Vardhanabhuti Saran, Katzenstein David, Bartlett John, Kumarasamy Nagalingeswaran, Wallis Carole L
Harvard T.H. Chan School of Public Health , Boston, Massachusetts.
Division of Infectious Diseases , Stanford University , California.
Open Forum Infect Dis. 2016 Aug 24;3(3):ofw154. doi: 10.1093/ofid/ofw154. eCollection 2016 Sep.
The mechanism of virologic failure (VF) of lopinavir/ritonavir (LPV/r) monotherapy is not well understood. We assessed sequence changes in human immunodeficiency virus-1 reverse-transcriptase (RT) and protease (PR) regions. Human immunodeficiency virus-1 sequences from 34 participants who failed second-line LPV/r monotherapy were obtained at study entry (SE) and VF. Sequence changes were evaluated using phylogenetic analysis and hamming distance. Human immunodeficiency virus-1 sequence change was higher over drug resistance mutation (DRM) sites (median genetic distance, 2.2%; Q1 to Q3, 2.1%-2.5%) from SE to VF compared with non-DRM sites (median genetic distance, 1.3%; Q1 to Q3, 1.0%-1.4%; < .0001). Evolution over DRM sites was mainly driven by changes in the RT (median genetic distance, 2.7%; Q1 to Q3, 2.2%-3.2%) compared with PR (median genetic distance, 1.1%; Q1 to Q3, 0.0%-1.1%; < .0001). Most RT DRMs present at SE were lost at VF. At VF, 19 (56%) and 26 (76%) were susceptible to efavirenz/nevirapine and etravirine (ETV)/rilpivirine (RPV), respectively, compared with 1 (3%) and 12 (35%) at SE. Participants who retained nonnucleoside reverse-transcriptase inhibitor (NNRTI) DRMs and those without evolution of LPV/r DRMs had significantly shorter time to VF. The selection of LPV/r DRMs in participants with longer time to VF suggests better adherence and more selective pressure. Fading NNRTI mutations and an increase in genotypic susceptibility to ETV and RPV could allow for the reuse of NNRTI. Further studies are warranted to understand mechanisms of PR failure.
洛匹那韦/利托那韦（LPV/r）单药治疗病毒学失败（VF）的机制尚未完全明确。我们评估了人类免疫缺陷病毒1型逆转录酶（RT）和蛋白酶（PR）区域的序列变化。
在研究入组（SE）和出现VF时，获取了34例二线LPV/r单药治疗失败参与者的人类免疫缺陷病毒1型序列。使用系统发育分析和汉明距离评估序列变化。
与非耐药突变（DRM）位点相比，从SE到VF，人类免疫缺陷病毒1型序列在DRM位点的变化更高（中位遗传距离，2.2%；第一四分位数到第三四分位数，2.1%-2.5%），而非DRM位点的中位遗传距离为1.3%（第一四分位数到第三四分位数，1.0%-1.4%；P<0.0001）。与PR（中位遗传距离，1.1%；第一四分位数到第三四分位数，0.0%-1.1%；P<0.0001）相比，DRM位点的进化主要由RT的变化驱动（中位遗传距离，2.7%；第一四分位数到第三四分位数，2.2%-3.2%）。在SE时存在的大多数RT DRM在VF时消失。在VF时，分别有19例（56%）和26例（76%）对依非韦伦/奈韦拉平和依曲韦林（ETV）/利匹韦林（RPV）敏感，而在SE时分别为1例（3%）和12例（35%）。保留非核苷类逆转录酶抑制剂（NNRTI）DRM的参与者和LPV/r DRM无进化的参与者到VF的时间显著更短。
在到VF时间较长的参与者中选择LPV/r DRM表明依从性更好且选择性压力更大。NNRTI突变的消退以及对ETV和RPV基因型易感性的增加可能允许重新使用NNRTI。有必要进一步研究以了解PR失败的机制。
