YOKOHAMA, Japan _ A new study presented at the 10th International Conference on AIDS has confirmed results of two clinical trials that acyclovir taken in combination with AZT can add up to a year's survival time for AIDS patients. And while researchers cannot explain the results, they said findings highlight the urgent need for more combination therapy trials. "This is the first time we've really had good news about survival with AIDS since AZT became available," said Neil Graham, associate professor of epidemiology at Johns Hopkins School of Public Health in Baltimore and author of a study published in the July 15 issue of Annals of Internal Medicine. The study analyzed the use of acyclovir, an anti-herpes virus drug first introduced in 1982, in 786 HIV-positive men enrolled in the Multicenter AIDS Cohort Study (MACS), a long-term study of HIV infection in homosexual and bisexual men. Researchers compared survival times and progression to AIDS in men who took only AZT with those who took acyclovir alone or in combination with AZT. What they found was that the combination of acyclovir and AZT did not reduce progression to AIDS, but did decrease the risk of death by 44 percent when acyclovir was taken after AIDS developed. "There appeared to be quite a jump in survival," Graham said. "The survival benefit we got was in the range of eight to 15 months on top of (the survival benefit of) AZT alone." Among men who started acyclovir one year after diagnosed with AIDS, 93 percent survived two years, compared with 86 percent who never took the drug. Among men who started acyclovir only after their CD4 cell counts fell below 50, 69 percent survived two years compared with 31 percent who never took the drug. Researchers found that survival time increased among most men who used acyclovir longer and without interruption. However, the dose of acyclovir did not appear to be a significant factor. The doses of the MACS group were 600 to 800 mg daily compared with 3,200 mg in earlier studies. The most accepted explanation is that herpes is a co-factor in HIV disease. Acyclovir therapy could suppress herpes simplex replication and therefore reduce HIV replication. Indeed, as reported in The Lancet this year, skin biopsies have detected an increased viral load of both HIV and herpes simplex in co-infected patients' tissue cells. "Two studies have shown that herpes can up-regulate HIV and we think this is the most likely explanation," Graham said. "If you can cut into the herpes level and also into the HIV level then you can have a double-pronged attack." With two clinical studies and one observational study showing the same effect, researchers say a comparative trial is warranted to study the interaction of acyclovir with anti-retroviral therapy. "This study is one example of the type of combination antiviral therapy that has a survival benefit. We need clinical trials of combinations extremely urgently," Graham said. One study that should provide additional information is ACTG 204, which is currently enrolling up to 1,200 patients and should have results by next year. Participants will be given different doses of acyclovir or valaciclovir (Valtrex), an experimental Burroughs Wellcome drug that is an ester of acyclovir. Participants also will be permitted to take antiretrovirals. The study will measure the drugs' impact on CMV disease and survival. Graham, however, said there is enough data to justify prescribing acyclovir to AIDS patients who have a history of herpes or herpes antibodies. "I would recommend they go on acyclovir at 600 to 800 milligrams daily plus AZT at about 300 to 500 mg a day," he said, adding that acyclovir is well tolerated and has no known pharmacologic interactions of increased toxicity when taken with AZT. The National Institute of Allergy and Infectious Diseases (NIAID), however, wants more data before making any guidelines. Lewis Schrager, medical officer in the division of AIDS for the NIAID in Bethesda, Md., is not convinced that the herpes connection is the whole answer. "Clearly it [the finding] is intriguing, but a lot of people would feel more comfortable to have a solid clinical trial that shows these results," he said. "I think we are going to have to take a hard look at these data and then see what comes out of ongoing trials. There are nooks and crannies that have not been explored and that would make a general recommendation to use it inappropriate at this time." n

-- Skip Connett

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