normal tissue. Ricin is chemically altered so that it will only slightly affect normal tissues. Preclinical studies of anti-B4 blocked ricin in monkeys demonstrated that its main toxicity is elevation of liver enzymes. A Phase I trial of the drug in 25 non-HIV infected patients with NHL was performed at the Dana Farber Cancer Institute.[12] The drug was given as a single one-hour bolus infusion for five days at doses ranging from 1mg/1kg/d to 60mg/1kg/d. The study confirmed that the main toxicity is elevated liver function tests. Two patients had a drop in platelet counts. One patient had a complete response, two had partial responses, and eight had mixed or transient responses. Other side effects of the monoclonal antibody include allergic reactions and weight gain due to fluid retention. One advantage seems to be that it does not cause significant neutropenia. A monoclonal antibody recognizing R24, an antigen found in HD, is also under investigation. The R24 antibody also recognizes T cell lymphoma cells, though these tumors are quite rare. For more information on the monoclonal antibody studies, call Dr. David Straus at Memorial Sloan Kettering Cancer Center at 212/639- 8365. Chemotherapy for Hodgkin's Disease An Italian research team reports the results of MOPP (a combination chemotherapy regimen including methotrexate, oncovin, prednisone, and procarbazine) with or without radiation therapy in a large group of HIV-infected persons with HD. Complete remissions occurred in 50 percent of patients and partial remissions in 45 percent.[13] Average survival was sixteen months; however, 61 percent of patients developed opportunistic infections during the follow-up period. None of the patients in this trial received AZT. In a related study, the researchers alternated MOPP with ABVD (a combination chemotherapy regimen including adriamycin, bleomycin, vinblastine, and dacarbazine): The alternating regimen was better tolerated than MOPP alone. In a smaller group of patients, chemotherapy was given with AZT. Only one opportunistic infection occurred, although the rates of complete and partial remissions were similar. One concern regarding use of chemotherapy in HIV-positive persons with HD has been the occasional transformation of HD into high- grade NHL, which has been reported in one case.[14] Conclusion Although treatment options for AIDS-related lymphomas are limited, new strategies with combination chemotherapy or monoclonal antibodies are being developed which may improve survival and extend remissions. The primary prevention of lymphomas, probably through inhibition of Epstein Barr Virus replication or other oncogenic agents, still needs to be pursued since cases of lymphoma are expected to increase as people with AIDS live longer in an immunosuppressed state. 1. Hessol NA, Katz MH, et al. Annals of Internal Medicine. 1992; 117:309-11. 2. Pluda JM, Yarchoan R, et al. Annals of Internal Medicine. 1990; 113:276-282. 3. Hessol NA, Katz MH, et al. Annals of Internal Medicine. 1992; 117:309-11. 4. Rothmann S, Tourani JM, Andrieu JM. New England Journal of Medicine. 1990;323:275-6. 5. Ziegler JL, Beckstead JA, et al. New England Journal of Medicine. 1984; 311:565-570. 6. Lowenthal DA, Straus DJ, et al. Cancer. 1988; 61:2325-2337. 7. Gill PS, Levine AM, et al. Journal of Clinical Oncology. 1987; 5:1322-1328. 8. Kaplan LD, Abrams DI. JAMA. 1989; 261:719-24. 9. Levine AM,Wenz JC, et al. JAMA. 1991; 266:84-88. 10. Tirelli U, Errante D, Oksenhendler E. JAMA. 1992; 267:509. 11. Scheinberg DA, Straus DJ, Yeh SD. Journal of Clinical Oncology.1990; 8:792-803. 12. Grossband ML, Freed AS, Ritz J. Blood. 1992:576-585. 13. Vaccher E, Tirelli U, Chieppa F. Abstract Mo0059. Presented at VIII International Conference on AIDS, Amsterdam, 1992. 14. Montalban C., Rodriguez JL, Aguado M. Blood.1990; Suppl 1:76. ================================= ================================= Treatment Briefs by David Gold Foscarnet/Ganciclovir Combo for CMV The combination of ganciclovir and foscarnet, both approved to treat CMV retinitis as monotherapies, may be effective in PWAs who have failed both drugs. In a study reported in The Journal of Infectious Diseases (May 1993:1184-8), ten patients with CMV were given a combination of ganciclovir and foscarnet at standard doses. Nine of the ten responded to therapy. Compared to those treated with foscarnet or ganciclovir alone, the patients on combination treatment had a higher rate of anemia (a reduced level of red blood cells). No other significant differences between monotherapy regimens and the combination were noted. A larger study examining combination ganciclovir/foscarnet was just initiated by the Federal Government's National Eye Institute. Accrual has just started; results are expected in a couple of years. New Study Results: Smoking Is Still Bad for You Two reports provide new evidence that smoking accelerates progression to AIDS in HIV-positive individuals. A British study reported in AIDS (May 1993: 705-710) compared 43 HIV-positive smokers (at least ten cigarettes per day) with 41 HIV-positive non- smokers. The study found that the smokers progressed to AIDS in a median time of 8.2 months compared with 14.5 months for the nonsmokers. In addition, an abstract submitted to a joint meeting of the Association of American Physicians and five other organizations in Washington, D.C. suggests that smoking may increase the load of HIV in the lungs and accelerate the progression to AIDS. For more information, see "Tobacco Smoking and HIV" in Treatment Issues (December, 1992). Gynecological Care Manual for HIV-Positive Women Risa Denenberg, an AIDS activist and family nurse practitioner, has written Gynecological Care Manual for HIV-Positive Women. The 173-page manual is designed to help primary care providers offer appropriate gynecological services to HIV-positive women. The manual features sections on General Information, Setting Up GYN Services, GYN Findings in HIV Infection, GYN Screening for HIV- Positive Women, Protocols for Gynecological Infections, and Resources. Call 800/225-0694 or fax 405/924-9414 to order copies or for more information. Merck Protease Trial Begins A phase I trial of Merck's new oral HIV protease inhibitor is currently enrolling at Thomas Jefferson University Hospital in Philadelphia. The trial will measure safety, tolerability, and antiviral activity of the drug. The drug will be given for twelve days, and a washout from other antiretrovirals is required. Participants may not have an AIDS-defining condition. Accommodations are provided to those from out of town. Call J. Plentka, RN at 215/955- 8575 for more information. Dr. Lew Katoff, Pioneer AIDS Activist, Dies Lew Katoff, Director of GMHC's Technical Assistance Program, died of AIDS-related complications on May 15, 1993. Lew completed ground-breaking studies on long-term survivors that were presented at the VII International Conference on AIDS. He will be missed. International Conference Overviews A Community Forum on Treatment Developments at the IX International Conference on AIDS in Berlin will be held on June 29, 1993 at 7:00 p.m. at the Lesbian & Gay Community Center, 208 West 13th Street, NYC. The forum, which is free and open to all, is cosponsored by Gay Men's Health Crisis, the Community Research Initiative on AIDS, and the Treatment Action Group. The AIDS Treatment Data Network (ADTN) is sponsoring another seminar to review the conference on June 30, 1993. Call 212/966-9839 to register for the ADTN seminar. "Sperm Cleaners" Researchers at the University of Milan Medical School report in The Lancet a system to "clean" sperm of HIV. Their study offers hope to HIV discordant couples who want to conceive. 29 HIV-negative women were inseminated with "cleaned" semen from their HIV- positive partners. HIV is separated from the semen by spinning the semen in a centrifuge. This process spins the fluid and separates it into distinct particles. The uninfected sperm were then incubated, washed, and inseminated into the women. The researchers report that seventeen women became pregnant and ten babies have been followed. All are HIV seronegative and healthy; the oldest child is now three years old. The researchers also report that none of the 29 women became HIV-infected after six months. Eighteen women are confirmed HIV-negative after eighteen months. Despite this report, it should be noted that since 1988, the US Centers for Disease Control has recommended against insemination from HIV-positive men. Additionally, there are reports of women becoming infected after insemination with HIV-infected semen, including one woman who claims to have undergone a procedure similar to that used in Milan (see MMWR 1990; 39:249). A final note: Reports in The Lancet are not peer-reviewed and often must be viewed skeptically. ================================= ================================= Drug company watch by David Gold FDA Committee to Consider Vestar's NDA in June The FDA's Oncologic Drugs Advisory Committee will review Vestar's New Drug Application (NDA) for liposomal daunorubicin (DaunoXome) as a treatment for HIV-related Kaposi's sarcoma on June 17, 1993. DaunoXome is the result of a new pharmaceutical manufacturing technique which coats drugs in fatty cells (lipids). Vestar scientists believe the fatty coat increases the ability of the drug to reach its target cells, and reduces drug toxicities. DaunoXome is available via an expanded access program to KS patients in New York, San Francisco and Los Angeles. Call 800/247-3303 for enrollment information. Some analysts predict DaunoXome will be approved by the first quarter of 1994. Chiron Expands IL-2 Studies; Begins Immunoglobulin Trials Chiron announced plans to expand studies of its recombinant interleukin-2 (IL-2) for HIV-positive individuals, based on results from a study of six patients conducted by Dr. Cliff Lane of the National Institute of Allergies and Infectious Diseases (NIAID). The study claims impressive CD4 cell and antibody responses in patients given Chiron's IL-2 intravenously. Chiron also plans to begin collecting HIV immunoglobulins from participants its gp120 preventive vaccine trials to study as a post-needlestick prophylaxis. Japanese Company Invests in Vertex Kissei, a Japanese drug company, paid $20 million for Asian marketing rights to Vertex's HIV protease inhibitors. Vertex has several protease compounds in preclinical development. Vertex claims its protease compounds are more potent than Abbott's and more bioavailable than Roche's. Boehringer Road Show Boehringer Ingelheim recently completed a series of meetings nationwide to discuss nevirapine, its non-nucleoside reverse transcriptase inhibitor, with activists. The company presented data from ongoing trials (mostly dosage, toxicities, CD4 changes, p24 changes) and outlined a series of planned trials of nevirapine, AZT, and ddI. Trials of this three drug combination, the basis for the recent convergent combination hypothesis, are planned for different patient populations. However, the company appears to focus its efforts on the asymptomatic population. In light of the recent questions about the use of CD4 cells in this population, most participants agreed that virological data from these studies are more important. Meanwhile, a number of activists are calling for an expanded access or compassionate use program for nevirapine and other RT inhibitors. Others suggest this is premature. British Biotech HIV Vaccine in Europe British Biotechnology announced that Phase II trials of its p24- based therapeutic vaccine product have started in Europe. The dose- ranging study will include 72 asymptomatic HIV-infected individuals and will be expanded to sites in the U.S and Australia sometime in 1993. Repligen Meets with Activists Repligen held a series of meeting with activists to discuss development of the company's V3 loop HIV vaccine and Platelet Factor 4 (PF-4), its anti-Kaposi's sarcoma drug. The V3 loop is found on a stretch of the gp120 protein. Repligen researchers suggest that a V3 loop vaccine causes a strong immune response. A Phase I trial in 24 HIV-positive individuals is scheduled to begin shortly. The company also presented results from a Phase I trial of PF-4. In the study, the drug was administered at the site of KS lesions (intralesionally). The 12 trial participants had KS with a median CD4 count of 65. No "measured tumor regression" was seen (using standard measurements). However the company noted that the physicians, who were blinded as to which lesions were being treated with PF-4, were able to identify the treated lesions 67 percent of the time (we confess to being unsure as to exactly what this means). Repligen officials have thus concluded that "PF-4 appears to have slowed the growth of KS lesions in comparison to placebo." No major toxicities were seen and the company is planning to begin three trials this summer using three different methods of administering PF-4: intralesionally, subcutaneously, and intravenously. Burroughs Wellcome Plans To Improve AZT, Acyclovir At a recent investment analyst meeting in New York, Burroughs Wellcome shot-caller David Barry disclosed company plans to seek FDA approval for its acyclovir prodrug, valaciclovir (also known as BW 256) in 1994. BW256 is more readily absorbed than acyclovir and need only be taken two to three times per day (compared with five times per day for acyclovir). Burroughs is in a race against time to replace acyclovir before its exclusive US marketing rights to the drug expire in 1997. Acyclovir is the company's biggest money- earner, bringing in twice as much as AZT. Acyclovir earned $838 million for Burroughs in 1991. Burroughs is also reportedly working on a new anti-HIV nucleoside analogue. Are we the only ones who wonder why this company, which has made hundreds of millions of dollars from PWAs, fails to invest into other, more promising classes of anti-HIV therapies, such as protease inhibitors, tat, and non-nucleoside RT inhibitors?