[Electronic distribution for GayCom by the Backroom 718 951-8256] Volume 7 no. 2 March, 1993 Gay Men's Health Crisis: Treatment Issues > Convergent Combination Therapy > D4T Side Effects > Kaposi Sarcoma Update > First Large Simple Trial for AIDS Begins > Protease Inhibitor Efficacy Study Begins > treatment briefs by David Gold >> Possible Benefits of Beta-carotene >> Zinc Supplements Show Unimpressive Results >> Fluconazole Resistance in Fungal Infections >> Marinol Approved >> Free Transportation to Medical Appointments >> ADAP Plus >> Intramuscular Pentamidine for PCP Prophylaxis >> New Additions to Medical Information >> Notes from the Underground > Drug company watch by David Gold >> Magainin Reports Encouraging News from Sharks >> Megace: good news, bad news, and an FDA thumbs up >> More on Nystatin >> Injectable INH Approved for TB -- Again >> Ampligen for Chronic Fatigue Syndrome >> Roche Investing in Antisense (common sense may be next) > Glossary > Dedication: Bob Rafsky, Bradley Nance ^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^ Convergent Combination Therapy by Rick Loftus Introduction Just over a month ago, researchers at the Massachusetts General Hospital in Boston caused a media sensation when they announced that Yang-Kung Chow, a medical student, discovered "what may be the Achilles' heel" of HIV[1]. Chow's approach, called "convergent combination therapy" and reported in Nature[2], a respected British medical journal, combined three drugs -- AZT, ddI, and either nevirapine or the pyridinone L697,661 -- to stop completely HIV replication in the test tube. The scientific scrutiny of Chow's report is not yet complete. Some researchers suggest that the significance of the finding is limited because successful test tube experiments using new drugs often fail when the same drugs are given to humans. Chow's results may not work because the ideal conditions in the test tube, where all the virus comes in contact with all three drugs, does not occur in human bodies. [Editor's Note: John James in AIDS Treatment News Issue 170 writes a comprehensive analysis of the scientific strengths and weaknesses of the convergent combination hypothesis.] While most researchers do believe that Chow's work represents an important scientific advance, the ultimate test of convergent combination therapy will be in real patients. Nevertheless, Chow's findings offer hope that, with the right combination of antiretroviral drugs, HIV's reproduction in the body could be drastically slowed. What is "Convergent Combination Therapy"? The idea behind convergent combination therapy is to combine drugs which attack the virus at a single target--in this case, reverse transcriptase, a crucial enzyme needed by HIV to reproduce. Part of the reason the convergent combination theory has gained such considerable attention is because it contradicts accepted medical thought. The classic infectious disease model of combination chemotherapy, based on the treatment of bacteria and protozoa, is to attack the organism at different stages of its life cycle. According to Chow, convergent combination may work because it turns one of the virus' greatest strengths -- its ability to mutate, or change, and then resist anti-HIV drugs -- against itself. It is well documented that HIV can become resistant to single drug therapy with AZT or ddI. Reports from last year's International Conference on AIDS suggest that HIV may even become resistant to both AZT and ddI simultaneously.[3] However, according to Chow's theory, there may be a limit to HIV's ability to mutate. By using the combination of these three drugs, HIV is either forced to mutate to resist all three drugs, resulting in a genetically defective virus, or it remains susceptible to at least one of the drugs, and is inhibited through that compound's antiretroviral action. In either case, HIV replication will be inhibited. What are the Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)? Convergent combination therapy has attracted attention back to a class of compounds known as the "non-nucleoside reverse transcriptase inhibitors." The term "non-nucleoside reverse transcriptase inhibitors" (hereafter NNRTI) is a long and rather peculiar name. It refers as much to what the compounds are not -- nucleoside analogues like AZT, ddI, ddC, and d4T -- as to what they are -- compounds which inhibit HIV at the same point. Lumped together in the category of NNRTIs are a number of different classes of drugs, including the pyridinones (being developed by Merck); the BHAP drugs (being developed by Upjohn); and the thiobenzimidazolone (TIBO) derivatives (being developed by both Boehringer Ingelheim and Janssen). Early monotherapy studies of several NNRTIs showed that HIV mutates rapidly to resist these drugs. The degree of resistance seen with these compounds -- up to 10,000-fold -- led to serious doubts about their use even in combination with nucleoside analogs, much less as monotherapy.[4] Resistance evolved to nevirapine[5, 6] L-6617, the BHAP compounds,[8, 9] and the TIBO derivatives[10, 11] in as little as four to six weeks. Since early studies showed that these compounds targeted HIV at a common site,[12, 13] it was believed that resistance to one NNRTI would confer resistance to all of them.[14] Chow's results, however, have renewed interest in clinical trials of NNRTIs. In addition, some companies, such as Merck, plan to continue testing their NNRTIs in combination with agents that target other stages of HIV's life cycle, such as protease inhibitors. Furthermore, recent findings that the BHAP compounds have a distinct resistance profile has led researchers to speculate that different NNRTIs may be used in combination with one another.[15] The most promising NNRTIs in, or soon to be in, clinical trials are profiled below: Nevirapine Nevirapine (also known as BIRG-587), a TIBO compound made by Boehringer Ingelheim Pharmaceuticals in Connecticut, has attracted the greatest attention as the third member of a convergent combination with AZT and ddI. ACTG 241, a study expected to begin in a few months, will examine the efficacy of nevirapine combined with AZT and ddI in a group of 400 people nationwide (see side bar for trial locations). In the meantime, treatment activists from around the country began a campaign to pressure Boehringer Ingelheim to create an expanded access program for the drug. A 30-patient pilot pharmacokinetic study examining the combination of AZT, ddI and nevirapine started at the University of Alabama in November. The study is fully enrolled. To date, no adverse effects have been reported. Three small trials of nevirapine alone or in combination with AZT provide some basic data on drug dosing and safety. ACTG 164, a dose ranging trial of nevirapine in 53 people with less than 400 CD4 cells and a positive p24 antigen test at baseline, established that the maximum tolerated starting dose appears to be 400mg/day.[16] Major side effects include fever, muscle soreness, and a rash that appeared 10 days after the start of therapy. Over half of those on the 400mg/ day dose experienced the rash. However, the incidence of rash dropped to 11% when patients started with a dose of 200mg/day for two weeks before building to 400mg/day. Seven patients who escalated to 600 mg/day tolerated the drug, although one suffered serious rash. The overall incidence of rash at doses higher than 400mg/day is unclear. Abnormal liver function tests, another major side effect, occurred in three of seven study patients on drug for more than 24 weeks. The average decrease in p24 antigen level was 50%, with the greatest decreases seen at the 400mg/day dose. Initially the study researchers thought that the 400mg/day dose continued to suppress viral activity in the face of the rapid development of resistance; but Maureen Myers, Director of Clinical Research for Boehringer Ingelheim, speculates that this dose actually forces the virus to undergo another mutation that confers resistance at the price of slower reproduction.[17] Preliminary data from ACTG 168, a five-arm study of nevirapine combined with AZT in 50 people with under 400 CD4 cells, indicates that there is no significant interaction between the drugs. Resistance to nevirapine, however, developed rapidly in those treated with the drug combination. ACTG 208 examines nevirapine 400 or 600mg/day with a two-week start-up dose of 200mg/day in patients with greater than 500 CD4 cells. While no resistance data is yet available, the majority of those on the 400mg dose showed sustained reductions in p24 antigen levels.[18] L-661 L-661, a pyridinone drug under development by Merck, is the other NNRTI used successfully by Chow in the convergent combination test tube experiments. Since Merck has yet to conduct preliminary interaction studies of L-661 and ddI, they have no immediate plans to develop a convergent combination study with their drug. However, due to activist pressure and the media hype, Merck has agreed to do an L-661 and ddI interaction study. It should be noted that Merck remains very skeptical about the Nature report. The company indicated they will pursue a convergent combination study with L- 661 if future data warrant. However, for the time being, they will stick with the traditional approach of attacking the virus at different stages of its life cycle, using L-735,524, the company's new protease inhibitor, as the third partner with L-661 and AZT. Merck began human trials of its protease inhibitor on February 1 of this year. Three Merck-sponsored monotherapy studies using L-661 established that short term use of the drug is safe in humans[19], with headache being the major side effect.[20] L-661 rapidly lowered p24 antigen levels and HIV levels in the study population; however, resistance of 1000-fold evolved in as little as four to six weeks. All three studies were terminated early due to the emergence of resistance. No patient was on drug longer than 27 weeks. It is unknown whether this resistance is reversible when drug is withdrawn. Another Merck-sponsored study conducted in Frankfurt, Germany, examined the combination of L-661 and AZT in a 48-week trial which enrolled 120 patients with CD4 cell counts between 200-500. The AZT and L-661 combination revealed no unexpected adverse effects. However, the study did not demonstrate the superiority of any arm as measured by increases in CD4 counts or improvements in clinical parameters. Given the healthy status of the trial population and the small size of the study, no significant change in these areas was expected.[21] While resistance to L-661 evolved in the four arms of the Frankfurt study, high-level resistance did not occur in the combination arms. Rather, the combination arms developed only low-level (six to ten- fold) resistance to L-661, leading Merck researchers to believe it might be overcome with higher doses of either drug. Accordingly, Merck switched all patients to an open-label study and increased the dose to AZT 200mg with L-661 200 mg three times a day (hereafter TID). Merck reports that the initial dose of AZT 300 mg/day did not achieve adequate levels in the blood. In addition, Merck launched a small follow-up study in Germany comparing AZT 200mg TID with either 200mg or 400mg L-661 TID. The study will investigate the safety and drug levels associated with the higher dose of L-661. For patients with CD4 cell counts below 250, Merck began enrollment of a similar study in the U.S. As in the German study, the study will compare L-661 400mg with AZT 200mg TID to AZT alone. The study will also investigate the effect of L-661 on possible resistance to AZT. Upon completion of the protocol, patients will have the opportunity to remain on the combination of L-661 and AZT, or switch to it, if the trial results show merit. U-87 and U-90 The Upjohn Company has two BHAP compounds, U-87201e (hereafter U-87) and U-90152 (hereafter U-90), in development for HIV disease. Upjohn, in a meeting with activists, claims that 25% of its research budget is now spent on the BHAP compounds and other HIV- related projects. Both U-87 and U-90 were studied in healthy, HIV-negative volunteers. No side effects were reported with either drug. U-90 emerged as the lead compound because of intriguing laboratory findings. In the test tube, U-90 appears to be 50-100 times more potent than U-87 (also known as ateviridine) and can block replication of 25 different HIV-1 strains, including some resistant to AZT and ddI.[22] In cell culture, the drug has shown low cytotoxicity and proved superior to AZT in inhibiting the spread of HIV-1. U-90 alone completely prevented the spread of HIV-1 in vitro.[23] U-90 appears not to be cross-resistant with other NNRTIs -- in other words, the major mutations which cause resistance to nevirapine and L-661 do not appear to reduce the activity of the BHAP compounds.[24] Scientists at the NIH and Upjohn theorize that, if adequate blood levels can be achieved, this drug should be able to inhibit virus that is resistant to L-661 and nevirapine.[25] An even more intriguing finding with both BHAP compounds is that they induce a novel mutation in HIV's reverse transcriptase enzyme which increases viral susceptibility seven to ten times to other NNRTIs such as nevirapine, L-661, and the Janssen TIBO drug R82,913.[26] Upjohn believes, based on this data, that U-90 may be another potential component of a convergent combination. Upjohn plans two clinical trials of U-90 to start April 1; one at the NIH Clinical Center and the other at the Upjohn Clinical Research Center in Kalamazoo, MI (see side bar). The Michigan study is a small, thirty- person interaction study of U-90 with nucleoside analogs. Upjohn will give enrollment priority to people from Michigan in this study. The NIH study, open to people nationwide, will have four arms comparing U-90 alone to U-90 with AZT to U-90 with AZT and ddI to AZT with ddI. The triple combination arm will have five patients enrolled at each dose level of U-90. The purpose of these trials is to establish the safety and proper dosing of this BHAP compound; once the proper dose is established, Upjohn wants to move forward with a large efficacy trial of more than 1000 patients. The company has also promised an expanded access program if the drug demonstrates efficacy. Although U-87 was the first BHAP compound in clinical studies, it is no longer the lead BHAP compound. ACTG 199, a 24-week study of U- 87 of twenty patients, showed no severe drug toxicities, although four people were withdrawn from the study due to fever and rash. While complete information from this study is forthcoming, two patients showed ten-fold resistance to U-87 after 24 weeks of therapy. There were no mutations associated with AZT resistance. While the study is far too small to obtain meaningful and reliable efficacy data, Upjohn researchers stated that patients showed a slight CD4 cell increase. Since this study was not designed to gather efficacy data, it is difficult to interpret the company's statement about CD4 increases. U-87 can readily cross the blood-brain barrier, according to Upjohn spokespersons. Therefore, Upjohn plans a trial, to be conducted in Europe, of U-87 in people with neurocognitive disorders. Presently, ACTG 187 is looking at U-87 monotherapy over eight weeks to see whether this drug has significant antiviral effects by itself. Other TIBO Compounds Other companies have NNRTIs in earlier stages of development, most prominent among them being Janssen Pharmaceutica, a division of Johnson and Johnson, Inc. Janssen developed several TIBO compounds, including R86,183 which has been studied in humans in the United Kingdom. However, Janssen reports that production problems have delayed the start of larger-scale studies of this compound. Furthermore, Janssen researchers reported at the March, 1993 ACTG meeting on R89,439 a new compound from the alpha-APA subclass of the TIBO derivatives. Janssen researchers[27] stated that R89,439 blocked reproduction of various strains of HIV-1 in vitro, but not HIV-2.[28] The inhibitory concentration of R89,439 is more than 50,000 times lower than its cytotoxic concentration, indicating the drug may be much less toxic than AZT. Moreover, the compound has shown synergistic anti-HIV-1 activity in vitro with AZT, ddI, and Ro-31-8959, Hoffman-LaRoche's protease inhibitor. A U.S. study of the compound is planned for later this year. Conclusion The NNRTIs include several classes of compounds that appear to be less toxic than the nucleoside analogs, based on data from early phase I studies. In 1991 these drugs were found rapidly to induce resistance in HIV, leading to serious doubts about their usefulness. Chow's discovery of convergent combination in the test tube, however, has brought attention back to these agents, raising hopes that the NNRTIs will ultimately prove beneficial when combined with nucleosides, other NNRTIs, or other new antiretroviral agents. 1. Massachusetts General Hospital. Press release, 17 February, 1993. 2. Chow,Y-K et al. Nature 1993;361:650-654. 3. Eron JJ et al. VIII Int Conf on AIDS, 1992. Abstract ThA 1569. 4. Personal communication with John Doorley, Executive Director of Communications, Merck & Co. 5. Merluzzi VJ et al. Science 250:1411-1413, 1990; 6. Mellor JW et al. Mol Pharmacol. 1992; 41:446-451. 7. Goldman ME et al. Proc Natl Acad Sci USA 1991;88:6863-6867. 8. Romero DL et al. J Med Chem, submitted;. 9. Romero DL. Proc Natl Acad Sci USA 1991;88:8806-8810. 10. Debyser Z et al.Virology 1992;188:900-904. 11. Dueweke TJ et al. J Biol Chem 1992;267:27-30. 12. Nunberg JH et al. J Virol 1991;65:4887-4892. 13. Richman D et al. Proc Natl Acad Sci USA 1991;88:11241-11245. 14. Sardana VV et al. J Biol Chem, 267:17526-17530, 1992. 15. Primary Infection Committee Meeting, AIDS Clinical Trials Group, Washington, D.C., February 24, 1993. 16. Primary Infection Committee Meeting, AIDS Clinical Trials Group, Washington, D.C., February 24, 1993. 17. Personal Communication with Maureen Myers, 24 February, 1993. 18. Primary Infection Committee, AIDS Clinical Trials Group, 24 February, 1993 19. Kappes J et al. VIII Int Conf AIDS 1992. Abstract: PoB 3021. 20. AmFAR Treatment Directory, Apr 1991. 21. Personal communication with John Doorley, Executive Director of Corporate Communications, Merck & Co. 22. Dueweke TJ et al. Antimicrob Agents Chemother. Submitted. 23. Meeting with activists, NIH, and Upjohn, February 24, 1993. 24. Dueweke TJ et al. Proc. Natl. Acad. Sci. In press. 25. Meeting with activists, NIH, and Upjohn February 24 1993. 26. Ibid 27. Stoffels P. Presentation at Primary Infection Committee Meeting, AIDS Clinical Trials Group, Washington, D.C., February 24, 1993. 28. Pauwels R et al. Proc. Natl. Acad. Sci. 1993;90:1711-1715. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ D4T Side Effects by Gabriel Torres, M.D. Bristol Myers Squibb reports that twelve patients developed pancreatitis which may have been related to d4T, a nucleoside analog under development as an anti-HIV agent. Pancreatitis is a life-threatening inflammation of the pancreas, an abdominal internal organ involved in the digestion of fats and protein. Inflammation of the pancreas leads to severe nausea, vomiting, abdominal pain, and, in some cases, death. Eight of the patients who developed pancreatitis were on the d4T Parallel Track Program and two died from this complication. Physicians and patients are warned to be cautious in enrolling into the parallel track program patients who are at high risk of pancreatitis, such as those with a previous history of this condition, or those receiving other drugs associated with pancreatitis such as pentamidine. Alcohol use may cause pancreatitis and should be discouraged in those taking d4T. Peripheral neuropathy occurred in only five of 820 patients taking the 1mg/kg/day dose of d4T, significantly lower than the incidence of neuropathy in patients taking higher doses (above 2mg/kg/day) in the phase I and II studies. Other side effects which occurred in more than five percent of patients on Parallel Track include fever, headache, pain, depression, sweating, nausea, diarrhea, and abdominal pain. The Parallel Track protocol is a randomized comparison of two doses of d4T (20mg or 40mg twice daily) and is available only for patients who are intolerant to, or who have failed, both AZT and ddI. To enroll patients, physicians must call 1-800-842-8037 and drug will be sent free of charge. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Kaposi Sarcoma Update by Derek Link SP-PG Trial Finally Begins Daiichi Pharmaceuticals submitted an application to the FDA to approve the start of clinical trials for SP-PG (DS-4152), a potential anti-cancer compound which may inhibit tumors by preventing new blood vessel formation (see Treatment Issues, Vol.7, No.1, January 1993). Two trials are set to begin. Dr. Parkish Gill will oversee a study of SP-PG for Kaposi's sarcoma (KS) at the University of Southern California, 213/224-6668. The other trial will study the effects of SP-PG on solid tumors such as breast, prostate, and kidney cancer. This trial will be at the University of Texas in San Antonio under Dr. Daniel Von Hoff, 210/821-2791. Another proposed KS study, to be overseen by Dr. Robert Yarchoan at the National Cancer Institute, is now under consideration. Activists pressured the company for several years to develop SP-PG in a more rapid manner. Since Spring 1992, activists attempted to get the company to meet with the FDA for a pre-IND meeting to review preliminary pharmacology and animal toxicity data. Daiichi steadfastly refused to consider the activist proposals. While the beginning of the trials is certainly good news, the fact that activists had to initiate discussions between the company and the FDA indicates that a business-as-usual mentality still exists at Daiichi. Initial Shark Cartilage Results Disappointing There have been many anecdotal reports about the use of purified shark cartilage for KS (see Treatment Issues, Vol.7, No. 1, January 1993). The Search Alliance, a community-based AIDS research foundation in Los Angeles, reports initial results from a study of shark cartilage it conducted (Searchlight, March/April 1993). Thirteen patients with KS were enrolled, but only six remained evaluable at study end. Most left the study due to shark cartilage's extremely foul taste or nausea. Of the patients who remained in the study, there was "no discernible spontaneous regression of KS lesions after two to three months of follow-up" according to Erik Fleishman, D.O., the study investigator. The study concludes that "in general, at least for a short-term treatment, this study did not prove shark cartilage to be effective. Furthermore, new lesions did occur in patients during the study, suggesting that there was no prophylactic effect against KS." Fleishman notes, however, a "very striking and promising observation" that shark cartilage seemed to improve the effect of radiation therapy on patients in the study. It is unclear what observation Fleishman refers to, and what criteria he uses to judge improvement in radiation patients. DaunoXome on limited compassionate release in three cities DaunoXome, a new lipid encapsulated form of daunorubicin made by Vestar, Inc of California, is now available through a limited compassionate program to people with advanced KS in New York City, Los Angeles, and San Francisco. A phase III study of daunoXome for people with KS who have never taken chemotherapy before is enrolling nationwide. Vestar says the compassionate program is limited due to drug supply problems; as more drug becomes available, the program will be expanded to include other cities. Patients outside of the three cities will be placed on a waiting list until more drug becomes available. To enroll in the program, or for information about the phase III study, call the DaunoXome Information line at 1-800-247-3303. In addition, Vestar submitted a New Drug Application (NDA) to the FDA for daunoxome in early March, 1993. Lipid encapsulation is a new pharmaceutical manufacturing technology whereby drugs are coated with fatty cells. The outer fatty layer may increase the ability of the drug to reach its target cells, hopefully boosting efficacy while reducing toxicity. The final efficacy studies proving the superiority of lipid drugs over traditional forms of chemotherapy are not complete, however. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ First Large Simple Trial for AIDS Begins by Douglas Beardslee ComPACT 1, the largest single clinical study ever launched against HIV, began amongst San Francisco community physicians last month. The San Francisco pilot study will enroll 200 individuals over the next six months; eventually 10,000 people are expected to enroll worldwide in the next five years. Donald Abrams, M.D. of the University of California and the Community Consortium, a community-based clinical trials network in San Francisco, is the study's principal investigator. The study attempts to answer a key clinical question which has troubled patients and physicians alike since antiretroviral therapy became widely available: Should an HIV-infected, asymptomatic person begin antiretroviral therapy immediately, or wait until the first symptoms of AIDS appear? "Research on AZT, ddI, and ddC suggests that they may slow disease progression, at least temporarily, but can sometimes cause side effects, or lose their effectiveness against HIV with long-term use. What we don't know is at what state of HIV disease patients should begin taking anti- HIV drugs to have the best chance of long term survival. Should they take it at first diagnosis, at the time of onset of symptoms, or when CD4 cells drop to a certain level?" explains Abrams. The trial examines the effect of the strategy and timing of therapy rather than the efficacy of a specific drug or dose. The trial is designed to detect whether even a moderate survival advantage is conferred by one strategy over the other. Needless to say, the answer to this question has far-reaching implications for the treatment of people with HIV. A large simple trial is a controversial form of human experimentation which does not conform to the usual way clinical trials are designed. However, they can be used to measure with certainty whether a particular treatment has an effect on survival. The "simple" in large simple trial refers to simplifying the study design so that researchers do not have to collect much information. For instance, in comPACT, only three pieces of information are required each year. Additionally, the paper work required to enroll a patient in the study is greatly reduced. The study is supported by AmFAR, the American Foundation for AIDS Research, and has been designed by Dr. Richard Peto of Oxford University. Peto developed the methodology for large simple trials, and used them successfully in several major European studies of cardiovascular disease. Information about the trial can be obtained from the Community Consortium in San Francisco, 415/476-9554. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Protease Inhibitor Efficacy Study Begins by Derek Link The first U.S. efficacy study of an HIV protease inhibitor began nationwide, according to statements released on March 26 by the National Institutes of Health and Hoffman LaRoche, the drug's manufacturer. The study combines the drug, designated Ro-31-8959, with AZT and AZT/ddC. This is the first triple combination study to use drugs targetted at different points of the viral life cycle. The triple combination will be compared to combination AZT and ddC. Protease inhibitors are a new class of antiviral agents which may interrupt the ability of HIV-infected cells to make new copies of the virus. Many informed observers believe that protease inhibitors are a significant new approach to AIDS drug development. The study will randomize 300 people to receive one of the three drug combinations for 24 weeks. Participants must have 50-300 CD4 cells. It is unknown why people with fewer than fifty CD4 cells are excluded from the study. In fact, many argue that this group has the most to gain from a new antiviral approach. Already activists are questioning the company and the NIH about the CD4 restriction. The study will enroll at ten sites nationwide: New York City, Philadelphia, Birmingham, AL, Chicago, Rochester, NY, Denver, Columbus, Galveston, and Seattle. Contact 1-800-TRIALS-A for enrollment information and local phone numbers. Ro-31-8959 was the first protease inhibitor to enter human studies. Early phase I studies of the drug, conducted in Europe, demonstrated that it is safe for short-term use in humans. However, the European studies also demonstrated that the drug is poorly absorbed when given orally. Nevertheless, Roche remains committed to developing the drug as an oral agent. Other companies are also involved in protease research. Abbott Laboratories and Merck are widely expected to begin protease efficacy studies next. Bristol Myers, Ciba Geigy, Glaxo, Kyoto Pharmaceuticals, Lilly, Parke Davis, Pfizer, Searle, SmithKline Beechum, and Vertex Pharmaceuticals all have active, but more preliminary, protease development programs. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ treatment briefs by David Gold Possible Benefits of Beta-carotene ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Many speculate about the possible beneficial effects of beta- carotene on the immune system. A study, published in the Journal of Acquired Immune Deficiency Syndrome (6:272, March 1993), randomized 21 HIV-positive individuals to receive either beta- carotene (180 mg per day) or placebo for four weeks, and then cross over to the other arm for another four weeks. It found that beta- carotene use was associated with a statistically significant increase in total white blood cell counts, per cent change in CD4 count, and per cent change in CD4/CD8 ratio compared to placebo. In addition, the absolute CD4 count, absolute CD4/CD8 ratio, total lymphocytes, and B-lymphocytes increased in patients on beta- carotene, although not to statistically significant levels. No toxicities were observed. The authors conclude that larger studies are needed to determine whether beta-carotene has a role as an adjunct therapy for HIV. It should be noted 1) this is a very small study, making definitive conclusions impossible and 2) beta- carotene converts to vitamin A in the body and some studies indicate that extremely high doses of vitamin A may suppress certain immune functions. Zinc Supplements Show Unimpressive Results ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Some suggest that zinc deficiency causes immune dysfunction. Zinc is a mineral and a crucial nutrient. AIDS Weekly (3/15/93) reports an abstract from a meeting of the American Academy of Allergy and Immunology which evaluates the effect of oral zinc supplements on HIV-infected children. The study gave thirteen HIV-infected children (median age: 6.4 years) 1.8-2.2mg/kg of zinc supplements each day for three to four weeks. While 6/13 increased serum levels of zinc, only two had increased CD4 counts and no p24 positive patients had reduced p24 levels. Fluconazole Resistance in Fungal Infections ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ In a meeting with AIDS activists, Pfizer officials provided more detailed information about the development of fluconazole-resistant strains of Candida albicans (thrush) and other fungal infections in people with HIV. Resistant Candida strains have been noted in a few studies and have been reported by a number of physicians. Pfizer claims that higher doses of fluconazole may overwhelm or inhibit resistant strains. However, we're sure this is not the final word on this very serious issue. More studies examining the issue are expected to be released at the International Conference on AIDS in Berlin this June. In the meantime, as fluconazole use increases among PWAs for primary prophylaxis, researchers expect more cases of fluconazole-resistant fungal infections and some advise a more cautious approach to the use of the drug. Marinol Approved ^^^^^^^^^^^^^^^^ In December 1992, the FDA approved a supplemental New Drug Application for Marinol in the treatment of HIV-associated anorexia and weight loss. The active ingredient of Marinol is a synthetic derivative of marijuana known as THC. Marinol received original approval as a treatment for nausea and vomiting in chemotherapy patients. Free Transportation to Medical Appointments ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The American Red Cross in Greater New York provides free transportation to medical and health related appointments for people with AIDS/HIV. The service is available between 9 am and 4 pm and is limited to people in the five boroughs of New York City. Call 212/875-2200 to register for this service. ADAP Plus ^^^^^^^^^ The New York State Department of Health operates the AIDS Drug Assistance Program (ADAP) which provides reimbursement for most AIDS drugs for NYS residents with an annual income under $44,000. ADAP Plus is a new program which provides primary care coverage for people with AIDS/HIV who are uninsured and ineligible for Medicaid. Call 1-800-542-2437 for more information on ADAP and ADAP Plus and 1-800-MEDS-4-HIV (in NYS only) for the NYS AIDS Institute's Treatments Info-line. Intramuscular Pentamidine for PCP Prophylaxis ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ A team from Mount Sinai Medical Center in New York reports in Clinical Infectious Disease that monthly intramuscular injections of pentamidine are effective in preventing PCP. The study is a retrospective review of 96 patients who were intolerant to sulfa drugs, neutropenic, or intolerant to aerosolized pentamidine. Patients received 300mg of pentamidine (or 4mg/kg if they weighed less than 50 kg) every month. The injections were administered by the Z-track method which involves pulling the skin of the upper outer quadrant of the buttock firmly to one side and inserting the needle at a 90-degree angle, checking for blood, and then injecting. Only three cases of PCP occurred in the follow-up period which varied from 350-426 days. More than 73% of the patients were also on AZT. Side effects of intramuscular pentamidine include two episodes of low blood pressure, three abscesses at the sites of injection, two glucose intolerances, and one case of low blood sugar. The advantages of intramuscular pentamidine over aerosolized pentamidine include the fact that intramuscular administration allows for systemic distribution of the drug, which can prevent PCP outside of the lungs. It also prevents the spread of tuberculosis, which has occurred when persons receiving aerosolized pentamidine cough after their inhalation treatments. Aerosolized pentamidine has also been associated with collapsed lungs (pneumothoraces), severe bronchospasm (asthma) and recurrence of PCP in the upper lobes of the lungs. Although trimethoprim-sulfamethoxazole (Bactrim or Septra) remains the drug of choice to prevent PCP, with dapsone as a second alternative, intramuscular pentamidine may be a third alternative for those who cannot take the oral drugs. New Additions to Medical Information ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Derek Link has joined the staff of GMHC as Editor of Medical Information. Derek's primary responsibility is to oversee production of Treatment Issues. Derek has worked with many organizations, including ACT UP/Boston, ACT UP/NY, and the Treatment Action Group. He co-authored ACT UP's Countdown 18 Months Project and edited TAG's recent report AIDS Research at the NIH: A Critical Review. Most recently, he was the Director of Research and Development at the PWA Health Group and editor of the newsletter. Notes from the Underground ^^^^^^^^^^^^^^^^^^^^^^^^^^ Saundra Johnson also joins the Medical Information Program for the next two months. Saundra is a case worker for the Chicago Women's AIDS Project. She is also a member of the Community Constituency Group (CCG) of the AIDS Clinical Trials Group (ACTG) and sits on the Women's Health Committee and Tuberculosis (TB) Working Group of the ACTG. Saundra has already begun working on an overview, and perhaps a special edition, of Treatment Issues on TB treatment. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Drug company watch by David Gold Magainin Reports Encouraging News from Sharks ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Sharks are unusual in that they appear to lack cellular immunity, do not reject grafts, and do not mount an antibody response when vaccinated. In essence, they appear profoundly immunocompromised, while remaining perfectly healthy. Magainin Pharmaceuticals discovered squalamine, a compound from the immune defense system of the sand shark. In laboratory experiments, squalamine demonstrates activity against a broad range of bacteria and fungi. Preclinical tests will be performed to assess activity against mycobacteria (MAC, TB), protozoa (PCP), and viruses. The chemical structure of this compound should enable it to be administered orally. If squalamine continues to demonstrate an unprecedented anti-infective spectrum, the potential for broad prophylaxis in immunocompromised humans should be explored. The first published data on squalamine is expected to appear soon in the Proceedings of the National Academy of Sciences. Megace: good news, bad news, and an FDA thumbs up ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The FDA's Antiviral Drugs Advisory Committee recommended (by a narrow 5 - 4 vote) that Megace (megastrol acetate) be approved for the treatment of AIDS-related anorexia and wasting. The good news is that in two 12-week controlled trials conducted by Bristol-Myers, the drug's manufacturer, 400 - 800 mg per day of megace demonstrated a five to seven pound weight gain in PWAs with wasting syndrome compared to an average loss of two pounds in the placebo group. The bad news is that there was a trend towards higher mortality rates in the megace arms (twenty deaths out of 283 patients) versus the placebo arms (two out of 86). Those on the FDA panel who supported approval noted that the studies were not designed to look at survival and that, since no one particular cause of death was noted, it was unlikely to be drug-related. However, Deborah Cotton, M.D., M.P.H., another member of the panel, said she was "very concerned about the trend. It is biologically plausible that a steroid would increase opportunistic infection rates." Megace is already approved as a palliative treatment for breast and endometrial cancer patients. More on Nystatin ^^^^^^^^^^^^^^^^ Argus Pharmaceuticals developed an intravenous lipid formulation of nystatin called AR-121. Nystatin, an oral suspension used to treat thrush, has anti-HIV properties in vitro. In a presentation to investment analysts, Argus reports that a phase I study of AR-121 in 17 HIV-infected individuals demonstrates the safety of the formulation. In addition, a phase I/II study (0.5mg/kg IV every other day) study in HIV-positive people with 200 to 500 CD4 cells is in progress. Thirteen people are enrolled and six completed three months of therapy. Safety was again confirmed. According to the company, of 11 individuals on whom data is available, two had increases in CD4 cells and eight had increases in CD8 cells. A phase II/III trial comparing AR-121 to AZT will begin in mid-1993 in 180- 240 AZT-naive asymptomatic individuals. Injectable INH Approved for TB -- Again ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Bristol-Myers announced that the FDA approved the re-introduction of injectable INH (isoniazid/"Nydrazid") for the treatment of tuberculosis. Because of low demand and a shortage of raw material, Bristol-Myers removed injectable INH from the market in 1992. The FDA and CDC requested that Bristol-Myers re-introduce the drug in response to the rise in TB cases. The drug should now be available at pharmacies. Ampligen for Chronic Fatigue Syndrome ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ For those suffering from chronic fatigue syndrome (CFS), or those who believe that AIDS is, in fact, a form of CFS, a phase II/III trial of Ampligen will begin this spring, according to HEM Pharmaceuticals, its manufacturer. Ampligen was originally studied as a treatment for AIDS, but now is being tested primarily as a CFS treatment. The trial will randomize 230 patients to 400mg of Ampligen (infused twice weekly) or placebo for 24 weeks with an additional 24-week open label phase when all patients will receive the drug. Roche Investing in Antisense (common sense may be next) ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Antisense is an experimental mechanism to prevent unwanted genes from functioning and replicating. Researchers hope that antisense can more effectively target and destroy unwanted genes, such as those in cancer cells and viruses, without harming healthy cells. Most present treatment for viruses and cancer also destroys healthy cells, further weakening the immune system. Now comes word that Hoffmann-LaRoche, a Swiss drugs giant with a major AIDS research program, is investing in Hybridon, a Massachusetts company seeking to develop antisense treatments for viral infections. Other drug companies investing in antisense research include Hoechst AG, Glaxo, Ciba-Geigy, and Wyeth-Ayerst. It makes sense to us. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Glossary AIDS Clinical Trials Group (ACTG): a group of about fifty research centers around the country where federally-funded human AIDS trials are conducted. Anorexia: diminished appetite, or inability to eat. Antiviral: a substance that stops or suppresses the activity of a virus. AZT-failure: conditions which indicate that a patient taking at least 500 mg/day of AZT for more than six months, is worsening. For example, the appearance of more than three OIs or cancers within six months of treatment, or disability requiring special care and hospitalization. Cytotoxic: harmful to cells. Dose-ranging: a kind of human trial, usually phase I, in which participants receive a varying dose of an experimental drug to determine safety. Liver function tests: blood tests which measure the levels of specific enzymes and proteins in the blood indicating how well the liver is functioning. Sometimes referred to as AST, ALT, SGOT, or SGPT. Neutropenia: a decrease in a certain type of white blood cell, called neutrophils. Non-Nucleoside Reverse Transcriptase Inhibitor: an inhibitor of HIV's reverse transcriptase enzyme, but not a nucleoside analog. Nucleoside analogue: a class of drugs of the same chemical type with potent antiviral activity, including acyclovir, AZT, ddI, d4T, and, ddC. p24 Antigen Levels: the level of a core protein fragment (p24) of HIV in the blood. High levels of p24 antigen indicate increased viral activity. Parallel Track: an FDA-approved program to allow patients who are not in trials, but who meet certain criteria, to take an experimental drug. In the program, doctors monitor patients' response and report data to the pharmaceutical company sponsoring the drug and the program. Pharmacokinetics: the action, movement, distribution, binding, and elimination of drugs in the body over a certain period of time. Protease Inhibitor: an inhibitor of HIV's protease enzyme, a protein needed to assemble new virus. Resistance: the ability of an organism to change to avoid or counteract the effects of a useful treatment. For instance, HIV sometimes changes to become resistant to AZT therapy. Reverse transcriptase (RT): the part of HIV which copies viral RNA into host DNA, an essential step in the life cycle of the virus. NNRTI/Convergent Combination Studies Currently Enrolling: ACTG 241: a study comparing triple drug combination with nevirapine to double drug combination. Arm 1: Nevirapine 400mg/day with AZT 600mg/day and ddI 400mg/day versus Arm 2: AZT 600mg/day with ddI 400mg/day Total Patients: 400 CD4 Level: <350 Study Duration: 48 weeks Sites: Boston: 617/726-3819 Bronx, NY: 718/430-3659 New York: 212/746-4177 Miami: 305/547-3838 Birmingham, AL: 205/934-3690 Chicago: 312/908-9636 Denver: 303/270/8551 San Francisco: 415/476-9296 There are also sites in Indianapolis, Philadelphia, San Diego, Cincinnati, Minneapolis, Chapel Hill, and Los Angeles. Contact 1- 800-TRIALS-A for phone numbers of these sites. Merck Protocol 027: a study to determine the safety, antiviral activity, and resistance profile of higher-dose L-661 in combination with AZT. Arm 1: L-661 400mg with AZT 200mg TID versus Arm 2: AZT 200mg TID Total Patients: 100-120 CD4 Level: < 250 Duration: 8-24 weeks Sites: Providence, Philadelphia, and Pittsburgh Contact: Linda Distlerath, 908/423-4165 for more information. U-90 NIH Study: a dose-escalating study of U-90 compared to conventional nucleoside treatment. (Note: The trial is not written, although screening has begun. The study is expected to begin in early April. The study seeks to determine the maximum tolerated dose of U-90; therefore, the dosage schedule for the drug is not known at this time. In addition, a small interaction study of U-90 with AZT is open at the Upjohn Clinical Center in Kalmazoo, MI. People from Michigan are given top priority for enrollment in the Kalamazoo study. To contact the Upjohn Center, call 616/384-9646.) Arm 1: AZT 600mg/day with ddI 400mg/day versus Arm 2: U-90 alone versus Arm 3: U-90 with AZT 600mg/day versus Arm 4: U-90 with AZT 600mg/day and ddI 400mg/day Total Patients: 80 CD4 Level: 0-300 Duration: at least 24 weeks Contact: Doreen Chaitt at 800/772-5464, ext 312 or Betsey Herpin ext 304 for enrollment into the NIH site. ACTG 187: an open-label monotherapy study of U-87 to determine blood levels, safety, and proper dosing of the drug. (Note: After 8 weeks on U-87 alone, participants will be able to continue on U-87 combined with AZT or ddI for an additional 24 weeks.) Arms: escalating doses of U-87 monotherapy Total Patients: 30 CD4 Level: <500 Sites: Columbus, OH: 614/293-8112 Rochester, NY: 716/275-5873 St. Louis: 314/454-7504 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Drug company watch by David Gold Magainin Reports Encouraging News from Sharks Megace: good news, bad news, and an FDA thumbs up More on Nystatin Injectable INH Approved for TB -- Again Ampligen for Chronic Fatigue Syndrome Roche Investing in Antisense (common sense may be next) Glossary Dedication ^^^^^^^^^^ This edition of Treatment Issues is dedicated to two special individuals who recently died of AIDS-related causes: Bob Rafsky Bob Rafsky was a member of ACT UP/New York and the Treatment Action Group (TAG). He was a dynamic, passionate, and outspoken AIDS activist. Bob received national media attention last year when he confronted candidate Bill Clinton during a campaign stop in New York City and publicly challenged him on the issue of AIDS. Bob had Kaposi's sarcoma (KS) and some of his work focused on fighting for the rapid development of new treatments for KS. Bob was among those who occupied the U.S. headquarters of Daiichi Pharmaceuticals in the fall of 1991 in an attempt to get the company to move quickly in developing SP-PG, their promising KS treatment. In August 1992, at a meeting between activists and senior Daiichi officials, Bob made an eloquent plea for the immediate initiation of SP-PG trials. When it became clear that the company would not proceed rapidly, Bob put his leg on the conference table, rolled up his pants, and gave startled company officials a vivid view of his multiple KS lesions. Despite Bob's attempt, company officials were unyielding. On February 27, 1993, over seven months after that meeting and 18 months after activists occupied Daiichi's headquarters, Daiichi finally submitted an application to the FDA to begin clinical trials of SP-PG (see related note). Bob Rafsky died of AIDS-related KS on February 20, 1993. He will be greatly missed. Bradley Nance ^^^^^^^^^^^^^ Bradley Nance was a volunteer for the GMHC Medical Information Program as well as other programs within GMHC. He began volunteering for Medical Information in August 1992. He gave to the program as long as his health permitted. Bradley was a kind, gentle man, and a fighter. We will miss him. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ For a hard copy of Volume 7 #2 or subscription information write to: Paul Warren Medical Information, 2nd Floor 129 West 29th Street New York, NY 10011