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Between 1998 and 1999, three large randomized clinical trials were initiated to evaluate antiretroviral strategies in treatment-naive patients. Results from two of the trials — ACTG 384 (ACC Jan 1 2004) and INITIO (Lancet 2006; 368:287) — have already been reported, and now, investigators have published the results of the third trial, entitled FIRST (Flexible Initial Retrovirus Suppressive Therapies).
The study addressed two main questions: (1) Are triple-class initial regimens (NRTI + PI + NNRTI) better than standard triple-drug, dual-class regimens; and (2) Among such standard regimens, is it better to begin with two NRTIs plus a PI or two NRTIs plus an NNRTI? At 80 research sites in the U.S., 1397 patients were randomized to be treated with a PI-based strategy (PI + 2 NRTIs), an NNRTI-based strategy (NNRTI + 2 NRTIs), or a triple-class strategy (PI + NNRTI + 2 NRTIs). The specific agents used were selected by the patients’ primary physicians and were not provided by the study. Typical of practice patterns at the time, AZT/3TC and d4T + 3TC were the most commonly used NRTI combinations, and nelfinavir was the most commonly used PI (>60%). NNRTI use was split pretty evenly between efavirenz and nevirapine (approximately 55% and 45%, respectively). At baseline, the median CD4 count was 162 cells/mm3, and the median viral load was 144,000 copies/mL. The primary endpoint for the comparison of PI- versus NNRTI-based strategies was a composite of an AIDS-defining event, death, or CD4-count decline to <200 cells/mm³. The primary endpoint for the triple- versus dual-class comparison was the average change in CD4-cell count at or after 32 months. Median follow-up was 5 years.
No difference was observed in the primary endpoint between PI- and NNRTI-based strategies. However, as was seen in both ACTG 384 and INITIO, virologic failure was less common with NNRTI-based strategies than with PI-based strategies (hazard ratio, 0.66; 95% CI, 0.56–0.78). In addition, patients receiving NNRTIs — in either the dual-class or triple-class strategy — had a more rapid decline in viral load than those receiving two NRTIs plus a PI. Also similar to these other studies was that the use of three classes upfront provided no virologic, immunologic, or clinical benefit, regardless of baseline disease stage. Indeed, treatment-related discontinuations due to toxicity occurred more commonly with triple-class therapy (HR, 1.58 compared with dual-class therapy; P<0.0001). Immunologic responses, as measured by mean increase in CD4-cell counts during 6 years of follow-up, were similar in all three treatment arms. Development of resistance was most common in those randomized to the dual-class, NNRTI-based strategy.
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.
Abgrall S. Initial strategy for antiretroviral-naive patients. Lancet 2006 Dec 16; 368:2107-9.
Comment
This large randomized trial provides additional support favoring NNRTI-based regimens as initial therapy, at least based on the criterion of virologic efficacy. An unavoidable limitation of the study is the extensive use of nelfinavir, an agent that is no longer endorsed by either the U.S. Department of Health and Human Services or the International AIDS Society-USA guidelines as a preferred component of initial treatment. Nonetheless, this and other studies make it abundantly clear that using all three of the currently available major classes of antiretroviral agents upfront provides no additional benefit and only adds toxicity. An accompanying editorial summarizes and compares the results of FIRST, ACTG 384, and INITIO.