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

doi:10.1016/S0140-6736(04)15997-7

The Lancet

Volume 363, Issue 9417, 17 April 2004, Pages 1253-1263

https://doi.org/10.1016/S0140-6736(04)15997-7 Get rights and content

Summary

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 log₁₀ 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.

Introduction

Several randomised clinical trials in antiretroviral-therapy-naive patients have shown that a regimen based on a nonnucleoside reverse-transcriptase inhibitor (NNRTI) is at least as effective as a regimen that includes a protease inhibitor.1, 2, 3 During the past few years, the use of NNRTI-based antiretroviral therapy as the first regimen of choice has become increasingly popular. Among the reasons for this change are the lower pill burden of such a regimen and the perceived toxicity associated with protease-inhibitor-based regimens. Furthermore, NNRTI-based antiretroviral therapy does not necessitate any restrictions on food intake. These factors can contribute to better adherence to therapy by the patient, which is crucial for a sustained effect of treatment.4, 5, 6

The two most used NNRTI drugs are nevirapine and efavirenz. No large randomised comparison between these two drugs has yet been undertaken. Several large cohort-studies have suggested that efavirenz is more effective than nevirapine.7, 8, 9 However, interpretation of cohort studies might be hampered by the possible biases that are inherent in this design.

We report the results of the 2NN Study, a large randomised trial in patients with chronic HIV-1 infection who had not previously received antiretroviral therapy, comparing the efficacy and safety of treatment with two nucleoside-analogue reverse-transcriptase inhibitors (NRTI) and either nevirapine once daily, nevirapine twice daily, efavirenz, or the combination of nevirapine and efavirenz. The study addressed several questions. First, it compared the standard dose of nevirapine (twice daily) with efavirenz. Second, it compared the standard twice-daily regimen of nevirapine with a once-daily dose. The use of once-daily dosing helps to simplify treatment. Although once-daily dosing is used widely, no large formal comparison with nevirapine twice daily has been done. Third, the study assessed the relative merit of combining the two NNRTI drugs. This combination has never been investigated in a clinical setting, and in-vitro data on the combination are inconclusive.10, 11

Section snippets

Participants

Study participants were recruited during regular visits to HIV treatment centres in North and South America, Australia, Europe, South Africa, and Thailand. Eligible patients were antiretroviral-therapy naive, chronically infected with HIV-1, and aged at least 16 years, and had a plasma concentration of HIV-1 RNA of more than 5000 copies per mL. There was no inclusion criterion for the number of CD4-positive T lymphocytes or disease stage. Reasons for exclusion were: pregnancy or lactation;

Results

Of 1432 patients screened, 1216 underwent randomisation between February, 2000, and June, 2001. 5 months after the start of enrolment, a group to receive nevirapine twice daily was opened for treatment allocation as described above. 50 patients, who potentially knew their treatment allocation, never started their study drugs. In total, 1166 patients started follow-up, of whom 981 (81% of those randomised) reached week 48 (figure 1). The baseline characteristics of all randomised patients were

Discussion

For each randomisation period separately, and overall, we found a significant difference in the proportion of patients with treatment failure at week 48, which was driven by the higher risk of failure in the group assigned nevirapine plus efavirenz. Although, overall, treatment failure was numerically lower in the efavirenz group than in the nevirapine-only groups, our findings show no evidence that efavirenz is superior to nevirapine twice daily in terms of treatment failure. However, we could

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ArticlesComparison 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*

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Participants

Results

Discussion

Lancet

J Emerg Med

Hepatology

Clin Ther

Hepatology

Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults: Study 006 Team

N Engl J Med

A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients

AIDS

A randomized clinical trial comparing nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine Study)

Antivir Ther

The consistency of adherence to antiretroviral therapy predicts biologic outcomes for human immunodeficiency virus-infected persons in clinical trials

Clin Infect Dis

Impact of adherence and highly active antiretroviral therapy on survival in HIV-infected patients

J Acquir Immune Defic Syndr

Adherence to antiretroviral therapy and outcomes in HIV-infected patients enrolled in an induction/maintenance randomized trial

Antivir Ther

Virologic and immunologic response to regimens containing nevirapine or efavirenz in combination with 2 nucleoside analogues in the Italian Cohort Naive Antiretrovirals study

J Infect Dis

Comparison of nevirapine- and efavirenz-containing antiretroviral regimens in antiretroviral-naive patients: a cohort study

HIV Clin Trials

Virological suppression at 6 months is related to choice of initial regimen in antiretroviral-naive patients: a cohort study

AIDS

In vitro anti-HIV-1 synergy between non-nucleoside reverse transcriptase inhibitors nevirapine and efavirenz

Antivir Ther

Potency of nonnucleoside reverse transcriptase inhibitors (NNRTIs) used in combination with other human immunodeficiency virus NNRTIs, NRTIs, or protease inhibitors

Antimicrob Agents Chemother

The steady-state pharmacokinetics of efavirenz and nevirapine when used in combination in human immunodeficiency virus type 1-infected persons

J Infect Dis

Articles
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*