YOKOHAMA, Japan _ A new study presented at the 10thInternational Conference on AIDS has confirmed results of two clinicaltrials that acyclovir taken in combination with AZT can add up to ayear's survival time for AIDS patients. And while researchers cannotexplain the results, they said findings highlight the urgent need formore combination therapy trials."This is the first time we've really had good news about survival withAIDS since AZT became available," said Neil Graham, associateprofessor of epidemiology at Johns Hopkins School of Public Health inBaltimore and author of a study published in the July 15 issue ofAnnals of Internal Medicine.The study analyzed the use of acyclovir, an anti-herpes virus drug firstintroduced in 1982, in 786 HIV-positive men enrolled in theMulticenter AIDS Cohort Study (MACS), a long-term study of HIVinfection in homosexual and bisexual men. Researchers comparedsurvival times and progression to AIDS in men who took only AZTwith those who took acyclovir alone or in combination with AZT.What they found was that the combination of acyclovir and AZT didnot reduce progression to AIDS, but did decrease the risk of death by44 percent when acyclovir was taken after AIDS developed."There appeared to be quite a jump in survival," Graham said. "Thesurvival 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 withAIDS, 93 percent survived two years, compared with 86 percent whonever took the drug. Among men who started acyclovir only after theirCD4 cell counts fell below 50, 69 percent survived two years comparedwith 31 percent who never took the drug.Researchers found that survival time increased among most men whoused acyclovir longer and without interruption. However, the dose ofacyclovir did not appear to be a significant factor. The doses of theMACS group were 600 to 800 mg daily compared with 3,200 mg inearlier studies.The most accepted explanation is that herpes is a co-factor in HIVdisease. Acyclovir therapy could suppress herpes simplex replicationand therefore reduce HIV replication. Indeed, as reported in TheLancet this year, skin biopsies have detected an increased viral load ofboth HIV and herpes simplex in co-infected patients' tissue cells."Two studies have shown that herpes can up-regulate HIV and wethink this is the most likely explanation," Graham said. "If you can cutinto the herpes level and also into the HIV level then you can have adouble-pronged attack."With two clinical studies and one observational study showing thesame effect, researchers say a comparative trial is warranted to studythe interaction of acyclovir with anti-retroviral therapy."This study is one example of the type of combination antiviral therapythat has a survival benefit. We need clinical trials of combinationsextremely urgently," Graham said.One study that should provide additional information is ACTG 204,which is currently enrolling up to 1,200 patients and should haveresults by next year. Participants will be given different doses ofacyclovir or valaciclovir (Valtrex), an experimental BurroughsWellcome drug that is an ester of acyclovir. Participants also will bepermitted to take antiretrovirals. The study will measure the drugs'impact on CMV disease and survival.Graham, however, said there is enough data to justify prescribingacyclovir to AIDS patients who have a history of herpes or herpesantibodies. "I would recommend they go on acyclovir at 600 to 800milligrams daily plus AZT at about 300 to 500 mg a day," he said,adding that acyclovir is well tolerated and has no knownpharmacologic 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. LewisSchrager, medical officer in the division of AIDS for the NIAID inBethesda, Md., is not convinced that the herpes connection is the wholeanswer."Clearly it [the finding] is intriguing, but a lot of people would feelmore 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 dataand then see what comes out of ongoing trials. There are nooks andcrannies that have not been explored and that would make a generalrecommendation to use it inappropriate at this time." n

-- Skip Connett

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