University of Pittsburgh, Pittsburgh, Pennsylvania, USA
University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Antimicrob Agents Chemother. 2020 Apr 21;64(5). doi: 10.1128/AAC.02101-19.
Etravirine (ETR) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) used in treatment-experienced individuals. Genotypic resistance test-interpretation systems can predict ETR resistance; however, genotype-based algorithms are derived primarily from HIV-1 subtype B and may not accurately predict resistance in non-B subtypes. The frequency of ETR resistance among recombinant subtype C HIV-1 and the accuracy of genotypic interpretation systems were investigated. HIV-1 containing full-length RT from HIV-1 subtype C-positive individuals experiencing virologic failure (>10,000 copies/ml and >1 NNRTI resistance-associated mutation) were phenotyped for ETR susceptibility. Fold change (FC) was calculated against a composite 50% effective concentration (EC) from treatment-naive individuals and three classifications were assigned: (i) <2.9-FC, susceptible; (ii) ≥2.9- to 10-FC, partially resistant; and (iii) >10-FC, fully resistant. The Stanford HIVdb-v8.4 was used for genotype predictions merging the susceptible/potential low-level and low-level/intermediate groups for 3 × 3 comparison. Fifty-four of a hundred samples had reduced ETR susceptibility (≥2.9-FC). The FC correlated with HIVdb-v8.4 (Spearman's rho = 0.62; < 0.0001); however, 44% of samples were partially (1 resistance classification difference) and 4% completely discordant (2 resistance classification differences). Of the 34 samples with an FC of >10, 26 were HIVdb-v8.4 classified as low-intermediate resistant. Mutations L100I, Y181C, or M230L were present in 27/34 (79%) of samples with an FC of >10 but only in 2/46 (4%) of samples with an FC of <2.9. No other mutations were associated with ETR resistance. Viruses containing the mutation K65R were associated with reduced ETR susceptibility, but 65R reversions did not increase ETR susceptibility. Therefore, genotypic interpretation systems were found to misclassify ETR susceptibility in HIV-1 subtype C samples. Modifications to genotypic algorithms are needed to improve the prediction of ETR resistance for the HIV-1 subtype C.
依曲韦林（ETR）是一种非核苷类逆转录酶抑制剂（NNRTI），用于治疗有经验的个体。基因型耐药测试解释系统可以预测 ETR 耐药性；然而，基于基因型的算法主要来自 HIV-1 亚型 B，可能无法准确预测非 B 亚型的耐药性。研究了重组亚型 C HIV-1 中 ETR 耐药的频率和基因型解释系统的准确性。对经历病毒学失败（>10,000 拷贝/ml 和 >1 种 NNRTI 耐药相关突变）的 HIV-1 阳性个体的全长 RT 中包含的 HIV-1 进行了 ETR 敏感性表型分析。针对来自治疗初治个体的复合 50%有效浓度（EC）计算了折叠变化（FC），并分配了三种分类：（i）<2.9-FC，敏感；（ii）>2.9 至 10-FC，部分耐药；和（iii）>10-FC，完全耐药。斯坦福 HIVdb-v8.4 用于基因型预测，将易感/潜在低水平和低水平/中水平组合并为 3×3 比较。在 100 个样本中有 54 个样本的 ETR 敏感性降低（>2.9-FC）。FC 与 HIVdb-v8.4 相关（Spearman 的 rho = 0.62；<0.0001）；然而，44%的样本部分（1 个耐药分类差异）和 4%完全不一致（2 个耐药分类差异）。在 34 个 FC 值>10 的样本中，26 个被 HIVdb-v8.4 分类为低中级耐药。在 27/34（79%）FC 值>10 的样本中存在 L100I、Y181C 或 M230L 突变，但在 46 个 FC 值<2.9 的样本中只有 2 个（4%）存在这些突变。没有其他突变与 ETR 耐药性相关。含有 K65R 突变的病毒与 ETR 敏感性降低有关，但 65R 回复突变不会增加 ETR 敏感性。因此，基因型解释系统被发现会错误分类 HIV-1 亚型 C 样本中的 ETR 敏感性。需要对基因型算法进行修改，以提高对 HIV-1 亚型 C 的 ETR 耐药性的预测。
