The advent of the protease inhibitor era has brought with it substantial reductions in plasma HIV-1 RNA concentration, increase in CD4 cell count and clinical improvements over previously available therapies and has radically altered the goals of treatment. Despite these advances, approximately 10-50% of subjects may not achieve a complete virologic response (<200 copies/ml plasma HIV RNA) or may fail virologically after initially achieving a plasma HIV-1 RNA level below the limit of quantification of currently available assays. The proportion of subjects who experience drug failure is influenced by the potency of the regimen, the stage of disease, the prior antiretroviral exposure, the drug susceptibility profile, interpatient variability in pharmacokinetics, and adherence to the regimen. Given the importance of the protease inhibitor class of drugs for the long-term clinical outcome of HIV infected subjects and the threat that cross-resistance within this class may severely limit future options, it is imperative that alternative treatment regimens be developed for subjects who either do not achieve or lose virologic control while receiving the currently approved protease inhibitors. Given the recognized difficulty in achieving virologic suppression in individuals who have experienced virologic failure, this study has been designed with purposes of : a) providing maximally potent, albeit complex regimens utilizing combinations of currently approved protease inhibitors and experimental agents drawn from the protease inhibitor (amprenavir), nucleoside (abacavir), nucleotide (adefovir dipivoxil), and non-nucleoside (efavirenz) reverse transcriptase inhibitor classes of agents; b) investigating the salvage potential of amprenavir in dual protease inhibitor containing regimens; c) determining if the potential for salvage is greater if a moderately liberal definition of virologic failure is employed; and d) determining if a strict definition of virologic success in the setting of protease inhibitor failure is realistic with the therapeutic agents on the immediate horizon. A number of studies both within and outside the ACTG have been initiated or are in development to try to address the issue of alternative treatments for subjects who either do not achieve or lose virologic control while receiving protease inhibitors. This is a phase II, randomized, partially placebo-controlled, 4-arm trial comparing amprenavir (APV) in a single-PI regimen versus APV in combination with saquinavir soft-gel capsules (SZVsgc), indinavir (IDV) or nelfinavir (NFV) in HIV infected subjects currently failing indinavir (IDV), ritonavir (RTV), saquinavir (SZV) or nelfinavir (NFV) as part of a single or dual PI regimen, as evidenced by plasma HIV-1 RNA concentration of > 1000 copies/ml.
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