Human Immunodeficiency Virus-1 Sequence Changes and Drug Resistance Mutation Among Virologic Failures of Lopinavir/Ritonavir Monotherapy: AIDS Clinical Trials Group Protocol A5230.
Human Immunodeficiency Virus-1 Sequence Changes and Drug Resistance Mutation Among Virologic Failures of Lopinavir/Ritonavir Monotherapy: AIDS Clinical Trials Group Protocol A5230.
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洛匹那韦/利托那韦单一疗法病毒学失败中的人类免疫缺陷病毒-1 序列变化和耐药性突变：艾滋病临床试验组方案 A5230。
DOI：
10.1093/ofid/ofw154
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发表时间：
2016
影响因子：
4.2
通讯作者：
Wallis,CaroleL
中科院分区：
文献类型：
--
作者：
Vardhanabhuti,Saran;Katzenstein,David;Bartlett,John;Kumarasamy,Nagalingeswaran;Wallis,CaroleL
背景：洛匹那韦/利托那韦（LPV/r）单药治疗病毒学失败（VF）的机制尚不清楚。我们评估了人类免疫缺陷病毒-1逆转录酶（RT）和蛋白酶（PR）区域的序列变化。方法：在研究进入（SE）和VF时，从34名二线LPV/r单药治疗失败的参与者中获得人类免疫缺陷病毒-1 polsequences。序列变化采用系统发育分析和Hamming distance.Results.Human immunodeficiency virus-1序列变化在耐药突变（DRM）位点（中位数遗传距离，2.2%; Q1到Q3，2.1%-2.5%）从SE到VF高于非DRM位点（中位数遗传距离，1.3%; Q1到Q3，1.0%-1.4%;P<0.0001）。DRM位点的进化主要是由RT（中位数遗传距离，2.7%; Q1至Q3，2.2%-3.2%）与PR（中位数遗传距离，1.1%; Q1至Q3，0.0%-1.1%;P< .0001）的变化驱动的。SE时出现的大多数RT DRM在VF时丢失。VF时，分别有19例（56%）和26例（76%）患者对依法韦仑/奈韦拉平和依曲韦林（ETV）/利匹韦林（RPV）敏感，而SE时分别有1例（3%）和12例（35%）患者对ETV/RPV敏感。参与者谁保留非核苷类逆转录酶抑制剂（NNRTI）DRMs和那些没有演变的LPV/r DRMs有显着较短的时间VF。结论。LPV/r DRMs的参与者选择较长的时间VF表明更好的依从性和更多的选择性压力。NNRTI突变的消退和对ETV和RPV的基因型易感性的增加可能允许NNRTI的重复使用。进一步的研究是必要的，以了解PR失败的机制。
Background.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.Methods.Human immunodeficiency virus-1polsequences 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.Results.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%;P< .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%;P< .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.Conclusions.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.