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AZT/ddI SIMULTANEOUS THERAPY PRODUCES DURABLE INCREASE IN CD4 CELL COUNT

Executive Summary

AZT/ddI SIMULTANEOUS THERAPY PRODUCES DURABLE INCREASE IN CD4 CELL COUNT in HIV-symptomatic and AIDS patients, while an alternating dosing regimen results in a decrease in CD4 cell counts, Robert Yarchoan, et al., National Cancer Institute, reported July 20 at the VIII International Conference on AIDS. The study, which enrolled 41 patients, was designed to evaluate the activity and toxicity of AZT (Burroughs Wellcome's Retrovir) and ddI (Bristol-Myers Squibb's Videx) combination retroviral therapy in both alternating and simultaneous dosing regimens. At 54 weeks, "patients on the simultaneous arm still had a mean increase of 75 CD4 cells" per mm, Yarchoan stated. In contrast, patients in the alternating arm had "a mean decrease of 12 CD4 cells." The alternating arm dosing regimen was 600 mg AZT daily for three weeks, alternating with 500 mg ddI for three weeks; the simultaneous arm featured a combined daily dose of 300 mg AZT and 250 mg ddI. Patients in the simultaneous arm also had somewhat more pronounced increases in weight, and decreases in p24 antigen. There was one death due to pancreatitis; toxicities did not otherwise vary significantly between the two groups. Further research is planned to study the development of drug resistance. At a July 19 forum on "HIV Treatment Strategies for the 1990s" sponsored by the Wellcome Foundation, R.T. Schooley, University of Colorado Health Sciences Center, discussed interim data from an ongoing three-arm trial comparing AZT alone versus AZT and ddI versus AZT and ddC (Hoffman-La Roche's Hivid). While the primary endpoint is to see if combination therapy "up front" prevents the emergence of resistant virus, a secondary goal is to look at the effect on CD4 cell counts, Schooley said. Data to date show that "people who are on combination therapy with ddC compared to AZT alone had a rise of about 100 CD4 cells," he stated. "People on AZT alone had a rise of about 50 CD4 cells and were back down to baseline in about six months. People on combination therapy were still above the baseline at this period of time." No data are yet available for the ddI arm. Schooley predicted that "it may well be that...as the field moves along, and there are more alternatives, we will approach this very much as we do antihypertensives and choose regimens based to some extent on complications for individual patients and avoid drugs that have toxicities that one would want to avoid in a given patient." He added that a large AIDS Clinical Trials Group protocol, ACTG 175, will look at AZT alone and should provide substantially more data on the comparative effects of combination therapy and monotherapy. That trial, which aims to enroll 2,400 subjects, is about 75% accrued. At a poster session of the conference, researchers from the University of California at San Francisco presented results of a study of ddI monotherapy in 160 HIV-infected people. They found that patients who began the study with more than 100 CD4 cells per microliter of blood were more likely to respond to ddI and have a longer duration of response than patients with fewer than 100 CD4 cells at the beginning of the study. Patients were followed for an average of 18 months. The subjects who had an increase in CD4 cells while on ddI therapy lived longer and spent more time free of opportunistic infections than those on ddI who did not have increases in CD4 cells, the researchers reported. "We don't know know yet whether the increase in CD4 count translates directly into improved survival and a longer time free of opportunistic infections, or if the ability to have an increase in CD4 cells in response to the drug indicates a less damaged immune system," UCSF researcher Edwin Charlebois stated in a release. In another combination trial presented at the International AIDS Conference by Mike Youle of the Kobler Centre in London, patients received high-dose acyclovir (800 mg every six hours) for the prevention of cytomegalovirus disease in late-stage HIV. While the trial was terminated last November because interim analysis showed no reduction in the risk of developing CMV disease, subsequent analysis shows a significant survival benefit in the acyclovir treatment group. "High-dose acyclovir significantly reduced the probability of dying by one year," Youle reported. The benefit was most pronounced among patients with CD4 counts under 50. Burroughs Wellcome markets acyclovir as Zovirax. At the Wellcome forum, Schooley hypothesized that "it's quite clear in vitro, at least, that if you turn a T cell on that is latently carrying HIV, one is likely also to turn on HIV. One could hypothesize that preventing new T cell activation required to deal with herpes virus infection could lead to decreases in HIV replication."

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