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One HAART regimen may be best for first-line HIV therapy
  NEW YORK (Reuters Health) - A regimen of zidovudine, lamivudine and efavirenz is more effective and less toxic than other three-drug highly active antiretroviral therapy (HAART) combinations that were assessed by members of the AIDS Clinical Trials Group 384 Team. This three-drug combination did not seem to be improved by the addition of nelfinavir.
Because the optimal sequencing of HAART regimens is unknown, Dr. Gregory K. Robbins at Harvard Medical School, Boston, and colleagues compared different combinations and sequences of antiretroviral drugs in treatment-naive, HIV-positive patients.
Study patients were enrolled between 1998 and 1999, the team reports in The New England Journal of Medicine for December 11th. According to the authors, their study differed from previous trials in that they followed patients for at least 2 years and included responses to subsequent regimens after the failure of a first. The researchers also collected data on the primary end point of inadequate viral suppression, toxic effects, or premature discontinuation of study medications.
In the first part of the study, four three-drug regimens were compared in groups of 155 patients each. At 82 sites in the US and Italy, subjects were randomly assigned to start treatment with two nucleoside reverse transcriptase inhibitors, zidovudine and lamivudine or stavudine and didanosine. Alternatives for the third drug were the non-nucleoside reverse transcriptase inhibitor efavirenz or the protease inhibitor nelfinavir.
The primary study end point was achieved by 56 patients who were initially treated with zidovudine, lamivudine and efavirenz. This figure was significantly lower than the 76 patients who started with didanosine, stavudine plus efavirenz, and the 74 who began with zidovudine and lamivudine plus nelfinavir.
According to the authors, patients in the zidovudine, lamivudine and efavirenz group fared significantly better than the others in time to failure of the first regimen and first virologic failure. Because of increased toxicity, they suggest that "the combination of didanosine and stavudine should probably no longer be considered for use as part of an initial antiretroviral regimen."
In a second Journal article, the same team reports comparisons between four-drug regimens that included both efavirenz and nelfinavir versus the three-drug regimens.
The duration of viral suppression was similar for two consecutive three-drug regimens and a single four-drug regimen. Here, too, the combination of zidovudine, lamivudine and efavirenz was considered optimal, partly because of its simplicity and because it "allowed most subjects who began therapy with this regimen to reserve protease-inhibitor therapy for the future."
They do note, however, that genotypic resistance to antiretroviral agents was often lower in the four-drug groups.
The AIDS Clinical Trials Group 384 team cautions that their findings cannot be generalized to regimens including other drugs from the same classes.
In an editorial, Dr. Paul R. Skolnik, from the Boston University School of Medicine, maintains that choice of initial therapy remains a "balancing act."
Thus, he suggests, "for individual patients, the exact balance of risks and benefits -- namely, the chance for long-term viral suppression, the risk of certain side effects, the possibility of induction of drug resistance, and the ability to adhere to particular regimen -- is best addressed by open discussion between care providers and their patients."
N Engl J Med 2003;349:2293-2315,2351-2352.
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