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

马拉维妇女从依非韦伦转为多替拉韦前后的艾滋病病毒抑制：将病毒结果与强大的抵抗力和客观的依从性措施结合起来

• 批准号: 10263158
• 负责人: MINA CHRISTINE HOSSEINIPOUR
• 金额: $ 15.75万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263158
• 关键词: Adherence; Africa South of the Sahara; Anti-Retroviral Agents; Antiretroviral resistance; Blood; Blood specimen; Clinical; Cohort Studies; Country; Data; Dose; Drug Exposure; Drug resistance; Drug toxicity; Drug usage; Enrollment; Event; Failure; Frequencies; Future; Genetic; HIV; Hair; Health Benefit; Health Personnel; Integrase; Lamivudine; Malawi; Measures; Minority; Monitor; Nucleosides; Outcome; Patients; Pattern; Persons; Pharmaceutical Preparations; Policies; Policy Developments; Positioning Attribute; Prospective Studies; Prospective cohort study; Public Health; RNA-Directed DNA Polymerase; Regimen; Residual state; Resistance; Reverse Transcriptase Inhibitors; Risk; Role; Specimen; Study models; Techniques; Tenofovir; Testing; Time; Treatment Failure; Treatment outcome; Variant; Vertebral column; Viral; Viral Load result; Visit; Woman; World Health Organization; acquired drug resistance; antiretroviral therapy; base; blind; cohort; cost; cost effective; deep sequencing; efavirenz; emtricitabine; inhibitor/antagonist; low income country; next generation sequencing; non-nucleoside reverse transcriptase inhibitors; novel; resistance frequency; resistance mutation; response; scale up; side effect; success; treatment response; viral resistance

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.

抽象的 在撒哈拉以南非洲（SSA）中，有近1500万人接受抗逆转录病毒（ARV）治疗的人。 尽管在治疗的扩大方面取得了成功，但仍有许多障碍以实现最佳的ARV治疗结果， 包括有限的病毒载荷（VL）监测，发射和获得药物的速率增加 耐药性和药物毒性导致治疗中断。为了应对这些挑战，世界 卫生组织最近修订了推荐的一线ARV方案，保留了核苷的反向 - 转录酶（NRTI）主链，但取代efavirenz（EFV），一种非核苷逆转录酶抑制剂 （nnrti），具有更大的潜力，耐受性较高且更普遍的集成链转移抑制剂 （Insti）DoluteGravir（DTG）。为了对这种变化做出反应，包括马拉维在内的SSA各国正在切换所有 目前，基于EFV的疗程是基于DTG的方案。 VL的可用性有限 更稀少的抵抗性测试将是“盲切”，而没有有关病毒抑制的信息 （VL <1000份/ml）或耐药性。这种策略可能会损害长期公共卫生益处 DTG，在依从性差或无意中DTG单一疗法的情况下冒着DTG失败或抵抗力的风险（即 无残留的NRTI-BACKBONE活动）。马拉维的约有1400名妇女正在进行的前瞻性队列研究，〜1000 在EFV上将入学的人，提供了一个独特而及时的机会来评估ARV结果， 在从EFV转换为DTG之前和之后，包括病毒抑制和抗性。因此，我们提出 使用从队列研究中收集的现有存储的标本来评估这些结果的子研究。目的 1将测量从EFV转换为DTG之前和之后的病毒抑制速率，对存储进行VL测试 DTG开关之前收集的血样，并收集了大约6个月的标本 （+/- 3个月）切换到DTG（n = 1000）。 AIM 2将描述ARV电阻的频率和模式 在转换时病毒衰竭或开始DTG后6个月（〜10％，n = 100）的人中 在储存的血样上生成测序，并采用新颖的技术来识别和量化多数和量化 NRTI和Insti抗性的少数族裔变体。最后，在EFV或DTG-患有病毒衰竭的女性中 基于方案（〜10％，n = 100），AIM 3将使用头发中的lamivudine药物浓度评估依从性， 两种方案共有的NRTI。这将是对现实世界中的EFV到现实艾滋病毒结局的第一项前瞻性研究 DTG开关范式通过新颖的深度测序和客观药物暴露（即依从性）进行了上下文 数据。通过将我们的子研究嵌入几乎完全注册的队列研究中，我们将能够访问 可用的存储标本，快速进行分析，并更快地评估公共卫生 盲目切换从EFV转换为DTG的含义。我们的结果与马拉维的政策制定有关 DTG过渡的其他国家 /地区的其他国家 /地区也将为未来的VL提供信息 鉴于DTG的效力和阻力障碍，可能会改变的监视和阻力监视策略。