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1500万艾滋病毒携带者正在接受抗逆转录病毒治疗。 尽管在扩大治疗方面取得了成功，但实现最佳抗逆转录病毒治疗结果仍然存在许多障碍， 包括有限地获得病毒载量(VL)监测，增加传播和获得药物的比率 耐药性，以及导致治疗中断的药物毒性。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ARV方案，保留了核苷逆转- 转录酶(NRTI)骨架，取代非核苷类逆转录酶抑制剂EFV(EFV) (NNRTI)，具有更有效、更好的耐受性和更强大的基因整合酶链转移抑制剂 (Insti)多洛替格韦(DTG)。为了应对这一变化，整个SSA的国家，包括马拉维，正在改变所有 目前正在接受以EFV为基础的方案的人改为以DTG为基础的方案。VL的可用性有限，甚至 更稀缺的耐药性测试，这将是一个“盲目开关”，没有关于病毒抑制的信息 (VL&lt；1000拷贝/毫升)或耐药。这样的战略可能会损害长期的公共卫生利益 在粘附性差或无意的DTG单一治疗的情况下，冒着DTG失败或抵抗的风险(即， 没有剩余的NRTI主干活动)。一项正在进行的前瞻性队列研究，涉及马拉维约1400名妇女，其中约1000人 谁将在EFV期间登记，提供了一个独特和及时的机会来评估ARV的结果， 包括病毒抑制和抗药性，从EFV转换为DTG前后。因此，我们建议 一项子研究，利用从队列研究中收集的现有储存标本来评估这些结果。目标 1将测量从EFV切换到DTG前后的病毒抑制率，对存储的 在DTG转换前立即采集的血液样本和大约6个月采集的样本 (+/-3个月)改用DTG(n=1000)。目标2将描述抗逆转录病毒病毒的频率和模式 在转换时或开始使用NEXT后6个月病毒失败的人中(~10%，n=100) 利用新技术对储存的血液样本进行世代测序，以识别和量化大多数和 NRTI和INSTI耐药性的少数变种。最后，在使用EFV或DTG的病毒失败的女性中- 基于方案(~10%，n=100)，Aim 3将使用头发中拉米夫定的药物浓度来评估依从性， NRTI是两种方案的共同之处。这将是第一个关于真实世界EFV-to-HIV结果的前瞻性研究。 通过新的深度测序和目标药物暴露(即，依从性)实现DTG转换范式 数据。通过将我们的子研究嵌入到几乎完全登记的队列研究中，我们将能够访问 提供保存的标本，快速进行分析，更快地评估公共卫生 盲目从EFV转换为DTG的影响。我们的结果与马拉维的政策发展和 预计或正在进行DTG过渡的SSA其他国家/地区，并将通知未来的VL 考虑到DTG的效力和抵抗障碍，可能会改变的监测和耐药性监测政策。

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.