National Cancer Institute, Frederick, MD 21702, USA.
Proc Natl Acad Sci U S A. 2011 May 31;108(22):9202-7. doi: 10.1073/pnas.1105688108. Epub 2011 May 16.
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.
在一项研究中，最初的抗逆转录病毒治疗（ART）在女性中暴露于单剂量奈韦拉平（sdNVP）≥6 个月前，主要终点（病毒失败或死亡）在含 NVP 的治疗组中明显比含洛匹那韦/利托那韦的治疗组更频繁。在研究开始时通过标准人群基因型检测到的血浆病毒中的 NVP 耐药性与 NVP 组的主要终点密切相关，但三分之二的终点发生在没有 NVP 耐药性的女性中。我们假设，通过人群基因型漏检的低频 NVP 耐药突变体解释了 NVP 治疗组的过度失败。在研究开始时，通过等位基因特异性 PCR 对来自 232 名参与者的血浆样本进行分析，以量化 103N 和 190A 下的 NVP 耐药突变体低至 0.1%，181C 下低至 0.3%。在通过人群基因型无 NVP 耐药性的 201 名女性中，有 70 名（35%）通过等位基因特异性 PCR 检测到 NVP 耐药突变体。在这 70 名女性中，NVP 组的主要终点发生在 38 名女性中的 12 名（32%），而在含洛匹那韦/利托那韦的组中发生在 32 名女性中的 3 名（9%）（危险比=3.84）。NVP 组主要终点的发生与 NVP 耐药突变体频率>1%的 K103N 或 Y181C NVP 耐药突变体的存在显著相关。与 NVP 耐药突变体水平相关的研究终点风险并未随时间降低。因此，在先前暴露于 sdNVP 的女性中，低频 NVP 耐药突变体与 NVP 耐药 ART 失败的风险增加相关。讨论了选择 sdNVP 暴露女性初始 ART 的意义。
