HIV viral suppression among women in Malawi before and after switch from efavirenz to dolutegravir: contextualizing viral outcomes with robust resistance and objective adherence measures

摘要 在撒哈拉以南非洲，有近1 500万艾滋病毒感染者正在接受抗逆转录病毒治疗。 尽管在扩大治疗规模方面取得了成功，但在实现最佳抗逆转录病毒治疗结果方面仍然存在许多障碍， 包括病毒载量（VL）监测的机会有限，传播和获得药物的比率增加， 耐药性和导致治疗中止的药物毒性。为了应对这些挑战，世界 卫生组织最近修改了其推荐的一线抗逆转录病毒治疗方案，保留了核苷逆转录病毒， 转录酶（NRTI）骨架，但取代依法韦仑（EFV），非核苷逆转录酶抑制剂 （NNRTI），与更有效，更好的耐受性，更强大的遗传整合酶链转移抑制剂 （III）度鲁特韦（DTG）。为了应对这一变化，包括马拉维在内的撒哈拉以南非洲国家正在将所有 目前正在接受基于EFV的方案的患者改为基于DTG的方案。由于VL的可用性有限， 更稀缺的耐药性测试，这将是一个“盲目的开关”，没有关于病毒抑制的信息 (VL<1000拷贝/ml）或耐药性。这种策略可能会损害长期的公共卫生利益， DTG，在依从性差或意外DTG单药治疗的情况下有DTG失败或耐药的风险（即， 没有残留的NRTI骨架活性）。一项针对马拉维约1400名妇女、约1000名 将在EFV期间入组，为评估ARV结局提供了独特而及时的机会， 包括从EFV转换为DTG之前和之后的病毒抑制和耐药性。所以我们提出 使用从队列研究中收集的现有储存标本进行子研究，以评价这些结局。目的 1人将在从EFV转换为DTG之前和之后测量病毒抑制率，对储存的病毒进行VL检测。 DTG转换前即刻采集的血液标本和约6个月采集的标本 （+/-3个月）（n=1000）。目标2将描述抗逆转录病毒药物耐药的频率和模式 在转换时或开始DTG后6个月病毒失败的患者中（约10%，n=100），使用下一个 对储存的血液标本进行世代测序，采用新技术鉴定和定量大多数 NRTI和NRTI抗性的少数变体。最后，在EFV或DTG治疗病毒失败的女性中- 基于方案（~ 10%，n=100），Aim 3将使用头发中的拉米夫定药物浓度评估依从性， 两种方案的NRTI相同。这将是第一个在现实世界中对艾滋病毒结局进行的前瞻性研究。 通过新型深度测序和客观药物暴露（即，坚持） 数据通过将我们的子研究嵌入到几乎完全入组的队列研究中，我们将能够访问 可用的储存样本，快速进行分析，更迅速地评估公共卫生 盲目地从EFV切换到DTG的影响。我们的研究结果与马拉维的政策制定有关， 预计或正在进行DTG过渡的SSA其他国家，也将通知未来的VL 鉴于DTG的效力和耐药性屏障，监测和耐药性监测政策可能会发生变化。

ABSTRACT There are nearly 15 million persons living with HIV on antiretroviral (ARV) treatment in sub-Saharan Africa (SSA). Despite success in scale-up of therapy, many barriers remain to achieving optimal ARV treatment outcomes, including limited access to viral load (VL) monitoring, increasing rates of transmitted and acquired drug resistance, and drug toxicities resulting in treatment discontinuation. In response to these challenges, the World Health Organization recently revised its recommended first-line ARV regimen, retaining the nucleoside reverse- transcriptase (NRTI) backbone but replacing efavirenz (EFV), a non-nucleoside reverse-transcriptase inhibitor (NNRTI), with the more potent, better-tolerated, and more genetically robust integrase strand transfer inhibitor (INSTI) dolutegravir (DTG). Reacting to this change, countries across SSA, including Malawi, are switching all persons currently on an EFV-based regimen to a DTG-based regimen. With limited availability of VL and even more scarce resistance testing, this will be a “blind switch”, without information regarding viral suppression (VL<1000 copies/ml) or drug resistance. Such a strategy may compromise long-term public health benefits of DTG, risking DTG failure or resistance in the setting of poor adherence or inadvertent DTG monotherapy (i.e., no residual NRTI-backbone activity). An ongoing prospective cohort study of ~1400 women in Malawi, ~1000 of whom will be enrolled while on EFV, provides a unique and timely opportunity to evaluate the ARV outcomes, including viral suppression and resistance, before and after switching from EFV to DTG. Therefore, we propose a sub-study to evaluate these outcomes, using existing stored specimens collected from the cohort study. Aim 1 will measure rates of viral suppression before and after switch from EFV to DTG, conducting VL tests on stored blood specimens collected immediately prior to DTG switch and specimens collected approximately 6 months (+/-3 months) after switch to DTG (n=1000). Aim 2 will describe the frequency and patterns of ARV resistance among persons with viral failure at time of switch or 6 months after starting DTG (~10%, n=100) using next generation sequencing on stored blood specimens, with novel techniques to identify and quantify majority and minority variants for NRTI and INSTI resistance. Finally, among women with viral failure on either EFV or DTG- based regimens (~10%, n=100), Aim 3 will evaluate adherence using lamivudine drug concentrations in hair, the NRTI common to both regimens. This will be the first prospective study of HIV outcomes in a real-world EFV-to- DTG switch paradigm contextualized by novel deep sequencing and objective drug exposure (i.e., adherence) data. By embedding our sub-study into an almost completely enrolled cohort study, we will be able to access available stored specimens, quickly conduct analyses, and more expeditiously evaluate public health implications of blindly switching from EFV to DTG. Our results are relevant to policy development in Malawi and other countries across SSA where the DTG transition is anticipated or underway, and will also inform future VL monitoring and resistance surveillance policies that may change given DTG's potency and barrier to resistance.