Impact of HIV-1 Resistance-Associated Mutations on Susceptibility to Doravirine: Analysis of Real-World Clinical Isolates.
Impact of HIV-1 Resistance-Associated Mutations on Susceptibility to Doravirine: Analysis of Real-World Clinical Isolates.
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DOI：
10.1128/aac.01216-21
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发表时间：
2021-11-17
影响因子：
4.9
通讯作者：
Grobler JA
中科院分区：
文献类型：
--
作者：
Asante-Appiah E;Lai J;Wan H;Yang D;Martin EA;Sklar P;Hazuda D;Petropoulos CJ;Walworth C;Grobler JA
人类免疫缺陷病毒1型（HIV - 1）感染的临床治疗可能会受到获得性或传播性耐药性的负面影响。在此，我们旨在加深对耐药相关突变（RAMs）对临床分离株对非核苷类逆转录酶抑制剂（NNRTI）多拉韦林敏感性影响的理解。从2018年8月至2019年8月收集了接受多拉韦林及其他已批准的NNRTI（依曲韦林、利匹韦林、依非韦伦和奈韦拉平）敏感性常规检测的HIV - 1感染者的临床分离株。使用抑制相对倍数变化的临界值（患者病毒的50%抑制浓度[IC50]与野生型参考毒株的IC50之比）来确定存在/不存在NNRTI和核苷（酸）类逆转录酶抑制剂（NRTI）突变时的敏感性。对多拉韦林研究了3 - 15倍变化的生物学临界值，对其他NNRTI使用预先确定的临界值。在4070份临床分离株中，42.9%具有≥1个NNRTI耐药相关突变。对多拉韦林敏感的分离株（92.5% - 96.7%）比对依曲韦林（91.5%）、利匹韦林（89.5%）、依非韦伦（81.5%）或奈韦拉平（77.5%）敏感的分离株更多。基于3倍临界值，在对另一种NNRTI耐药的分离株中，有44.7% - 65.8%对多拉韦林仍敏感，在对所有其他检测的NNRTI耐药的分离株中，有28.5%对多拉韦林仍敏感。包括胸苷类似物突变在内的NRTI耐药相关突变的存在，与一些分离株对多拉韦林的高敏感性有关，特别是在不存在NNRTI耐药相关突变的情况下。这些结果支持多拉韦林良好的耐药特性，鉴于获得性和传播性耐药带来的挑战，这一点尤为重要。
Clinical management of human immunodeficiency virus type-1 (HIV-1) infection may be negatively impacted by either acquired or transmitted drug resistance. Here, we aim to extend our understanding of the impact of resistance-associated mutations (RAMs) on the susceptibility of clinical isolates to the nonnucleoside reverse transcriptase inhibitor (NNRTI) doravirine. Clinical isolates from people living with HIV-1 undergoing routine testing for susceptibility to doravirine and other approved NNRTIs (etravirine, rilpivirine, efavirenz, and nevirapine) were collected from August 2018 to August 2019. Susceptibility in the presence/absence of NNRTI and nucleos(t)ide reverse transcriptase inhibitor (NRTI) mutations was determined using cutoffs for relative fold change in inhibition (ratio of the 50% inhibitory concentration [IC50] of patient virus compared with the IC50 of a wild-type reference strain). Biological cutoffs of 3- to 15-fold change were investigated for doravirine, with preestablished cutoffs used for the other NNRTIs. Of 4,070 clinical isolates, 42.9% had ≥1 NNRTI RAM. More isolates were susceptible to doravirine (92.5–96.7%) than to etravirine (91.5%), rilpivirine (89.5%), efavirenz (81.5%), or nevirapine (77.5%). Based on a 3-fold cutoff, doravirine susceptibility was retained in 44.7–65.8% of isolates resistant to another NNRTI and 28.5% of isolates resistant to all other tested NNRTIs. The presence of NRTI RAMs, including thymidine analog mutations, was associated with doravirine hypersusceptibility in some isolates, particularly in the absence of NNRTI RAMs. These results support the favorable resistance profile of doravirine and are of particular importance given the challenge posed by both acquired and transmitted resistance.