HIV Pathogenesis Research Unit, University of the Witwatersrand, Johannesburg 2193, South Africa.
Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Science, University of the Witwatersrand, Johannesburg 2193, South Africa.
Viruses. 2024 Sep 20;16(9):1493. doi: 10.3390/v16091493.
Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with efficacy against some NNRTI-resistant mutants. Although DOR resistance mutations are established for HIV-1 subtype B, it is less clear for non-B subtypes. This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y188L caused high-level resistance, in agreement with the predictions. These mutations are frequently observed in patients failing efavirenz- or nevirapine-based first-line regimens. However, they are also observed in those failing a protease inhibitor-based second-line regimen, as we have observed in our database. Genotypic drug resistance testing is therefore vital prior to the initiation of DOR-based treatment for those previously exposed to efavirenz or nevirapine.
多伟拉韦（DOR）是一种非核苷类逆转录酶抑制剂（NNRTI），对一些 NNRTI 耐药突变体有效。尽管已经确定了 HIV-1 亚型 B 中 DOR 的耐药突变，但对于非 B 亚型的情况还不太清楚。本研究调查了 HIV-1 亚型 C 中 DOR 敏感性相关的常见 NNRTI 耐药突变。从南非的基因型耐药检测数据库中确定了常见的耐药突变。将突变，单独或组合，引入复制缺陷型假病毒中，并在体外评估 DOR 敏感性。单一的 V106M 和 Y188L 突变导致高水平耐药，而其他突变则对 DOR 敏感性没有显著影响。我们观察到我们的体外实验结果与斯坦福 HIVdb 预测的敏感性之间存在一致性。然而，F227L 突变被预测会导致高水平的 DOR 耐药性，但在体外却是敏感的。包含 K103N、V106M 或 Y188L 的突变组合导致高水平耐药，这与预测结果一致。这些突变在那些曾经接受过依非韦伦或奈韦拉平为基础的一线治疗方案失败的患者中经常观察到。然而，我们在数据库中也观察到它们在那些接受蛋白酶抑制剂为基础的二线治疗方案失败的患者中存在。因此，在开始基于 DOR 的治疗之前，对于那些之前曾暴露于依非韦伦或奈韦拉平的患者，进行基因型耐药性检测是至关重要的。
