Drug Resistance Genotypic and Phenotypic Correlates of Efavirenz and Dolutegravir based Treatment Outcomes across Non-B HIV-1 subtypes

摘要 抗逆转录病毒疗法（ART）对于改善艾滋病毒感染者（PLHIV）的健康状况，减少艾滋病毒感染， 在资源有限的情况下， （RLS）。然而，艾滋病病毒抗逆转录病毒药物耐药性（HIVDR）可能会阻碍全球控制艾滋病的努力 实现艾滋病规划署的90 - 90 - 90目标。治疗前耐药性（PDR）和治疗中- 获得性耐药（ADR）与病毒学失败（VF）和发病率增加有关， mortality. PDR和ADR的相关性尚不完全清楚， 在个体和群体中，特别是在RLS中，缺乏DRM。我们的大部分 对HIVDR基因型-表型-结果相关性的理解来自于发达的 主要流行的HIV毒株为HIV-1 M组B亚型的国家。然而，在社区 艾滋病病毒感染者是世界上艾滋病病毒1型感染率最高的人，感染艾滋病病毒的是非B亚型， A、C、D亚型和循环重组形式CRF01_AE和CRF02_AG。艾滋病毒/艾滋病及其相关因素 对这些HIV-1毒株的病毒抑制和结果的研究很少。现代艺术的成功 RLS中的方案，如TDF-3TC-EFV（TLE）和计划推出的基于度鲁特韦（DTG）的方案 (TLD)可能会受到新出现的艾滋病毒/艾滋病广泛传播的证据的阻碍。这项建议旨在扩大我们的 了解艾滋病毒/艾滋病及其相关因素，以及艾滋病毒/艾滋病在低收入和中等收入国家的后果， 1例非B亚型循环。为实现这些目标，我们提出以下三个具体目标： 1.确定与TLE或TLE病毒学失败相关的PDR突变的数量和宽度， 感染HIV-1亚型A、C、D、CRF01_AE或CRF02_AG的成人和儿童。 2.确定成人和儿童VF时已知和新的DRM，包括DRM频率 按治疗方案（TLE和TLE）和HIV-1亚型进行队列分析。 3.确定体外表型耐药试验与基因型DRM之间的相关性 HIV-1非B亚型（A、C、D、CRF01_AE和CRF02_AG）。 为了实现这些目标，我们将使用最先进的和创新的测定来量化DRM的频率， 个体的ART前准种，并使用表型测定来更好地理解DRM相互作用。我们 新的研究将确定（1）特定PDR DRM和HIV-1非B亚型少数变异的风险 （2）DRM之间的相互作用，其决定与VF相关的表型抗性;以及 (3)在VF时通过TLE和TLE方案选择突变。这项提案的长期目标是提供数据 在一系列资源有限的环境中实现艾滋病毒1型护理的最佳做法。

Abstract Antiretroviral therapy (ART) is critical to improving the health of people living with HIV (PLHIV), to reducing HIV transmission and to maintaining the effectiveness of the current ART programs in resource-limited settings (RLS). However, HIV antiretroviral drug resistance (HIVDR) can hamper global efforts to control the AIDS epidemic and achieve the UNAIDS 90-90-90 targets. Pre-treatment drug resistance (PDR) and on treatment- acquired drug resistance (ADR) are associated with virologic failure (VF) and increased morbidity and mortality. The correlates of PDR and ADR are not fully understood, and the level and breath of HIVDR mutations (DRM) circulating in individuals and populations, especially in RLS is lacking. Much of our understanding of HIVDR genotype-phenotype-outcome correlations have been derived from developed countries where the predominant circulating HIV strain is HIV-1 Group M subtype B. However, in communities with the highest prevalence of HIV-1 infection across the world, PLHIV are infected by non-B subtypes, such as subtypes A, C, D and circulating recombinant forms CRF01_AE and CRF02_AG. HIVDR and the correlates of viral suppression and outcome for these HIV-1 strains has been poorly studied. The success of modern ART regimens in RLS such as TDF-3TC-EFV (TLE) and the planned roll-out of dolutegravir (DTG) based regimens (TLD) could be impeded by emerging evidence of widespread HIVDR. This proposal seeks to expand our understanding of HIVDR and its correlates and consequences in low-and-middle income countries where HIV- 1 non-B subtypes circulate. To accomplish these goals, we propose the following three Specific Aims: 1. Determine the number and breadth of PDR mutations that correlate with virologic failure to TLE or TLD in adults and children infected with HIV-1 subtype A, C, D, CRF01_AE or CRF02_AG. 2. Determine known and novel DRMs at the time of VF in adults and children, including DRM frequencies across cohorts by regimen (TLE and TLD) and by HIV-1 subtype. 3. Determine the correlations between in vitro phenotypic drug resistance testing against genotypic DRMs across HIV-1 non-B subtypes (A, C, D, CRF01_AE and CRF02_AG). To address these aims we will use state-of-the-art and innovative assays to quantify the frequency of DRM in individual’s pre-ART quasispecies and use phenotypic assays to better understand DRM interactions. Our novel studies will determine (1) the risks of specific PDR DRM and minority variants across HIV-1 non-B subtypes for VF; (2) interactions between DRM that determine phenotypic resistance associated with VF; and (3) mutations selected by TLE and TLD regimens at VF. The long-term goal of this proposal is to provide data to enable the best practices for HIV-1 care across a range of resource-limited settings.