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Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study.

van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, Cahn P, Lalloo UG, van der Westhuizen IP, Malan DR, Johnson MA, Santos BR, Mulcahy F, Wood R, Levi GC, Reboredo G, Squires K, Cassetti I, Petit D, Raffi F, Katlama C, Murphy RL, Horban A, Dam JP, Hassink E, van Leeuwen R, Robinson P, Wit FW, Lange JM; 2NN Study team. Lancet 2004 Apr 17;363(9417):1253-1263.

Abstract

Background The 2NN Study was a randomised comparison of the non-nucleoside reverse-transcriptase inhibitors (NNRTI) nevirapine and efavirenz. Methods In this multicentre, open-label, randomised trial, 1216 antiretroviral-therapy-naive patients were assigned nevirapine 400 mg once daily, nevirapine 200 mg twice daily, efavirenz 600 mg once daily, or nevirapine (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine, for 48 weeks. The primary endpoint was the proportion of patients with treatment failure (less than 1 log(10) decline in plasma HIV-1 RNA in the first 12 weeks or two consecutive measurements of more than 50 copies per mL from week 24 onwards, disease progression [new Centers for Disease Control and Prevention grade C event or death], or change of allocated treatment). Analyses were by intention to treat. Findings Treatment failure occurred in 96 (43.6%) of 220 patients assigned nevirapine once daily, 169 (43.7%) of 387 assigned nevirapine twice daily, 151 (37.8%) of 400 assigned efavirenz, and 111 (53.1%) of 209 assigned nevirapine plus efavirenz. The difference between nevirapine twice daily and efavirenz was 5.9% (95% CI -0.9 to 12.8). There were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per mL at week 48 (p=0.193) or the increases in CD4-positive cells (p=0.800). Nevirapine plus efavirenz was associated with the highest frequency of clinical adverse events, and nevirapine once daily with significantly more hepatobiliary laboratory toxicities than efavirenz. Of 25 observed deaths, two were attributed to nevirapine. Interpretation Antiretroviral therapy with nevirapine or efavirenz showed similar efficacy, so triple-drug regimens with either NNRTI are valid for first-line treatment. There are, however, differences in safety profiles. Combination of nevirapine and efavirenz did not improve efficacy but caused more adverse events.

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Reviewed by Susa Coffey, MD

Comment

This large open-label randomized clinical trial compared the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine in initial therapy of HIV-infected individuals. It evaluated the efficacy and safety of 4 treatment arms: efavirenz, nevirapine dosed 2 times per day, nevirapine dosed 1 time per day, and efavirenz + nevirapine, each in combination with lamivudine and stavudine.

The 2NN study was first presented at the 10th Conference on Retroviruses and Opportunistic Infections in 2003 (for description and analysis of the study, see http://www.aidsetc.com/aidsetc?page=croi-10-02 ). Statistical analysis was based on 4 pairwise comparisons between treatment groups. By intention-to-treat analysis, there were no statistically significant differences at 48 weeks in rates of treatment failure (a composite endpoint) among the single-NNRTI efavirenz and nevirapine groups . Other important points include the following:

	The efavirenz and the twice-daily nevirapine groups had statistically similar rates of virologic failure (virologic failure was defined as no HIV RNA measurements <50 copies/mL or sustained increase to >50 copies/mL after viral suppression).

	The once-daily nevirapine group had a lower rate of virologic failure than the twice-daily nevirapine group (11.4% vs 18.9%, p = .016); however, by the broader criterion of treatment failure, the 2 nevirapine groups were equivalent.

	In all treatment groups, patients with high baseline viral loads (HIV RNA level >100,000 copies/mL) experienced higher rates of virologic failure than patients with lower baseline viral loads. In the single NNRTI groups, nevirapine appeared to be less effective than efavirenz at higher viral loads (the differences were not statistically significant).

	Increases in CD4 lymphocyte counts were similar in all treatment groups.

	The nevirapine groups showed higher rates of hepatotoxicity, especially in the once-daily dosing arm.

	The combination of nevirapine + efavirenz was associated with a higher rate of adverse events and showed no greater efficacy than therapy with a single NNRTI.

The 2NN study offers the first large randomized comparison of efavirenz and nevirapine. Its findings provide considerable evidence that nevirapine is not inferior to efavirenz in the initial treatment of HIV infection and that the choice between these 2 NNRTIs may be based on individual patient characteristics.

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