Portal de Periódicos da CAPES

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

2011; National Academy of Sciences; Volume: 108; Issue: 22 Linguagem: Inglês

10.1073/pnas.1105688108

1091-6490

Valerie F. Boltz, Yu Zheng, Shahin Lockman, Feiyu Hong, Elias K. Halvas, James McIntyre, Judith S. Currier, Margret C. Chibowa, Cecelia Kanyama, Apsara Nair, Willis D. Owino‐Ong'or, Michael D. Hughes, John M. Coffin, John W. Mellors,

HIV/AIDS Research and Interventions

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.