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The effect of efavirenz versus nevirapine-containing regimens in the HIV-CAUSAL Collaboration: reply to Llibre and Podzamczer and additional results

Cain, Lauren E.a; Hernán, Miguel A.bon behalf of the HIV-CAUSAL Collaboration

Author Information
doi: 10.1097/01.aids.0000432446.15061.27

We recently reported a mortality hazard ratio of 1.59 [95% confidence interval (CI) 1.27–1.98] for nevirapine versus efavirenz non-nucleoside reverse transcriptase inhibitor (NRTI)-based first-line regimens [1]. Llibre and Podzamczer [2] refer to our findings as ‘unanticipated’. However, as we reported in our article, our findings were in line with those of a recent Cochrane Collaboration meta-analysis of randomized clinical trials [3], including the 2NN study [4] referenced by Llibre and Podzamczer [2], which found an increased risk of death comparing nevirapine 400 mg once daily with efavirenz 600 mg. After we excluded one trial that included patients who were also receiving a protease inhibitor [5], the mortality risk ratio was 1.97 (95% CI 0.95–4.07) for nevirapine (all doses) versus efavirenz.

Llibre and Podzamczer [2] question our decision to increase statistical efficiency by including patients with any baseline CD4 cell count in our main analysis and allowing 6 months to complete a regimen. Neither decision seems critical as our results did not change appreciably when we restricted to patients with baseline CD4 cell counts for which nevirapine is recommended and required patients to initiate all of the drugs in their regimen simultaneously. Details were provided in our article.

Llibre and Podzamczer [2] suggest that our description of analyses involving hepatitis C coinfection is incomplete. We agree so we are providing additional information here. Table 1 shows the definition and distribution of categories of chronic hepatitis C virus infection for our mortality analysis (the table shows the most recently available data in the HIV-CAUSAL Collaboration). Table 2 shows the updated effect estimates, with and without adjustment for hepatitis C coinfection (we collapsed the definite/probable and none/unknown categories), in the subset of the population with hepatitis C data. These estimates suggest that adjustment for hepatitis C coinfection in the full study population would not result in appreciable reductions in our reported effect estimates.

Table 1
Table 1:
Definition and distribution of categories of chronic hepatitis C infection, HIV-CAUSAL Collaboration.
Table 2
Table 2:
Clinical, immunologic and virologic outcomes for regimens based on efavirenz (24 286 individuals) versus nevirapine (13 824 individuals) in the subset of the population with hepatitis C data, HIV-CAUSAL Collaboration.

We did not have sufficient data to adjust for NRTI backbone in our analyses or to repeat our analyses in subsets defined by NRTI backbone. As we acknowledge in our article, the fact that we may not be able to completely adjust for this and other potential confounding factors is a limitation of our analysis. It is therefore reassuring that our estimates are in the same direction as – but more precise than – those from randomized clinical trials.


The research was supported by NIH grant R01 AI102634.

Conflicts of interest

There are no conflicts of interest.


1. The HIV-CAUSAL CollaborationThe effect of efavirenz versus nevirapine-containing regimens on immunologic, virologic and clinical outcomes in a prospective observational study. AIDS 2012; 26:1691–1705.
2. Llibre JM, Podzamczer D. Effect of efavirenz versus nevirapine in antiretroviral-naive individuals in the HIV-CAUSAL Collaboration Cohort. AIDS 2012; 26:2117–2118.
3. Mbuagbaw LCE, Irlam JH, Spaulding A, Rutherford GW, Siegfried N. Efavirenz or nevirapine in three-drug combination therapy with two nucleoside-reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral-naïve individuals. Cochrane Database Syst Rev 2010; CD004246.
4. van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, et al. 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. Lancet 2004; 363:1253–1263.
5. van den Berg-Wolf M, Hullsiek KH, Peng G, Kozal MJ, Novak RM, Chen L, et al. Virologic, immunologic, clinical, safety, and resistance outcomes from a long-term comparison of efavirenz-based versus nevirapine-based antiretroviral regimens as initial therapy in HIV-1-infected persons. HIV Clin Trials 2008; 9:324–336.
© 2013 Lippincott Williams & Wilkins, Inc.