Feng Meizhen, Sachs Nancy A, Xu Min, Grobler Jay, Blair Wade, Hazuda Daria J, Miller Michael D, Lai Ming-Tain
Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania, USA.
Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
Antimicrob Agents Chemother. 2016 Mar 25;60(4):2241-7. doi: 10.1128/AAC.02650-15. Print 2016 Apr.
Doravirine (DOR), which is currently in a phase 3 clinical trial, is a novel human immunodeficiency type 1 virus (HIV-1) nonnucleoside reverse transcriptase inhibitor (NNRTI). DOR exhibits potent antiviral activity against wild-type virus and K103N, Y181C, and K103N/Y181C mutant viruses, with 50% inhibitory concentrations (IC50s) of 12, 21, 31, and 33 nM, respectively, when measured in 100% normal human serum (NHS). To assess the potential for DOR to suppress NNRTI-associated and rilpivirine (RPV)-specific mutants at concentrations achieved in the clinic setting, inhibitory quotients (IQs) were calculated by determining the ratio of the clinical trough concentration over the antiviral IC50for each virus with DOR and RPV and efavirenz (EFV). DOR displayed IQs of 39, 27, and 25 against the K103N, Y181C, and K103N/Y181C mutants, respectively. In contrast, RPV exhibited IQs of 4.6, 1.4, and 0.8, and EFV showed IQs of 2.5, 60, and 1.9 against these viruses, respectively. DOR also displayed higher IQs than those of RPV and EFV against other prevalent NNRTI-associated mutants, with the exception of Y188L. Both DOR and EFV exhibited higher IQs than RPV when analyzed with RPV-associated mutants. Resistance selections were conducted with K103N, Y181C, G190A, and K103N/Y181C mutants at clinically relevant concentrations of DOR, RPV, and EFV. No viral breakthrough was observed with DOR, whereas breakthrough viruses were readily detected with RPV and EFV against Y181C and K103N viruses, respectively. These data suggest that DOR should impose a higher barrier to the development of resistance than RPV and EFV at the concentrations achieved in the clinic setting.
多拉韦林（DOR）目前正处于3期临床试验阶段，是一种新型的1型人类免疫缺陷病毒（HIV-1）非核苷类逆转录酶抑制剂（NNRTI）。在100%正常人血清（NHS）中检测时，多拉韦林对野生型病毒以及K103N、Y181C和K103N/Y181C突变病毒均表现出强大的抗病毒活性，其50%抑制浓度（IC50）分别为12、21、31和33 nM。为了评估多拉韦林在临床环境中达到的浓度下抑制NNRTI相关和利匹韦林（RPV）特异性突变体的潜力，通过确定每种病毒的临床谷浓度与多拉韦林、RPV和依非韦伦（EFV）的抗病毒IC50的比值来计算抑制商（IQ）。多拉韦林对K103N、Y181C和K103N/Y181C突变体的IQ分别为39、27和25。相比之下，RPV对这些病毒的IQ分别为4.6、1.4和0.8，EFV对这些病毒的IQ分别为2.5、60和1.9。除Y188L外，多拉韦林对其他常见的NNRTI相关突变体的IQ也高于RPV和EFV。在用RPV相关突变体分析时，多拉韦林和EFV的IQ均高于RPV。在多拉韦林、RPV和EFV的临床相关浓度下，对K103N、Y181C、G190A和K103N/Y181C突变体进行了耐药性选择。使用多拉韦林未观察到病毒突破，而使用RPV和EFV分别很容易检测到针对Y181C和K103N病毒的突破病毒。这些数据表明，在临床环境中达到的浓度下，多拉韦林对耐药性发展的阻碍应高于RPV和EFV。
