Nevirapine- versus lopinavir/ritonavir-based initial therapy for HIV-1 infection among women in Africa: a randomized trial

Abstract

Background: Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART.

Methods and findings: In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naïve HIV-infected women with CD4<200 cells/mm(3) were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for ≥48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF]) (plasma HIV RNA<1 log(10) below baseline 12 weeks after treatment initiation, or ≥400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm(3), HIV RNA = 5.2 log(10)copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow-up. 42 women (37 VFs, five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56-1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p<0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms (HR = 1.7, 95% CI 1.2-2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at time of VF.

Conclusions: Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatment discontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naïve women with CD4<200 cells/mm(3).

Trial registration: ClinicalTrials.gov NCT00089505.

Conflict of interest statement

M. Hughes reports receiving fees as a member of the data and safety monitoring boards for Boehringer Ingelheim, Medicines Development, Pfizer, Tibotec, and Virionyx and the receipt by his department of financial support from Schering-Plough and Merck for an annual educational workshop; J. McIntyre, receiving financial support from the Abbott Speakers Bureau; M. Hosseinipour, receiving financial support from Abbott Virology for educational presentations (M. Hosseinipour has given an educational lecture at the 2009 IAS conference and the 2010 INTEREST conference for Abbott virology on the topic of antiretroviral resistance in Malawi); L. Mohapi, receiving reimbursement for travel expenses from Pfizer Laboratories (L. Mohapi received travel, accommodation and registration assistance for the XVII AIDS Conference in Mexico City, August 2008, from Pfizer); J. Mellors, serving on the scientific advisory board for Gilead Sciences, receiving consulting fees from Merck, Idenix Pharmaceuticals, Chimerix, RFS Pharmaceuticals, Panacos Pharmaceuticals, and Abbott Laboratories, receiving grant support from Merck, having stock options in RFS Pharmaceuticals, and receiving reimbursement for travel expenses from Gilead Sciences, Merck, Chimerix, Idenix Pharmaceuticals, RFS Pharmaceuticals, and Panacos Pharmaceuticals; R. Schooley, receiving consulting fees from Glaxo-SmithKline and Abbott Laboratories and reimbursement for travel expenses from Abbott Laboratories (and serves on the scientific advisory board for Gilead Sciences); and J. Currier, receiving consulting fees from GlaxoSmithKline and grant support from Merck and Tibotec. All other authors have declared that no competing interests exist.

Figures

Figure 1. Consort diagram.

Per protocol, participants were not mandated to switch regimens in instances of VF (this decision was left to the discretion of study staff and participants). More women experienced VF in the LPV/r arm (43 or 17%) compared with the NVP arm (37 or 15%) in ITT analysis; however, a higher proportion of women experiencing VF in the NVP arm were switched to LPV/r compared with vice versa.

Figure 2. Kaplan-Meier plot of time to primary endpoint (VF or death) by randomized treatment arm.

Figure 3. Kaplan-Meier plot of time to early discontinuation of initial randomized treatment for any reason (toxicity, intolerance, VF, death), by randomized treatment arm.