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)对于改善艾滋病毒携带者(PLHIV)的健康至关重要，对于减少HIV 以及在资源有限的情况下保持当前ART方案的有效性 (RLS)。然而，艾滋病毒抗逆转录病毒耐药性(HIVDR)会阻碍全球控制艾滋病的努力 并实现艾滋病规划署90-90-90的目标。治疗前耐药(PDR)和治疗中- 获得性耐药(ADR)与病毒学衰竭(VF)和增加的发病率和 死亡率。PDR和ADR的相关性尚不完全清楚，HIVDR的水平和呼吸 缺乏在个体和群体中循环的突变(DRM)，特别是在RLS中。我们的大部分人 对HIVDR基因型-表型-结局相关性的理解源于 艾滋病毒主要流行毒株为艾滋病毒-1 M组B亚型的国家。 由于HIV-1感染的流行率是世界上最高的，PLHIV由非B亚型感染，如 A、C、D亚型和循环重组CRF01_AE和CRF02_AG。HIVDR及其相关因素 对这些HIV-1毒株的病毒抑制和结局的研究很少。现代艺术的成功 RLS中的方案，如TDF-3TC-EFV(TLE)和计划推出的基于多洛替格韦(DTG)的方案 HIVDR广泛传播的新证据可能会阻碍TLD。这项提议旨在扩大我们的 在低收入和中等收入国家了解艾滋病毒/艾滋病及其相关性和后果 1例为非B亚型。为了实现这些目标，我们提出了以下三个具体目标： 1.确定与TLE或TLD病毒学失败相关的PDR突变的数量和广度 感染HIV-1 A、C、D、CRF01_AE或CRF02_AG亚型的成人和儿童。 2.确定成人和儿童VF时的已知和新的DRM，包括DRM频率 按方案(TLE和TLD)和HIV-1亚型跨队列。 3.确定体外表型耐药试验与基因分型DRM的相关性 跨HIV-1非B亚型(A、C、D、CRF01_AE和CRF02_AG)。 为了达到这些目标，我们将使用最先进和创新的分析方法来量化DRM在 利用表型分析更好地了解DRM的相互作用。我们的 新的研究将确定(1)特定的PDR DRM和少数变异在HIV-1非B类病毒中的风险 VF的亚型；(2)决定VF相关表型抗性的DRM之间的相互作用；以及 (3)TLE和TLD方案选择的VF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情况下实现艾滋病毒-1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.