title: Role of low-frequency HIV-1 variants in failure of nevirapine-containing antiviral therapy in women previously exposed to single-dose nevirapine.
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.
authors.affiliation: National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Valerie F
authors.initials: VF
authors.lastname: Boltz
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.forename: Shahin
authors.initials: S
authors.lastname: Lockman
authors.forename: Feiyu
authors.initials: F
authors.lastname: Hong
authors.forename: Elias K
authors.initials: EK
authors.lastname: Halvas
authors.forename: James
authors.initials: J
authors.lastname: McIntyre
authors.forename: Judith S
authors.initials: JS
authors.lastname: Currier
authors.forename: Margret C
authors.initials: MC
authors.lastname: Chibowa
authors.forename: Cecelia
authors.initials: C
authors.lastname: Kanyama
authors.forename: Apsara
authors.initials: A
authors.lastname: Nair
authors.forename: Willis
authors.initials: W
authors.lastname: Owino-Ong'or
authors.forename: Michael
authors.initials: M
authors.lastname: Hughes
authors.forename: John M
authors.initials: JM
authors.lastname: Coffin
authors.forename: John W
authors.initials: JW
authors.lastname: Mellors
mesh_terms: D000483:Alleles; D019380:Anti-HIV Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000401:mortality; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D009154:Mutation; D019829:Nevirapine / Q000008:administration & dosage*; D016133:Polymerase Chain Reaction / Q000379:methods; D012306:Risk; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D019829:Nevirapine