Subject: Stockholm; Cryptococcal Meningitis; Vaccines Date: Jul 18 1988 (695 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& TREATMENT ISSUES -- The GMHC Newsletter of Experimental AIDS Therapies &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Volume 2 Number 5 July 18, 1988 In this issue: The Stockholm AIDS Conference Cryptococcal Meningitis AIDS Vaccine Developments Notes from Stockholm: The Fourth International AIDS Conference The Fourth International Conference on AIDS was held in Stockholm, Sweden from June 11 to June 16. The largest AIDS conference ever held, there were more than 7,000 registrants and over 6,000 abstracts submitted. We left for Stockholm with eager anticipation. But dollar for dollar spent and mile for mile travelled, the Fourth Interna- tional AIDS Conference was the most disappointing one to date from the perspective of AIDS therapy. Held in Stockholm's enor- mous conference center, exhibits and lectures were so distant that track shoes would have been the most appropriate attire. Because of the sheer volume of information presented, it was impossible to follow developments in all the facets of AIDS: one was lucky to get through the day assimilating only the data on AIDS treatments. So, unlike previous conferences, it was impos- sible to get an overall view of the increasingly diverse aspects of AIDS. The developments in treatments for AIDS were meager. Drugs which looked promising last year in Washington either received no further attention or were studied in less-than-reliable proto- cols. NIH's ACTG (AIDS Clinical Trials Group -- formerly known as ATEUs) presented a total of 25 abstracts, about half of which pertained to experimental treatments. The drugs they reported on were AZT, Foscarnet, Interferon, Doxorubicin (an anti-KS drug), and Trimetrexate. Notably absent were NIH-funded pilot studies on AL721, Imuthiol, Dextran sulfate, and others. Even more disap- pointing was the absence of data from two key trials -- the half-dose AZT trial (it was decided to extend this trial one year further before any conclusions can be drawn) and the AZT/Acyclovir trial. It is not clear why the latter trial has not yet generated any meaningful results. The article that follows is subdivided by drug. It is not footnoted in the typical Treatment Issues format; instead, abstract numbers appear in parentheses rather than at the bottom of the page. Anyone wishing to read or photocopy the original abstract may do so by appointment at the Department of Medical Information. AL721 There were 3 abstracts presented dealing with AL721 -- none of which were very convincing. The first (#3531) from a German group, treated 10 patients with advanced AIDS with 30 grams daily of lipids for 12 weeks. By the end of the study, 6 out of 10 patients developed opportunistic infections: 4 PCP cases (it is not known whether patients took prophylaxis or not), one severe herpes simplex, and one case of cryptosporidium. The experiments found no measurable increases in T4 cells, but they had diffi- culty in isolating HIV in 40% of patients by week 8. Their con- clusion in the printed abstract, "...In conclusion, oral adminis- tration of certain lipid mixtures appear to have measurable effects on patients lymphocytes and virus replication.", differs substantially from the poster presented in Stockholm, which said something to the effect that "no clinical benefit was observed." Finally, critics of the study (most notably Dr. Skornik from Israel) were quick to point out that the substance used in this trial had a 6:3:1 ratio, which, he maintained, is "totally use- less." Dr. Skornik and the group from Israel presented the two other papers on AL721. The first (#3530) reported a reduction of p24 antigen (thought to be indicative of the degree of viral activity in the body) in 8 patients taking 10 grams of AL721 daily. The patients ranged from asymptomatic seropositives to people with full-blown AIDS. Overall, 60% of patients had measurable reduction in p24 antigen, but out of the patients with full-blown AIDS, this figure was only 40%, leading the research- ers to conclude: "These results suggest that AL721 can be effec- tive in reducing the viral level at an early stage of HIV infec- tion." The third study, also presented by the Israeli group, reported on 32 patients (20 AIDS, 12 ARC) treated for at least 6 months (some as long as 21 months). No increases in T4 cells were seen, but in a subset of 5 patients, HIV activity as meas- ured by viral culturing "was reduced by 80-90%." They report: "Significant improvement in overt clinical parameters was observed in most patients, including fever defervescence, reduc- tion in diarrhea, increase in appetite, weight gain and clearing of skin rashes." In fact, upon careful inspection, the poster claimed that all of these symptoms were improved in all of the patients initially exhibiting them (with two exceptions: only 16 out of 20 AIDS patients had a reduction in fever, and only 19 out of 20 AIDS patients had an increase in body weight). At first glance, quite impressive indeed. Sound suspicious? You bet it does. There isn't a physician in New York City who has seen 100% improvement in fever, diar- rhea, appetite and weight in patients taking AL721, which seri- ously questions the patient selection reported in this study. In fact, critics of the researchers claim that there were a large number of "drop-outs", patients who left the study (presumably because they were not doing well) and did not return for follow- up. Clearly, the Israelis have treated more than 32 patients with AL721, but when asked directly about drop-outs, Skornick, obvi- ously offended by the question, said that such positive results are irrefutable. Are they? Not reported in Stockholm, the NIH mini-trial of AL721 is apparently finished, and federal researchers have been quoted as saying that the drug appears "non-toxic," scientific proof of the obvious. If immunologic and/or virologic assessments were made, they have not yet been released. Does AL721 work? Unfortunately, this three-year-old ques- tion has still not been answered. Anecdotal reports from several New York physicians seem to indicate that it does not, yet this is not a basis to draw any firm conclusions. While most physi- cians do not dissuade patients from taking AL721, few are advo- cates. The CRI (Community Research Initiative) is conducting a careful study of two different doses of AL721 which is perhaps the only reliable study of the substance. [Note: A comprehensive article on AL721 appeared in Volume 2, number 1 of Treatment Issues.] Dextran sulfate There were a few papers presented on this promising antiviral substance, although most studies were test-tube experi- ments and not clinical trials in PWAs. It seems that everybody has confirmed the potent antiviral effect. At least three more groups (#3141, #3536 [Dr. Broder's group at NIH], and #3537) confirmed this fact. But clinical tri- als of the substance in AIDS patients were sadly lacking. Dr. Abrams from San Francisco General Hospital presented data on his short trial (#3580) which has already been reported on in this publication. Basically, Dextran sulfate was shown to be a drug of low toxicity; side effects were negligable at doses of up to 3600 milligrams daily. Although two patients at lower doses (one at 900, one at 2700 milligrams daily) were removed from the study because of low white counts, these patients started out with very low counts. There were no significant rises in T-cells. p24 levels were drawn, but only one patient started out p24 positive; his p24 did not appreciably change. Two patients who started out p24 negative had significant rises during the study, not an encouraging sign of Dextran's antiviral effect in patients. Not presented in Stockholm but released in a public forum on June 29 were data from Dr. Barbara Starrett's informal monitoring project with Dextran. Her 8-week study of 54 patients (26 with AIDS, 12 with ARC, and 16 seropositives) can be seen as a series of 54 anecdotal observations, as many patients were on drugs other than Dextran. 24 patients were on AZT, 24 were on Acyclo- vir, and 14 were on both; 5 were on naltrexone; 21 were on Anta- buse; 5 were on Imuthiol. But there were 6 patients on Dextran sulfate alone (more on them later). All patients received 600 mg Dextran sulfate three times daily on an empty stomach. T-cells and p24 antigen were measured at the beginning of the trial and at 8 weeks. Presented first were the data on p24 levels. Ideally, an antiviral drug will cause those patients with positive p24 levels to revert to negative. In Dr. Starrett's study, 13 patients started out p24 positive. Unfortunately, only 3 reverted to p24 negative. Similarly disappointing is the fact that 5 patients who started out p24 negative wound up p24 positive at the end of the study. It must be emphasized that our knowledge of p24 antigen testing is rudimentary. Investigators have reported wide fluc- tuations in p24 antigen during a single day. Furthermore, as many as half of patients with severe ARC and AIDS are p24 nega- tive, so we cannot put all our eggs in the p24 basket in evaluat- ing antiviral drugs. As far as T-cells were concerned, the data was a bit more encouraging. Of the full-blown AIDS patients, 38% had rises in T4 counts. Of those with ARC, 50% had rises, and 56% of seropo- sitives exhibited a rise. An analysis of the magnitude of these rises has not yet been done. Of particular interest were the 6 patients on Dextran sul- fate alone. There were 4 patients in this group with significant rises in T-cells: One patient went from 400 to 1100; one from 551 to 614; one from 464 to 605; and one from 165 to 251. Clearly this group was a little healthier and started out with higher T-cells, but these kinds of increases are encouraging nevertheless. The 6 patients on Dextran sulfate alone all started out p24 negative; none changed to positive during the study. There were no side-effects noted during the study. There were no cases of lowered white blood cell count, red blood cell count, or liver function. Overall, there were 3 deaths during the study. Although this study probably presents more useful data than any conducted to date, it still does not answer the ultimate question about Dextran. That will take more time and more resources than one community physician can provide. Clearly, the consensus of noted researchers is that Dextran sulfate is an extremely promising drug; for anxious PWAs, more definitive data is critical. [Note: Treatment Issues has been following the saga of Dextran sulfate for some time. See Volume 1, number 2 and Volume 2, numbers 2, 3, and 4.] The Stockholm summary continues in our next issue: We'll have a summary of the numerous abstracts on AZT, the AZT/Acyclovir com- bination, various KS treatments, and more. Cryptococcal Meningitis by William Byne, Ph.D. Cryptococcal infection is the most common cause of fungal meningitis in the United States, and is an especially significant cause of morbidity and mortality in immunocompromised patients (1). Infection is thought to be acquired by inhalation of the yeast-like fungus, Cryptococcus neoformans. Pulmonary infection may resolve spontaneously or spread via the blood stream to other sites including the skin, urinary tract and brain. C. neoformans is ubiquitous in nature but is especially associated with weath- ered pigeon droppings. Infected patients, however, are usually not aware of any unusual exposure. Cryptococcal infection also occurs in animals, especially cats. Transmission from animals to humans or from one person to another has not been documented (2). At the time of diagnosis, most patients have meningoen- cephalitis (infection of the brain and the meninges that surround it). This form of infection is invariably fatal without treat- ment. Early manifestations include headache, nausea, gait dis- turbances, blurred vision, irritability, confusion and dementia. Fever and neck stiffness are often mild or absent. Swelling of the optic disc (indicative of increased intracranial pressure) is present in about a third of patients at the time of diagnosis and may result in visual disturbance. The infection often involves the cranial nerves (which run in pairs from the skull), typically causing asymmetrical damage to these nerves. As an untreated infection progresses, deepening coma and death finally intervene. Various therapeutic regimens have been tried in cryptococcal meningitis, but none has been uniformly effective without serious toxicity. These regimens have focused on the use of Amphotericin B (AMP B) or flucytosine, although both drugs are problematic when used alone. Prior to the introduction of amphotericin B (AMP B) in the late 1950's, cryptococcal meningitis was almost uniformly fatal, with a mortality rate of 75% in the first year (3). Though AMP B is a highly toxic drug, especially to the kidneys, and is poorly tolerated by many patients, most current treatment regimens still rely on it. Flucytosine is undesirable as a single agent treat- ment due to a low cure rate and the emergence of drug resistance. In the study by Bennett and coworkers, 11 of 34 patients receiv- ing flucytosine had adverse reactions (none of which were life threatening) and 6 chose to withdraw from flucytosine therapy because of these reactions. Further, according to John Stern (4) over 50% of patients in his experience have had adverse reactions to flucytosine. Flucytosine-associated deaths have also been reported. In 1975, Utz reported that AMP B in combination with oral flucytosine gave a cure rate comparable to that when AMP B was used alone (5). The advantages of the combination treatment were that a lower dose of AMP B could be used and the length of treatment reduced from 10 to 6 weeks. Thus, toxic reactions were less frequent. The findings of Utz et al. were corroborated by Bennett in 1979 in a prospective, controlled, randomized study (6), and this combination therapy has since become standard. Dismukes and his collaborators speculated that the duration of AMP B and flucytosine combination therapy might be shortened from 6 to 4 weeks without compromising efficacy, thereby reducing tox- icity even further. The results of their prospective randomized study suggested, however, that 4 weeks of treatment were effective only for patients without neurological complications, underlying disease, or immunosuppressive therapy. Favorable prognostic indicators included headache as a symptom, normal mental status, and a cere- brospinal fluid white-cell count above 20 per cc. Sugar and Lev- itz (7) have criticized that study, pointing out that therapy failed in 15% of even the low risk patients treated for 4 or 6 weeks. They suggest that if existing therapeutic regimens are to be studied, longer, not shorter periods of treatment should be investigated. Based on the work of Dismukes and coworkers, MacGregor (8) suggests that a short course of therapy with AMP B (3 to 4 weeks) combined with a longer course of flucytosine (6 to 10 weeks) should be tried. An initial short period of AMP B and flucyto- sine combination therapy might reduce the fungal population suf- ficiently so that a more extended period of therapy with flucyto- sine alone would carry a lesser risk of resistance. MacGregor suggests further that if this approach were successful, hospital- ization could be shortened to the 3-4 weeks required for intravenous administration of AMP B, and the extended treatment necessary to eradicate the remaining cryptococci could be carried out on an out-patient basis with oral flucytosine. The National Institute of Allergy and Infectious Diseases (NIAID) Mycoses Study Group, however, is concerned about potential serious flu- cytosine toxicity, especially in an unmonitored outpatient set- ting. Even though AIDS patients with cryptococcal meningitis have several of the factors associated with a poor prognosis, their initial response to therapy has been surprisingly good and is similar to the mortality rate during initial therapy of immuno- competent non-AIDS patients. The major problem in treating AIDS patients has been the high rate of relapse. For this reason, life long maintenance therapy with a single weekly dose of AMP B (100 mg) has been recommended. Because AMP B must be given intravenously, requiring hospitalization, maintenance therapy with an oral antifungal agent such as ketoconazole would be attractive. Unfortunately, however, cryptococcal meningitis has developed in patients receiving up to 600 mg ketoconazole daily for other reasons. The possibility that larger doses (1 g) would be effective in preventing relapse is presently under investiga- tion. It is clear that the optimal treatment for cryptococcal men- ingitis has yet to be found. Currently, the NIAID Mycoses Study Group and the AIDS Clinical Trials Group of the National Insti- tutes of Health, in cooperation with Pfizer Central Research, are evaluating the experimental drug, fluconazole (FLU) for both pri- mary and maintenance therapy of cryptococcal meningitis. FLU is an azole compound but differs from other azoles currently in use (e.g., ketoconazole) in that it readily penetrates the blood- brain barrier (9). The unique ability of FLU to penetrate the blood-brain barrier and its low toxicity make it particularly promising as a potential adjunct or sole agent in the treatment of fungal meningitis. In the U. S. the main focus of FLU trials has been in major life-threatening fungal infections resulting from AIDS or other immunodeficiences. In Europe, Pfizer Central Research (Sandwich, Eng.) has studied FLU for less serious fungal infections such as vaginal candidiasis or fungal skin infections (10). To date only two accounts of FLU in the treatment of human cryptococcal meningitis have been published. One of these was a letter in the May 1987 Annals of Internal Medicine by 2 physi- cians at the Pasteur Institute (11) describing the course of treatment in a single patient with AIDS. Primary therapy with intravenous AMP B and oral flucytosine was successful and his CSF (cerebral spinal fluid -- the fluid obtained during a spinal tap) cultures became negative. After 2.5 months of maintenance therapy, treatment had to be stopped due to the development of neutropenia (a reduction of white blood cells). The patient remained well for several months and then developed high fever, headache and stiff neck. CSF was positive for cryptococcus, indicating relapse. Because of the previous adverse reaction to AMP B and persisting blood cell abnormalities, the patient was treated with FLU (150 mg per day with morning meal). Improvement occurred by the fourth day of treatment when his temperature decreased. By the tenth day of treatment, the patient was able to walk in his room and his headache was gone. By the seven- teenth day the patient had no fever. He was discharged on maintenance FLU therapy of 150 mg per day and after a month was switched to 150 mg twice a week. At the time of publication, the patient had been followed for 5 months after the end of daily treatment and was in excellent general condition with no signifi- cant toxicity. The other study was conducted by John Stern and his col- leagues at the University of Texas Medical School - San Antonio and at New York Hospital - Cornell Medical Center. The results of this study were published in the Program and Abstracts of the Twenty-seventh Interscience Conference on Antimicrobial Agents and Chemotherapy (12). The abstract reports results obtained 24 weeks into the study. The following account is based on a per- sonal communication from J. Stern and updates the results to 64 weeks of study. Fourteen patients were enrolled who had been diagnosed with cryptococcal meningitis and successfully treated with AMP B as evidenced by CSF cultures negative for cryptococcus. These patients were started on an oral dose of 50 mg FLU per day; in the absence of toxicity this dose was raised to 100 mg per day. Thirteen of these patients have remained culture negative during follow-up. The remaining patient relapsed on 100 mg; his dosage was increased to 200 mg and he became culture negative in two weeks. One patient was enrolled who had been successfully treated with AMP B for cryptococcal pneumonia. This patient died of complications unrelated to cryptococcal infection at 20 weeks. Three patients with extraneural (outside the brain) cryptococcal infection that failed to be cleared by AMP B were also treated with FLU. Two reverted to culture negativity; the other remained positive. Two patients with cryptococcal meningitis received primary therapy with FLU and both became culture negative. Three patients with extraneural infection received primary therapy with FLU but two of these went on to develop CNS disease. According to Stern, FLU was well tolerated. One patient had a moderate increase in liver function tests, and another had a seizure on the initial dose of FLU after having completed AMP B therapy. FLU was stopped in both of these cases. One patient with cryptococcal meningitis was switched to FLU after failing AMP B and showed clinical improvement at eight weeks despite moderately elevated liver function tests. In summary, the results suggest that FLU is well tolerated and can suppress cryp- tococcal disease in AIDS patients. The FLU trials at New York Hospital are currently under the direction of Kathleen Squires. John Stern will be continuing his studies at Pennsylvania Hospital in Philadelphia. In a communication to John James a researcher at Pfizer stated that FLU has been tried on over 150 patients with serious systemic fungal infections and many others with less serious con- ditions. No serious toxicity has been noted and very few side effects have been definitely related to the drug. Early trials have focused on cryptococcal meningitis because it is life- threatening, easily diagnosed, and its course is easy to follow. Tucker has shown that FLU has shown promising results in the treatment of coccidioidal meningitis. The AIDS Clinical Trials Group of the NIH is currently recruiting patients for clinical trials of FLU in both primary and maintenance therapy of cryptococcal meningitis. The NIH Investigational Review Board met in Bethesda, Maryland on July 7 & 8, 1988 to draw up the protocol for the use of FLU in the pri- mary therapy of cryptococcal meningitis. The study will be a randomized comparison of FLU versus AMP B for 52 weeks. Patients must have recovered from a first acute episode of cryptococcal meningitis within 4 months, and either must be on maintenance AMP B or have completed AMP B within 3 weeks. Patients will be excluded who have received any of the fol- lowing drugs: ketoconazole, fluconazole, itraconazole, or micona- zole. The centers involved in these studies are the University of California, San Francisco (415) 821-5531; University of Califor- nia, Los Angeles (213) 206-6414; University of Southern Califor- nia, Los Angeles (213) 226-5225; Memorial Sloane Kettering, New York (212) 794-8206; Mount Sinai, New York (212) 241-8902; New York Hospital - Cornell Medical Center, New York (212) 472-4769; New York University, New York (212) 340-6565; Harvard University, Boston (617) 726-5596; Jackson Memorial Hospital, Maimi (305) 549-7323; University of Rochester, Rochester, New York (716) 275-5871; and Washington University, St. Louis (314) 454-0058. According to Dr. Donald Armstrong, chief investigator of the FLU study, other NIH centers will eventually become involved (13). These studies will be double blind, comparing therapy with FLU alone to combination therapy with AMP B and flucytosine. Thus, patients with any condition that contraindicates the use of AMP B cannot be enrolled. Those patients, however, should be eligible for compassionate use of FLU. Physicians can obtain FLU for compassionate use if AMP B has failed or cannot be tolerated. For further information physi- cians should call Pfizer Central Research, Groton, Connecticut, (203) 441-4112. Two other studies of fluconazole (FLU) are getting underway at St. Vincents Hospital. The first study will compare the safety and effectiveness of FLU and AMP B, with or without flu- cytosine, as treatment for acute cryptococcal meningitis. Parti- cipants will be patients with acute cryptococcal meningitis either previously untreated or relapsed after previous successful treatment for acute cryptococcal meningitis. Patients will be randomly assigned in a 2:1 (fluconazole: amphotericin B) ratio to primary therapy with either daily oral doses of fluconazole or intravenous amphotericin B, with or without oral flucytosine, for 10 weeks. Patients with AIDS who respond satisfactorily to flu- conazole will receive maintenance therapy to prevent relapse for an additional 12 months. During the study period, there will be close monitoring, which will involve several spinal taps. The second study will compare the safety and effectiveness of flu- conazole and amphotericin B as maintenance therapy for prevention of relapse of cryptococcal meningitis in patients with AIDS. Participants in this study will be patients with AIDS who have been successfully treated for acute cryptococcal meningitis. Patients will be randomly assigned to receive maintenance treat- ment for one year with either daily oral doses of fluconazole or weekly intravenous doses of amphotericin B. AZT is allowed in this study. During the study period, there will be close moni- toring, which will involve several spinal taps. For further information on either of these trials, interested physicians can call Dr. David Kaufman at (212) 620-0144. The Quest for an AIDS Vaccine: Report of Current Trials by Victoria Nott Early results of trials in humans and experiments on animals of different AIDS vaccines were reported by American and European researchers at the International Conference on AIDS held in Stockholm last month. While these preliminary studies suggest that the vaccines are safe in the short term, increases in anti- body levels were mixed -- and not too encouraging. Answers to whether such vaccines would protect someone from HIV infection are way down the road. A phase I trial of the first AIDS vaccine approved for test- ing by the FDA began recruiting healthy, HIV-negative volunteers last September. A recombinant (genetically-engineered) HIV envelope glycoprotein, gp160, made by MicroGeneSys, West Haven, CT, is being given in small doses, up to 40 micrograms, with two thirds of the subjects receiving a booster dose one month after primary immunization. Researchers from the National Institutes of Health reported (#6569) that in the first 34 subjects, there were no important adverse effects, no detectable changes in immune function and no antibody responses. The next step will be to increase the doses. Dr. Daniel Zagury of the Pierre and Marie Curie University, Paris, made news by self administering the first AIDS vaccine in November 1986, and he has been working with volunteers in France and Zaire. Dr. Zagury reported (#6558) that he has been getting good antibody levels against HIV gp160, as well as other indica- tions of immune response. He has been using a recombinant vac- cinia virus, into which the HIV envelope protein gp160 is inserted as a primary vaccine. This vaccine is given in conjunc- tion with booster shots of killed infected cells taken from volunteers who received the primary vaccine. This protocol is impractical for a larger trial, and Dr. Zagury is working on a new preparation of gp160 molecules, which he hopes will induce similar immune reactions while being suitable for a clinical trial. A recombinant gp120 vaccine was tried on chimpanzees by researchers from Genetech, Inc., New England Deaconess Hospital and other centers (#6562; #6570). Humoral (antibody) and cellu- lar immune responses were detected, but the preparation failed to prevent viral infection when the animals were injected with HIV. In another chimp study by a group from the Pasteur Institute and other centers (#6576), significant antibody levels to envelope and other proteins were obtained by injecting whole inactivated virus. Two of the three animals had been preimmun- ized with a vaccinia virus expressing gp160 (similar to Zagury's preparation), to see if there is any advantage in preimmunizing with a live recombinant vaccine. However, whether the animals are actually protected against HIV infection remains to be deter- mined. Immunizing Seropositives: While most of the foregoing vaccines are based on components of the outer coating, or envelope, of HIV, Dr. Jonas Salk, working at the Salk Institute and with a group at the University of Southern California, prefers the approach of an inactivated whole-virus vaccine, along the lines of the polio virus vaccine that he developed years ago. Note: Salk's AIDS vaccine testing has nothing to do with use of the Salk polio vaccine as an experimental treatment in a few HIV patients by Dr. Ferris Pitts, who has reported improvements in HIV-positive patients, although they seemed pretty healthy to begin with (14,15). Nothing further has been reported on Pitts' therapy. Proteins extracted from the outer envelope of HIV (like what is being used in the ongoing NIH trial) doesn't seem to do any- thing, Salk contends, and since we don't know which of the many antigens of the virus induce a protective effect, he proposes using a noninfectious form of the whole virus to immunize seropo- sitive individuals. Worries about even inactivated viral DNA becoming incorporated into the person's DNA -- a consideration in uninfected volunteers -- would not be relevant in someone already seropositive. In a commentary in Nature, (16) he theorized that the long incubation period between infection and developing AIDS may be due to an immune response to the initial infection which persists with health and wanes with disease. A post-exposure immunization might be effective, as with rabies and hepatitis B, in which it is possible to prevent pathology for a short period of time after as well as before exposure to the respective viruses. Salk argues that, if effective, immunizing seropositive people would have a greater and more rapid effect on morbidity and mortality -- and perhaps on host contagiousness, and thus new infections -- than would immunizing the sero-negative population. If this could be done, people would want to be tested, accelerating case finding and early treatment. In Stockholm, Salk described an experiment (#6567) on 9 gay men with ARC and active viremia who were given 100 micrograms of killed whole virus. The virus had been irradiated and stripped of its outer coat of proteins. No signs of toxicity were observed at a median of 8 weeks after inoculation. Antibody lev- els to HIV did not change, and one patient subsequently developed AIDS. However, the absence of toxicity and the presence of small but definite improvements in DTH (delayed type hypersensitivity to standard skin test antigens) in all 9 men encouraged Salk to expand the study to 54 asymptomatic HIV positive volunteers. Should the "vaccine" work in these individuals with a more intact immune system -- Salk says it is really an immunomodulator, that is a treatment to assist the body's own defenses, rather than a preventive vaccine -- he will try to develop a similar vaccine to prevent infection in seronegative people. Other scientists besides Salk are dubious about the effec- tiveness of a vaccine based on an envelope protein because of "genetic drift," the constantly changing and evolving surface structure of the virus. Questions of safety have also been raised. Some research indicated recombinant gp120 might itself be capable of causing immune damage, as newer studies point to the gp120 protein as a potential cause of AIDS-related neurologic disease. AIDS research may be about to shift toward core pro- teins, which are deep inside the virus. One biomedical research firm, Cel-Sci Corp., Alexandria, VA, a joint venture of Interleukin-2, Inc. and Alpha Biomedicals, Inc., has been developing a prototype AIDS vaccine, HGP-30, a synthetic peptide which targets the p17 protein lying below the surface. p17 appears to be important to the virus's reproductive ability. In vitro and animal studies have established the vaccine's ability to produce neutralizing antibodies, but the critical trials lie ahead. Human trials will begin in England this summer. Treatment Issues is GMHC's newsletter devoted to experimental AIDS therapies. Describing an experimental therapy should not be construed as recommending it. All new treatments should be done under a physician's care. Treatment Issues is published ten times yearly. Copyright 1988 Gay Men's Health Crisis, Inc. All rights reserved. Non-commercial reproduction is encouraged. Subscription lists are kept confidential. Editor: Barry Gingell, M. D. Managing Editor: Kevin Armington GMHC, Department of Medical Information, 132 West 24th Street, Box 274, New York, NY 10011 1 Dismukes WE et al. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. NEJM 317:334, 1987. 2 Bennett JE. The deep mycoses. In Harrison's Principles of Internal Medicine, Petersdorf et al. (eds) p 1056, McGraw Hill Book Co, New York, 1983. 3 Pons UG et al. Nonviral infections of the central nervous sys- tem in patients with acquired immunodefficiency syndrome. In AIDS and the Nervous System, Rosenbaum ML et al. (eds.) p 263, Raven Press, New York, 1988. 4 Stern, J (personal communication). 5 Utz JP et al. The therapy of cryptococcosis with a combination of flucytosine and amphotericin B. J Infect Dis 132:368, 1875. 6 Bennett JE et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal men- ingitis. NEJM 301:126, 1979. 7 Sugar AM and Levitz SM Treatment of cryptococcal meningitis (letter) NEJM 318:381, 1988. 8 MacGregor RR Treatment of cryptococcal meningitis (letter) NEJM 318:380, 1988. 777, p 232. [text lost] 10 James, JS Fluconazole: a major advance for cryptococcal men- ingitis and other systemic fungal infections? Aids Treatment News 41:1, 1987. 11 Dupont B and Drouhet E Cryptococcal meningitis and flucona- zole. Ann Internal Med 106:778, 1987. 12 Stern J et al. Fluconazole (FLU) therapy in AIDS patients with cryptococcosis. Program and abstracts of the twenty-seventh interscience conference on antimicrobial agents and chemotherapy. Abstract 948. p 262. 13 Armstrong D (personal communication). 14 Pitts, et al. Clinical improvement of 2 patients with T lym- photropic retrovirus disease after polio vaccine hyperimmuniza- tion. Clin. Immunol. Immunopathol. 277:43, 1987. 15 Pitts, et al. Improvement of 4 patients with HIV-1 related symptoms after hyperimmunization with killed poliomyelitis (Salk) vaccine. Clin. Immunol. Immunopathol. 46:167, 1988. 16 Salk, J et al. Prospects for the control of AIDS by immunizing seropositive individuals. Nature p. 43, 1987. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display