Subject: Carrisyn; Fusidic; Dextran; New Studies Date: Feb 8 1988 (1014 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& TREATMENT ISSUES -- The GMHC Newsletter of Experimental AIDS Therapies &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Volume 2 Number 1 February 8, 1988 In this issue: AZT: One Year Later AL721 -- An Overview AIDS Research and the NIH Typhoid Vaccine Therapy In Brief New Studies AZT: One Year Later It has now been almost one year since AZT became generally available, and still it remains a subject of intense controversy. It is, seven years into the epidemic, the only approved AIDS drug. Many say it has saved their lives, while others say it is poison and refuse to have anything to do with it. Even physi- cians are divided as to whether the drug is worth pursuing for PWAs: many say it is life-saving while others consider it "margi- nally effective." Certainly, the way AZT was approved is like no other drug in history. A placebo trial of AZT began in February 1986. 24 weeks after the study began, it became clear that there were sig- nificant differences between the placebo recipients and the AZT recipients: by September 1986, 19 patients receiving placebo died during the 24-week period versus only one taking AZT. Also, the probability that an opportunistic infection would develop during the 24-week study was significantly lower in the AZT group than in the placebo group (considering that PCP prophylaxis was not allowed during the trial, this result could have been even more striking). Because of these significant differences, all patients in the trial receiving placebo were given AZT. By February, 1987, AZT was available on a "Treatment IND" (investi- gational but available) basis. Eager to get a drug on the market for AIDS, the FDA approved AZT as a New Drug in March, 1987. Allegations have been made that this trial was seriously flawed, and that FDA's approval of AZT was impetuous. These allegations may never be answered. Almost a year has passed since AZT became widely available, and we may now ask the question: What is the long term effect of AZT on AIDS patients? The statistically-significant results found in the AZT study were short-term ones (over 24 weeks). Is this effect sustained? AZT's long-term therapeutic effect In the original paper describing the AZT trial (1), the authors added some preliminary long-term results. As of April 30, 1987, 10% of the original AZT recipients (who had taken the drug for 1 year) had died. They compare this figure to a 40% mortality at 36 weeks seen in patients not on AZT. Based on other studies, the latter figure seems reasonable: the New York City Survival Study has reported approximately 50% one-year mor- tality figures for AIDS (2). This figure is comparable since the data in the New York City study were collected before widespread use of AZT. A paper to be released shortly reports on patients taking AZT for 72 weeks, and for them, there is a similar reduction of mortality. 30% of patients taking AZT during the 72-week period have died, compared to 62% of people not on AZT. [The New York City study showed a similar 72-week figure -- about 60%]. Thus, over 72 weeks, AZT seems to have improved survival. One would hope that, with improved treatment of opportunistic infections and the increasing use of PCP prophylaxis, these mortality fig- ures could be lowered even further. Informal conversations with a large number of AIDS physi- cians in New York City generally confirm this conclusion -- that patients on AZT generally do better -- although many feel that this improvement lasts only a few months to a year. The benefit may be temporary because of AZT's toxic side effects. What about AZT's toxicity? While the above figures are encouraging in terms of a long- term therapeutic benefit from AZT, the data regarding toxicity is considerably more sobering. The original paper describing the toxicity observed during the AZT study (3) was to be an accurate predictor of the significant degree of side effects now being observed. The most significant toxicities are related to a suppressive effect on the bone marrow, where blood cells are made -- both red and white. Red cells can be supplemented by transfu- sions, but white cells cannot. There is at present little to do in the case of reduced white cells (called neutropenia) except to reduce or discontinue AZT. When a person is neutropenic, (s)he is at increased risk of developing bacterial infections. Widespread use of AZT may be a factor in the increasing frequency of bacterial infections seen in AIDS (4). Fortunately, the suppressive effect of AZT is reversible when the drug is reduced or discontinued. In the original AZT study, 21% of patients required multiple red cell transfusions and 16% had serious reductions in white cells. In longer-term studies currently underway, the figures are even higher -- over 40% of patients experience serious bone mar- row suppression after 72 weeks of AZT. These effects may be first noticed after more than a year of successful AZT therapy. After one year of AZT therapy, 50% of patients are on half-dose and 25% are off the drug completely because of toxicity. Because of this high degree of toxicity, most experts feel that AZT will never be considered a sole therapy for AIDS. Finally, there is the strong possibility that AZT may be carcinogenic (cancer-causing). For the person with severe ARC or AIDS, this consideration is less serious (after all, AIDS is cancer-causing), but for the asymptomatic seropositive indivi- dual, the risk seems more substantial. Minimizing AZT's toxicity There are four approaches being studied to minimize the tox- icity associated with AZT. The first is simply to reduce the dose. A large study is currently underway examining whether reduced (i.e. half) dose AZT is as effective as full-dose AZT. Results from this study have not been released, although they should be soon. Other studies are on the drawing board comparing various doses of AZT. The second approach is using a lower dose of AZT in combina- tion with another antiviral drug. Two drugs are called synergis- tic when the effects produced in combination are greater than the sum of the effects of each drug singly. By using drugs that are synergistic with AZT, one could hopefully reduce the dose of AZT and thereby reduce toxicity. A synergistic effect has been shown in the test tube between AZT and Ampligen (5), AZT and Dextran sulfate (see Treatment Issues Vol. 1 no. 2), AZT and interferon (6), and AZT and acyclovir (Zovirax -- an approved drug for geni- tal herpes infections) (7). Only the latter two combinations are in clinical trials with PWAs. It is too early to make any gen- eralizations about the AZT-interferon trials, although it is hoped that this combination will be particularly effective with KS. The AZT-acyclovir combination: Studies of low-dose AZT plus acyclovir have yielded some encouraging results. A large study underway in the U.S. is using 3 doses of AZT (200 mg, 100 mg or 50 mg every 4 hours) with acy- clovir (800 mg [4 capsules] every 4 hours). The study, however, is small and researchers feel they need more subjects to achieve statistically meaningful results. One promising observation in this study is the reduction of p24 antigen in 4 patients over a 12-week period while taking only 50 mg of AZT plus acyclovir (8) [The p24 antigen test indicates how active the virus is in the blood. Since HIV infection is generally considered to be life- long, it is probably more important to measure the level of activity of HIV than the presence of HIV (so the lower the value the better.) An article on the p24 test will appear in a later issue.]. John James uncovered some data on the AZT-acyclovir combina- tion collected during the original AZT study (Aids Treatment News, Issue 46). Obtained by Project Inform through the Freedom of Information Act, the documents read: "Seventy of the 282 patients enrolled in this trial (25%) received acyclovir in addi- tion to their study medication. Thirty-four were patients ran- domized to receive AZT [i.e., were on the combination] ... no increase in hematologic toxicity ... Only 2 of the 34 patients (6%) who received acyclovir in addition to AZT developed oppor- tunistic infections over the course of the trial compared to 22 of 111 (20%) of the AZT recipients who did not receive acyclovir during the study." Thus, in the short term, the combination seems to have been advantageous. A collaborative group in Europe has recently announced encouraging results from their study of the AZT-acyclovir combi- nation. There were two groups of patients: 55 patients took 250 mg of AZT 4 times daily (slightly less than the "standard" dose; unfortunately, the researchers did not look at half-dose AZT) and 800 mg acyclovir 4 times daily. 53 patients just took AZT. At the end of 36 weeks, 28% of the group taking only AZT died com- pared to 9% of the AZT-acyclovir group (9). There were also fewer episodes of herpes infections and CMV (cytomegalovirus) infec- tions in the AZT-acyclovir group. Experts caution that these figures, though announced at a recent conference, are preliminary and have not been examined by other researchers. Based on the original AZT study and doctors using AZT in their practices, a 28% mortality after 36 weeks of AZT therapy seems a bit high. AZT in earlier HIV infection. The third method of improving on the toxicity profile of AZT may be to give it at an earlier stage of HIV infection -- at an early phase of ARC or even at the asymptomatic seropositive state. The original AZT study noted that side effects were more common and more pronounced in people with less than 100 T4 (helper) cells and in people whose red cells started out low. People in earlier stages of HIV infection presumably have more "bone marrow reserve" than advanced ARC or AIDS and probably will tolerate AZT better. Studies are underway to look at these two populations, but it is too early for any statements to be made. (The two studies, which being conducted at the ATEUs, are recruiting patients.) Considering that only a fraction of seropositives will go on to develop AIDS, it does not appear wise to treat everyone who is infected with antiviral drugs, particularly those drugs which have toxic side effects. A stronger argument could be made for less toxic antivirals in seropositives, although available candi- dates (e.g., AL721, dextran sulfate, carrisyn) have not yet proved their merit. We need a reliable, predictive test to determine which sero- positives are more likely to get sick. The T-cell count and the p24 antigen test seem to be the best tests to make this predic- tion, although the latter test has not been FDA approved and is therefore not yet available. Most physicians would seriously consider treating seropositives with declining T-cells or rising p24 antigen. At present, different physicians have various cut- offs for initiating antiviral therapy, and until further studies are done, we have only the savvy of experienced physicians to guide us. AZT with bone marrow stimulants The fourth way of possibly reducing the toxicity of AZT is combining it with substances that stimulate the bone marrow to produce more white cells or red cells. These substances (which are actually hormones) are normally produced by the body to replenish blood cells and may be effective in ameliorating the side effects of AZT. Erythropoietin is a hormone routinely pro- duced by the body to stimulate the production of red cells. Tri- als are underway to observe the effect of erythropoietin on AZT- induced anemia. (This study is being conducted in New York City by the Community Research Initiative. Interested physicians may contact the CRI at 212-463-8981.). An analogous substance called GM-CSF stimulates the production of white blood cells, especially the type (called neutrophils) which is hardest hit by AZT. A preliminary trial of GM-CSF alone was encouraging (10) but so far no data is in on the combination of GM-CSF with AZT. (An article on GM-CSF will appear in a later issue.) Conclusions: So where does all this leave us? Is AZT worth pursuing? How is AZT-induced toxicity best managed? Unfortunately, we can- not make definite statements at present. For those people with severe ARC (i.e., less than 200 T4 [helper] cells) or AIDS, AZT reduces mortality and serious opportunistic infections and this observation is borne out by doctors in the field. AZT has a well defined ability to block the replication of HIV, and it makes sense, considering what we know about AIDS, to use an antiviral drug. Although other antiviral drugs exist (e.g., dextran sul- fate, AL721, ribavirin), AZT is at present the one with the most convincing evidence behind it. But AZT exacts an expensive price, both financially and in terms of side effects. Just how to manage these side effects has not been clearly established, and different physicians have dif- ferent philosophies on AZT dose reduction (or discontinuance) and when to administer blood transfusions. Most physicians are reducing the dose of AZT (some go as low as 400 mg daily -- one- fourth of the "standard" dose) rather than maintaining full-dose AZT and repeatedly transfusing patients. The AZT-acyclovir combination deserves serious consideration by anyone on AZT, particularly by those who cannot tolerate full-dose AZT. Another potentially significant combination is low-dose AZT plus Dextran sulfate (see Treatment Issues, Vol. 1 no. 2). We will be reporting important developments on AZT. AL721 -- An Overview No treatment since AZT has garnered as much intense curios- ity and enthusiasm in the AIDS community as AL721, also known as egg lipids. Unfortunately, AL721 has not been approved by the FDA, is not available, and has not been subjected to the kind of controlled clinical studies that produce significant scientific results. However, a generic, "work-alike" substitute has been in use for over a year now, providing anecdotal information about its effect, and the theoretical research behind the use of egg lipids has increased. This article will look at the history of AL721 and its use in the treatment of AIDS. Background "AL721" stands for "active lipids in a ratio of 7 to 2 to 1." Technically, it is a trademarked name for egg lipids (fats) in a ratio of seven parts neutral lipids, two parts phosphatidyl- choline (purified lecithin), and one part phosphatidylethanolam- ine (11). This ratio was arrived at by Dr. Meir Shinitzky and other cancer researchers at the Weitzmann Institute of Science in Rehovot, Israel, who were investigating the use of egg lipids to increase the membrane fluidity of lymphocytes in subjects whose immune systems had been damaged by advanced age. It has been known for a long time that an important way in which cells com- municate is through membrane contact. The Israeli doctors, who are engaged in the developing field of "membrane engineering," knew that many normal cellular functions were inhibited when the lipid fluidity of the cell membrane was reduced. But they observed that this loss of function was at least partially rever- sible with the use of AL721, which operated by extracting the cholesterol that caused the cell membrane to harden. It had been discovered in 1978 by researchers at the Univer- sity of Virginia that some viruses need large amounts of cholesterol in order to infect cells, and when the cholesterol was extracted the virus stopped being infective (12). Theory suggests that it might also help against other lipid-coated viruses such as CMV and Epstein-Barr (viruses implicated as cofactors in AIDS). In addition, phosphatidylcholine, one of the ingredients in AL721, has been shown in published studies in Europe to be useful in treating viral hepatitis (13,14). Originally, though, Dr. Shinitsky and his colleagues were not looking for an antiviral and their research had nothing to do with AIDS. The link was made in a letter published November 14, 1985, in the New England Journal of Medicine, saying 1) "Infec- tion by a virus requires the presence of an active site on the viral membrane that binds to a receptor on the host cell mem- brane"; 2) "modification of the active site resulting from the extraction of viral membrane cholesterol has been reported to reduce viral infectivity dramatically"; and 3) "AL721...has a demonstrated ability to extract cholesterol from cellular mem- branes both in vitro [in the test tube] and in vivo [in humans]." (15) Technical Background HIV can infect cells in one of two ways. A free virus par- ticle (called a virion) can attach itself to and infect a suscep- tible cell (e.g., a T-cell). Also, an infected cell can attach to a healthy cell and infect it directly. It has been currently thought that, if AL721 works, it probably works by altering the virion (i.e., the free virus) so that it cannot attach to cells. However, a recent report (16) showed AL721 to block infec- tivity of HIV in two different types of cells. One type of cell is infected by HIV directly while, in the other, cell-to-cell transmission is predominant. The fact that infection was blocked in both types of cells led researchers to suggest that "AL721 may block both virion-cell and cell-cell infection". Blocking both types of transmission will probably prove to be important to suc- cessful antiviral therapy. Very significantly, the New England Journal of Medicine let- ter also noted that "since AL721 does not directly inhibit reverse transcriptase, it should not produce the undesirable side effects that are associated with reverse transcriptase inhibitors." In other words, AL721 lacked the bone-marrow suppression and other toxic side effects connected with virtually every other treatment for HIV viral infection being considered. The letter was signed by Robert Gallo and Prem Sarin from the National Cancer Insti- tute, researchers from Yale and the University of Florida, and A. S. Lippa, a researcher representing Praxis Pharmaceuticals, Inc. Over two years have elapsed since that time and a large- scale trial of AL721 has yet to get underway. Studies have been announced in New York, Boston, Los Angeles, and London, but these trials have all experienced delays, for reasons that have never been made clear. The Weitzmann Institute sold the rights to manufacture the drug worldwide to Praxis Pharmaceuticals, a com- pany in Beverly Hills, California, which has since changed its name to Ethigen. Though AL721 is technically a food substance and could be marketed as such, Ethigen wants to market it as a drug because of the greater commercial potential and therefore refuses to allow anyone else to produce this substance on which they own the patent. (The patent has never been tested, and patent lawyers question whether it would hold up in court, since variants of egg lecithin have been on the market for years.) Yet the company, which has only nine employees, has no experience in conducting drug trials and has apparently had major difficulties manufacturing AL721 in quantity. It has been reported that Ethi- gen is considering marketing AL721 as a food product, to bypass the lengthy FDA approval process, in addition to pursuing its approval as a pharmaceutical product. AL721 was assigned a "low priority" by federal researchers at the National Institutes of Health. This was largely due to the lack of general knowledge of AL721 and how it is absorbed and metabolized by the body. But because of current widespread use of the substance, they have decided to undertake a small-scale "pilot" study. Ethigen could not supply sufficient quantities of the drug, thus delaying the study, but the NIH has apparently found another supplier. The study will look at AL721 in various doses to be given to patients with lymphadenopathy and ARC. Patients must have 200 T-cells or greater. It will be conducted at Memorial Sloan-Kettering Cancer Center (NYC) [212-794-8206]; Mount Sinai (NYC) [212-241-7856]; The University of Minnesota Health Center [612-625-1462]; The University of California San Francisco [415-821-5531]; The University of Southern California [213-226-5225]; the Institute for Immunological Disorders (Hous- ton) [713-691-3531 x247]; and Tulane University [504-587-7316]. Results to date in AIDS: To date, only two small studies on the effect of AL721 in treating people with AIDS have been reported. Dr. Shinitzky and two colleagues from the Weitzmann Institute, with special permis- sion from Ethigen, tried treating patients who had cancer with AL721. One of them, an AIDS patient with lymphoma, responded remarkably well, so they embarked on a trial of 10 AIDS patients, with promising but inconclusive results. "As far as the clinical appearance went -- gaining weight, stopping opportunistic infec- tions -- there was considerable improvement in all except one, who died," Shinitzsky said. Diarrhea and fevers also improved. In his study, T-cells did not increase, but qualitative tests of the level of T-cell function (called mitogen stimulation tests) did improve over a 5-month period. Viral cultures were reduced in 3 patients (17). Shinitzky sought to extend the trial but he was unable to get supplies of AL721 from Ethigen or permission to manufacture a substance that had originally been produced in his own laboratory. (The Weitzmann Institute has since made a deal with Ethigen permitting them to manufacture AL721 for treating patients in Israel.) In 1986 doctors at St. Luke's Roosevelt Hospital in New York were allowed to conduct a small trial of eight patients with lym- phadenopathy. Patients took 10 grams of AL721 twice daily, once before a fat-free breakfast and 2 hours after a low-fat dinner. In five of seven patients, there was a reduction in viral activity as measured by one test (viral culture) but another test (the p24 antigen test) showed improvement in only one of 5 patients (18). After the three-month trial, however, the virus immediately reappeared. One patient developed full-blown AIDS 10 weeks after the study ended. This has been called the "rebound effect" and has prompted caution in abruptly stopping AL721. (It probably occurs after abruptly stopping any antiviral drug). The researchers sought to continue the study, but had to wait more than six months for additional supplies from Ethigen. The long- term follow-up from the St. Luke's study has not been encourag- ing: out of 8 patients, 4 have developed full-blown AIDS and 2 have advanced ARC (19). It has been reported that recent analysis of the AL721 used in the St. Luke's study have shown an unacceptably low potency. If this is true, the results of the study are worthless. Since no large-scale clinical trials have been conducted to amass data on AL721, most information about how it works has come from first-person, necessarily subjective, anecdotal reports. In AIDS Treatment News, John S. James published a letter from a per- son with AIDS who went to Israel for treatment with AL721 in April of 1986. It took two weeks to feel any effect. But after two months of daily treatment, the patient reported a reversal of his weight loss, diarrhea, and various skin conditions. Return- ing to the United States, he continued treatment by taking a heaping tablespoon of granulated lecithin mixed with a raw egg yolk daily. For two months, his T-4 count rose, but then in August it began to decline. A return trip to Israel for another month's treatment resulted in another increase in T-4 count. On October 9, 1987, the Baltimore Jewish Times published a report on AL721 treatment in Israel. Apparently 52 of 60 people with AIDS treated with AL721 in the past year "have shown very considerable improvement in their general well being, sometimes within days of embarking on the treatment. They have lost much of the lassitude associated with AIDS, fevers have been reduced, other symptoms have diminished, and they have suffered no side effects. Three patients who were considered terminal are now in remission. Clinical tests showed a decline in viral infectivity." These reports are unconfirmed. People with AIDS have traveled to Israel for treatment with AL721. It has also been reported that the AIDS Treatment Center in Johannesburg, South Africa, treats people with AL721. These are extreme and expensive options, of course. In the absence of easy access to AL721, an underground sup- ply network has emerged providing various forms of AL721 to those interested in using it. In addition, instructions for making the laboratory formula of AL721 and a home formula substitute have been widely published. The home formula was developed by Steve Gavin, a chemist in the New York City area, in January, 1987. It is made by mixing butter or cooking oil with a soy lecithin preparation readily available in health-food stores. The propor- tions of the three ingredients approximate those of AL721, but they are not identical to AL721 made with egg products. For this reason, soy-based lecithin products are not recommended. In the spring of 1987, two versions of AL721 made with egg lecithin became available. "Eggsact," a product marketed by a company in Santa Cruz, California, combines egg lecithin with butterfat rather than egg oil, partly because egg oil is difficult to obtain and partly to avoid legal problems with the AL721 patent. In addition, two nonprofit organizations -- the PWA Health Group in New York and the Healing Alternatives Buyers Club in San Fran- cisco -- began to distribute an egg-based "workalike" very close to AL721. There is no way of knowing how many people have used or are using any of these AL721 substitutes, and there is no way of mon- itoring their experience. Last summer John S. James sent a ques- tionnaire about AL721 use to all 898 subscribers of AIDS Treat- ment News. Out of 147 responses, 10 had used AL721 or a substi- tute (some with soy lecithin, some with egg lecithin) for at least three weeks. Half of the 110 found it helpful, 15% found it not helpful, 35% were uncertain, and none found it harmful. These are, of course, subjective impressions and are in no way authori- tative. Based on anecdotal reports, AL721 seems to be most helpful in improving overall clinical condition. People report more energy, reduced or eliminated night sweats, clearing of skin con- ditions, and an improved sense of well being. Although some peo- ple report increased T-cell counts, these have not been confirmed by controlled studies or by informal reports of physicians moni- toring patients on egg lecithin. Some physicians think the treatment might work especially well combined with an immune modulator, but no studies have been done. Reportedly Israeli scientists are developing a treatment that combines AL721 with thymus hormones. What are the drawbacks of AL721? Although it seems that AL721 is entirely safe, since no bad side effects have been reported, most doctors are skeptical that it does any good. Many believe that when AL721 is eaten and dig- ested, the three ingredients are absorbed separately into the bloodstream, therefore it couldn't possibly work. Because of the "rebound effect", physicians are advising people not to start taking AL721 or substitutes unless they plan to continue; instead of abruptly discontinuing AL721, patients are advised to taper it gradually, either by reducing the daily dose or taking it on alternate days for a couple of weeks. Too much lecithin can cause nausea, diarrhea, mental depression, and loss of appetite, but it is not believed to have lasting ill effects. In some cases, nausea or diarrhea attributed to AL721 turned out to be intesti- nal parasites, which can be treated. AL721 is inconvenient. It requires constant refrigeration, so that traveling becomes a problem. Moreover, the dietary res- trictions are difficult to follow strictly. Availability In light of the burgeoning underground market for AL721 wor- kalikes, the PWA Health Group has issued a number of warnings to potential purchasers of egg lipids advertised in publications such as the New York Native, the Advocate, and the Village Voice: l) beware of manipulative advertising and false claims; 2) beware of any company who will not tell you the precise chemical analysis of the lipids they are selling; 3) beware of any company which does not guarantee that each lot of lecithin is tested for potential bacterial, fungal or chemical contaminants as well as for ratio of lipids and phospholipids; and 4) beware of companies which charge a lot of money for lipids. The most significant difference between lipid products is the percentage of phosphatidylethanolamine (PE). Ideally, an egg lipid product should contain 10% PE. In today's market, this is not difficult to achieve. For more information about AL721 and how to obtain it: PWA Health Group, Box 234, 70-A Greenwich Ave., New York, N.Y. 10011. Telephone: 212-995-5846. PWA Health Group sells con- sistently high-grade lipids at the lowest cost possible. PE con- tent ranges from 9.5% and up. Healing Alternatives Buyers Club, P. O. Box 411107, San Francisco, CA 94141. 415-641-6208. Steve Gavin, who devised the "home recipe" for AL721, can be reached at 201-677-2795. For information about Eggsact, call Bill Powell at 408-429- 1596. This product is inferior, ranging around 6.5% PE. Summary AL721 is a non-toxic substance that has good laboratory evi- dence as an antiviral against HIV. There is also theoretical reason to believe it may be active against CMV and EBV, so-called "cofactor" viruses in the development of AIDS. Based on the stu- dies available to date, 20 grams daily seems to be a reasonable dose. It is not known if dividing it up is better than taking it at once; it is probably best taken on an empty stomach, with no fats ingested 2 hours before or 2 hours after. Unfortunately, published and anecdotal observations in patients taking AL721 have not lived up to the promising test- tube studies. Israeli doctors have reported improvements in gen- eral overall condition, fevers and skin problems. The results of the St. Luke's study are not so encouraging (although, as men- tioned, they may have used an inferior product). If taken, AL721 is probably best combined with another antiviral (e.g., AZT, Dex- tran sulfate, or ribavirin). Some have cautioned that there may be interactions between AL721 and other drugs, but there is no evidence to support this theory. We will be reporting on the upcoming NIH trial as informa- tion becomes available. [Ed. note: We are indebted to Don Shewey for researching and writing the bulk of this article.] Your Tax Dollars At Work: The NIH AIDS Effort Congress began appropriating money for AIDS research in 1982. Each successive year, the budgeted amount has increased substantially. Dueling groups of critics complain respectively that the government is either spending too much or too little investigating therapies for HIV related disease. Regardless of their particular viewpoint, observers have a common concern in a responsible accounting for the money spent. People are demanding to see results. The National Institutes of Health apportion funds earmarked for AIDS research to the various agencies under its aegis. The lion's share of this money goes to the National Institute of Allergy and Infectious Diseases (NIAID). Approximately a year and a half ago, NIAID created a clinical studies program to test experimental drugs with potential antiviral or immunomodulating activity. In June 1986, plans were unveiled to establish a net- work of 14 AIDS Treatment Evaluation Units (ATEUs), linking hos- pitals and medical schools where clinical trials would be moni- tored. The system was designed to "provide significant research advantages and speed the evaluation of drugs with therapeutic potential against AIDS." Six months later, an additional five ATEUs were named. The NIAID further augmented their AIDS Program by creating 17 Clinical Studies Groups (CSGs) in October 1987. As well as bolstering drug investigation with basic sciences research, the CSGs would extend access to clinical trials to patients outside of the major medical centers. In any complex bureacracy with so many acronyms, the poten- tial for inefficiency is almost insurmountable. Indeed, an abun- dance of problems have surfaced since the program's inception, and critics have wasted no time in highlighting them. On the surface, the most striking deficiency is patient accrual. NIAID had projected a total enrollment of 2000 by the program's first anniversary. The actual figure was 845, and many of the approved protocols had not recruited a single patient by the end of that first year. Perhaps the most blatant weakness of the system, however, is the preponderance of trials studying AZT. Fully 87% of patients in ATEU trials as of June 1987 were receiving AZT, an antiviral drug that has serious side effects, and cannot be tolerated by a substantial percentage of AIDS patients (30-50%). Meanwhile, a host of interesting drugs have been allowed to lan- guish in the pipeline while AZT is exhaustively explored. A third, somewhat obtuse charge is that progress is hampered by institutional apathy. AIDS activists argue that researchers would work more quickly and efficiently if imbued with a greater sense of urgency. Researchers, for their part, complain of dif- ficulty hiring ancillary staff given the nature of the research. In June 1987, NIAID's director, Dr. Anthony Fauci, who was also head of the AIDS Program then, appointed a committee to review the system. The Clinical Trials Advisory Panel released some preliminary suggestions last Fall. The panel focused on the lethargic approach to protocol development and the flow of infor- mation within the system. It criticized communication between ATEU/CSG institutions and with NIAID and labeled the computerized data collection system inefficient. The panel also warned that current protocol application procedures, which are burdensome and convoluted, actually discourage investigator ingenuity. These criticisms, coupled with tenacious public pressure from groups such as ACT-UP, prompted a reorganizational meeting at NIH's headquarters in Bethesda, Maryland on December 17-18. NIAID proposes a restructuring, or an "evolutionary process" of the AIDS Program to eliminate the most palpable inefficien- cies. Dr. Dan Hoth, who is the new director of NIAID's AIDS Pro- gram under Dr. Fauci, outlined the agency's plans to invigorate their program in a letter to participating investigators in December 1987. The agency hopes to accomplish its goals by relaxing some of the strictures that have inhibited smooth opera- tion of the clinical trials program. Whereas it had evolved a "top-down" structure, NIAID now wants to cultivate investigator participation in defining priorities and developing trials. In other words, NIAID is now soliciting ideas from various sources. Other plans for reform include a simplification of the bureau- cratic procedures to set a clinical trial in motion and fine tun- ing the computerized data collection system. NIAID's central office will also assume some of the more administrative tasks now performed by the institutions. The most radical change announced is the agency's intention to combine the ATEUs and the CSGs. All participating institutions will be known as AIDS Clinical Cooperative Groups (ACCGs). Pharmaceutical companies will be invited to play a more aggressive role in protocol development, and they will have more direct access to ACCGs. Addressing the paucity of different drugs in clinical trials, NIAID seems to be encouraging suggestions for experimental trials. To facilitate this, the administration is attempting to clarify the process of protocol approval. Ideas for new protocols must be submitted in the form of a "concept sheet" to the appropriate science commit- tees, which are staffed by ACCG investigators. These committees are responsible primarily for developing a research agenda and implementing studies. They will work more autonomously within the new system. Investigators are free to join any of the 10 committees: Primary Infection, Opportunistic Infection, Phar- macology and Pharmacokinetics, Biological Response Modifiers, Oncology, Pediatric, Virology, Immunology Data Management or the Neurology Subcommittee. Once a committee approves a protocol, it is favorably referred to the AIDS Clinical Drug Development Com- mittee. This committee is charged with choosing drugs to recom- mend to the AIDS Program. The Drug Development Committee consists of 21 affiliates who have been selected for a 3 year period. Some of the members are clinical trials researchers. In addition to making recommendations about drugs that merit further investi- gation through an experimental protocol, this body designs tri- als. The final stage in study design is the appointment of a protocol team. This team comprises a study chairperson, a NIAID physician, a biostatistician, a "protocol specialist", and possi- bly a representative of the appropriate pharmaceutical company. The protocol specialist position is new; these individuals will be responsible for assembling and editing protocols. They will accelerate the flow of paper through the system and will provide logistical support to the ACCGs. Once the protocol team is func- tioning, a clinical trial can actually begin recruiting partici- pants. Whereas in the past, little importance was attached to trial size, NIAID plans to favor two basic structures for new proto- cols. Small, Phase I pilot studies will be liberally approved to propel more promising, obscure drugs into clinical trials. For the most part, pilot studies will take place at one research center. If an experimental drug is well tolerated by partici- pants in toxicity trials (Phase I), it can be expedited to an efficacy study (Phase II-III). Large numbers of patients will be recruited for phase II and III studies, which will be coordinated by several institutions in cooperation. This approach is intended to shorten what has been, at times, an epic venture for experimental drugs through the labyrinth of FDA licensing. The current mixture of active protocols, the majority of which incor- porate AZT, are of various sizes. The few that were designed to be large, multi-institution trials are certainly not filled to capacity. If the new guidelines are followed in good faith, the clinical trials program should become much more focused and streamlined. Typhoid Vaccine Therapy Mr. Sal Catapano has been treating AIDS patients with injec- tions of Typhoid vaccine for several months in Valley Stream, NY. His therapy, which made the national media early in September, consists of repeated injections of typhoid vaccine in an attempt to stimulate the immune system. Since this report, Catapano, not a licensed physician, has been treating about 70 AIDS/ARC patients. Until recently, he was giving injections in the den of his home but he has now teamed with a licensed doctor who admin- isters the medication in an office. According to recent reports, a second physician is giving the injections in a Manhattan office. Payment is on a sliding scale, and many people are treated for free if they cannot pay. Catapano has not published any results, nor will he discuss them in detail over the telephone. He states that his results are "enough to rock the great big Queen Mary ship." He reports that dramatic reductions in KS have occurred. However, he does admit that many patients have experienced opportunistic infec- tions while on his therapy. He does not believe in T-cell count- ing or other currently accepted methods of monitoring immune function. Many patients report high fevers and flu-like symptoms after injection -- this is a strong jolt to the immune system. He takes patients off all medications, including AZT and agents for Pneumocystis prophylaxis (Bactrim, Dapsone, etc.). He believes that AZT "tears down" the immune system and refuses to even see patients that have been on long-term AZT. Catapano, trained as a syphilologist, apparently believes that syphilis plays an important role in the development of AIDS, and he treats patients with penicillin as well as the typhoid injections. Catapano will not divulge the details of the therapy itself, for which he claims to have applied for a patent. Interested physicians must sign an agreement with Catapano before he will release any information on the treatment. This agreement includes a royalty, payable to Catapano, for each office visit for each patient treated. This is certainly a questionable way of getting an effective treatment to PWAs. We caution: this is an essentially unknown therapy being tried on AIDS patients without any formal evidence of effective- ness. Moreover, there is a strong theoretical argument for dec- lining this kind of therapy: it is a powerful stimulant of the immune system -- exactly the kind of stimulation that makes HIV flourish. This fact alone makes Catapano's therapy an extremely risky proposition. Interested parties can contact Mr. Catapano at 516-385-2437 or 516-825-6226. In Brief Family Pharmaceuticals of America, Inc. is making AZT avail- able at wholesale cost -- $169.75 per hundred, including ship- ping, handling and charge card fees. It is delivered in heat sealed, tamper proof packages by UPS. There is no indication on the outside of the contents. Turnaround time is about one week. Records for insurance reimbursement are provided. Call 1-800- 922-3444 9AM-6PM Monday through Friday, 9AM-1PM Saturday. Medpro, Inc. has generously donated 600 of their Air Support Systems to PWAs. It is an inflatable tubular device which is designed to prevent bed sores. Each individual air tube in the Air Support System rotates as the patient moves, so tissues cannot pull or stretch. The units are valued at $49.95 each. Call Recreation at 212-645-8861. New Studies Doctors at Metropolitan Hospital Center are recruiting patients with ARC for an Ampligen study. Patients must not have full-blown AIDS, and have fewer than 300 T-cells. Based on prel- iminary studies, Ampligen is an extremely promising drug. Half of patients will receive Ampligen, and half will receive placebo. Patients whose condition deteriorates will be switched immedi- ately to Ampligen if they were on placebo; if they were on Ampli- gen, the dose will be doubled. The study will last nine months. Interested physicians can call Dr. Theodore Lenox (212-230-6035). The Community Research Initiative (CRI) is beginning a large (200 patient) study of Aerosolized Pentamidine for prophylaxis of PCP in persons with AIDS. Patients will receive either 100 mg or 150 mg of pentamidine every other week. Both doses, from previ- ous studies, seem likely to be effective in preventing PCP. A good nebulizer which delivers the proper droplet size will be used. This is a great study and a way to get pentamidine for free. Anyone with CDC-defined AIDS who has not received aerosol- ized pentamidine for more then 3 months is eligible. Interested physicians can call the CRI at 212-463-8981. For more informa- tion on aerosolized pentamidine, see Treatment Issues, Vol. 1 no. 1. A new 3-month study of Ribavirin is recruiting patients at New York Hospital. Researchers are looking for patients with Lymphadenopathy and otherwise asymptomatic. T-cells must be in the 200-600 range. The study will be using a higher dose of Ribavirin -- 1600 mg daily -- which researchers feel is more likely to be effective than studies previously conducted. Physi- cians may call Dr. Richard Roberts at 212-472-4580. Doctors at Columbia Presbyterian are conducting a 6-month study of tricyclic antidepressants (Tofranil) in gay men with depression. People with full-blown AIDS are excluded. All patients will receive Tofranil for 3 months. At that time, half will be switched to placebo and half will remain on Tofranil. All treatments and psychotherapy are free. Physicians may call Judith Rabkin, Ph.D. at 212-960-5762. A similar study will be conducted at Cornell Medical Center. Patients with ARC who are depressed are eligible; some will receive Tofranil (an antidepressant medicine) and others will receive placebo. Non-responders to placebo will be offered a 6- week course of Tofranil. Physicians will be monitoring patients medically as well as psychologically. Donna Manning, M.D. may be contacted at 212-472-5058. Correction The last issue of Treatment Issues incorrectly listed the address of DeVeras, Inc., suppliers of stabilized Aloe vera extract. Their correct address is: 3404 Greenville Ave #104, Dallas, TX 75206. Other Resources American Foundation for AIDS Research (AMFAR) has compiled a catalog of trials involving experimental drugs. The "AmFAR Directory of Experimental Treatments for AIDS & ARC" also includes some background information, updated regularly, about AIDS. Write to AMFAR at 40 West 57th St., New York, N.Y. 10019, or call (212) 333-3118. "AIDS Treatment News" is a short, biweekly report which chroni- cles current developments in experimental and alternative treat- ments and deals with public policy issues. Contact John S. James at P.O. Box 411256, San Francisco,CA 94141 or call (415) 282-0110. "PWA Coalition Newsline", published "by and for people with AIDS and AIDS Related Conditions," is a grass-roots news magazine that appears monthly. The publication reports news developments deal- ing with the health crisis as well as alternative treatments. Editorials and literary contributions add another interesting dimension to this excellent source of information. Write PWA Coalition Inc., 263A West 19th St., Room 125, New York, N.Y. 10011, or call (212) 627-1810. Ask about their other publica- tion, "Surviving and Thriving with AIDS". "ATIN" (AIDS Targeted Information Newsletter) performs a monthly search of hundreds of medical journals worldwide. Definitely aimed at doctors and researchers, it is the best ongoing litera- ture search available. It has an impressive cast of editors who comment on the significance of the studies cited. Published by Williams & Wilkins, P.O. Box 23291, Baltimore, MD 21203 or phone 1-800-638-6423. Project Inform publishes an excellent newsletter called "PI Per- spective" which deals with experimental treatments and focuses special attention on drug regulatory issues and public policy. Another valuable resource is their up-to-date drug hotline. Call them at 1-800-822-7422. "Body Positive" is a new organization established by and for HIV-antibody-positive people to exchange information, advocate research, fight discrimination, and provide mutual emotional sup- port. They publish a monthly newsletter called "The Body Posi- tive." Write to: 263A West 19th Street, New York, NY 10011 or call 212-633-1782. Coming Next Month The p24 Antigen Capture Assay is a blood test that should prove important to PWAs and seropositives alike. In fact, it may turn out to be the most accurate predictor of those seropositives who are most likely to get sick. For PWAs, it will also be important in monitoring antiviral therapy and judging a person's response to antiviral drugs. Look for the p24 test becoming as important as the T-cell test. Next month, Treatment Issues will flesh out the published and anecdotal information on Imuthiol. Do T-cells rise on Imuthiol? Is Antabuse really an equivalent to Imuthiol? What is a reason- able dose of Antabuse? We'll also be reporting on the U.S. tri- als conducted to date as well as reviewing the published litera- ture on Imuthiol. There is increasing interest in the antiviral drug Dextran sul- fate (see Treatment Issues, Vol. 1 no. 2). We'll be reporting on availability of Dextran and on how people taking Dextran are doing, both in the San Francisco study and locally as well. 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. Associate Editor: Kevin Armington GMHC, Department of Medical Information, 132 West 24th Street, Box 274, New York, NY 10011 Footnotes: 1 Fischl MA et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind, placebo-controlled trial. NEJM 317(4):185, 1987. 2 Rothenberg R et al. Survival with the acquired immunodefi- ciency syndrome. NEJM 317(21):1298, 1987. 3 Richman DD et al. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. NEJM 317(4):192, 1987. 4 Laurence, J. Bacterial infections in AIDS. Infections in Sur- gery, November, 1987, p. 623. 5 Mitchell WM et al. Mismatched Double-stranded RNA (Ampligen) reduces concentration of zidovudine (AZT) required for in-vitro inhibition of human immunodeficiency virus. The Lancet, 4/18/87, p. 890. 6 Hartshorn KL et al. Effects of combination antiviral therapy on LAV/HTLV-III replication in vitro. II International Confer- ence on AIDS, Paris, 1986. 7 Yarchoan R et al. Development of antiretroviral therapy for the acquired immunodeficiency syndrome and related disorders: a progress report. NEJM 316:557, 1987. 8 Corey L. Personal communication. 9 Corey L. Personal communication. 10 Groopman JE et al. Effect of human granulocyte-macrophage colony stimulating factor on myelopoiesis in AIDS. NEJM 317(10):593, 1987. 11 Lyte M et al. A special lipid mixture for membrane fluidiza- tion. Biochimica et Biophysica Acta 812:133, 1985. 12 Moore NF et al. Interaction of vesicular stomatitis virus with lipid vesicles: Depletion of cholesterol and effect on virion membrane fluidity and infectivity. Journal of Virology 27(2):320, 1978. 13 Kosina F et al. Essential cholinephospholipids in the treat- ment of viral hepatitis. Casopis Lekaru Ceskych 120(31-32):957, 1981 (transl.) 14 Jenkins PJ et al. Use of polyunsaturated phosphatidyl choline in HBsAg-negative chronic active hepatitis: results of prospec- tive double-blind controlled trial. Liver 2:77, 1982. 15 Sarin PS et al. Effects of a novel compound (AL721) on HTLV- III infectivity in vitro. NEJM 313:1289, 1985. 16 Crews FT et al. Modification of HIV lipids, protein structure and infectivity by AL721, a unique lipid mixture. 27th Intersci- ence Conference on Antimicrobial Agents & Chemotherapy, 1987, #371. 17 Skornick Y. et al. Treatment of AIDS patients with AL721 in an open trial. Unpublished. 18 Greico MH et al. Open study of AL721 in HIV-infected subjects with generalized lymphadenopathy syndrome (LAS). III Interna- tional Conference on AIDS, Washington, DC, 1987, TP.223. 19 Lange M. Personal communication. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display