Lockman S, Hughes M, Sawe F, Zheng Y, McIntyre J, Chipato T, et al. Nevirapine- Versus Lopinavir/Ritonavir-Based Initial Therapy for HIV-1 Infection among Women in Africa: A Randomized Trial. PLoS Med 9(6): e1001236. doi:10.1371/journal.pmed.1001236 (12 June 2012)
To compare the efficacy of nevirapine (NVP)-containing antiretroviral therapy (ART) regimens vs. lopinavir/ritonavir (LPV/r)-containing ART regimens in ART-naïve women receiving treatment for their own health.
Ten African sites (one each in Botswana, Malawi, Uganda, Zambia and Zimbabwe; two in Kenya, and three in South Africa).
Randomized controlled equivalency trial (RCT).
ART-naïve, HIV-1-infected adult women who were not pregnant or breastfeeding, without previous exposure to single-dose NVP (sdNVP), and with CD4 <200/µL. Previous short-course zidovudine (AZT) exposure was permitted.
Time to virologic failure (VF), death, discontinuation of the regimen for any reason, change in CD4 count, toxicity diagnosed during the initially-assigned regimen, drug resistance. Analysis was by intention to treat.
Women were randomized to one of the following: 1. Open-label LPV/r, 400 mg/100 mg, twice daily; plus co-formulated tenofovir (TDF)/emtricitabine (FTC), 300 mg/200 mg, once daily; or 2. NVP, 200 mg, twice daily; plus TDF/FTC, 300 mg/200 mg, once daily (after a 14-day lead-in with NVP, 200 mg, once daily). In the event of VF or toxicity, patients could switch from the NVP-based regimen to second-line treatment with the LPV/r-based regimen, or vice versa, at the discretion of the patients and study staff. Efavirenz (EFV) was temporarily substituted for NVP and LPV/r during rifampin-containing tuberculosis treatment.
Clinical visits occurred at 2, 4, 8, 12, 16, and 24 weeks after treatment initiation, and every 12 weeks thereafter. HIV-1 RNA and CD4 levels were assessed at baseline, and every 12 weeks thereafter. Lipids were evaluated at baseline, 24, and 48 weeks, and every 48 weeks thereafter.
Five hundred two women were randomized, 251 to LPV/r + TDF/FTC, and 251 to NVP + TDF/FTC. Two women on the NVP arm withdrew before beginning ART, and their data were omitted from all analyses. Median patient age in both arms was 34 years (26 to 45); median CD4 count at baseline was 121/µL (38/µL to 204/µL). Median HIV-1 RNA was 5.15 log10 copies/mL (4.21 log10 copies/mL to 5.86 log10 copies/mL). Four hundred sixty-nine women (94%) had supporting evidence for self-reported lack of previous sdNVP exposure. From a random subgroup of 126 samples at baseline (60 from the NVP arm, 66 from the LPV/r arm), NVP resistance was detected in only one (0.8%). No other major resistance mutations were noted at baseline. The median duration of follow-up on the initially assigned treatment was 109 weeks (95 weeks in the NVP arm, 119 weeks in the LPV/r arm). The overall median duration of follow-up in the study was 118 weeks.
According to pre-specified statistical criteria,1 the NVP and LPV/r regimens were equivalent in maintaining virologic suppression and preventing death (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.56 to 1.29, p=0.43). Thirty-seven women (15%) in the NVP arm experienced VF, vs. 43 (17%) in the LPV/r arm. Five women (2%) in the NVP arm died without previously experiencing VF vs. seven (3%) in the LPV/r arm. One additional woman in the LPV/r arm died subsequent to confirmed VF.
One of the five deaths (20%) on the NVP arm (due to acute renal failure) was deemed likely to have been treatment-related. Three of the eight deaths (37.5%) on the LPV/r arm (due to acute renal failure, hepatic encephalopathy and severe gastroenteritis) were considered to be possibly treatment-related. Similar numbers of women in the two arms experienced disease progression to a higher WHO stage.
A significantly larger proportion of women in the NVP arm than in the LPV/r arm discontinued their initial regimens, 70 (28%) vs. 23 (9%) respectively (HR 3.45, 95% CI 2.15 to 5.52, p<0.001). Reasons for discontinuing the NVP-containing regimen included death (n=5), adverse events (AEs) (n=35), VF (n=15), and other reasons (n=15). Investigators considered all 35 AEs to possibly be treatment-related. In the LPV/r arm, reasons for discontinuing the regimen included death (n=8), VF (n=4), and other reasons (n=11); no women discontinued the LPV/r regimen due to an AE.
The mean increase in CD4 levels trended higher in the LPV/r arm than it did in the NVP arm. At week 48, the mean change was 183/µL in each arm (p=0.99). At week 96, it was 245/µL in the NVP arm, vs. 279/µL in the LPV/r arm (p=0.045); at week 96, it was 303/µL in the NVP arm, vs. 345/µL in the LPV/r arm (p=0.15).
With regard to toxicity in their initial treatment regimens, similar proportions of women in the NVP arm (n=34, 14%) and the LPV/r arm (n+41, 16%) experienced Grade 3 or higher signs or symptoms or Grade 3 or higher laboratory abnormalities (NVP arm: n=64, 26%; LPV/r arm: n=54, 22%).
Nearly half of the women tested in the NVP arm developed drug resistance. In women experiencing VF, genotypes from the time of VF showed that 13 (45%) of 29 women in NVP arm and six (15%) of 40 women in the LPV/r arm had nucleoside reverse transcriptase inhibitor (NRTI)- or non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated resistance mutations. All 13 (45%) women in the NVP arm vs. three (8%) women in the LPV/r arm had ≥1 NNRTI-associated mutation at VF.
Twenty-nine (6%) women were lost to follow-up; of these, 20 (4%) were lost to follow-up without first experiencing VF. Two patients from the NVP arm and seven from the LPV/r arm were lost to follow-up after experiencing VF.
The authors conclude that in ART-naïve women with CD4 count <200 cells/µL, initial ART with either LPV/r + TDF/FTC or NVP + TDF/FTC is equivalent in achieving and maintaining virologic suppression and preventing mortality, but that treatment cessation due to toxicity concerns, and drug resistance at the time of VF, are higher with NVP-containing ART. Higher rates of discontinuation and new drug resistance, however, occurred in the NVP arm than in the LPV/r arm.
Although not all women could provide supporting evidence of no previous sdNVP exposure, the overall risk of bias in this trial is low. Randomization was computer-generated using balanced block randomization. Randomized assignment was provided electronically from a remote, central data management center in the United States to each clinical site. Access to the block size and the sequence of treatment assignments was restricted to the data center staff who set up the randomization. The trial was not blinded. The primary analysis was by intention-to-treat, and missing outcome data are addressed appropriately. The trial compares favorably to its protocol.(1)
This is "Trial 2" of the two concurrent Optimal Combination Therapy After Nevirapine Exposure (OCTANE) open-label ART trials. "Trial 1" was conducted in women with previous exposure to sdNVP.(2) In that trial, the LPV/r-containing regimen was significantly more efficacious than the NVP-containing regimen. (2) LPV/r-containing ART regimens are more expensive than NVP-containing ART and in resource-limited settings are generally used in second-line regimens. It could be cost-effective in women with previous sdNVP exposure to use LPV/r-containing regimens in initial therapy,3 but the results of this trial, equivalent in its primary endpoints and mixed in its secondary endpoints, do not contribute to that discussion.
NVP is an NNRTI. NVP + TDF/FTC is one of the most commonly-used ART regimens. LPV/r is a "boosted" protease inhibitor (bPI). The World Health Organization (WHO)'s 2010 guidelines on ART for adults and adolescents recommend the use in initial therapy of an NNRTI and two NRTIs, one of which should be AZT or TDF. The preferred initial regimen for pregnant women without previous sdNVP exposure is AZT + 3TC + NVP.4 For patients who are unable to tolerate this regimen or for whom it is contraindicated, an alternative triple NRTI regimen (either AZT + 3TC + ABC or AZT + 3TC + TDF) should be used. New WHO guidelines on ART will be released in 2013.
In keeping with current WHO guidelines, pregnant women without previous sdNVP exposure should initially be given AZT + 3TC + NVP, unless this is otherwise contraindicated.
- Protocol: A5208/OCTANE: Optimal Combination Therapy After Nevirapine Exposure.(linked near bottom of the page)[Accessed July 1, 2012]
- Lockman S, Hughes MD, McIntyre J, Zheng Y, Chipato T, et al. (2010) Antiretroviral therapies in women after single-dose nevirapine exposure. N Engl J Med 363: 1499-1509.
- Ciaranello AL, Lockman S, Freedberg KA, Hughes M, Chu J, et al. (2011) First-line antiretroviral therapy after single-dose nevirapine exposure in South Africa: a cost-effectiveness analysis of the OCTANE trial. AIDS 25: 479-492.
- WHO (2010) Antiretroviral therapy for HIV infection in adults and adolescents: Recommendations for a public health approach. 2010 Revision. Geneva: World Health Organization. [Accessed July 1, 2012]