TreatmentUpdate56, Vol 7, No. 2 - February 1995 ************************************************************* published by Community AIDS Treatment Information Exchange, Suite 420 - 517 College St., Toronto, Ontario, Canada M6G 4A2 ************************************************************* HIV/AIDS THEORY A. HIV and cytokines-testing the theory * BACKGROUND There are two types of responses the immune system can make when it senses an infection. One response is called CMI (cell-mediated immunity, also known as a type 1 response). Very simply, CMI involves T cells that fight invading microbes and destroy infected cells. To boost CMI the immune system makes cytokines such as: - interferon-gamma - interleukin-2 - interleukin-12 As a general rule, CMI is needed to fight infections caused by viruses and other microbes that infect and 'hide' inside cells. The other type of response is called humoral immunity or a type 2 response. Here the immune system relies largely on antibodies made by B cells. To strengthen this response the immune system releases cytokines such as: - IL-4 - IL-6 - IL-10 Interestingly, these cytokines cause cells to make less of the cytokines needed for CMI. As well, interferon gamma can cause cells to decrease production of the cytokines needed for humoral immunity. Some researchers think that, over time, the immune systems of HIV-infected patients make less of the chemicals needed to boost CMI while making more of the chemicals that help humoral immunity. This 'shift' may be one reason people with HIV/AIDS (PHAs) develop life-threatening infections. Researchers have also found cells that release both types of cytokines, and their role in the loss of CMI is not clear. * CYTOKINE THERAPY Some researchers suggest that PHAs ought to be treated with cytokines that can boost CMI. This idea is being tested; subjects in Vancouver, California and New York are receiving IL-2 and/or IL-12. Intravenous cytokine therapy may not work because cytokines: - quickly break down - are needed at very small and particular sites - can be toxic when taken in large doses Some researchers are beginning to suspect that there will not be any single 'magic' cytokine for treatment of HIV/AIDS. Leading immunologists suspect this is the case because there is usually a 'mix' of cytokines that cause certain effects. In TreatmentUpdate 55 we reported data from several experiments with cytokines or anti-cytokines for treating arthritis and cancer. In the section on immunomodulators in this issue of TreatmentUpdate, we report results from a study using interferon-gamma to boost the immune systems of subjects with HIV/AIDS REFERENCES: 1. Clerici M and Shearer G. The Th1-Th2 hypothesis of HIV infection: new insights. Immunology Today 1994;15(12): 575-581. 2. Mossmann TR. Cytokine patterns during progression to AIDS. Science 1994;265:193-194. 3. Meyaard B, Otto SA, Keet IPM, et al. Changes in cytokine patterns of CD4+ cell clones in Human Immunodeficiency Virus infection. Blood 1994;84(12):4262-4268. 4. Autran B, Legac E, Blanc C and Debre P. A ThO/Th2-like function of CD4+ CD7 - T helper cells from normal donors and HIV- infected patients. Journal of Immunology 1995;154(3):1408-1417. II ANTI-HIV AGENTS A. Cholesterol drug for HIV? * BACKGROUND AZT and related drugs are supposed to work by interfering with an enzyme needed to make new viruses. HIV can become resistant to these drugs, so researchers are testing drugs that can affect other parts of the viral life cycle such as protease (or proteinase) inhibitors and tat inhibitors. The outer part of a cell has a layer of lipids (fat-like substances) that helps to hold the cell together. This outer layer is called a membrane. The shell protecting the virus is also made of lipids. Several research teams have found that when cells become infected with HIV the types of lipids in the membrane change. Drugs that interfere with the type and amount of lipids in the cell membrane could be used to damage HIV and infected cells. * LOVASTATIN Lovastatin is a drug that causes cells to make less cholesterol. Researchers in France have been conducting experiments on HIV-infected cells with lovastatin. They found that lovastatin reduces production of lipids by 60% to 70%. HIV-infected cells treated with lovastatin survived longer than HIV-infected cells not treated with the drug. As well, the level of the essential viral enzyme RT (reverse transcriptase) fell to 10% of its normal value in cells treated with lovastatin. * TOXICITY The researchers stated that lovastatin is well tolerated by patients who use the drug to reduce their production of cholesterol. The concentration of lovastatin used in these experiments can be reached by patients taking 40 mg/day. The researchers suggested lovastatin and 'related' drugs should be considered as potential anti-HIV therapy. Lovastatin (Zocor(R)) is licensed in North America to reduce production of cholesterol. * LOVASTATIN IN MONTRAL Researchers in Montral have been studying the effect of lovastatin on the immune system. This is because white blood cells need to make cholesterol to build their cell membranes. This is particularly important when the immune system is under attack and needs to make many cells to fight back. If cells cannot make enough cholesterol then production of white blood cells may not be enough to contain the infection. In some laboratory experiments using lovastatin at concentrations 10 times above the normal value, the ability of cells of the immune system to respond to infection (in simulated tests) fell between 25% and 50%. The Montral researchers gave 52 adult (non-HIV-infected) subjects 40 mg/day of lovastatin for 8 weeks. During the 8 weeks no significant decline in the performance of white blood cells occurred. There were no decreases in numbers of T cells. The researchers did not provide any information on CD4+ and CD8+ cell numbers. Researchers noted a slight decrease in production of antibodies. It is possible that there may have been other effects on the immune system that this research team did not detect. REFERENCES: 1. Maziere JC, Landureau JC, Gird P, et al. Lovastatin inhibits HIV-1 expression in HIV infected-human T lymphocytes cultured in cholesterol-poor medium. Biomedicine and Pharmacotherapy 1994;48:63-67 2. McPherson R, Tsoukas C, Baines MG, et al. Effects of lovastatin on natural killer cell function and other immunological parameters in man. Journal of Clinical Immunology 1993;13(6):439-444. III IMMUNOMODULATORS A. Interferon-gamma for HIV/AIDS * STUDY DETAILS In the late 1980s researchers in California conducted a small study on the effect of interferon-gamma (INF-y) in 12 subjects with AIDS who also had Kaposi's sarcoma. The average CD4+ cell count was 56 cells and the average CD8+ cell count was 511 cells. The researchers did not provide details about the gender of subjects. Subjects received various doses of INF-y (up to 20 million units) "three times per week [either intravenously] or five times per week [via injections into muscles] for up to 8 weeks." Subjects received INF-y on one of two schedules; either on Monday/ Wednesday/Friday or Monday through Friday. * RESULTS No subject had increased blood levels of CD4+ or CD8+ cells while in the study. Despite receiving high doses of INF-y several subjects developed life-threatening lung infections after the study. REFERENCES: 1. Martinez-Maza O, Mitsuyasu RT, Miles SA, et al. Gamma-interferon-induced major histocompatibility complex class II antigen expression in individuals with Acquired Immunodeficiency Syndrome. Cellular Immunology 1989;123:316-324. B. Interferon-gamma in the eye? * INTERFERON-GAMMA Researchers in the USA have been conducting experiments with one herpes virus (HSV) in the eyes of mice. These researchers injected interferon-gamma (INF-y) into the eyes of mice. They found that injections of that immune booster protected the eye from attack by HSV. In some mice, injection of INF-y into one eye protected the other eye from infection. There is a direct connection between the brain and eye. Infection of those connecting nerves can allow the virus to enter the brain. In these experiments, although the eye was protected, treatment with INF-y "did not prevent the virus from spreading to the brain." * PROTECTION The researchers conducting these experiments could not explain why the eye recovered from the viral infection but the brain did not. Nor did they understand why the untreated eye could resist viral infection. This is especially interesting because in a recent study on CMV retinitis in HIV-infected humans, researchers expected "90% of untreated eyes ...would [develop CMV retinitis] within 6 weeks". The researchers suggested that interferon may have restored the ability of the local immune system (in the eye) to alert other cells about the infection. Once alerted, CD8+ cells may have been able to control the infection in the eye but not its spread to the brain. If other researchers can confirm the protective effect of INF-y against herpes viruses, including CMV, then perhaps experiments on the eyes of CMV-infected humans may be considered. REFERENCES 1. Mossman TR. Cytokine patterns during progression to AIDS. Science 1994;265:193-194. 2. Geiger K, Howes EL and Sarvetnick N. Etopic expression of gamma interferon in the eye protects transgenic mice against intraocular herpes simplex virus type 1 infections. Journal of Virology 1994;68(9):5556-5567. 3. Martin DF, Parks DJ, Mellow SD, et al. Treatment of cytomegalovirus retinitis with an intraocular sustained-release ganciclovir implant. Archives of Ophthalmology 1994;112(12):1531-1539. IV INFECTION FIGHTERS A. CMV in the eye * BACKGROUND CMV (cytomegalovirus) infection is common in North American patients who are also infected with HIV. Interestingly, CMV infection does not always "result [in symptoms]" in HIV-infected patients. CMV can cause the sight-threatening infection CMV retinitis. As well, this virus can attack the intestines, lungs and nerves. Nearly all cases of CMV infection occur in patients with less than 100 CD4+ cells. Indeed, 75% of serious complications caused by CMV happen in patients with less than 75 CD4+ cells. * CMV In North America, patients who have access to medical care and who are able to get preventative doses of antimicrobial drugs appear to be living longer compared to patients with AIDS at the beginning of the epidemic. Although these patients can survive PCP, their immune systems continue to weaken, placing them at risk for other infections such as CMV and MAC (Mycobacterium avium complex). In one study subjects with AIDS/ARC had a 15% chance of developing complications due to CMV over a 2-year period. In subjects with less than 100 CD4+ cells the risk was 21%. In another study, where subjects received drugs to prevent PCP, 40% of subjects eventually developed symptoms of CMV infection. * TREATMENT Standard treatment for CMV infection consists of either ganciclovir (Cytovene(R), DHPG) or foscarnet (Foscavir(R), sodium phosphonoformate). Ganciclovir can damage the bone marrow and appears to affect the immune system, particularly CMI (cell-mediated immunity). Based on results from a controlled study, HIV-infected patients treated with foscarnet tend to survive about 4 months longer than similar patients getting ganciclovir. Foscarnet can cause kidney problems which can then result in seizures. Doctors and their patients are looking for alternative ways to deliver anti-CMV drugs to the eye. Some doctors inject anti-CMV drugs directly into the eye. Patients will need to get twice weekly eye injections once the retinitis clears and may be at high risk of developing complications such as detached retinae. One new method of delivery is to place a slow-release form of ganciclovir directly into the eye. One problem with all of these therapies is that they do not deal with the underlying cause of these infections; the loss of CMI (cell-mediated immunity). REFERENCES: 1. Jacobson MA. Current management of cytomegalovirus disease in patients with AIDS. AIDS Research and Human Retroviruses 1994;10(8):917-923 B. Eye implant for CMV * STUDY DETAILS Researchers in the USA enrolled 26 adult HIV-infected subjects of whom 25 were male and 1 female. Overall, their CD4+ cell counts were below 25 cells. Potential subjects for this study had never received anti-CMV drugs (ganciclovir or foscarnet) or had any complications due to CMV infection. As well, subjects were well enough to undergo the eye surgery necessary for this study. At the time they entered the study, all subjects had been newly diagnosed with CMV retinitis which was not yet sight-threatening. Doctors randomly assigned subjects to one of two groups in this study. Within 48 hours of entering the study, subjects in group 1 had surgeons open and insert a small device--the implant--which slowly released ganciclovir. Subjects in group 2 were closely monitored for worsening retinitis. Should doctors decide that the retinitis was becoming worse, or that CMV was infecting some other part of the body, they recommended intravenous ganciclovir or foscarnet. Those subjects with worsening retinitis but no other indication of CMV infection could choose between intravenous ganciclovir/foscarnet or the implant. * RESULTS Researchers inserted implants into 39 eyes during the study (some eyes had their implants replaced). Fourteen eyes had implants inserted within 48 hours of entering the study and researchers monitored 16 other eyes for signs of worsening retinitis. Another 11 eyes entered the study free from retinitis, but later developed this infection. * 226 DAYS About half the eyes that received the implant were protected from worsening retinitis for at least 226 days. At first, the implant gave all 39 eyes protection against retinitis. Indeed 30 of 39 eyes did not have retinitis that became worse. * THE OTHER EYE Twenty-one subjects entered the study with only 1 eye having retinitis. In 14 of those subjects, the other eye became infected with CMV during the study. By the 203rd day at least half of the 21 subjects had retinitis develop in the previously uninfected eye. * SURVIVAL About 1/3 of subjects eventually had CMV attack parts of the body other than the eye, usually "lungs and [intestines]". Half of the subjects died about 10 months after entering the study. Data from a controlled study comparing foscarnet against ganciclovir (both given intravenously) suggested that half of subjects receiving foscarnet survived 12.5 months and those receiving ganciclovir 8.5 months. * EFFECTIVENESS Results from this trial suggests that the implant is clearly effective in treating CMV retinitis. About half the subjects whom the doctors assigned to be monitored (group 2) developed retinitis within 15 days of diagnosis. By contrast, half the subjects whom the doctors assigned to receive the implant immediately were free from retinitis for 295 days. This difference between the two groups was statistically significant; that is, not likely due to chance alone. Researchers did not detect any retinitis that was resistant to treatment with the implant. In theory the implant was supposed to be empty "between 32 and 38 weeks". Some implants ran out of ganciclovir before 32 weeks (because they released the drug faster than others). This faster release may have been why 9 subjects developed retinitis before the 32nd week. Clearly, the implant is not perfect and the manufacturer needs to take action so that future versions have a more reliable performance. * ACCESS AND COST In June 1994, doctors in Vancouver first inserted the implant in a Canadian patient with CMV retinitis. Eye surgeons in Canada who have patients newly diagnosed with CMV retinitis may call the Emergency Drug Release Programme in Ottawa and request that their patient be considered for receiving an implant. Chiron Vision Canada may then decide to send the implant. The cost of an implant is currently $5,000 (CND) and this is paid for by the patient. Canadian doctors who want further information can call the company at 1-800-263-3557. Doctors in the USA may call Chiron Vision at their office in Irvine, California. That number is 1-800-553-3354. REFERENCES: 1. Martin DF, Parks DJ, Mellow SD, et al. Treatment of cytomegalovirus retinitis with an intraocular sustained-release ganciclovir implant: a randomized controlled clinical trial. Archives of Ophthalmology 1994;112:1531-1539. C. Issues about the implant * FIFTY PERCENT Given low doses of antimicrobial drugs, some patients with AIDS in North America are living longer. While these drugs may delay or prevent the appearance of life-threatening infections, they do not help the immune system recover. Thus more patients are living longer despite low CD4+ cell counts. Some researchers think that as many as 50% of patients with AIDS in North America will develop the sight-threatening infection CMV retinitis. Doctors in the USA estimate that it costs about $70,000 US to treat one patient with retinitis with intravenous ganciclovir or foscarnet for 1 year. In relation to the cost of the implant this may be cheaper. But the fight against CMV carries with it more than it seems. According to one San Francisco doctor, those who care for patients with AIDS know that blindness from CMV is what many fear most. It is all too often the final insult that leads a patient to decide either to commit suicide or stop all medical support. * A "CLUMSY DEVICE" One of the advantages of the implant is that concentrations of anti-CMV drugs 4 to 5 times higher than can be achieved with intravenous therapy can get into the eye. The device is not perfect. Indeed, one doctor describes it as "clumsy", but it is a start in the direction of better quality of life for patients. Hopefully, over time, the manufacturer will create more sophisticated devices. Perhaps more importantly, they might reduce the cost of an implant to a level that most patients and/or health care plans can afford. REFERENCES: 1. Irvine AR. Intraocular sustained release devices. Editorial. Archives of Ophthalmology 1995;113:25-26. D. A virus for Kaposi's sarcoma? * BACKGROUND At the start of the AIDS epidemic in North America doctors noticed the appearance of formerly rare "purple blotches" or lesions on the skin of their gay/bisexual patients. Ordinarily seen in elderly men living in Mediterranean countries, Kaposi's sarcoma (KS) was not usually fatal. The KS seen with the AIDS epidemic often caused complications that killed patients. Although there are many theories about what causes KS, none have been proven. Whatever causes the aggressive KS in HIV-infected gay/bisexual men appears to be spread through sex. The most recent theory suggests that a new herpes virus may be the cause of KS. The research team that put forward this theory has not found a virus, just traces of one. Even if the team found a virus, they would still have to prove it causes KS. The research team is working on a simple blood test that could then allow them to screen patients with HIV/AIDS to see if they are infected with the new herpes virus. If KS is caused by a herpes virus then doctors and their HIV-infected patients with KS may wish to experiment with anti-herpes drugs. Researchers in Sweden have been conducting such experiments and we now report their results in the section below. REFERENCES: 1. Cohen J. Is a new virus the cause of KS? Science 1994;266:1803-1804. 2. Schulz TF and Weiss RA. Kaposi's sarcoma: a finger on the culprit. Nature 1995;373:17-18. 3. Chang Y, Cesar E, Pessin MS, et al. Identification of herpes virus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 1994;266:1865-1869. E. Foscarnet for KS? * BACKGROUND Doctors in Stockholm noticed that 2 HIV/AIDS patients who had CMV infection and who received the anti-herpes drug foscarnet also had their KS lesions shrink. The doctors then did a pilot study on 5 male adult subjects with AIDS who had "recently developed" KS and gave them foscarnet. * STUDY DETAILS Four of the 5 subjects had CD4+ cell counts below 30 cells. Testing samples of their lesions confirmed that they were indeed KS. The subjects received foscarnet in the following schedule: - 60 mg/kg every 8 hours for the first 5 days - 90 mg/kg every 12 hours for the next 5 days * SUBJECT 1 Over a period of months the lesions changed, became thinner and nearly disappeared 12 months after receiving foscarnet. Seventeen months after entering the study all the former lesions reappeared. * SUBJECT 2 This subject had all 15 of his lesions clear and 20 months after receiving foscarnet he remained free from lesions. * SUBJECT 3 He received 2 courses of foscarnet and his 29 lesions faded and he remained free from lesions 15 months after receiving foscarnet. * SUBJECT 4 One subject with 6 CD4+ cells had lesions that continued to grow despite 2 courses of foscarnet within three months and his overall condition became worse. * SUBJECT 5 The final subject had only a partial course of foscarnet and his overall health also became worse as did the size and spread of his lesions. It is interesting that in the first 3 subjects lesions on the skin as well as others inside the body shrank. In the last 2 subjects whose overall health was also declining, foscarnet therapy had little, if any, effect. Based on these results, foscarnet may not work in every case of KS. It may be that some parts of the immune system need to be intact if the drug is to work. Larger, controlled studies testing foscarnet and other anti-herpes drugs may confirm these promising results. ACKNOWLEDGEMENTS 1. We thank Steve Johnston for access to research papers. REFERENCES: 1. Morfeldt L and Torssand J. Long-term remission of Kaposi's sarcoma following foscarnet treatment in HIV-infected patients. Scandinavian Journal of Infectious Diseases 1994;26;749-752. F. Vancouver: Complications from PCP * BACKGROUND In North America, the most common life-threatening lung infection is PCP (Pneumocystis carinii pneumonia). What can kill patients even if they receive antibiotics is the inflammation and fluid build up in the lungs which can then cause the patient to stop breathing (ARF; acute respiratory failure). When patients develop ARF they can sometimes be saved by being taken to an intensive care unit (ICU) and connected to a respirator. To try and reduce these complications doctors sometimes prescribe corticosteroids. Doctors in Vancouver have been looking at hospital records to note the effect of complications from PCP and patient survival. * RESULTS-SURVIVAL FALLS Over a 4 year period (1987-1991) doctors diagnosed 456 episodes of PCP, 9% (42 patients) developed ARF. Twenty-seven of the 42 patients had to be put on a respirator so that they could continue breathing. Despite help from the respirator, 24 of the 27 patients died. The 3 patients who survived because of their care in the ICU later died within 6 months of leaving the ICU. During the years between 1987 and 1991, deaths from "PCP-related ARF" climbed from 75 % to 100%. The researchers compared records from 1981 to 1987. During those early years of the AIDS epidemic, doctors diagnosed "127 episodes of PCP". Twenty-seven of those patients were sent to the ICU and hooked up to a respirator. Fifty percent of the 27 patients survived and could leave the ICU. This huge difference in survival rates between the early and later years of the AIDS epidemic was statistically significant. In the period after 1987 more patients began to receive corticosteroids in addition to anti-PCP therapy. * CHANGES IN CARE The Vancouver researchers suggest that patients who develop ARF despite treatment with antibiotics and low-dose steroids may have a poor chance of survival. Their review of hospital records shows that overall, death due to PCP remained relatively the same between 1981-1991. The researchers suggest that between 1981 and 1987 increased use of steroids resulted in fewer deaths from PCP-related ARF. After 1987, even more doctors began to use corticosteroids and they also used them earlier in the course of PCP. As a result there were fewer cases of ARF related to PCP. However, the few patients who developed ARF despite use of corticosteroids all died. REFERENCES: 1. Hawley PH, Ronco IJ, Guillemi SA, et al. Decreasing frequency but worsening mortality of acute respiratory failure secondary to AIDS-related Pneumocystis carinii pneumonia. Chest 1994;106(5):1456-1459. V TESTING A. Predicting eye damage from CMV * BACKGROUND In the USA, more patients with AIDS are surviving despite low CD4+ cell counts. Researchers estimate that as many as 50% of these patients will eventually develop the sight-threatening infection CMV retinitis. Doctors cannot yet precisely predict when patients will develop CMV retinitis. Currently, regular eye exams are the only way doctors can diagnose retinitis. Although some patients report 'floaters' across their vision this does not always mean that retinitis has begun. Indeed, healthy, non-HIV-infected people can also have 'floaters' and this does not mean that they have eye diseases. Current anti-CMV treatments are costly and have side effects. If doctors could predict when retinitis will appear then patients could begin anti-CMV therapy only when necessary. * BLOOD TESTS Researchers in San Francisco have been experimenting with white blood cells taken from subjects with and without HIV/AIDS and CMV retinitis. Technicians looked at the amount of CMV in white blood cells from those subjects. Using PCR (polymerase chain reaction) the researchers found that subjects without HIV infection had the lowest level of CMV in their blood cells. The next highest were subjects having between 100 and 800 CD4+ cells. They were followed by subjects with less than 100 CD4+ cells. On average, the subjects with the highest level of CMV were those with retinitis. Only 50% of samples from subjects with retinitis had high levels of CMV. * ONLY 50% That laboratory tests could not detect high levels of CMV in nearly 50% of patients with retinitis suggests that these tests will not be useful for every patient. One possible reason for this result is that some subjects had the infection restricted to their eyes. In the other cases the infection had spread beyond the eyes. According to the researchers, "[nearly] 80% of patients in any given year with CD4+ cell counts below 100 cells remain free from [symptoms of CMV] infection." The researchers will continue to try and improve their tests. According to their preliminary results, patients who have high blood levels of CMV infection but do not have retinitis develop this condition within 4 months of being tested. REFERENCES: 1. Rasmussen L, Morris S, Zopeto D, et al. Quantitation of Human Cytomegalovirus DNA from peripheral blood cells from Human Immunodeficiency Virus-infected patients could predict Cytomegalovirus retinitis. Journal of Infectious Diseases 1995;171-182. B. AZT-rate of release affected by hormones and other drugs? * GETTING RID OF DRUGS When patients take a drug, the body processes it and it is eventually released, usually into the urine or feces. The body can also get rid of substances by releasing them into a number of fluids, including sweat, tears and breath. * STUDY DETAILS Doctors in Amsterdam studied 63 men and 5 women to see how the body processes and gets rid of AZT. As well, they also looked at the interaction(s) of other drugs with AZT. The doctors collected data from 68 subjects some of whom had symptoms of AIDS and others who were symptom-free. Subjects were not supposed to eat overnight nor in the morning and their blood was collected before the subjects ate breakfast. Samples were taken both before and after subjects took their morning dose of AZT. * RESULTS-SEX According to their results, the researchers reported that women's bodies appear to get rid of AZT about 42% slower than men's. The doctors checked "other possible [factors]" such as weight, severity of illness, drug use and liver dysfunction to see if they could by themselves affect the results. The researchers stated that none of those factors appeared to be the cause of the difference in "clearing" AZT. This difference between men and women was statistically significant, that is, not likely due to chance alone. There were only 5 women used in this experiment and perhaps a study with more women might have found different results. However, some of the researchers were not surprised at the different rate of clearance of AZT. They noted that several other drugs such as "codeine, [Tylenol(R), Valiums and related compounds]", are processed in a similar manner to AZT and are released more slowly by women than men. This difference in the clearing rates of drugs may be caused by hormones. * OTHER DRUGS The researchers did not find age or liver/kidney dysfunction to affect the rate at which the body released AZT. The researchers also noted that many patients with HIV/AIDS take a variety of other medications and they tried to find any interactions. Patients taking methadone had a 45% decrease in the rate at which they got rid of AZT. This difference was statistically significant and may mean that patients given both AZT and methadone may need careful monitoring for AZT toxicity. Ganciclovir and rifampin appeared to increase the rate at which AZT is released from the body. Other drugs tested which did not have any significant effect on the release of AZT included: ddI, fluconazole, Bactrim/Septra(R), pyrimethamine, acyclovir, ketoconazole, cimetidine and related drugs. REFERENCES: 1. Burger DM, Meenhorst PL, ten Nopel CHH, et al. Pharmacokinetic variability of Zidovudine in HIV-infected individuals: subgroup analysis and drug interactions. AIDS 1994;8(12):1683-1688. Copyright (c) 1995 - CATIE. 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