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Highly active antiretroviral therapy (HAART) is the standard treatment for infection with the human immunodeficiency virus (HIV). HAART regimens consist of protease inhibitors or nonnucleoside reverse transcriptase inhibitors combined with two or more nucleoside reverse transcriptase inhibitors (NRTIs). DPC 817, 2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (PSI 5582 D-D4FC) is a potent inhibitor of HIV type 1 replication in vitro. Importantly, DPC 817 retains activity against isolates harboring mutations in the reverse transcriptase gene that confer resistance to lamivudine (3TC) and zidovudine (AZT), which are frequent components of initial HAART regimens. DPC 817 combines this favorable resistance profile with rapid uptake and conversion to the active metabolite DPC 817-triphosphate, which has an intracellular half-life of 13 to 17 h. Pharmacokinetics in the rhesus monkey suggest low clearance of parent DPC 817 and a plasma half-life longer than that of either AZT or 3TC. Together, these properties suggest that DPC 817 may be useful as a component of HAART regimens in individuals with resistance to older NRTI agents.

A randomized, double-blind, placebo-controlled trial compared efavirenz (600 mg every 24 h) plus indinavir (1000 mg every 8 h) with placebo (every 24 h) plus indinavir (800 mg every 8 h) among 327 nucleoside analogue reverse-transcriptase inhibitor (NRTI)—experienced human immunodeficiency virus (HIV)—infected adults. Patients received ⩽2 concomitant NRTIs. Eligible patients had CD4 cell counts >50 cells/mm 3 , >10,000 plasma HIV-1 RNA copies/mL, and no prior protease inhibitor or non-NRTI therapy. Patients had a mean of 2.8 years of prior NRTI therapy. At 24 weeks, plasma HIV-1 RNA level was

Combination therapy approaches are becoming the mainstay of treatment for a variety of neoplastic and infectious diseases, including human immunodeficiency virus (HIV)-1 infections. The advantages of combination therapy include potentially additive-to-synergistic antiviral interactions, decreased emergence of or wider coverage against resistant viruses, and broadened effect both in terms of cell types and tissue reservoirs. However, combination drug interactions may range from synergy to antagonism. Both in vitro and in vivo studies have identified agents demonstrating additive-to-synergistic effects when used together and support the use of combination strategies in clinical practice. These will be reviewed in the context of their use in the setting of healthcare worker postexposure prophylaxis.

Human immunodeficiency virus type 1 (HIV-1) protease inhibitors are a promising class of antiretroviral agents that compromise enzymatic function through substrate mimicry. The in vitro susceptibility of a panel of HIV-1 clinical isolates demonstrating various drug resistance phenotypes to combinations of the HIV-1 protease inhibitors saquinavir and indinavir was determined. Antiviral effect was assessed by an HIV-1 p24 antigen reduction assay in phytohemagglutinin-stimulated peripheral blood mononuclear cells after harvesting of cell-free supernatant fluids at peak antigen production (days 4-7). Drug interactions were determined by median-dose-effect analysis, with the combination index (CI) calculated at several inhibitory concentrations (IC50, IC75, IC90, IC95, IC99). The interactive effects ranged from synergy at low efficacy doses to antagonism at higher doses against a pan-susceptible clinical isolate of HIV-1. Against a zidovudine-resistant isolate as well as a multidrug-resistant isolate, the combination of saquinavir and indinavir demonstrated antagonism at all doses.