Potential role of doravirine for the treatment of HIV-1-infected persons with transmitted drug resistance.
Potential role of doravirine for the treatment of HIV-1-infected persons with transmitted drug resistance.
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DOI：
10.1186/s12981-023-00503-5
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发表时间：
2023-02-07
影响因子：
2.2
通讯作者：
Shafer, Robert W. W.
中科院分区：
文献类型：
--
作者：
Rhee, Soo-Yon;Schapiro, Jonathan M. M.;Saladini, Francesco;Zazzi, Maurizio;Khoo, Saye;Shafer, Robert W. W.
多拉韦林具有独特的耐药特征，但这种特征如何在病毒敏感人群的一线治疗之外增加其效用尚未得到充分研究。我们试图确定多拉韦林对来自未接受抗逆转录病毒治疗（ART）且存在传播性耐药（TDR）的人群的分离株仍具有活性的情况，并找出现有多拉韦林敏感性数据中的空白。
我们分析了已发表的多拉韦林体外敏感性数据，并将结果应用于2017年至2021年期间发表的来自未接受ART的人群的42,535个逆转录酶（RT）序列。非核苷类逆转录酶抑制剂（NNRTI）耐药突变（DRM）被定义为那些在斯坦福HIV耐药数据库中多拉韦林罚分单独存在或与其他突变组合存在的突变。
V106A、Y188L、F227C/L、M230L和Y318F与多拉韦林敏感性的最大降低相关。然而，一些缺乏这些典型耐药突变的NNRTI DRM和DRM组合的敏感性降低了>10倍，包括G190E、1个含G190S的分离株、3个含L100I + K103N的分离株、1个含K103N + P225H的分离株，以及含L100I + K103N + V108I和K101E + Y181C + G190A的分离株。在42,535个未接受ART的序列中，3,374个（7.9%）包含NNRTI DRM，其中2,788个（82.6%）包含1个DRM（n = 33种不同突变），426个（12.6%）包含2个DRM（79种不同的突变对），143个（4.2%）包含≥3个DRM（86种不同的突变模式）。在2,788个含1个DRM的序列中，112个（4.0%）与多拉韦林敏感性降低≥3.0倍相关，而2,625个（94.2%）与敏感性降低<3.0倍相关。51个序列（1.8%）中单个NNRTI DRM的数据不可用。在426个含2个NNRTI DRM的序列中，180个（42.3%）与多拉韦林敏感性降低≥3.0倍相关，而只有32个（7.5%）敏感性降低<3.0倍。214个（50.2%）含2个NNRTI DRM的序列数据不可用。
含多拉韦林和两种核苷类逆转录酶抑制剂（NRTI）的一线治疗有望对大多数TDR患者有效，因为超过80%的TDR序列有单个NNRTI DRM，并且超过90%的含单个DRM的患者预计对多拉韦林敏感。然而，对于有一个以上NNRTI DRM的患者使用多拉韦林时需要谨慎，即使这些DRM都不是典型的多拉韦林耐药突变。
网络版包含补充材料，可在10.1186/s12981 - 023 - 00503 - 5获取。
Doravirine has a unique resistance profile but how this profile might increase its usefulness beyond first-line therapy in persons with susceptible viruses has not been well studied. We sought to determine scenarios in which doravirine would retain activity against isolates from ART-naïve persons with transmitted drug resistance (TDR) and to identify gaps in available doravirine susceptibility data. We analyzed published in vitro doravirine susceptibility data and applied the results to 42,535 RT sequences from ART-naïve persons published between 2017 and 2021. NNRTI drug resistance mutations (DRMs) were defined as those with a Stanford HIV Drug Resistance Database doravirine penalty score either alone or in combination with other mutations. V106A, Y188L, F227C/L, M230L, and Y318F were associated with the greatest reductions in doravirine susceptibility. However, several NNRTI DRMs and DRM combinations lacking these canonical resistance mutations had > tenfold reduced susceptibility including G190E, one isolate with G190S, three isolates with L100I + K103N, one isolate with K103N + P225H, and isolates with L100I + K103N + V108I and K101E + Y181C + G190A. Of the 42,535 ART-naïve sequences, 3,374 (7.9%) contained a NNRTI DRM of which 2,788 (82.6%) contained 1 DRM (n = 33 distinct mutations), 426 (12.6%) contained 2 DRMs (79 distinct pairs of mutations), and 143 (4.2%) contained ≥ 3 DRMs (86 distinct mutation patterns). Among the 2,788 sequences with one DRM, 112 (4.0%) were associated with ≥ 3.0-fold reduced doravirine susceptibility while 2,625 (94.2%) were associated with < 3.0-fold reduced susceptibility. Data were not available for individual NNRTI DRMs in 51 sequences (1.8%). Among the 426 sequences with two NNRTI DRMs, 180 (42.3%) were associated with ≥ 3.0 fold reduced doravirine susceptibility while just 32 (7.5%) had < 3.0 fold reduced susceptibility. Data were not available for 214 (50.2%) sequences containing two NNRTI DRMs. First-line therapy containing doravirine plus two NRTIs is expected to be effective in treating most persons with TDR as more than 80% of TDR sequences had a single NNRTI DRM and as more than 90% with a single DRM were expected to be susceptible to doravirine. However, caution is required for the use of doravirine in persons with more than one NNRTI DRM even if none of the DRMs are canonical doravirine-resistance mutations. The online version contains supplementary material available at 10.1186/s12981-023-00503-5.
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影响因子：
4.9
作者：
Asante-Appiah E;Lai J;Wan H;Yang D;Martin EA;Sklar P;Hazuda D;Petropoulos CJ;Walworth C;Grobler JA
通讯作者：
Grobler JA
影响因子：
4.9
作者：
Lai, Ming-Tain;Feng, Meizhen;Miller, Michael D.
通讯作者：
Miller, Michael D.
影响因子：
4.9
作者：
Feng, Meizhen;Wang, Deping;Lai, Ming-Tain
通讯作者：
Lai, Ming-Tain
临床发育过程中参与者在参与者中确定的多韦林抵抗模式的综述。
DOI：
10.1097/qai.0000000000002496
发表时间：
2020-12-15
期刊：
Journal of acquired immune deficiency syndromes (1999)
影响因子：
--
作者：
Martin EA;Lai MT;Ngo W;Feng M;Graham D;Hazuda DJ;Kumar S;Hwang C;Sklar P;Asante-Appiah E
通讯作者：
Asante-Appiah E
DOI：
10.1097/qai.0000000000001031
发表时间：
2016-08-15
期刊：
Journal of acquired immune deficiency syndromes (1999)
影响因子：
--
作者：
Smith SJ;Pauly GT;Akram A;Melody K;Ambrose Z;Schneider JP;Hughes SH
通讯作者：
Hughes SH