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Two large randomized studies (ACTG 384 and INITIO) showed that initiating HIV therapy with three classes of HIV medications — two nucleoside reverse-transcriptase inhibitors (NRTIs), a nonnucleoside RTI (NNRTI), and a protease inhibitor (PI) — was no better than starting therapy with NRTIs and either an NNRTI or a PI.
The Flexible Initial Retrovirus Suppressive Therapies (FIRST) trial examined similar strategies. However, the drugs chosen within each class were not prespecified, as they were in the other two studies, and follow-up time was longer (median, 5 years). In this trial, investigators in the multisite Community Programs for Clinical Research on AIDS network randomized 1397 treatment-naive HIV-infected patients to initial treatment with a three-class strategy (PI+NNRTI+NRTI), a two-class NNRTI-based strategy (NNRTI+2 NRTIs), or a two-class PI-based strategy (PI+2 NRTIs). The most commonly prescribed PI was nelfinavir, although use of ritonavir-boosted PIs increased during the later years of the study. The most common NNRTI was efavirenz, and the most common NRTI combination was zidovudine plus lamivudine. Analyses were intention-to-treat.
The researchers found no evidence of improved immunologic or clinical outcomes with the three-class strategy compared with the two-class strategies. Immunologic and clinical outcomes were also similar between the PI- and NNRTI-based strategies, although the odds of achieving virologic suppression during follow-up were significantly higher in the NNRTI group than in the PI group. Discontinuation of one or more drugs due to adverse events was significantly more common with the three-class strategy than with either of the two-class strategies.
MacArthur RD et al. A comparison of three highly active antiretroviral treatment strategies consisting of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): A long-term randomised trial. Lancet 2006 Dec 16; 368:2125-35.
Comment
The FIRST trial provides further support for our current paradigm: initial HIV treatment with two NRTIs plus either a PI or an NNRTI. Three-class therapy with a PI, an NNRTI, and an NRTI adds toxicity without improving clinical or immunologic outcomes. Some of the drugs used in the FIRST trial are prescribed less frequently now; more-modern choices include ritonavir-boosted PIs, rather than nelfinavir, and newer combination NRTIs such as tenofovir/emtricitabine and abacavir/lamivudine. Clinical trials are now underway to compare efficacy and safety between ritonavir-boosted PIs and efavirenz-based therapy, as well as among the newer combination NRTIs.