Role of low-frequency HIV-1 variants in failure of nevirapine-containing antiviral therapy in women previously exposed to single-dose nevirapine.

TitleRole of low-frequency HIV-1 variants in failure of nevirapine-containing antiviral therapy in women previously exposed to single-dose nevirapine.
Publication TypeJournal Article
Year of Publication2011
AuthorsBoltz VF, Zheng Y, Lockman S, Hong F, Halvas EK, McIntyre J, Currier JS, Chibowa MC, Kanyama C, Nair A, Owino-Ong'or W, Hughes M, Coffin JM, Mellors JW
JournalProc Natl Acad Sci U S A
Volume108
Issue22
Pagination9202-7
Date Published2011 May 31
ISSN1091-6490
KeywordsAlleles, Anti-HIV Agents, Antiviral Agents, Drug Administration Schedule, Drug Resistance, Viral, Female, Genetic Variation, Genotype, HIV Infections, HIV-1, Humans, Mutation, Nevirapine, Polymerase Chain Reaction, Risk, Treatment Outcome
Abstract

In the OCTANE/A5208 study of initial antiretroviral therapy (ART) in women exposed to single-dose nevirapine (sdNVP) ≥ 6 mo earlier, the primary endpoint (virological failure or death) was significantly more frequent in the NVP-containing treatment arm than in the lopinavir/ritonavir-containing treatment arm. Detection of NVP resistance in plasma virus at study entry by standard population genotype was strongly associated with the primary endpoint in the NVP arm, but two-thirds of endpoints occurred in women without NVP resistance. We hypothesized that low-frequency NVP-resistant mutants, missed by population genotype, explained excess failure in the NVP treatment arm. Plasma samples from 232 participants were analyzed by allele-specific PCR at study entry to quantify NVP-resistant mutants down to 0.1% for 103N and 190A and to 0.3% for 181C. Of 201 women without NVP resistance by population genotype, 70 (35%) had NVP-resistant mutants detected by allele-specific PCR. Among these 70 women, primary endpoints occurred in 12 (32%) of 38 women in the NVP arm vs. 3 (9%) of 32 in the lopinavir/ritonavir-containing arm (hazard ratio = 3.84). The occurrence of a primary endpoint in the NVP arm was significantly associated with the presence of K103N or Y181C NVP-resistant mutations at frequencies >1%. The risk for a study endpoint associated with NVP-resistant mutant levels did not decrease with time. Therefore, among women with prior exposure to sdNVP, low-frequency NVP-resistant mutants were associated with increased risk for failure of NVP-containing ART. The implications for choosing initial ART for sdNVP-exposed women are discussed.

DOI10.1073/pnas.1105688108
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID21576473
PubMed Central IDPMC3107269
Grant List1 U01-AI068634 / AI / NIAID NIH HHS / United States
1 U01AI068636-01 / AI / NIAID NIH HHS / United States
1U01 AI069494-01 / AI / NIAID NIH HHS / United States
3U01AI32775-13S5 / AI / NIAID NIH HHS / United States
5 U01AI069518 / AI / NIAID NIH HHS / United States
5U01AI069455-03 / AI / NIAID NIH HHS / United States
5U01AI069456-03 / AI / NIAID NIH HHS / United States
AI-069501 / AI / NIAID NIH HHS / United States
AI69426 / AI / NIAID NIH HHS / United States
AI69453 / AI / NIAID NIH HHS / United States
IAAY1AI8374 / AI / NIAID NIH HHS / United States
K24 AI056933 / AI / NIAID NIH HHS / United States
U01AI068636 / AI / NIAID NIH HHS / United States
U01AI069436 / AI / NIAID NIH HHS / United States
U01AI69463-03 / AI / NIAID NIH HHS / United States