[Electronic distribution for GayCom by the Backroom 718 951-8256] Volume 7 no. 9 October, 1993 Gay Men's Health Crisis: Treatment Issues > Examining Ecstasy > FDA Reviews ddC > AZT liver Toxicity Syndrome More Common in obese Women > Merck Protease Trial to Begin > Treatment briefs >> Controversy Amidst Severe Flu Season >> RAC Approves New Anti-HIV Trials >> GMHC Begins PCP Education Campaign >> GMHC Treatment Library >> Women in Clinical Studies >> d4T Side Effects >> New Mandarin Orange Flavor ddI >> Oral Ganciclovir, ddI, and Pancreatitis >> Nutrients May Reduce Progression to AIDS > Washington Watch: Harold Varmus > On the Edge: Antisense, Other Gene Modulators in Development > AIDS Treatment Resources ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Examining Ecstasy by Derek Link "Ecstasy" is the popular name for methylenedioxymethamphetamine (MDMA), a common, illicit recreational drug. MDMA is an amphetamine ("speed") with hallucinogenic properties. Most people who use MDMA believe the drug is safe. However, MDMA has caused serious toxicities in some people and, in rare cases, has been linked to death. Although there are no conclusive data on the long-term toxicities of the drug, some researchers believe that frequent, long-term MDMA use can cause brain damage or complicate underlying psychiatric disorders. Although MDMA is certainly not an AIDS treatment, many physicians who treat people with HIV report that large numbers of their patients use the drug recreationally. Yet most physicians also report they have no knowledge about MDMA. This article reviews information from the medical literature and credible unpublished reports on the drug, including its clinical effects, toxicities, incidence, and use patterns. History and Overview MDMA was unsuccessfully developed as a weight loss pill by a German drug company in 1912. The drug remained obscure and forgotten until its psychedelic properties were rediscovered in the 1960s. MDMA emerged fully into public view in the late 1970s and early 1980s when a group of psychotherapists openly advocated for its use as an adjunct to therapy and underground chemists began producing it for recreational users. MDMA is often called a designer drug, but for reasons different than most people realize. In pharmaceutical drug development, designer drugs refer to compounds synthesized using sophisticated, computerized modeling techniques. In the case of recreational drugs, designer drugs are chemically altered forms of illicit drugs which retain similar effects but have not yet been legally proscribed. MDMA is neither difficult to make nor was it designed to produce its pleasurable effects. MDMA possession, distribution, and manufacture were criminalized in 1985 by the Drug Enforcement Agency (DEA), the Federal government's lead agency in the "War Against Drugs." Ecstasy is a Schedule I drug, which means the DEA has determined it has no medical use and a high potential for abuse. Penalties for manufacture and distribution of a Schedule I drug are fifteen years in prison and fines up to $125,000. The DEA reports that in fiscal year 1992 it made no arrests for MDMA distribution and seized 11,753 dosage units of the drug. Incidence of MDMA Use Data on the extent of recreational MDMA use are limited and incomplete, frustrating attempts to understand the drug. Yet some small studies and anecdotal information confirm that MDMA is widespread among some populations and that its use grew in the 1980s. The DEA estimates that MDMA production has increased dramatically since the 1970s. One Texas manufacturer reportedly made 10,000 doses in all of 1978, but increased production to 30,000 per month in 1985. One operation claimed to have manufactured and distributed 2 million doses in one month alone in 1985.[1] The National Institute of Drug Abuse (NIDA) collects data on drug use patterns in young adults aged 19 to 28.[2] Since 1989, NIDA has collected data on MDMA use. Based on a sample of 2600 people, 3.9 percent in 1992 reported using MDMA at some point in the past, 1 percent reported using MDMA within the last twelve months, and 0.3 percent reported using it within the last 30 days. According to the NIDA data, MDMA use has remained at a constant level in this population since 1989. MDMA was perceived as one of the least harmful illegal drugs when taken intermittently by the young people in this survey. For unknown reasons, though, NIDA did not ask how respondents perceived MDMAs harmfulness when taken frequently. Most respondents perceived the harm of other drugs, including other amphetamines, to increase with chronic use. Peroutka published an informal study of the incidence of MDMA use on the Stanford University campus in 1987.[3] He found that 39 percent of randomly selected Stanford undergraduates reported using MDMA recreationally. Most respondents reported using MDMA an average of five times. Most observers agree that MDMA is most commonly used by urban populations. MDMA seems to be particularly popular with "college students, gays, yuppies, and New Age seekers of psychological and spiritual growth."[4] Data from several other countries extend these observations. British health authorities estimate that a half million young people may have used MDMA in that country.[5] An Australian study examined MDMA use patterns among Sydney residents. Based on a sample of 100 MDMA users, the Australian study concludes that a typical MDMA user in Sydney is a 27-year- old, employed, college-educated person who lives in the inner city area.[6] Seventy-two percent reported using MDMA at social events and dance parties. Finally, a study conducted at the Kobler Center, an outpatient HIV clinic in London, confirms the observation that HIV-infected people, at least in Britain, are using MDMA in large numbers. Mansfield and colleagues studied 196 patients at their clinic. Recreational drug use was common overall; forty percent reported MDMA use within the last year.[7] MDMA and Unsafe Sex Recreational drug use, and MDMA in particular, may be related to unsafe sexual practices and HIV infection among gay men, according to two reports. Coates and associates report that MDMA was significantly correlated with HIV seropositivity among men who have sex with men.[8] Although other recreational drugs were associated with HIV infection, once frequency of receptive anal sex was statistically controlled, only MDMA remained significantly correlated with HIV infection in this group. Interestingly, neither injection drugs nor needle sharing were correlated with increased HIV infection in this group. The Kobler center study examined the sexual practices of gay men attending an HIV clinic in London. Users of Ecstasy, LSD, amphetamines, and cocaine were more likely to engage in unprotected sex and had more sexual partners. MDMA Clinical Effect MDMA is most commonly sold in doses of 100 to 150mg. Most MDMA users ingest the drug orally, although some report snorting or injecting. Twenty minutes to one hour after ingestion, MDMA produces an initial burst of energy and euphoria. These effects continue for approximately two to three hours. A slow "coming down" period is the followed by a characteristic MDMA hangover which usually lasts about one day. The hangover typically involves depression, irritability, and fatigue. MDMA increases the release of 5-HT (also called serotonin), a brain chemical which is believed to play a significant role in mood, sleep, and sexual function, from reserve storage in tissues. This burst of 5-HT causes more neurons (brain cells) to respond in a rapid period, producing the effect of "ecstasy." However, once released from reserve storage, 5-HT levels are greatly diminished, producing the hang over effect. 5-HT reserves are slowly replenished over the next 24 hours. Interestingly, studies in rats suggest that MDMA 5-HT depletion may be biphasic -- that is, once reserves have been restored 24 hours after MDMA use, another transient decline occurs approximately seven days later.[9] Several informal clinical studies have been conducted with the drug. For the most part, these studies rely on volunteer self-assessment questionnaires and a limited amount of physical data to make their conclusions. The studies were conducted primarily in healthy, adult men, although a few women were also enrolled. No study described the racial or ethnic background of its participants. It should be noted that this research was conducted primarily by renegade psychiatrists, usually from California, who are also advocates for the use of MDMA in psychotherapy. This research was conducted prior to MDMA's classification as a Schedule I drug. Unfortunately, rigorous clinical studies of MDMA are now impossible since MDMA's Schedule I status prohibits further clinical research. However, MDMA research continues in other countries, most notably Switzerland, so more clinical data may become available in the future. Downing conducted an informal study of MDMA with twenty-one volunteers given the drug at a dose of their own choosing.[10] Volunteers were recruited in San Francisco in October 1984. Doses ranged from 0.8 to 1.9mg/LB with a mean dose of 1.14mg/LB. Eight women volunteered for the study. The study volunteers were better educated and earned higher incomes than the general population and all reported previous MDMA use. Liester and colleagues conducted an observational MDMA study in Southern California with twenty psychiatrists who had previously used MDMA.[11] Two psychiatrists were women. The psychiatrists reported their previous MDMA experiences on questionnaires. Greer and Tolbert administered MDMA to volunteers in San Francisco and Santa Fe between 1980 to 1983.[12] Twenty nine volunteers were administered 75 to 150mg of MDMA in their own homes. When the drug's effect began to diminish, usually after about two hours, volunteers were offered a second dose of 50mg to "prolong the session and to provide a more gradual return to their usual state of consciousness." These studies all point to the same conclusion: when used in a controlled environment, MDMA can be relatively safe, with no life-threatening toxicities. The side effects typically seen with the drug in these studies include dilated pupils, clenched jaw, grinding teeth, elevated blood pressure, nausea, vomiting, dizziness, headache, decreased appetite, eyelid twitches, muscle aches, insomnia, and other general stimulant effects. Reports of MDMA-Related Deaths If these informal studies demonstrate that MDMA can be relatively safe when used in a controlled environment, wide- scale recreational use has shown its dangers. Several deaths linked to MDMA have been reported in the medical literature. However, in virtually every reported death, toxicology data (that is, testing body fluids to see if MDMA is actually present) were unavailable and other drugs were reportedly consumed along with MDMA. Furthermore, many deaths classed as MDMA-related resulted from impaired judgment while on the drug. One report describes a young man who climbed an electrical tower while on MDMA and fell to his death. Despite the small number of cases and the difficulty collecting data on the drug, at least two deaths have been reported where MDMA appears to be the sole cause of death. In both cases, the users collapsed suddenly and died of cardiac arrhythmias. Interestingly, arrhythmias are a well-recognized mechanism of sudden death with amphetamine overdoses.[13] Although the numbers are far too small to draw firm conclusions, several points emerge from an examination of deaths where MDMA was the sole or contributing cause of death. Thus far, researchers have not determined if MDMA deaths result from a rare, idiosyncratic reaction to the drug or overdose reactions. Since MDMA's pharmacokinetics are unknown and overdose levels have not been determined, this question remains unresolved. However, in cases where MDMA was reported as the sole or significant cause of death (and where toxicology data are available), blood levels greater than 1mg/L of the drug have been found. In cases where MDMA was an incidental cause of death, blood levels of MDMA did not exceed 0.39mg/L.[14] Furthermore, Greer recommends that individuals with "hypertension, heart disease, hypothyroidism, diabetes, hypoglycemia, seizure disorders, glaucoma, diminished liver function, or those who are pregnant" avoid the drug.[15] MDMA-Associated toxicities Several reports in the medical literature describe serious toxicities related to MDMA use. Hayner and McKinney summarize the immediate and residual toxicities experienced by recreational MDMA users in San Francisco.[16] This information is based on case reports from the medical literature as well as anecdotal reports from health care clinics and drug treatment programs. Although serious toxicities have been reported in MDMA users, their causal mechanism and rate of occurrence are unknown. Most observers agree, however, that while serious toxicities are possible with MDMA, they are very rare. Furthermore, many MDMA users consume other drugs concomitantly, complicating a thorough toxicity analysis. Thus far, researchers do not know if MDMA toxicities are related to dose level, frequency of use, environmental factors, or idiosyncratic reactions to the drug. Several observers note that hyperthermia reactions to MDMA may be related to strenuous physical activity and inadequate fluid consumption while on the drug. MDMA-related hyperthermia seems to occur most commonly in people who use the drug while dancing at clubs. Several physicians stress that MDMA users should rest frequently, avoid alcohol use, and drink plenty of water, soft drinks, or juices while on the drug. One report describes a serious drug interaction between MDMA and a monoamine oxidase inhibitor (MAOI), a class of antidepressant drugs. Psychiatrists who prescribe MAOI consul their patients to avoid using other drugs, particularly those with central nervous system effects. Patients treated with MAOIs should not use MDMA.[17] MDMA may exacerbate or provoke underlying psychiatric illness, according to the anecdotal, unpublished observations of some psychiatrists. Clinicians from the Haight-Ashbury Free Clinic in San Francisco describe a "delayed anxiety disorder" in MDMA users. A New York psychiatrist describes a "persistent perceptual disorder" in MDMA users. Thus far no published reports confirm these observations. When asked to sum up the toxicity data, a clinical psychiatrist familiar with MDMA said: "If someone takes MDMA and they develop high temperatures and/or muscle rigidity, they should seek medical attention immediately at the nearest emergency room." Possible Neurotoxic effects No data prove that MDMA causes brain damage in humans. However, this question has not been addressed adequately due to prohibitions on MDMA research and the difficulty studying this problem in humans. Yet some researchers believe that MDMA does have neurotoxic effects, particularly when used chronically. These researchers cite animal data which suggest that chronic MDMA use permanently impairs the brain's 5-HT system.[18, 19, 20, 21, 22, 23, 24] They speculate that chronic MDMA use may permanently diminish the amount of 5-HT stored in tissues and impair the brain's complex system of 5-HT- sensitive neurons. Two research teams have performed preliminary studies on people who use MDMA frequently and found little clinical or neurochemical evidence of brain damage. In fairness, though, these studies have been small, preliminary attempts to answer this question and did not possess sufficient statistical power to draw firm conclusions. Kystal and colleagues examined the performance of nine chronic MDMA users on a standard battery of neuropsychologic tests.25 These chronic users consumed an average of 1.9 monthly doses of MDMA (+/- 1.7 doses) for an average of 5.1 years (+/- 2.3 years). No differences were seen in tests which measure affect (mood). Slight differences were observed in tests of attention and memory. These differences were too small to be observed clinically. However, given the small number of patients studied and the large number of tests performed, these differences could be the result of chance alone. The authors conclude: "These preliminary data raise the possibility that individuals with extensive MDMA use histories exhibit mild, subclinical impairments in cognitive function, but not affective disorder." Price and associates performed a complex neurochemical study on the same group of chronic MDMA users. They measured serum prolactin response to intravenous L-tryptophan, an indirect surrogate marker of 5-HT function.[26] Although this test is imprecise, a decreased serum prolactin response to l-tryptophan has been linked to other diseases associated with abnormal 5-HT function, such as depression. Also, several antidepressant drugs which have known effects on 5-HT function increase the serum prolactin response.[27] The serum prolactin response was reduced in MDMA users, though not to statistically significant levels. The authors conclude, "MDMA users seemed less likely to manifest the very marked prolactin responses demonstrated by some healthy subjects, suggesting a degree of blunting in those subjects ordinarily most sensitive to l-tryptophan." Is MDMA Addictive? Researchers do not agree if MDMA is addictive. Most reports describe MDMA's abuse potential as low. However, scant data on the extent and frequency of MDMA use make it difficult to know for certain if MDMA addicts exist. In fact, two animal studies demonstrate that MDMA can be addictive in primates. Rhesus monkeys and baboons will self-administer MDMA.[28, 29] Tests of this sort -- determining if primates will self- administer a drug -- are a classic, well-known method of determining if a substance is addictive. MDMA has been considered "nonaddictive" because most reports describe a pattern of use with the drug that is unusual for addictive substances. Most users report a disinclination to use MDMA frequently, waiting at least a week between doses. Furthermore, the pleasurable effects of the drug diminish while the negative effects increase with frequent use, according to several reports.[30] Underground MDMA MDMA is manufactured illegally by underground chemists. Thus no regulations govern its manufacture. As a result, there is no certainty that street MDMA is actually MDMA. There are numerous anecdotal reports of purported MDMA which turned out to be some other substance. In addition, some researchers question whether contaminants in MDMA could be responsible for some MDMA deaths and toxicities. Renfroe describes an important and unique service called Analysis Anonymous sponsored by the not-for-profit group PharmChem Laboratories in California.31 During its period of operation from 1972 to 1984, recreational drug users could submit samples of their drugs for an analysis of purity. During this period, 101 MDMA samples were submitted for analysis. Most samples came from the San Francisco area, New York, and Los Angeles. Of the 101 samples analyzed, 59 contained MDMA only. Twenty-four samples contained MDMA with other substances, usually MDA, a closely related but more toxic compound, or chemical precursors from MDMA's manufacturing process, usually methylamine. Fifteen samples contained MDA alone or with its own chemical precursors. One sample "contained a nondescript amphetamine." Two samples contained no MDMA, MDA, or other known drugs; the constituents in these two samples could not be identified. Analysis Anonymous ceased operations before MDMA was criminalized. It is unknown what effect, if any, criminalization may have had on the purity of MDMA samples. Treatment Issues was unable to obtain information on the purity of MDMA now available on the street. Conclusion MDMA is a popular illicit drug widely used by some urban populations, including gay men and some HIV-infected people. Inadequate data describe the extent of MDMA use. MDMA is associated with increased risk of HIV infection in men who have sex with men. Although rare, MDMA use has been linked to serious toxicities and death. While no data support the belief that MDMA causes brain damage, scientific studies have not adequately addressed this question. MDMA addiction has not been described in humans, although it has been observed in two species of primates. MDMA is a street drug with unknown purity. Possible MDMA-Related Toxicities Tachycardia (rapid heartbeat) Hypertension progressing to Hypotension Hyperthermia (highly elevated body temperature) Hypertonicity (increased pressure of body fluids) Intravascular coagulation Kidney Failure Hallucinations Rhabdomyolysis (serious muscle degeneration) Possible Residual Effects of MDMA Flashbacks Anxiety Attacks Persistent Insomnia Psychotic Reactions Depression 1 Beck J. Public Health Consequences of MDMA. In: Ecstasy. Peroutka SJ (ed). 1990. Kluwer: Amsterdam. 2 Personal Communication. [Data on file at GMHC] 3 Peroutka SJ. New England Journal of Medicine. 317 (24) 1987: 1542-3 (letter). 4 Beck J. op cit. 5 Randall T. Journal of the American Medical Association. 268(12): 1992. 1505-6 6 Solowij J, et al. Survey of Ecstasy Users in Sydney. 1991. NSW Health Dept Research Grant Report DAD 91-69. [Data on file at GMHC.] 7 Mansfield S, et al. The Use of Ecstasy and Other Recreational Drugs in Patients Attending an HIV Clinic in London. 1993. [Data on file at GMHC] 8 Coates RE, et al. American Journal of Epidemiology. 128(4):1988. 729-39. 9 Schmidt CJ. Journal of Pharmacology and Experimental Therapeutics. 240:1987.1-7. 10 Downing J. Journal of Psychoactive Drugs. 18(4): 1986. 335-9. 11 Liester MB, et al. Journal of Nervous and Mental Disease. 180(6): 1992. 345-52. 12 Greer G, et al. Journal of Psychoactive Drugs. 18(4): 1986. 319-326. 13 Dowling G. Human Deaths Attributed to MDMA. In: Ecstasy. Peroutka SJ (ed). 1990. Kluwer: Amsterdam. 14 Ibid. 15 Greer G. op cit. 16 Hayner GN, et al. Journal of Psychoactive Drugs. 18(4): 1986. 341-7. 17 Smilkstein ML, et al. Clinical Toxicology. 25:1987. 149- 159. 18 Stone DM, et al. European Journal of Pharmacology. 128: 1986. 41-8. 19 Battaglia G, et al. Journal of Pharmacology and Experimental Therapy. 242:1987. 911-6. 20 Commins DL, et al. Journal of Pharmacology and Experimental Therapy. 241: 1987. 338-45. 21 Mokler DJ, et al. European Journal of Pharmacology. 138: 1987. 265-8. 22 Schmidt CJ. Journal of Pharmacology and Experimental Therapeutics. 240:1987.1-7. 23 Ricaurte GA, et al. JAMA. 260: 1988. 51-5 24 Ricaurte GA, et al. Brain Research. 446:1988. 165-8. 25 Krystal JH, et al. American Journal of Drug and Alcohol Abuse. 18(3):1992. 331-41. 26 Price LH, et al. Archives of General Psychiatry. 46:1989. 20-22. 27 Price LH, et al. Archives of General Psychiatry. 46:1989. 13-19 28 Beardsley PM, et al. Drug and Alcohol Dependency. 18:1986, 149-157. 29 Lamb RJ, et al. Psychopharmacology. 91:1987. 268-272. 30 Peroutka SJ. Archives of General Psychiatry. 46:1989. 191. (letter) 31 Renfroe CJ. Journal of Psychoactive Drugs. 18(4): 1986. 363-9. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ FDA Reviews ddC by Derek Link ddC Approved and Withdrawn In a two-day meeting full of ironic twists, the FDA Antiviral Advisory Committee voted on September 20 to fully approve ddC monotherapy and withdraw combination AZT/ddC's accelerated approval. Advisory Committee decisions carry no official authority, although FDA usually follows them. The monotherapy approval was based on CPCRA 002, an open-label, non- randomized comparison of ddC and ddI in advanced AIDS patients who were intolerant or failing AZT. Hoffmann LaRoche, the New Jersey-based affiliate of the Swiss drug company that manufactures ddC, also submitted data from earlier monotherapy studies, the ddC monotherapy control arm of ACTG 155, and the ddC expanded access program to support the approval. During the vote, Fred Gordin, MD, VA Medical Center in Washington DC, a committee member said, "we use ddC monotherapy as salvage therapy in advanced patients. This brings the indication in line with its clinical use." In a separate decision, the committee voted to withdraw ddC combination therapy's accelerated approval. Accelerated approval is a new regulatory mechanism which allows marketing approval before a drug's clinical efficacy has been established. AZT/ddC combination therapy obtained the first accelerated approval in June 1992. Committee members cited several reasons for the withdrawal including insufficient data supporting efficacy of the combination, lack of ddC access problems, and doubts that accelerated approval could be implemented after ddC received a full monotherapy approval. AZT liver Toxicity Syndrome More Common in obese Women On the second day, the committee reviewed data on FIAU, the experimental hepatitis B virus treatment that killed five patients in phase II studies. Jay Hoofnagle, the principal investigator of the FIAU study, detailed the horrible chronology of this clinical research disaster. The patients died from severe drug-induced liver damage characterized as lactic acidosis and hepatic steatosis, leading to organ failure and death. A preliminary report from Yung-chi Cheng of Yale University suggests that the FIAU syndrome may be caused by damage to mitochondrial DNA. Mitochondrial DNA is responsible for energy production in cells. FIAU, a nucleoside analog, may become integrated into mitochondrial DNA so that it continues to block DNA function even if the drug is discontinued. The FIAU tragedy ignited fears that other nucleoside analogs could produce a similar syndrome. The Committee reviewed data on six deaths due to lactic acidosis and hepatic steatosis, reported to the FDA's post-marketing surveillance system, that may have been caused by AZT. Five of the six deaths occurred in women, four of whom were obese. Obese women are, however, at higher risk for fatty liver and lactic acidosis in general. While these cases appear similar to the FIAU syndrome, no AZT-related mechanism has yet been found. AZT does not appear to have a FIAU-like effect on mitochondrial DNA, according to Cheng's preliminary report. Dr. David Barry, Vice President of Burroughs Wellcome, AZT's manufacturer, presented an overview of lactic acidosis and hepatic steatosis reports from AZT clinical studies, post- marketing surveillance, and hospital records. This analysis includes cases that did not result in death. Forty-three cases have been identified thus far. Again the rate appears higher in women than in men. Although the data are incomplete, preliminary information suggests that the syndrome occurs at a rate of 6/100,000 for men, and 20/100,000 for women. AZT's label has already been amended to reflect this new information and Burroughs Wellcome mailed out a "Dear Doctor Letter" to all physicians describing what is now known. However, the mechanism of these toxicities and their relationship to AZT remains unclear. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Merck Protease Trial to Begin by David Gold In a meeting with AIDS activists in September, Merck and Co., Inc. disclosed details of its ongoing HIV protease inhibitor program. The company reported that a Phase I trial of its lead protease inhibitor compound, L-735, 524, will begin in October 1993. Protease is an enzyme on HIV which is required for the virus to reproduce. The protease enzyme cuts newly produced viral precursors separating the final viral elements (such as p24) in preparation for viral assembly. In laboratory tests, when HIV proteins are not processed by the protease enzyme, virions are non-infectious. A number of pharmaceutical companies, including Merck, Hoffmann-LaRoche, Abbott Laboratories, Monsanto Searle, Vertex and Du Pont Merck, are developing HIV protease inhibitor compounds. According to Merck researchers, L-735, 524 has demonstrated in laboratory tests that it can strongly inhibit replication of HIV. In fact, they believe that the drug is substantially more potent than RO-31-8059, the protease inhibitor currently in clinical trials and being developed by Hoffmann-LaRoche. It is hoped that L-735, 524 can either prevent or limit the development of viral resistance to HIV. Historically, the development of HIV protease inhibitors has been slowed by difficulties in insuring sufficient oral bioavailability (that is making sure the body absorbs the drug when it is administered by mouth). Apparently, HIV protease inhibitors are a type of modified peptide which the liver usually eliminates from the body. In the words of Merck scientists, the compounds are "difficult to get into to the body and when they do- they usually don't stay around for too long." A twelve-day safety and pilot study of L-735, 524 began in June 1993 in HIV positive, P-24 positive patients. Eight patients were given 400mg every six hours (q6h). After the dose appeared safe and tolerable, 600mg q6h was given to another four patients for up to four weeks. However, the 600mg dose appeared to cause some increases in bilirubin levels (a bile pigment level that appears in high levels when the liver is inflamed). These four patients were then given the 400mg dose and have continued on that dosage. In terms of anti viral activity, early data on this very small number of patients indicate that L-735, 524 was able to achieve p24 reductions in the area of 50 percent on all patients, except one (Merck researchers have found no evidence of L-735, 524 in the blood of this one patient, leading them to believe that he/she was not taking the drug on a regular basis). The reduction in p24 levels is comparable to that sometimes seen with the initiation of AZT therapy. However, Merck scientists hope that, unlike with AZT or the non-nucleoside reverse transriptase inhibitors, viral resistance will not develop or will develop far more slowly. Nevertheless, officials at the company emphasize that "since the information on anti-viral activity comes from only a few patients given drug for only up to eight weeks in total, we are unable to draw any conclusions about the anti viral effect of L-735, 524 except that we have enough information to proceed with the clinical program."[1] The Phase I trial will enroll 60 HIV-positive, p24 positive, asymptomatic volunteers with CD4 counts of less than 500 at three sites. The sites will be as follows: NYU Medical Center, NYC (contact Mary Ann Kiernan, RN, 212/263-6565), University of Pittsburgh (contact: Nancy Mantz, RN, 412/647- 8125) and University Hospital, Stony Brook (contact Ruth Ann Burk, RN, 516/444-1658). Participants will be randomized to one of three arms: 1) L- 735, 524-400mg, q6h, 2) L-735, 524-200mg, q6h, and 3) AZT 200mg, every eight hours (q8h). A two week washout of AZT, ddI or ddC will be required. In the meeting, Merck officials also discussed the cancellation of the company's non-nucleoside reverse transriptase inhibitor, L 697, 661 and progress on the effort to increase collaboration among drug companies involved in AIDS research. In addition, Merck researchers disclosed that they are working on development of protease inhibitors for cytomegalovirus (CMV) and herpes simplex infections. 1 Standby Statement on HIV Protease Inhibitor L-735, 524, Merck & Co., Inc., September 22, 1993. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Treatment briefs by David Gold ^^^^^^^^^^^^^^^^ Controversy Amidst Severe Flu Season The Centers for Disease Control and Prevention (CDCP) issued a warning that this year's influenza season could start earlier and be more severe than in previous years. The warning is based on reports of recent flu outbreaks in two Louisiana nursing homes. These flu outbreaks occurred earlier than usual. The flu season normally begins in December and peaks in the first two to three months of the year. The CDCP also reports that the strain of flu responsible, Type A Beijing flu, is associated with more severe disease and higher death rates than other strains. An abstract at the Ninth International AIDS Conference in Berlin has generated controversy because it suggests that flu shots can increase HIV replication. The abstract, from O'Brien and colleagues at UCLA, has received considerable attention in several AIDS newsletters (Abstract PO-A12-0209). The study examined the amount of replicating virus in sixteen HIV-infected people who received the flu shot. Five HIV- infected people who were not immunized served as controls. Nine of the sixteen immunized subjects had "significant increases in virus replication," measured by infectious virus titers. Viral increases peaked one to two weeks after immunization and approached baseline after "several months." Although the O'Brien abstract has received significant attention, another less-discussed abstract from the conference addresses the same issue, and draws opposite conclusions (Abstract PO-B22-1929.) Yerly and colleagues in Geneva examined viral RNA PCR, HIV provirus in PBMCs by PCR, p24 antigenemia, and CD4 counts before and four weeks after influenza immunization in twelve HIV-infected people (eight adults, four children). No differences were detected in any of the four tests. The authors conclude that "immunizations should thus be part of routine prophylaxis for HIV-infected children and adults, without fear of triggering HIV replication or disease acceleration. " RAC Approves New Anti-HIV Trials At its September meeting, the Recombinant DNA Advisory Committee (RAC) of the NIH approved two new gene therapy protocols for HIV infection. The RAC must approve every gene therapy protocol conducted at institutions which receive NIH money. In practice, virtually all American medical research organizations receive some NIH money. The newest protocols will be conducted by Stan Ridell and Phillip Greenberg of the Fred Hutchinson Cancer Center in Seattle and Flossie Wong- Staal of the University of California at San Diego. The Ridell-Greenberg study will examine if genetically altered CD8 cells persist in patients. The Wong-Staal protocol will examine the effect of an anti-HIV RNA ribozyme transduced into autologous lymphocytes. The RAC also took preliminary steps toward reducing its oversight role. The number of gene therapy protocols has increased substantially since the RAC began. Many researchers now believe that compulsory RAC review of every gene therapy protocol is unnecessary. Although no official decision has been made, RAC members concluded that certain types of gene therapy protocols, such as those using familiar techniques, may not require routine review in the future. GMHC Begins PCP Education Campaign PCP remains a leading opportunistic infection in people with HIV, despite highly effective prevention and treatment. The New York City Department of Health reports that PCP is still, by far, the leading opportunistic infection, accounting for 49 percent of diseases diagnosed in people with AIDS. In response, GMHC began a city-wide PCP education campaign to raise awareness that effective, low-cost (or free) PCP prevention exists. The campaign, which began in September, includes subway posters, brochures and radio ads. GMHC has distributed details about the campaign to over 7,000 AIDS organizations and health departments. GMHC Treatment Library The GMHC Treatment Library is open from 10AM-1PM on Mondays, Tuesdays and Fridays at 129 West 20th St, NY, NY. Special thanks to volunteer Helen Kane, R.N., whose extraordinary work makes our expanded hours possible. Women in Clinical Studies The FDA published new guidelines for the enrollment of women into clinical trials. The new guidelines, published in the Federal Register July 22, would replace earlier guidelines developed in the 1970's that excluded women from clinical trials. Garance Franke-Ruta, a New York-based AIDS activist, said that the new guidelines "were a step in the right direction, but didn't go far enough." She added that the FDA needs to develop guidelines specifically for women with life- threatening diseases. Written public comments on the new regulations are due by November 19 to: Dockets Management Branch, HFA-305, Food and Drug Administration, Room 1-23, 12420 Parklawn Dr. Rockville, MD 20857. In written comments, note "Docket Number 93D-0236." For more information, contact Patrick Savino at the FDA 301/295-8012. d4T Side Effects Bristol Myers Squibb, the New York-based drug company that manufactures d4T, reports that over 7,000 patients have participated in its expanded access program for d4T, a new anti-HIV nucleoside analog. Another 1,000 patients are participating in clinical trials of the drug. According to the company's June 1993 quarterly safety summary of all patients taking d4T, 43 cases of pancreatitis have been reported, including three pancreatitis-associated deaths. The company claims that the pancreatitis occurred in patients who received concurrent medications known to cause pancreatitis (such as IV or aerosolized pentamidine) or had a history of chronic alcohol abuse. The quarterly report advises physicians to continue to "exercise caution in the monitoring of patients on the parallel track program at high risk of pancreatitis, such as those with a prior history of the condition, or those receiving medicinal agents known to be associated with pancreatitis." In addition, in a letter to physicians, the company indicated that there were some anecdotal reports of insomnia and irritability in a number of individuals on the d4T expanded access program. However, the company points out the safety board has determined that "no safety issues were apparent that would prevent the programs from continuing." Individuals on the d4T access program are encouraged to report all side effects to their physicians. The company expects to submit a New Drug Application (NDA) for licensing approval of d4T in December 1993. New Mandarin Orange Flavor ddI Bristol-Myers Squibb, which also manufactures ddI, submitted an application to the FDA to change the drug's formulation to a smaller, softer, "mandarin orange" flavored tablet. Many patients found the original "winter green" flavored ddI tablets too large, difficult to chew, and distasteful. The FDA must approve all changes, including flavorings, made to drug formulations. No regulatory problems are expected. No word on whether kiwi-flavored d4T is on the horizon. Oral Ganciclovir, ddI, and Pancreatitis Preliminary data suggest that oral ganciclovir, an experimental drug under development for CMV prophylaxis, may increase the risk of pancreatitis in patients taking ddI. Oral ganciclovir is a new form of intravenous ganciclovir, an approved treatment for CMV disease. Eight cases of pancreatitis occurred in oral ganciclovir studies, seven in those on drug, and one case in a person on placebo. Five patients who developed pancreatitis received both oral ganciclovir and ddI. Syntex, ganciclovir's manufacturer, has alerted FDA, study investigators and study participants of the findings. Thus far, no information suggests an increased pancreatitis risk in patients receiving intravenous ganciclovir and ddI. Nutrients May Reduce Progression to AIDS A study followed 296 HIV-positive men over a six-year period and found that intake of certain nutrients was associated with reduced risk of progression to AIDS (Journal of AIDS, 1993; 6:949-958). This nonrandomized, observational study followed the cohort's intake of nutrients through questionnaires and observed whether they progressed to AIDS. The study did not directly compare different nutrient regimens. The authors state that the study group consisted of "well-nourished, well-educated HIV-seropositive homosexual and bisexual men." They conclude "the risk of AIDS decreased as consumption increased" for all nutrients examined -- i.e. vitamin A, carotene, retinol, vitamin C, vitamin E, folic acid, riboflavin, thiamin, niacin, iron, and zinc. Higher intake of these nutrients was also associated with a higher CD4 cell count at baseline. Iron, vitamin E, and riboflavin reduced the risk of progression to statistically significant levels. Vitamin C, thiamine and niacin approached statistical significance. Higher intake of vitamin A, riboflavin, vitamin E, retinol and thiamine was associated with having more than 500 CD4 cells at baseline. However, when differences in baseline CD4 counts were controlled in the analysis, progression to AIDS became non-significant in this cohort. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Washington Watch: Harold Varmus by Derek Hodel ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ President Clinton moved in August, after months of delay, to nominate Harold E. Varmus, MD, to head the sprawling National Institutes of Health (NIH), the nation's premier biomedical research organization. Varmus, a Nobel laureate cancer researcher from the University of California at San Francisco, will replace Bernadine Healy, MD, whose controversial tenure was marked by infighting at the agency, and just plain fighting on Capitol Hill. AIDS activists, though mostly pleased to see Healy go (with the exception of Project Inform's Martin Delaney, who urged the Clinton administration to retain Healy, a Bush appointee), reacted with a mixture of caution and outright suspicion to news of Varmus' nomination. Many were familiar with the Nobel laureate only by reputation at UCSF ("brilliant," "impossibly arrogant," "doesn't suffer fools,") or through a letter Varmus wrote, urging his colleagues to oppose the Office of AIDS Research reforms, an activist initiative recently signed into law as Title XVIII of the National Institutes of Health Revitalization Act of 1993 (S.1). AIDS activists were of mixed views as to how to respond to Varmus' nomination. Many, including the AIDS Action Council, the Treatment Action Group, AmFAR, and GMHC, took no position before or after the nomination, opting instead to respond only if specific allegations surfaced suggesting that Varmus would be unsuitable. Project Inform took the opposite approach, and in a letter to President Clinton signed by founding director Delaney, heavily criticized the nomination process, while stopping just short of opposing Varmus altogether. Delaney cited the need to appoint another woman to head the agency, the lack of input from the AIDS community, and Varmus' opposition to Title XVIII as his chief concerns. In fact, the debate around Title XVIII had been heated, with scientists and activists alike divided about the amendment's relative merits. As with so many Washington debates, support for the two opposing sides (essentially the reformists v. the status quo-ists) was fired up by Washington-based lobbyists, spearheaded by the AIDS Action Council on one hand and the old-guard biomedical research lobby, led by the American Association for Medical Colleges (AAMC) on the other. One way of doing that was to solicit letters from scientists and other big wigs, and of course, a Nobel laureate like Varmus was the biggest wig of all. (Dr. David Korn, dean of the Stanford Medical School, took a lead in opposing the legislation; Dr. David Ho, director of the Aaron Diamond AIDS Research Center, took the lead in supporting it.) Varmus' letter was standard lobbying fare -- filled with inflammatory language and characterized by a misleading interpretation of the legislation, it was designed to push alarm buttons on the Hill. Varmus co-signed the letter with Mark Kirschner, PhD, his colleague at UCSF, and sent it to 21 Massachusetts research scientists, urging them to sign, in turn, an enclosed letter to Senator Kennedy, the principal Senate sponsor of S.1, opposing the Title XVIII provisions. Apparently the letter's appeal was not universal, however, as Kennedy's office reports that they never received it. Interestingly, in a "Policy Forum" column in Science magazine (Vol 259, p. 444-5, 22 January 1993), co-authored with colleagues J. Michael Bishop and Kirschner, entitled "Science and the New Administration," Varmus makes a variety of observations on the administration of science that presumably are more reflective of his personal views. In an ironic echo of AIDS activists, Varmus notes that "agencies that should be working together to promote research in the life sciences instead remain separated in competing departments." He offers recommendations that seem surprisingly consistent with Title XVIII, including proposals to "generate a comprehensive plan for the best use of federal funds for biomedical research"; "establish the NIH as an independent federal agency and consolidate the authority of the director over the individual institutes"; and "...increase the NIH budget by 15 percent per year, which would double the budget in current dollars by 1998." Hmmm. Sounds familiar. Outside the AIDS community, rumors of Varmus' nomination had circulated in the Beltway for months. Varmus has strong support among many scientists inside and outside the agency, particularly bench scientists. They speak of Varmus' background as a basic (as opposed to clinical) researcher with reverence, and herald his ascension as the advent of a new dawn for the troubled agency. Basic scientists love Varmus because he, unlike many of his predecessors, would bring considerable laboratory experience to the job, having spent much of his career inside a research laboratory. (Varmus won the Nobel Prize with Bishop in 1989 for their discovery that oncogenes, cancer-causing genes found in many cells, are present in the human genetic code, and are not foreign intruders.) Though four other Nobel winners worked at the NIH, Varmus will be the first to head the agency. The reputed second runner-up for the nomination was Judith Rodin, PhD, a psychologist and provost at Yale. Behavioral scientists, predictably less enthused about Varmus than their biomedical colleagues, for the most part threw their support behind Rodin, who also had the advantage of being a woman. In light of Clinton's commitment to diversifying federal leadership, the prospect of replacing Dr. Healy, the first woman to head the NIH (a white male bastion if ever there was one) with yet another white male, caused quite a little consternation. In a particularly Washingtoniana twist, when the Varmus nomination seemed imminent, supporters of Dr. Rodin, led by the American Psychological Society, took an unusual but effective course: they called AIDS activists in an effort to increase opposition to the Varmus nomination, and they called the media, claiming that AIDS activists were opposed to Varmus. Since the "AIDS activists v. real scientists" characterization had been very effectively shaped and employed by the title XVIII opponents, they recognized it immediately and raced into action. The AAMC rushed out an "Action Alert" to their Council of Deans, to alert them that "elements of the AIDS community" were threatening Varmus' nomination, and that immediate action was critical. Meanwhile, the Clinton administration, still true to form, stalled for two more months. In that time, a group of AIDS activists requested -- and was immediately granted-- a meeting with Dr. Varmus. At the meeting, which was held on the Bethesda, MD, NIH campus, representatives from AAC, GMHC, TAG, and AmFAR chatted with Dr. Varmus about their support for Title XVIII -- and his opposition. During the meeting, Varmus listened attentively and asked several pointed questions. While declining to discuss his views in detail, he did indicate a need to better understand exactly how the original OAR (established by Congress in 1988) had failed to be effective. Later, in a letter to meeting participants, Varmus said, "I now have a much clearer idea of what you are trying to achieve by expanding the role of the Office of AIDS Research and of why you have taken the positions reflected in S.1. My views on some of the issues have been altered by our conversation, and I now believe that we probably agree about most methods (the objectives were never in doubt). The next big job is to find an outstanding person to serve as Director of the OAR, and you can be assured that I will be looking for someone with energy, commitment, and strong scientific credentials." As we go to press, it seems likely that Varmus will easily pass confirmation hearings when the Senate reconvenes in September. It seems just as likely that Secretary Shalala will cede significant authority for hiring an OAR director to Varmus, and that he, in turn, will play an important role in shaping the AIDS research agenda for the next several years. Clinton said, upon nominating Varmus, "as one of the world's leading medical researchers, Harold Varmus will bring great strength and leadership to the National Institutes of Health." >Derek Hodel is the Treatment Issues Director at the AIDS Action Council, a federal lobbying organization that represents 950 community-based AIDS service and advocacy organizations nationwide.< On the Edge ^^^^^^^^^^^ An occasional series examining the frontiers of AIDS research. Antisense by Michael Ravitch Gene therapy is a new branch of medicine with revolutionary potential. One type of gene therapy, called "gene transfer," implants new, functional genes into cells to alter their function or confer resistance to infection. (See Treatment Issues May, 1993) Gene transfer experiments are on-going in several congenital diseases such as cystic fibrosis and ADA- deficiency, as well as cancer and AIDS. Yet other gene therapy strategies do not insert new genes into cells, but rather attempt to inhibit or repress specific genes already in the cell. Antisense, the first example of these strategies to enter clinical studies, attacks the RNA, a crucial messenger in the life cycle of HIV. Background and Overview All viral infections, including AIDS, can be described as acquired genetic diseases. Viruses are packages of genetic material that insert themselves into DNA, the double-stranded chain of genes inside the nucleus of every cell, and transform the cell into a factory for producing new copies of the virus. Each sequence on the DNA provides the blueprint for the production of a specific protein. Proteins are complex structures which form the building blocks of all life. Human DNA contains all the necessary information to produce the proteins that compose our bodies. However, once infected by the virus, the DNA also programs the cell to manufacture the component proteins of HIV. In order to produce proteins, the DNA must transmit its information to a messenger RNA (mRNA) molecule, also known as the sense strand. The mRNA uses this information to organize the building and assembly of proteins into the finished product -- usually essential cellular components but, in the case of infected cells, new copies of HIV. An anti-sense drug is the exact opposite (i.e. the mirror image) of a specific "sense" strand. Antisense drugs attach to mRNA, and thereby block the production of particular proteins at the genetic level. Traditional drugs attack proteins, which, in the case of anti-HIV treatments, include reverse transcriptase, protease, and other familiar targets. However, proteins are large, complex structures that are produced in massive quantities by infected cells. In order to be successful, traditional drugs must disable every copy of the protein. Traditional drugs often attack healthy, normal proteins as well, and cause toxicities. Antisense is an attractive option because each mRNA molecule produces large numbers of each protein. Anti- sense technology, by attacking a single mRNA strand which is responsible for producing large quantities of single protein, may be a more efficient way of eliminating large quantities of unwanted proteins at once. Since an antisense drug only binds with its exact opposite, it should be extremely specific, producing minimal toxicities. Whereas proteins are large and complex, RNA is composed of various combinations of just four well-known amino acids -- adenosine, cytosine, thymidine, and guanosine. Antisense proponents have discovered that the real world does not follow theory as quickly nor as easily as they would like. As simple and elegant as it seems, antisense has not yet translated into clinical reality. The technological challenges are numerous. Since antisense drugs will be administered in traditional ways -- intravenously or subcutaneously -- scientists face significant hurdles. The compounds must be large enough to be extremely specific to the right piece of RNA, but stable enough to avoid destruction by the body, and small enough to reach and penetrate target cells. Chemists have been modifying antisense compounds for years in order to solve these problems, with as yet unknown success. Even with an optimal compound, the therapy, in the case of HIV at least, would have to be taken chronically, and probably in high doses. Viral resistance, as with regular antivirals, could theoretically develop. Furthermore, the expense could be staggering because large-scale production of these compounds is still costly and difficult. For all these reasons, the first efforts with antisense drugs have been for topical, rather than systemic, uses. The first antisense drug to enter clinical trials was a therapy aimed at genital warts caused by Human Papilloma Virus (HPV). Isis Pharmaceuticals, a Seattle-based biotechnology company, began this first antisense trial in 1992. Thus far, the company has no evidence of efficacy, but reports about absorption and safety are promising. Again, this is only topical use, and its lessons for systemic HIV therapy are limited. The First AIDS Trial Hybridon, a Worcester, MA-biotechnology company, seems poised to put the first systemic antisense drug into HIV-positive individuals. GEM-91, its lead compound, blocks HIV's gag gene. The gag gene of HIV is common to all retroviruses and encodes for the critical core proteins of HIV, such as p9, p17, and p25 (the nucleiod shell). If gag, production is blocked, the Hybridon investigators theorize HIV replication could be dramatically slowed. Phase I trials are currently planned to begin in United States at the University of Alabama at Birmingham and through the ANRS, the French national AIDS research network. The French study could enroll its first patient in October. Hybridon believes GEM-91 may have two unique features. Laboratory studies indicate mRNA may not be the only target. HIV, like all other retroviruses, enters the cell as a piece of viral RNA (vRNA). GEM-91 may also inhibit vRNA before its integration into DNA. This suggests that GEM-91 might interfere with both early and late stages in HIV's replication cycle. Hybridon also claims another advantage to its compound over the traditional antisense model. Instead of merely disabling a single RNA strand, its drug might be able to destroy many RNA strands. According to Hybridon, GEM-91 first binds to the target RNA strand, then activates a cellular enzyme (RNAseH) which destroys the strand, leaving the drug free to attack more RNA. Even if GEM-91 fails in humans, Hybridon is positioned to be a leading player in antisense research. Hybridon has already synthesized GEM-92, its second generation product. Also, the company claims broad patent rights over all antisense approaches to AIDS, although this has not been tested in the courts. In addition, Hybridon believes it has resolved manufacturing issues. The company was recently awarded a patent that covers new, more efficient methods of antisense production and has started construction of a large manufacturing facility. The company believes that it will have sufficient supply of the compound to meet the needs of clinical research. Conclusion Since the genes of HIV have been extensively studied by molecular biologists, researchers can design antisense compounds aimed at specific mRNA molecules that produce proteins essential to HIV's survival. Although very few clinical trials have actually begun, and clinical efficacy is a long way from certain, the pharmaceutical industry has devoted significant resources to this burgeoning field. Its proponents believe antisense will radically transform medicine and open up the possibility for new treatments for AIDS and other viral diseases. Other Gene Modulators in Development Other gene therapy approaches similar to antisense are in more preliminary stages of development. Triple Helix DNA An innovative twist on the antisense idea is the "Triple Helix" technology being developed by several companies. Whereas naturally-occurring DNA consists of two interlocking strands in the famous double helix structure, scientist have developed the means to attach a third strand of DNA to the double helix, effectively blocking transcription. Now they are working to synthesize small strands of DNA which are targeted against specific sequences of the HIV genome. In the same way that RNA-targeted therapeutics are more efficient than drugs which bind with proteins, Triple Helix promises to be more efficient than conventional antisense. The compound would bind to the DNA itself, rather that to the thousands of mRNA transcripts. Thus less drug would be needed, greater efficacy would be achieved, and transcription of the unwanted gene would cease completely. However, this technology is at an earlier stage of development, and many biochemical obstacles remain. Ribozymes Another promising variation on antisense are a class of compounds called Ribozymes. These are naturally-occurring RNA molecules which function as catalytic molecular scissors, chopping up RNA strands at selected sites. Ribozymes can be synthesized, and targeted against specific RNA sequences, just like antisense compounds. However since ribozymes can effectively destroy many targets, according to its proponents, lower levels of drug might be needed, and therapy could be more thorough. However, chemists have not yet figured out how ribozymes can reach and penetrate cells in the body. Recently the RAC approved the first clinical study of ribozymes (see page 6). The investigator is Flossie Wong-Staal at the University of California at San Diego. In the test tube, her so-called "hairpin" ribozyme completely blocked HIV infection. In order to overcome the pharmacological difficulties, Wong-Staal is attempting a gene therapy double whammy: she will plant a gene in the CD4 cells of the subjects that will produce the ribozyme. One hope is the creation of a ribozyme which can cleave DNA, rather than RNA, and thus could simply cut the viral genes out of the host cell DNA. If such a compound were in existence, it would be an extremely promising modality for HIV treatment. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ AIDS TREATMENT RESOURCES This list is by no means a complete list of available sources of information about AIDS/HIV treatments. Treatment Issues will continue to provide additional sources of information over the next few months. The AIDS Drug Assistance Program (ADAP) pays for several drugs commonly used by people who are HIV-infected. Eligible individuals must be New York State residents, who earn less than $44,000 annually and cannot have a health insurance plan covering 100% of prescription costs. For more information and a list of drugs that are covered, call 1-800-542-2437. AIDS Targeted Information Newsletter (ATIN) performs a monthly search of medical journals. Written for doctors and researchers, it is one of the best ongoing literature searches available. It is funded by AmFAR and published by Williams & Wilkins, call 1-800-638-6423. AIDS Treatment News is a biweekly report which chronicles current developments in AIDS research and experimental and alternative treatments for AIDS/HIV. It is published by John James. Write PO Box 411256, San Francisco, CA 94141, or call 1-800-TREAT-1-2. [Also available on GayCom] AIDS/HIV Experimental Treatment Directory is published quarterly by the American Foundation for AIDS Research(AmFAR). AmFAR also publishes the AIDS HIV Clinical Trial Handbook. Call 1-800-39-AMFAR. AIDS Weekly is a weekly newsletter with short abstracts on AIDS-related news items, journal reports, and conference abstracts. AIDS Weekly also publishes AIDS Therapies, AIDS Abstracts, TB Weekly, Cancer Weekly and Blood Weekly. Call 1- 800-633-4931. Body Positive publishes a monthly newsletter called The Body Positive. For more information or a subscription write to 2095 Broadway, Suite 306, New York, NY 10023 or call 212/633- 1782. The Common Factor is a monthly newsletter published by The Committee of Ten Thousand, an organization by, for, and of people infected with HIV through blood and blood products. Write The Committee of Ten Thousand, The Packard House, 583 Plain Street, Stoughton, MA 02072 or call 617/344-9634. The Experimental Treatment Guide, a guide to clinical trials and expanded access programs in the New York State area, is published by the AIDS Treatment Data Network. It is available free of charge to New York State residents. Call 212/268- 4196. The New York State Treatment Info-Line provides information on expanded access and clinical trials in the New York State area. Call 1-800-MEDS 4 HIV. Notes from the Underground is a grass roots publication focusing on drugs available through the underground network. Write to: PWA Health Group at 150 West 26th St., Suite 201, NY, NY 10001 or call 212/255-0520. Project Inform publishes PI Perspective and offers an excellent drug hotline. Call 1-800-822-7422. The NIH, CDC, and FDA operate a toll-free hotline to provide information on all HIV-related clinical trials in the U.S. Callers may request a Spanish speaking operator. Lines are open between Monday and Friday, 9:00 to 7 p.m., EST. The number is 1-800-TRIALS-A. The Positive Women is a bi-monthly newsletter by, for, and about HIV-positive women. The newsletter provides information on traditional medical and holistic practices, as well as articles concerning general coping, spiritual issues, and living-well with HIV. Write to The Positive Woman., PO 334372, Washington, DC 20043, or call 202/898-0372. Treatment & Data Digest reviews issues being addressed by the Treatment & Data Committee of ACT UP/New York. Write ACT UP/NY, 135 West 29th Street, NY, NY 10001. WORLD publishes a monthly newsletter on women and HIV/AIDS. Available in English and Spanish. Write WORLD, PO Box 11535, Oakland, CA 94611 or call 415/658-6930.