[Electronic distribution for GayCom by the Backroom 718 951-8256] Volume 7 no. 19 November, 1993 Gay Men's Health Crisis: Treatment Issues > Tuberculosis and HIV >> TB Drugs: Clinical Trials and Drug Availability Programs >> TB Chest Clinics in New York City >> TB Resources > ICAAC Overview: Anti-Viral and Miscellaneous Reports > TI Interview: Martin Delaney > Treatment Briefs >> MAC Prophylaxis and Treatment Guidelines >> Help Wanted at NIH >> Megace Approved >> More on ADAP >> NMAC Expands AIDS Treatment Work >> New "Living With AIDS" Guide from GMHC >> Our Treatment Library Needs a New PC >> AIDS Newsletter for Children and Parents > Drug Company watch >> Over the Counter Acyclovir for US? >> GP160 Vaccine Saga Grinds On; Single Product Trial Unlikely >> Bristol Myers Plans D4T Filing by End of Year >> Roche Sales Up 15%; Claims Research Spending Too High > Andrew S. Zysman, M.D. 1955-1993 Note to Our Readers: The December 1993 and January 1994 editions of Treatment Issues will be a combined 32-page special edition devoted solely to "Alternative Therapies for HIV." This special edition will be mailed in the end of December. We wish all our readers the best of the holiday season, and a happy and healthy New Year. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Tuberculosis and HIV by Saundra Johnson and David Gold Tuberculosis (TB) is an infectious disease caused by the organism Mycobacterium tuberculosis (MTB). Over eight million cases of active TB occur in the world each year, resulting in three million deaths.[1] In the developing world, TB is considered the most common HIV-related opportunistic infection. In 1993, the Centers for Disease Control (CDC) included pulmonary TB as an AIDS defining illness and the World Health Organization (WHO) recently declared the emerging TB epidemic an international public health emergency. Until recently, it was believed that TB would be eradicated by the end of the century. However, widespread homelessness, substance abuse, and high rates of HIV-infection, have enabled TB to reemerge in many American cities. Moreover, new drug-resistant strains of TB have developed which are difficult to treat and often deadly. In New York City, the number of cases of active TB increased 143 percent from 1980 to 1991 and rates of coinfection with HIV and TB are believed to be similar to those seen in Central Africa.[2] While all people are at risk for TB infection, people with HIV are estimated to have over 100-times greater likelihood of developing active disease once infected with TB.[3] In the U.S., between 5 to 10 percent of symptom-free HIV-positive individuals may develop active TB within a year of HIV diagnosis.[4] TB Infection TB is transmitted when a person with active TB coughs or sneezes, releasing microscopic particles into the air. These particles, also called droplet nuclei, contain live tubercle bacteria, and may result in infection when inhaled by another person. Once infected by TB, most people, remain healthy and develop only latent infection. People with latent infection are neither sick nor infectious. However, they do have the potential to become sick and infectious with active TB. Active TB The immunological factors which allow latent TB infection to develop into active disease are unknown. It is estimated that, once infected with TB, HIV-negative people have a 10 percent life-time risk of developing active TB disease. For people with HIV, the risk is much higher, estimated to be 8 to 10 percent per year after infection.[5] It is believed that some people with HIV will develop active disease from a newly acquired infection due to their inability to mount a sufficient immune response.[6] TB Transmission Although TB is spread through the air, infection usually occurs only after prolonged exposure to someone with active TB. According to the National Institute of Allergy and Infectious Diseases, (NIAID), there is a 50 percent chance of infection after being with someone with active TB for eight hours a day over six months or 24 hours a day over two months.[7] However, the exact nature of what is required for TB transmission is still unclear. Documented TB outbreaks have been primarily associated with hospitals, clinics, nursing homes, prisons, shelters for the homeless, and other places where persons who may have TB congregate. One recent report, however, suggested that a flight attendant with active TB may have transmitted TB to co-workers aboard an aircraft.[8] It has been reported by one study that the likelihood of transmission is similar for both drug resistant and drug sensitive TB.[9] Clinical Symptoms of TB The most common site of active TB is the lungs. This is called pulmonary TB. However, TB may affect any part of the body (extrapulmonary TB), including the skin, bone marrow, liver, spleen, kidney, bones and even the breast and may occur simultaneously as pulmonary and extrapulmonary disease. General symptoms of disease include fever, night sweats, dramatic weight loss and a feeling of malaise. Symptoms of TB in the lungs include these symptoms, as well as unexplained cough lasting longer than three weeks and bloody sputum. Since the symptoms of TB can mirror the symptoms of a number of other infections, it is important that TB be considered along with Pneumocystis carinii pneumonia (PCP) and other mycobacterial infections such as MAI. The clinical manifestations of active TB in persons with HIV infection can vary considerably depending on the stage of disease. TB can occur early in HIV disease, when CD4 cell counts average 300 to 400.[10] At this stage of HIV disease, TB is usually localized to the lungs and the sputum is smear positive. As the CD4 count declines the presentation of TB may change, with more extra pulmonary disease, miliary lung involvement, negative sputum smears, and atypical chest x-ray patterns. In one large study from Rwanda, presented at the Ninth International Conference on AIDS , it was found that HIV positive patients with TB had a greater likelihood of extrapulmonary involvement, disease in the middle and lower lobes of the lung and anergy to PPD skin testing.[11] A study from the C“te d'Ivoire reported that HIV positive patients with extrapulmonary TB had lower CD4 counts than those with pulmonary TB.[12] TB Diagnosis The PPD Skin Test The purified protein derivative (PPD) skin test is the first step in diagnosing TB. PPD is injected under the skin of the forearm. After 48 to 72 hours, the injection site will be indurated (i.e. a red, hard bump) if a person has been infected with TB. This induration is caused by an immune response. Therefore, immunosuppressed persons may have little or no reaction to the test, even if they have been exposed to TB. According to the CDC, an HIV-infected individual with an induration of greater than or equal to 5mm is considered to be infected with TB.[13] However, some researchers believe that even the 5mm cutoff may underestimate the rate of true TB infection and suggest that a 2mm induration be considered a positive skin test in HIV-infected patients.[14] A positive PPD skin test does not mean that the person has active TB, only that the individual has been infected with the bacterium that causes TB. Lack of response to PPD skin test is more frequent when CD4 cells drop below 200.[15] The Anergy Test Along with a PPD test, HIV-positive individuals should receive an anergy test to verify immune competence. An anergy test consists of two or three common antigens, usually candida, mumps, or tetanus toxoid, which are injected under the skin. If there is a reaction to the antigens, the person is considered non-anergic and the TB skin test results are considered reliable. If there is no reaction to either the antigens or the PPD, the person is considered anergic. A negative PPD reaction should never be used to exclude the diagnosis of TB infection in persons who are anergic. Chest X-Rays and Sputum Tests A person who has a positive skin test or who has symptoms of active TB should have a chest radiograph (x ray) and sputum sample analysis. The sputum will be examined microscopically for the presence of acid fast bacilli (AFB) and cultured for TB. While an AFB smear can determine within minutes if there are mycobacteria in the specimen, it cannot distinguish among different types of mycobacteria, such as Mycobacterium avium intracellulare (MAI) and TB. A TB diagnosis relies on the ability to culture or grow the organism in the laboratory. Therefore, a person with suspected active TB (based on AFB in the sputum or clinical symptoms) might be placed on medication until laboratory confirmation is available. In addition, isolation in a private room will be required until the diagnosis has been confirmed or the person has been shown to be non-infectious (usually determined by the clearance of the AFB from the sputum). Individuals who are PPD positive but show no evidence of active TB, will be placed on preventive medication (prophylaxis) for a period of six to twelve months to prevent active TB from developing. A number of leading TB researchers recommend that chest x-rays be performed on all patients with HIV infection who present with respiratory or constitutional symptoms.[16] TB Treatment TB is treated with a combination of several antibiotics for at least six months. When effective therapy is given, symptoms typically improve within four weeks and sputum cultures become negative within three months. This pattern of clinical improvement and sputum conversion is seen in over 90 percent patients who are HIV-positive. The standard treatment of drug-sensitive TB in HIV-positive people includes the following[17]: Isoniazid (INH) (300mg/day) Rifampin (450 to 600mg/day), Pyrazinamide (PZA) (20 to 30mg/kg/day for nine months) Ethambutol (15 to 25mg/kg/day) or streptomycin (15/mg/kg/day). PZA should be given for the first two months; ethambutol or streptomycin should be given for at least six months beyond culture conversion. INH and rifampin should be continued for at least another seven months. Persons who cannot tolerate INH and rifampin together (or in whom resistance is suspected), should be treated for at least eighteen months with a minimum of three drugs to which the organism is sensitive.[3] Although most HIV-positive people respond well to standard treatment, there are some reports of continued progression or recurrence of disease, particularly in persons who do not complete the entire course of treatment. Because compliance is so crucial to successful outcome, directly observed therapy (DOT) is recommended for persons who may have difficulty finishing the entire treatment (possibly creating resistant strains in the process). Alternative treatment regimens which require less frequent medication include using INH, rifampin, PZA, and either ethambutol or streptomycin three times weekly from the onset or twice weekly after a two week daily regimen. These regimens should be administered under DOT. A study of supervised, short course therapy with three times weekly INH, rifampin, ethambutol and PZA showed the regimen to be highly successful.[18] The study, performed in Haiti, included 117 HIV-positive and 310 HIV negative patients with TB. Eighty-two percent of the HIV-positive and 91 percent of the HIV-negative TB patients completed greater than 80 percent of the therapy. However, the death rate among the HIV-positives was higher (9 percent) than in the HIV negatives (1 percent). Proven cures (defined as negative AFB smears, negative cultures, and radiologic resolution of disease) were more common among the HIV-negative patients. Relapses were equally as common in both groups. Among the HIV-positives, those who died had a lower CD4 count (116) than those who survived eighteen months (559). Multiple Drug Resistant TB TB is considered multi-drug resistant (MDR-TB) if it does not respond to two or more standard anti-TB drugs, usually INH and rifampin. MDR-TB usually occurs when treatment is interrupted thus allowing mutations to occur which confer drug resistance. However, primary infection with MDR-TB can occur as well. In 1991, cases of MDR-TB were reported in at least 36 states, Puerto Rico and the District of Columbia.[19] In one study in New York City, one-third of TB cases were resistant to at least one TB drug and 15 percent resistant to at least two drugs.[20] MDR-TB has serious public health implications due to the rapid progression to life threatening disease, the efficient transmission to others, and delays in diagnosis. It is estimated that the death rate from MDR-TB can be as high as 40 to 60 percent and possibly greater than 80 percent in individuals coinfected with HIV.[21] One outbreak among 38 patients in a NY hospital revealed an incubation period of 1.5 to six months and a mean survival of only nineteen weeks.[22] Survival was better among those who received at least two drugs to which the organism was susceptible within two weeks of diagnosis. Thus, delays in obtaining drug susceptibility tests make it more difficult to institute proper treatment. One TB susceptibility study in NY hospital found that only six and seven drug regimens conferred greater than 90 percent effectiveness as initial regimens.[23] A study by Fischl and colleagues reported that HIV-positive persons with MDR-TB were three times more likely to have both pulmonary and extrapulmonary disease than HIV-positive persons with drug sensitive TB.[24] Median survival from time of diagnosis of MDR-TB was 2.1 months compared to 14.6 months for persons with drug sensitive TB. The study also noted delays in prescribing effective TB drugs, suggesting that in areas with a high prevalence of MDR-TB, it may be advisable to begin therapy based on patterns of resistance rather than waiting for drug susceptibility tests to be completed. At least three TB-susceptible drugs should be used. Some of these drugs include the aminoglycosides (amikacin, kanamycin or capreomycin), the quinolones (ciprofloxacin, ofloxacin, sparfloxacin), ethionamide, cycloserine and para-amino sallcylic acid (PAS). TB Prophylaxis Prophylaxis with anti-TB drugs can prevent the development of active TB. Therefore, TB screening should be a routine part of HIV clinical management. HIV-positive individuals responding to the PPD test with an induration of greater or equal to 5mm should be considered as having TB infection and offered prophylaxis medication. Standard TB prophylaxis is INH (300mg/day) for twelve months, along with pyridoxine (vitamin B-6). Vitamin B-6 is given in order to prevent peripheral neuropathy, which can be a side effect of INH. INH is considered to be quite effective in preventing TB. One recent study followed 374 HIV positive patients in an area of Spain where TB is widely prevalent.[25] Of the 374 participants, 108 were PPD-positive, 154 were PPD-negative, and 112 were PPD-negative but were anergic. The risk of developing TB was significantly higher in PPD-positive patients (10.4 per 100 patient years) and anergic patients (12.4 per 100 patient years) compared to PPD-negative, non- anergic patients (5.4 per 100 patient years). Active TB developed in only one of 27 PPD-positive individuals who were given INH prophylaxis, compared to 29 of 94 PPD-positive patients who did not receive the drug. A placebo-controlled study released at the Ninth International Conference on AIDS demonstrated that INH can reduce the rate of development of active tuberculosis in HIV-infected people by 50 percent, from 5.3/100 person years to 2.3/100 person-years.[26] Research examining TB prophylaxis regimens of shorter duration and less frequent dosage appears promising. The New York City Department of Health has proposed a TB prophylaxis regimen of INH at a dose of 900mg twice weekly under supervised conditions. Combination regimens using rifampin and PZA are being studied in an attempt to shorten the time of prophylaxis. A recent study compared these two drugs, twice weekly for two months versus INH daily for six months in 784 HIV-positive, PPD-positive individuals. Both regimes were well-tolerated. However, compliance was higher in the rifampin/ PZA arm (64 percent) than in the INH arm (46 percent).[27] Rifampin should be used when infection with INH resistant bacteria is suspected. Prophylactic treatment of TB infection caused by MDR bacteria is especially difficult. Usage of unapproved drugs such as ofloxacin and sparfloxacin in combination with PZA and ethambutol is an option but may be poorly tolerated. TB Prophylaxis in Anergic Patients Deciding whether to give HIV-positive anergic patients INH prophylaxis can be a difficult question since the probability of developing TB infection is unknown. Several studies show that HIV-infected injecting drug users and persons from areas where TB is endemic (Spain, Latin America, Haiti) who are anergic, develop active tuberculosis at the same rate as those who are PPD-positive.[28] This has led to the practice of offering INH prophylaxis to HIV-positive anergic persons who belong to "high incidence groups," such as prisoners, homeless persons, and injecting drug users. It is unclear whether anergic HIV-positive persons who do not belong to high TB incidence groups, such as gay men, heterosexuals and women, should receive INH. A large federally funded CPCRA trial is comparing a six-month regimen of INH to placebo in a large sample of HIV-positive anergics, in order to answer this question. One concern with using INH as prophylaxis has been the risk of hepatitis, which occurs in a small percentage of those who take the drug, especially over the age of 35. Another concern is the lack of knowledge about the long-term effects of drug interactions between INH and the broad range of drugs that an anergic HIV-positive person may be taking (AZT, ddI, bactrim and fluconazole). TB Drug Toxicities Persons with HIV are more likely to suffer adverse reactions to anti-TB drugs and therefore require careful monitoring.[29] INH, rifampin and PZA can cause liver toxicities, hematological toxicities (blood), gastrointestinal (GI) upset, and skin rashes. The risk of INH-induced hepatitis increases after age 35.[30] Rifampin and PZA can cause hepatitis and liver function test elevations, and rifampin can also cause a reddish discoloration of the urine. Ethambutol can cause problems with vision and thus requires periodic ophthalmologic exams. The aminoglycosides cause kidney dysfunction and hearing loss and also require close clinical monitoring. Anti-TB drugs can also interfere with the absorption or concentration levels of other drugs such as fluconazole, ketaconazole, oral contraceptives and methadone. TB Vaccine The Bacille Calmette-Guerin (BCG) vaccine is the only TB vaccine currently available. While not used much in the U.S., BCG is widely used in parts of Africa and Asia where TB is endemic. BCG is not recommended for anyone who is immunocompromised, due to reported incidents of disseminated infection with the Calmette-Guerin bacillus.[31] BCG vaccination should only be given to immune competent children who are at unavoidable risk of exposure to TB and for whom other methods of prevention and control have failed or are not feasible. TB Transmission in Health care, Prison, and Residential Settings Since health care and prison workers have been infected with TB on the job, it is important that proper infection controls be in place at all times. Cough-producing procedures such as aerosolized pentamidine (AP) treatments and sputum induction should only be administered in properly ventilated rooms with at least ten air exchanges per hour.[32] Individuals hospitalized with suspicion of TB should be placed in isolation in a negative pressure room with a vent leading outside and the door closed. Hospitals, clinics, and some AIDS service organizations, such as GMHC, have installed high efficiency particulate air (HEPA) filters which remove TB bacteria from recirculating air. Although the use of germicidal ultraviolet lamps is controversial, the CDC still recommends their usage in settings where risk of TB transmission is high.[33] Those attending clinics who have a cough should be asked to use a mask and wait in a better ventilated hall outside the waiting room. All healthcare and service workers (including prison and social service workers) should have a PPD upon employment and a follow-up PPD annually. This allows tracking of PPD conversion rates. The CDC also recommends PPD testing every six months for persons working in areas with frequent exposure to persons with TB infection or who perform cough inducing procedures, such as AP and bronchoscopy.[34] Funding for TB Research and Control The American Lung Association reports that the President's 1994 budget of $128.8 million for TB control was cut by both the Senate and the House in final budget negotiations.[35] ACT UP's TB Working Group reports that an additional $26 million will go to the CDC for TB control among HIV-affected populations.[36] In 1993, the entire TB research program at NIAID was funded at less than $21 million dollars. In 1994, this figure is expected to increase to $27 million.[37] The World Health Organization (WHO) recently reported that a total of only $15 million is being spent on TB treatment and prevention in the entire developing world.38 The agency estimated twelve million deaths from TB could be avoided over the next ten years if aid for TB treatment were increased to $100 million annually. Conclusion HIV-positive individuals should receive a PPD test, with an anergy test, at least annually as a part of their routine medical examination. Individuals living or working in areas with high TB rates should be screened for TB every six months. If placed on TB medication, HIV-positive persons should be closely monitored for adverse reactions to the medications. Techniques for faster identification of MDR TB need to be placed on the development fast track. Funding must be allotted for TB screening and treatment in diverse care facilities (substance abuse treatment programs, mobile medical outreach units) in order to reach affected populations. Hospitals and clinics must continue to develop and implement detection and isolation protocols to prevent the spread of TB. Shelters, prisons, and AIDS service providers must employ infection controls to the extent possible (using ultra violet light and HEPA filters where ventilation to the outside is not available). Increased funding for TB screening, treatment and research must be allocated. 1 Barnes P et al. Annals of Internal Medicine. 1993; 119:400-410. 2 Selwyn P. New York State Journal of Medicine. June 1991; 233-235. 3 Ellner J. Oral Presentation. 33rd ICAAC. New Orleans. October 17-20, 1993. 4 Selwyn P, et al. New England Journal of Medicine. 1989; 320:545-550. 5 National Institutes of Health, NIAID. Backgrounder: Tuberculosis. 1992. 6 Daley CL, et al. New England Journal of Medicine. 1992; 326:231-5. 7 National Institutes of Health, NIAID. Backgrounder: Tuberculosis. 1992 8 Driver C, et al. Abstract 1369. 33rd ICAAC. New Orleans. October 17-20, 1993. 9 MTB. Grudert DE American Review of Respiratory Diseases. 1985;132:125. 10 Chaisson RE, Johnson MP. Tuberculosis and HIV infectiion. AIDS Clinical Care. 1991; 3:57-59. 11 Batungwanayo J, et al. Abstract WS-B09-1. Ninth International Conference on AIDS. Berlin. June 6-11, 1993. 12 Ackah A, et al. Abstract WS-B09-2. Ninth International Conference on AIDS. Berlin. June 6-11, 1993. 13 MMWR. 1989. 34:236-250. 14 Graham N et al. JAMA. 1992. 267:369-373. 15 Hopewell PC. Clinical Infectious Diseases 1992; 15:540- 547. 16 Chaisson et al. Journal of Infectuous Diseases. 1989; 159:96-100. 17 MMWR 1990; 39 (suppl RR-17) :1-29. 18 Holt E, et al. Abstract WS-B09-4. Ninth International Conference. on AIDS. Berlin. June 6-11, 1993. 19 National Institutes of Health,NIAID. Backgrounder: Tuberculosis. December 1992. 20 Friedland G. Oral Presentation. 16th ACTG Meeting February 1993 ACTG Meeting. 21 National Institutes of Health, NIAID. Backgrounder: Tuberculosis. December 1992. 22 Edlin BR, et al. Abstract WS-B09-6. Ninth International Conference on AIDS. Berlin. June 6-11, 1993. 23 Rose DN, et al. Abstract WS-B09-5. Ninth International Conference on AIDS. Berlin. June 6-11, 1993. 24 Fischl MA, et al. Annals of Internal Medicine. 1992; 117:184-190. 25 Moreno S, et al. Annals of Internal Medicine. 1993; 119:194-198. 26 Wadhawan D, et al. Abstract PO-B07-1114. Ninth International Conference on AIDS. Berlin. June 6-11, 1993. 27 Coberly J et al. Abstract PO-B07-1158. Ninth International Conference on AIDS. Berlin. June 6-11, 1993 28 Pape, J. The Lancet. 1993; 342:268-272. 29 Chaisson RE and Johnson MP. Tuberculosis and HIV infectiion. AIDS Clinical Care 1991; 3: 57-9. 30 Sherris JC and Plorde. Mycobacteria. Clinical Microbiology 1990; 443-61. 31 MMWR. 1988;37:663-75. 32 MMWR 1990; 39:1-29. 33 Ibid 34 Ibid. 35 Personal Communication. Robyn Henderson, American Lung Association. November 16, 1993. 36 Personal Communication. Iris Long. TB Working Group/ACT UP. November 16, 1993. 37 National Institutes of Health,NIAID. Backgrounder: Tuberculosis. December 1992. 38 "Agency Cites Urgent Need to Fight Increase in TB." The New York Times. November 16, 1993; C8. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ TB Drugs: Clinical Trials and Drug Availability Programs ACTG 177/CPCRA 004 -- This TB prophylaxis trial compares a two month regimen of rifampin and PZA versus one year of INH in HIV-positive, PPD-positive individuals. There are 53 trial sites. Call 1-800-TRIALS-A for more information. CPCRA 005 -- This TB prophylaxis trial is comparing six months of treatment with INH to placebo in persons with HIV who are anergic. Call 1-800-TRIALS-A for more information. ACTG 222/CPCRA 019 -- This trial compares two regimens for the treatment of pulmonary TB in HIV infected patients with primary drug resistance. A four-drug regimen plus or minus the drug L-ofloxacin is being used. Three sites in New York: Harlem Hospital (Joshua Standig, 212/939-2951), St. Vincent's Hospital (Margaret Granville, R.N., 212/790-8319) and Bronx Lebanon Hospital (Kathy Pollard, 718/293-2593). Thalidomide -- This trial examines the effect of thalidomide on tumor necrosis factor-induced immune activation which may be related to TB infection. The trial is under way at Rockefeller University under the direction of Dr. Gilla Kaplan. Fourteen participants have been enrolled. Women of childbearing age (except those who have been sterilized) have been excluded because thalidomide is known to cause severe birth defects. According to Dr. Kaplan, as soon as more is known about the action of thalidomide in the trial, the trial will be opened to women. Call Peggy Burroughs, study coordinator, at 212/327-7177. Interleukin-2 (IL-2) -- This trial will study IL-2 (proleukin) for the treatment of known INH-resistant tuberculosis in a phase 1- dose-escalating study. The drug is given as an injection every twelve hours. Trial is being conducted by Dr. David Perlman at Beth Israel Hospital 212/420-4470. Sparfloxacin -- Sparfloxacin is an antibiotic that shows activity against TB in the test tube. Parke Davis Pharmaceuticals reports that a comparative trial in MDR-TB, using standard anti-TB drugs has been approved by the FDA and will begin shortly. Sparfloxacin is available via a limited (case-by-case) compassionate use program for persons with MDR TB resistant to most of the current treatments. Physicians should call Dr. John Bender at 313/996-7297 for more information. Streptomycin -- In response to the reemergence of TB, Pfizer has resumed production of streptomycin and, to its credit, is providing the drug free of charge. Streptomycin should only be used in combination with other TB drugs. Physicians should call 1-800-254-4445 for information. Para-amino-salicylic acid (PAS) -- PAS is available from the CDC by calling 404/639-3670. Combination Anti-TB Drug -- Rifater, a combination three-in- one drug containing INH, rifampin, and PZA is still not available in the United States. Drug Availability and Pricing -- In 1991 the CDC received reports of severe shortages of anti-tuberculosis drugs. Since then the CDC and FDA have been exploring various options to monitor drug demand, increase drug supply, and oversee the development of new anti-TB drugs. Not surprisingly, along with increased demand for TB drugs comes increased prices. The CDC reports that between 1986 and 1992 the price of treating uncomplicated TB rose from $209 to $353 for a six- month course of therapy and that a two-year course of four drug therapy for MDR TB rose from $2,600 in 1986 to $8,720 in 1992.39 TB Chest Clinics in New York City Manhattan Chelsea Chest Clinic 303 Ninth Avenue 212/239-1749 Harlem Hospital 2238 Fifth Avenue 212/491-8403 Washington Heights Chest Clinic 600 West 168th Street 212/304-5438 Bronx Morrisania Chest Clinic 1309 Fulton Avenue 718/901-6536 Brooklyn Bedford Chest Clinic 485 Troop Avenue 718/574-2462 Brownsville Chest Clinic 259 Bristol Street 718/495-7258 Bushwick Chest Clinic 335 Central Avenue 718/574-2964 Fort Greene Chest Clinic 295 Flatbush Avenue Extension 718/643-8357 Kings Cty Hospital Chest Clinic 451 Clarkson Avenue, East Bldg. 718/245-3131 Queens Corona Chest Clinic 34-33 Junction Boulevard, Rm. 120 718/476-7638 Far Rockaway 6710 Rockaway Beach Blvd. 718/474-2100 Staten Island 51 Stuyvesant Place 718/983-4529 PPD skin tests & chest x rays only. TB RESOURCES New York City Department of Health TB Hotline for Physicians: 212/778-4162. TB Reporting : Information and Forms: 212/788-4162. Directly Observed Therapy Assistance in arranging a program for your patient: 212/788-4176. Education/Infection Control Training information, education materials in several languages, consultation on infection control policies and procedures: 212/566-1616. Laboratory Services Mycobacteriology Reference Laboratory, to submit specimens, cultures, or to obtain test results of previous submissions: 212/447-6745. Drug Susceptibility Results For information about your patient's previous treatment: 212/788-4162. New York State Department of Health TB Reporting Suspected or confirmed nosocomial transmission: 212/502-0855. TB Control Program: 518/474-4845. Other Resources New York Coalition to Eliminate TB A coalition of organizations and health care providers to advocate for better TB research, control, and treatment. Douglas Barry: 212/889-3370. Centers for Disease Control and Prevention Division of TB Elimination: 404/639-8120. National Jewish Center for Immunology and Respiratory Medicine Information, clinical consultation, pharmacology: 1-800-423-8891. American Lung Association TB Information: 202/785-3355. "The Continuing Challenge of Tuberculosis," is a 160-page report commissioned by Congress. It is considered a must read for anyone interested in TB prevention and control and is available for $9.50 by calling 202/783-3238. "Draft Guidelines for Preventing TB in Health Care Facilities" was published in the Federal Register (October 12, 1993). For more information or a copy, call Carmine Bozzi: 404/639-8027. TB Working Group/ACT UP This group has attempted to pressure governments at all levels and drug companies to respond effectively to the epidemics of TB and HIV. For more information on ACT UP's TB Working Group call Iris Long at 212/564-2437. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ICAAC Overview: Anti-Viral and Miscellaneous Reports by Derek Link The 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held October 17 to 20, 1993 in New Orleans, is the premier infectious disease conference and includes numerous HIV-related presentations. This article reviews anti-HIV presentations and miscelleneous clinical reports from the 1993 ICAAC. A review of opportunistic infection research reports at ICAAC will appear in an upcoming issue. Nuceoside Analogues Several new anti-HIV nucleosides were presented at ICAAC. FCU (935U83) is new nucleoside analog under development by Burroughs Wellcome, a North Carolina-based drug company. In test tube experiments, FCU is one-ninth as potent as AZT, but 1300-fold less toxic. FCU is active in vitro against both AZT- and ddI- resistant viral strains. According to the company, a phase I, twelve-patient pharmacokinetic study of FCU is completed and is now being analyzed. Efficacy studies, including a study of FCU-ddI combination, are planned for Europe, Australia, and the U.S.[1] Several studies were presented that suggest pharmacokinetic (i.e the way drugs move through and are eliminated by the body) differences with anti-HIV drugs in various populations. The Veterans Adminstration AIDS Cooperative group presented a study of AZT pharmacokinetics in white and black men. Eighteen men (nine white/nine black) received 200 mg AZT orally and intravenously. Intravenous, but not oral AZT appeared to have different pharmacokinetic profiles in the two groups. However, the groups were not matched by age (whites ranged from 41 to 68 years versus 30 to 47 for blacks), confounding the analysis of racial differences.[2] Bristol Myers Squibb, a New York-based drug company, presented toxicity data from the D4T expanded access program. As of September 26, 1993, 9165 patients were enrolled in the program: 95 percent of participants are white, 85 percent male, and 55 percent had fewer than 50 CD4 cells. Neuropathy has been the most common reported toxicity, seen in 63 cases. Nausea and vomiting, chills, and diarrhea were the next most common toxicities with fifteen, thirteen and twelve reported cases each respectively.[3] D4T and ddI can be given in combination without additional toxicities or altered pharmacokinetics, according to a pilot study performed by Bristol Myers. Ten HIV-infected men received ddI, d4T or the combination of both on successive days for one week. No difference was found in the pharmacokinetic profile of the combination compared to that of each individual compound.[4] The antacid buffer in ddI tablets does not affect the absorption of isoniazid (INH), according to a Canadian study. In this phase II study, twelve healthy volunteers received INH plus a ddI placebo tablet (containing the antacid found in the active medication) and INH alone. Plasma levels of INH were the same when given alone or with the ddI-antacid.[5] Reverse Transciptase Inhibitors Atevirdine (ATV) is a new reverse transcriptase inhibitor under development by Upjohn, a Michigan-based drug company. Resistance to ATV was examined in a phase I study of sixteen patients who received ATV and AZT for six to 28 weeks. Nine patients received drug for sixteen weeks or longer. Viral isolates from five of these patients remained ATV-sensitive. Isolates from four patients were ATV-resistant (one at six weeks, the others after twelve to 24 weeks of therapy.) Upjohn investigators are optimistic about this data since other non-nucleoside reverse transcriptase inhibitors induce resistance after only two to six weeks on therapy.[6] Researchers from Hoffmann-LaRoche, a New Jersey-based drug company, presented data on using benzodiazapene compounds as inhibitors of HIV reverse transcriptase. Roche originally developed these compounds as tat inhibitors, although they also act against HIV reverse transcriptase in the test tube. Roche dropped its tat inhibitor program earlier this year due to problems with their lead compound, RO-24-7429, and new research which casts doubt on tat's role in HIV's life cycle. Roche researchers suggest that other benzodiazapene compounds with anti-RT activity may "prove useful as single agents or in combination..."[7] Other Anti-Viral Therapies Gossypol is a cotton seed extract used as a contraceptive agent in China that has anti-HIV-activity in test tubes. Researchers from New York and Mexico conducted a phase I study of the drug in nineteen HIV-infected Mexican patients. Doses ranged from 20mg/day to 80mg/day. Doses under 50mg/day were well tolerated; higher doses caused reversible polyneuritis, hypokalemia (low levels of potassium), and hepatitis. No hematologic or renal toxicities were seen at the lower doses. Transient liver enzyme increases occurred at the lower doses, but resolved despite continued treatment. CD4 counts increased in three patients, remained unchanged in nine patients, and decreased in seven patients. Gossypol is also being investigated as a potential virocide (like nonoxynol-9) that may reduce HIV transmission during sexual intercourse.[8] SC-49483, manufactured by GD Searle, an Illinois-based drug company, is a prodrug of N-Buytl DNJ, an anti-HIV compound that produced significant gastrointestinal toxicities in phase I studies. The new pro-drug was evaluated in a 30 patient phase I study. SC-49483 was administered in single doses of 1.25g, 2.5g and 5g. After administration, only N-Butyl DNJ was detected in plasma samples, indicating that SC-49483 is effectively transformed into the active compound in the body. Oral bioavailability of N-Butyl DNJ was approximately 30 percent with the prodrug. No serious toxicities, including GI toxicities, were reported in the study.[9] Researchers from Applied Genetics, a Long Island-based company, report the development of transgenic mice which can be used as a model of HIV activation. When agents which are known to activate HIV in cell culture, such as ultraviolet light, were applied to the mice, increased HIV activity occurred, measured by genetic tests. However, when a liposomal formulation of vitamin E and vitamin C were topically applied to the mice, HIV activation was prevented. The authors suggest that the transgenic mice may be a useful means of measuring anti-HIV activity and that liposomal formulations of vitamin E and C may be worthy of study.[10] Mycoplasma and HIV The presence of mycoplasma DNA in the blood of HIV-infected patients is transient and not prognostic, according to a report from the Naval Medical Research Institute. Co-infection with Mycoplasma fermentans appears to increase the pathogenicity of HIV-infection in cell culture, leading some researchers and advocates to speculate that mycoplasma may be a necessary co-factor in disease progression. Using PCR techniques, this study identified six patients with detectable mycoplasma and seventeen patients without. Patients were followed for eighteen to 24 months and repeat PCR samples were obtained. Mycoplasma infection did not develop in the seventeen patients with no evidence of infection at baseline. Furthermore, all six mycoplasma- positive patients became negative for mycoplasma on repeat testing (only one mycoplasma-positive patient received antibiotics with anti-mycoplasma activity.) CD4 cell declines and disease progression were the same in both groups: one mycoplasma patient progressed to AIDS (1/6) during the study period compared with three mycoplasma-negative patients (3/17).[11] Colony Stimulating Factors G-CSF and GM-CSF have similar efficacy, but G-CSF is significantly better tolerated, according to a Belgian study that compared the two colony stimulating factors as acute salvage therapy in advanced HIV-infected individuals with neutropenia. Neutropenia refers to abnormally low levels of neutrophils, a type of white blood cell which fights bacterial infections. Twenty-four patients with an absolute neutrophil count below 1,000 were enrolled; twelve patients in each arm. All twelve patients who received G-CSF (1mcg/kg/day, subcutaneously) and nine of twelve who received GM-CSF (1mcg/kg/day, subcutaneously) had a hematologic response after three days of therapy. However, ten adverse events were reported in the GM-CSF arm, and only one in the G-CSF arm.[12] Smoking and HIV Smoking does not increase progression to AIDS or death, but may alter the clinical course of HIV disease, according to an observational study of 5113 HIV-infected patients. Current smokers, ex-smokers, and non-smokers were followed in the observational database of the Community Programs for Clinical Research on AIDS (CPCRA), a large, federally-funded research network. Participants were more likely to stop smoking as disease progression occurred. Current smokers were more likely to develop oral candidiasis and oral hairy leuloplakia, but less likely to develop cytomegalovirus disease. Heavy smokers (greater than one pack a day) were more likely to develop bacterial pneumonia compared with light smokers, non-smokers or ex-smokers. Finally, ex-smokers were more likely to develop PCP than non-smokers.[13] Flu Vaccine and HIV Influenza vaccination does not increase viral load in HIV- infected individuals, according to a study by Steigbigel and colleagues. The investigators followed ten patients who were given the vaccine. HIV viral load was measured by p24 antigen levels and quantitative plasma viremia. The authors found no evidence of increased HIV activation after immunization by either measurement.[14] HIV-Genital Ulcer Disease HIV-infection itself may cause genital ulcer disease (GUD) in infected women, according to a research team from Cornell Medical Center and Memorial Sloane Keterring Cancer Center, both in New York City. The researchers followed 307 women, with an average CD4 count of 197, for over twenty months. Of 42 new ulcers that were identified, 23 ulcers (55 percent) had no identifiable etiologic agent, leading the investigators to speculate that "HIV may play a local role in causation." The remaining nineteen lesions were caused by herpes simplex, cytomegalovirus, Chlamydia, Gardnerella Vaginalis, and two "unusual herpetic lesions."[15] Azithromycin Dr. Rosemary Soave, of Cornell Medical College in New York City, presented a study of oral azithromycin for cryptosporidiosis. The study randomized 90 patients with cryptosporidiosis to receive azithromycin 900mg/day or placebo for three weeks. Differences in bowel movement frequency, parasite shedding in stool, and overall clinical response between the azithromycin and placebo groups were not statistically significant. Plasma levels of the drug were analyzed in thirty-three patients. Azithromycin was poorly absorbed in many patients, according to the investigators. Patients who had detectable serum levels of azithromycin appeared to have a clinical response. 1 Daluge SM, et al. Program Abstract 41. 33rd ICAAC 1993. 2 Simberkoff M, et al. Prgram Abstract 325. 33rd ICAAC 1993. 3 Anderson R, et al. Program Abstract 684. 33rd ICAAC 1993. 4 Stewart M, et al. Program Abstract 720. 33rd ICAAC 1993. 5 Gallicano K, et al. Program Abstract 719. 33rd ICAAC 1993. 6 Demeter LM, et al. Program Abstract 45. 33rd ICAAC 1993. 7 Connell E, et al. Program Abstract 40. 33rd ICAAC 1993. 8 Koll B, et al. Program Abstract 687. 33rd ICAAC 1993. 9 Smith M, et al. Program Abstract 715. 33rd ICAAC 1993. 10 Morey, JD, et al.Program Abstract 1265. 33rd ICAAC 1993. 11 Frank D, et al. Prgram Abstract 562. 33rd ICAAC 1993. 12 Hermans P, et al. Prgram Abstract 697. 33rd ICAAC 1993. 13 Burns D, et al. Program Abstract 566. 33rd ICAAC 1993. 14 Steigbigel RT, et al. Program Abstract 1271. 33rd ICAAC 1993. 15 Laguardia KD, et al. Program Abstract 1169. 33rd ICAAC 1993. 16 Soave R, et al. Program Abstract 405. 33rd ICAAC 1993. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ TI Interview: Martin Delaney Martin Delaney is the Founding Director of Project Inform, a San Francisco-based AIDS treatment information and advocacy organization. In July of this year, Project Inform organized a meeting on "Future Directions in AIDS Research" in Madison, Wisconsin. David Gold of Treatment Issues spoke with Delaney about the Madison meeting and the current AIDS research effort. TREATMENT ISSUES (TI): Can you tell us about the meeting in Madison? MARTIN DELANEY: The purpose of the meeting was to bring together various forces engaged in discussions around AIDS research towards the question of how should it be managed - should the federal research effort be structured differently, are there inherent problems in what we're doing? And more or less, where are we? We brought together the tops in government, the Faucis (Anthony Fauci, Director of the National Institute of Allergies and Infectious Diseases), the Broders (Samuel Broder, Director of the National Cancer Institute), some Congressional representation, representatives in industry, a number of activists who've been vocal on these issues, Kristine Gebbie (the White House "AIDS czar") and university-based voices that have been speaking out on these issues. The goal was to see if there was anything these folks could agree upon as a first step toward proposing change. The first two-day meeting was largely aimed at getting a snapshot of what people agreed on. We got agreement on a list of scientific questions, as well as a list of organizational and structural questions. Our goal was simply to find where we could agree, and I was happy to see we drew up consensus on a number of those points. TI: And what were those? DELANEY: Well, on the "do-ability" of the problem itself. The agreement that people believe we can solve and manage this problem. TI: And that was agreed on by most people? DELANEY: That was universally agreed upon. And Broder even challenged us to take it farther and agree that we could literally remove the virus (HIV) from the body. People weren't quite willing to go that far. TI: Of course, that's at odds with some of the pessimism that came out of Berlin that seems to pervasive. DELANEY: It very much is, because the pessimism that came out of Berlin frankly was not based upon data. It was based upon emotional reaction and politics. One of the good things of the meeting was to confront some of that pessimism. The other areas of agreement got down to specific questions of funding, management practices, management styles, and specific problems of the government-industry interface. Now there's going to be a second meeting in Boston on November 22 to 23. In the meantime, four working groups have been put together which break up the areas of agreement from the first meeting. The working groups are attempting to draw up programmatic recommendations for how to address these problem areas that everybody agrees upon. TI: Obviously, if everything was truly wonderful in the AIDS research effort, something like this would not be needed. What's wrong with the government's AIDS research effort? DELANEY: AIDS research, like biomedical research in general, is not managed under the best accepted principles of project management and goal accomplishment. There are methods for managing basic research and discovery that are employed in industry and other parts of the government for managing work into the unknown. We've seen it in the space program, in military programs, and in the computer and other high technology fields. It's my belief that those technologies of management are not employed in biomedical research. There's a sort of profound belief in this notion of watering the garden - that we don't know where the answers are going to come from, you can't force a solution. So you water the garden freely. TI: What's wrong with that? DELANEY: It leaves far too much to serendipity, and it assumes that this process will somehow fairly distribute things to the right places. I don't think it does accomplish that. We've learned from industry and other fields in science that you're much more likely to accomplish a goal when you establish goals, develop strategic plans, continually scan for your knowns and unknowns, establish hypotheses to test and develop your knowledge - to push it forward a step at a time in a rational fashion. I don't see that happening in AIDS research. TI: What research effort would be a useful model to look at? DELANEY: A lot of the military research has been far more focused and much more likely to produce results. The grossest examples, of course, are in weapons development and weapons delivery. Folks like to think that was all some sort of engineering project over the last 50 years, but in fact, if you go back from 1940 and see where they went, they pushed the envelope in every imaginable aspect of our knowledge of physics. TI: Are you satisfied with the current leadership of the federal AIDS research effort? DELANEY: I believe in the need for stronger leadership, and by that - I don't mean a dictator, I mean a different process more than necessarily different people. TI: But isn't the job of the people who are in charge to really develop an effective process? DELANEY: Absolutely. And if I must be asked, yes, I think they fail to do so. Now the question, though is why? On the surface, they will argue that they don't believe in the other models - that they believe we must just sort of water the garden freely and maybe a flower will grow. TI: Some people also argue that the current leadership has been there, now for seven to eight years, and that the longer you're there, the more you become embedded and part of the system and thus cannot really develop substantial changes. DELANEY: Well, I think it's essentially true that the longer you're in a spot like that, the more baggage you bring to it. Some of this stuff starting to happen right now - certainly talk about strategic plans. Well, that's fine, except where was it in 1986? It's being forced on them politically, and I think reluctantly. I don't believe their heart is in it right now. So yeah, I support change in leadership. TI: Dr. Harold Varmus has been appointed to head the NIH (National Institutes of Health). Are you optimistic about his leadership? DELANEY: No, I'm not. As you know, I sort of stuck my neck out in opposing him and raising questions about him. And the principle reason for that is, when you get down to these arguments about how research ought to be managed, I think he frequently has been outspoken on the opposite view. He is not viewed as someone who looks to strong central leadership. TI: And how about the President himself? Do you believe he's provided any real leadership in trying to attract the best and the brightest? DELANEY: Up to this point, I would say the President has simply not given any attention whatever to it. So far, there simply hasn't been any clear leadership from the Administration in any form. Now, we're getting a lot of signals, like participation in our meeting and the support we've had from Shalala and Phil Lee. It seems like they want to do something, but I think they clearly haven't put the time into figuring out what they want to do. TI: Let me go back - you voiced optimism that it was, indeed, possible to develop effective therapies for HIV. What are you basing that on, and what particular therapies - or lines of therapies - do you see as most promising? DELANEY: I think there are really two basic points. One is that I think there is general agreement on the cause of the disease - unlike cancer, in which you're dealing with hundreds of different diseases, there's just no comparison to where we were or even are on the war on cancer. We're infinitely ahead of that. Secondly, even though we don't understand every last bit of pathogenesis - that doesn't bother me, because frankly, no disease that I can think of historically has ever required a perfect understanding of pathogenesis - the existing therapies --I think the general consensus is that they do have some activity against the disease. TI: You're talking about the nucleosides? (AZT, ddI, ddC) DELANEY: I'm saying the combination of anti-viral therapy, opportunistic infection therapies - each of those areas has shown some ability to modulate the outcome, change the time parameters, etc. What that says to me is that we're on the right track and that we're essentially in an engineering stage here. We're not fishing in the dark. What we're trying to do is build upon small knowledge to make larger gains. One of the great hopeful things about this epidemic is that we see any activity at all in response to anti-viral therapy. There's a bundle of studies out there that show there's some gain. Maybe it's a six-month gain used at a certain time in a certain way - whatever that gain is, that tells us that this goal, I think, is attainable. There are ways to slow [viral] replication ... to me, it's an engineering problem of how do we do that and there are several very promising avenues out there that are moving on that. TI: Are you optimistic about the protease inhibitors? DELANEY: Yes, mostly because of our experience with Merck so far has been pretty sober and solid. TI: Merck was actually pessimistic about their own drug (L-697,661) despite promising reports about convergent combination therapy. DELANEY: I like them a little more than the others in that regard. So I'm very hopeful about that. Protease inhibitors open up the potential for a broader kind of synergy in combination. Also, I'm encouraged by the progress that's going on in gene therapy right now. TI: Any particular therapies or are you just talking about areas of research? DELANEY: There are several technologies involved in that that I'm very hopeful about. There's a whole focus going on in immune-based therapies right now. It's very encouraging. Not because it's instead of anti-viral therapy, it's because we're working on another part of the problem, and that's progress to me. And opportunistic infection drugs are improving with each year. TI: Tell us about the work in immune restoration that was led by Jesse Dobson (of Project Inform). DELANEY: The areas that are under the most development right now are cellular transfer, be it from a twin or a non-matched sibling-cell transfer from another species, technology for doing things that will be in human beings before November. We're talking about a methodology that will allow the transfer of HIV-resistant stem cells from other simian species without rejection. It's another approach to gene therapy, but a much easier way. The whole cytokine area is kind of exploding - both in terms of correcting inappropriate cytokine signalling and replacing with some of the signals that seem to be missing. TI: What is the status of the Interluekin-2 (IL-2) trials? DELANEY: We're very pleased by the most recent data coming out of the IL 2 trials. There's reason to believe that they're coming upon a better way to use it, and it's supported by a limited number of cases with Lane's [Cliff Lane at the NIH] work, but we also have quite a bit of similar work done out here and in Stanford and in Larry Waite's group. We are seeing in both groups substantially elevated overall levels [of CD4 counts] and trends sustained for a long time. So that's significant. A number of individual physicians are duplicating Cliff Lane's protocol right now. TI: Are you concerned about the toxicities with some of these cytokines? DELANEY: With any of these drugs, sure. With all the cytokines, the challenges are in the rational way to use them. TI: There's been a lot of discussion about IL-12. What do you think? DELANEY: IL-12 is sort of the cytokine "du jour" right now in terms of its signals, its secondary pathway in immunity based on natural killer cells and interferon. It needs to be studied. I'm hesitant, though [that] it's going to be the whole answer. But it's another tool for fine-tuning the immune system, and I think the sooner we get it into studies, the better. TI: What about another "treatment du jour," the whole area of so-called "anti-oxidants"? DELANEY: Well, one could argue in a cryptic way that all cell death is due to oxidated stress - that's the way the body kills cells, through oxidated stress. So in that sense, anti- oxidants certainly make a lot of sense. Now again, it's the question of when, how much, and how far you can get from that approach. It's symptomatic treatment on a cellular level, and yeah, I think it may be helpful. It may slow cell death and cause a little less harm on the cellular level, but eating beta-carotene alone or pentoxifylline, as far as I can see, is not producing dramatic changes in outcomes. Should it be done? Of course it should. TI: What about pentoxifylline? DELANEY: I wouldn't discourage it, either. It seems of all the therapies we've looked at, it's one of the things that have the fewest downsides. So it may make sense. TI: And how do you evaluate the nucleoside analogues? DELANEY: My sense of nucleoside analogs is largely unchanged from what it's been for the last three years. If you look at what Concorde said, it simply fine-tunes our knowledge of how to use these things. All of us know people who've used nucleosides and had toxic effects and didn't see benefits. But I also hear of people who use them and did well, we really felt they benefitted for long periods of time. The weight of the evidence is, [that] these things, while imperfect, are tolerable in a lot of people and seem to be helpful in some of them. TI: Let me go back to the federal research program. The new position of the Office of AIDS Research Director has not been filled. Is there any individual that you think would be appropriate for the position? DELANEY: I think that's probably the toughest question out there right now. None of the candidates I've heard mentioned frankly excite me for this position. And the recommendation I've made so far is that: we not be limited in our thinking of people who are star producers in AIDS; secondly that it's eventually an administrative job, and what we need is a good politician and a good administrator in there; and third, I'm not even sure it's a medical researcher. The scientific calls should be coming from this advisory panel. Beyond that, what we need is a slick bureaucrat - an excellent bureaucrat. TI: Someone who would manage a research bureaucracy. DELANEY: Right. For me, that could be a behavioral scientist as easily as it could be a physical scientist, or it could even be someone who isn't even from the scientific field. TI: Or someone like the First Lady - hypothetically - who has the ear of people who would really make that person credible. DELANEY: That's right. Absolutely. TI: Are we setting that person (OAR Director) up for failure in the sense that he or she still has Tony Fauci, who opposed the changes and who's going to be running a big chunk of AIDS research dollars. In a sense, they'll be two competing operations. DELANEY: Yes. I think there's some real potential for problems in the structure. Especially because you're taking this secondary structure, the one that Fauci will run, is run by the guy who used to run the whole show. Intrinsically, I think that's a formula for sort of a two-headed monster here. But also I don't know a good way around that. I'm not suggesting that they should throw Fauci out or something. I'd be happy to see Fauci spend more of his time in science. TI: And less in administrative. DELANEY: Right. TI: How does the government maximize the efforts of private industry in AIDS research? DELANEY: Well, I think the first thing it needs to do is ask them. I think it's done a very poor job of sort of sitting down with industry and asking what it needs to be better involved in this. I was really struck last week when you saw Clinton on television, pulling togetherb the leaders of Ford, GM, and Chrysler announcing this government-industry collaboration to create cars that will get 80 miles per gallon. Well, you know, where the fuck is the collaboration with the President and industry on AIDS? Why isn't he there with the head of Merck and the head of Burroughs and these companies announcing a similar collaborative effort? TI: A good question to end on. Thank you for your time. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Treatment Briefs by David Gold MAC Prophylaxis and Treatment Guidelines A Public Health Service Task Force on Prophylaxis and Therapy for Mycobacterium Avium Complex (MAC) recommends that HIV- infected individuals with less than 100 CD4 cells receive 300mg per day of rifabutin (Mycobutin, Adria Labs) as MAC prophylaxis. If MAC develops, the task force recommends a multi-drug treatment regimen, which includes either clarithromycin or azithromycin. The Task Force states that physicians have added one or more of the following drugs as "second, third or fourth agents: clofazimine, rifampin, rifabutin, ciprofloxacin, and in certain cases, amikacin." Isoniazid (INH) and pyrazinamide, commonly used anti- tuberculous drugs, are not effective for MAC. Diagnosis, prevention and therapy for HIV-infected children under thirteen years should follow the same guidelines. The full recommendations appear in the The New England Journal of Medicine. (September 16, 1993, 329:828-833). Help Wanted at NIH Efforts to fill two critically important AIDS research positions at the National Institutes of Health (NIH) are underway. A search committee has been appointed to recommend Director of the Office of AIDS Research (OAR). This position is dramatically enhanced by passage of the NIH Revitalization Act of 1993 (S1/HR4). The committee was charged with conducting an active recruitment process. Members of the Search Committee include Art Amman (Pediatric AIDS Foundation), Derek Hodel (AIDS Action Council), Peggy Hamburg (formerly NYC Commissioner of Health), Kristine Gebbie (White House "AIDS czar"). Of some concern, the committee contains not less than nine members who currently hold positions within the NIH. The final decision on the OAR Director will be made by HHS Secretary Donna Shalala in early 1994. A search for the position of Director of the Division of AIDS (DAIDS) in NIAID is also underway. NIAID, whose Director is Tony Fauci, presently accounts for the bulk of federal AIDS research spending. The search committee for the DAIDS position is composed entirely of government people without any community representation. Among those believed to be under consideration are: Acting Director, Jack Killen; CPCRA head Lawrence "Bopper" Deyton; acting Associate Director Margaret Johnston; and the head of the Army's AIDS research program, Donald Burke, who may also be under consideration for the OAR position. Killen, Deyton, and Johnston are all considered responsive to community concerns. Burke is considered a "no-nonsense guy" but he may have been hurt by the gp160 controversy and, more importantly, is considered by some to be more committed to preventive HIV vaccine research than treatment research. What many believe is needed is an outsider who can institute changes in the DAIDS research program. Nevertheless, it is unclear whether Tony Fauci, who will make the ultimate decision on the DAIDS Director, can, or even wants to attract, a credible, well-respected outsider to fill the position. Megace Approved Megace Oral Suspension (Megestrol acetate) has been approved by the FDA for anorexia, cachexia or unexplained significant weight loss in PWAs. Manufactured by Bristol Myers Squibb, a New York-based drug company, the drug is a derivative of progesterone, a hormone used to correct abnormalities of the menstrual cycle. In two twelve-week studies, people with AIDS with wasting syndrome who were given 400 to 800mg of Megace demonstrated a five to seven pound weight gain compared to placebo. However, there was also a trend, though not to statistically significant levels, toward higher mortality rates among patients given the drug. In addition, impotence developed in some male patients on the drug. Megace is available, free of charge, to all patients who do not have adequate insurance coverage and can not otherwise afford the drug. Call 1-800-788-0123 for information on financial assistance for Megace or ddI, another Bristol Myers product. Call 609/897-2126 for more information about megace. More on ADAP The New York State Department of Health offers a number of programs that are designed to provide HIV-positive individuals with access to health care. These programs are part of the AIDS Drug Assistance Program (ADAP) and cover HIV Drugs, Primary Care and Home Care. New York State residents who are uninsured or underinsured are eligible. Call 1-800- 542-2437 for more information. NMAC Expands AIDS Treatment Work The National Minority AIDS Council (NMAC) has initiated the AIDS Treatment and Research Network to facilitate access to treatment information in communities of color. Call Moises Agosto at 202/544-1076 for more information. New "Living With AIDS" Guide from gmhc GMHC's revised edition of "Living with AIDS" - a guide of important information and resources for people with HIV - is now available. The book is free to GMHC clients and costs six dollars for others. To order, send a check for six dollars for each copy requested to: Myrtle Graham, GMHC, 129 West 20th St., NY, NY 10011. Our Treatment Library Needs a New PC GMHC's AIDS Treatment Library needs a new PC computer to run Medline, a computer database of the world's medical literature. Our Amdek 286 PC is (obviously) very old and does not have enough memory to support adequately the service. While our Medline CD-ROM system was generously donated by CD PLUS in New York and the NIH, they do not supply the computer to run the service. Medline service is available to all Treatment Library users and is used extensively by GMHC staff. Contact Paul Warren at 212/337-3695 to donate or sponsor the purchase of a new computer. AIDS Newsletter for Children and Parents JUST KIDS is a newsletter covering medical and social issues faced by HIV-infected children, teens and their parents. Yearly subscriptions are ten dollars for individuals, twenty dollars for professionals and institutions, and $30 for international orders. The newsletter is provided on a sliding scale or free upon written request. Send subscription requests to JUST KIDS, c/o 3 Corners, Inc. P.O. Box 42, Village Station, New York, NY 10014. Write checks or money orders to 3 Corners, Inc. All donations are tax-deductible. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Drug Company watch by Derek Link Over the Counter Acyclovir for US? Burroughs Wellcome, a North Carolina-based drug company, sponsored a forum at the 1993 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), to discuss their plans to seek over-the-counter approval for 200mg acyclovir tablets. Acyclovir (Zovirax) is an approved treatment for genital herpes virus infections. Approximately one-quarter of the American population is infected with HSV- 2, the virus that causes genital herpes. Acyclovir, which is Burroughs Wellcome's top-selling drug, is presently available only by prescription in the United States. A topical cream form of acyclovir was recently approved for over-the-counter use in the United Kingdom. But can patients with previously diagnosed genital herpes distinguish recurrences from other ulcerative sexually transmitted diseases (STD), such as syphilis or chancroid? And would inapproporiate use of acyclovir encourage drug-resistance? Gray Davis, M.D., a Burroughs Wellcome researcher, reported that data from previous studies show that patients can correctly identify recurrences over 97 percent of the time. As for resistance, no one knows. GP160 Vaccine Saga Grinds On; Single Product Trial Unlikely In a victory for GP160 opponents, the deadline for a decision on the controversial single-agent trial of the MicroGeneSys GP160 therapeutic vaccine has been extended to April 1994 by a House-Senate conference committee. MicroGeneSys, a Connecticut-based biotechnology company, helped by the lobbying efforts of former Senator Russell Long, received a $20 million Congressional earmark for the Department of Defense to study its product last year. The earmark, which is believed to be the first product-specific research allocation ever made by Congress, caused an outcry by many scientists and AIDS activists who protested political interference in scientific priority setting. The earmark officially remains in limbo until the FDA, NIH, and Department of Defense (DOD) agree on how the money should be spent, but most observers agree that the recent Congressional action is a set-back for MicroGeneSys. Both FDA and NIH are on record as opposed to a single agent GP160 trial. Kristine Gebbie, the White House "AIDS czar," who also opposes the single product trial, is pressing the DOD to follow suit. Since MicroGeneSys refuses to supply their vaccine to a multi-product trial, Gebbie and others propose that the money be used to fund basic AIDS research. Bristol Myers Plans D4T Filing by End of Year In a meeting with AIDS activists, Bristol Myers Squibb, a New York-based drug company, announced plans to file a New Drug Application (NDA) for D4T, a anti-HIV reverse transcriptase inhibitor, by the end of 1993. In addition to pharamacologic and safety data on the drug, the NDA will include efficacy data from a three-arm randomized comparison of D4T in 150 patients, and a two-arm randomized comparison of AZT and D4T in 832 patients. Data from the D4T Expanded Access Program, which enrolled over 9000 patients, and a European dose comparison study of the drug, will also be included in the submission. Initial efficacy claims will be based on surrogate markers, predominately CD4 cell responses. Clinical endpoint data on the drug are not expected until at least early 1994. Roche Sales Up 15 percent, But Claims Research Spending Too High Roche, the Swiss drug company with a New Jersey-based affiliate that makes ddC, reported a 15 percent increase in pharmaceutical sales in the first nine months of 1993, equivalent to $4.1 billion. Roche described the performance of its pharmaceutical division as "particularly satisfying." However, according to a report in Scrip, a pharmaceutical industry newsletter, Jurgen Drews, head Research and Development (R&D) for Roche, stated that research spending in the pharmaceutical industry was too high given the present cost-conscious climate. Drews, who made the comments at a press conference in Switzerland, suggested that this research money could be more profitably invested elsewhere. Roche presently invests 24 percent of sales into R&D, one of the highest rates in the industry. According to the report, Roche's R&D budget will be reduced to 17 to 18 percent of sales over the coming years by slowing its rate of growth in relation to sales. Scrip also reports that RO-31-8959, Roche's HIV protease inhibitor, was highlighted by Drews as a priority compound for the company. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Andrew S. Zysman, M.D. 1955-1993 AIDS activism lost another hero last month with the untimely passing of Andrew Zysman. Until his death from AIDS-related complications, Andy was a nationally known advocate for effective AIDS treatments and the rights of HIV-positive health care workers. As a physician, a member of ACT UP, and a person with AIDS, he encouraged hundreds of doctors to support ACT UP and held an annual physician-sponsored benefit for the group. Andy served on the Oncology Committee and the Community Constituency Group of the AIDS Clinical Trials Group (ACTG) and on the governing board of the American Association of Physicians for Human Rights. Earlier this year, he was honored as an "AIDS Hero" by the San Francisco- based Mobilization Against AIDS. Most recently, Andy led a successful drive which forced Burroughs Wellcome to put a ceiling on the price of acyclovir. Andy was perhaps best known for his work in advocating Kaposi's Sarcoma (KS) treatments. He was relentless in pushing both the government and drug companies to research KS drugs and helped organize GMHC's Forum on Future Directions in the Treatment of KS. One of Andy's most impressive skills as an activist was his pragmatism. He avoided the personality battles and always kept his eye on the goal -- pushing for effective therapies and a cure. On a personal level, those who knew Andy feel an immense loss. He was a person of incredible exuberance, in work, in play, and in his personal relationships. So many people were touched by his sense of humor, and, above all, generosity and decency. At Andy's memorial service, one speaker posed a question: why have so relatively few doctors actively supported the work of AIDS treatment activists at groups such as ACT UP, Project Inform, TAG, and GMHC? No one in the room, not even any of the doctors, could offer an answer. Andy's work is an example of what one person, particularly someone with a medical background, can do to push for more accelerated and effective AIDS research. His life is an example of how one person, through humor, kindness and decency, can touch many people's lives. Andy is survived by a loving family, including his mother, Eva, his father, Michael, his brother, Jules, other family members, and an extraordinary number of devoted friends, colleagues and fellow activists.