A Randomized Clinical Trial to Evaluate Solutions for the Management of Virologic Failure for Individuals on TLD in Sub-Saharan Africa

项目总结 意义：替诺福韦、拉米夫定和多洛替格韦(TLD)已成为主要的一线药物 撒哈拉以南非洲的抗逆转录病毒疗法(SSA)。而TLD上的病毒学故障相对来说 目前罕见的是，随着时间的推移，发病率将不可避免地上升，威胁到该地区的疫情控制。最优的 TLD上的病毒学故障管理目前尚不清楚，而且SSA的政策差异很大。创新：我们 提出第一项随机临床试验，以确定病毒学失败的最佳管理策略 SSA中的TLD。这项试验将评估一种新的个性化护理战略，该战略寻求解决多样化的患者- 病毒学失败的水平决定因素，包括依从性挑战、药物负担、患者偏好、方案 耐受性和抗药性。个体化护理策略结合了护理点尿替诺福韦 检测以及基因耐药测试，目标是在个体中挽救每天一次的方案 在TLD上出现病毒学故障。调查人员：我们的临床流行病学家专家团队(Suzanne McCluskey)， 实施科学家和临床试验人员(Mark Siedner、Monica Gandhi)、全球合作伙伴(Winnie Muyindke、Richard Lessells、Mahomed尤努斯·穆萨)、生物统计学家(Susanne Hoeppner)和决策 科学家(艾米丽·海尔饰)由早期调查员(麦克卢斯基饰)领导，处于独特的地位，能够提供政策- 对于回答这一具有重大公共卫生意义的问题，数据具有指导性。方法：我们将利用 建立了实用的临床试验基础设施，最近完成了由NIH R01资助的随机试验 在乌干达的姆巴拉拉和南非的德班完成以下具体目标：目标1)我们将 在六家公共部门诊所进行RESOLE试验，这是一项开放、平行、随机的临床试验，以 确定SSA一线TLD病毒学故障管理的最佳策略。我们会随机化 参与者采用以下策略之一：a)改用蛋白水解酶抑制剂(PI)维持TLD- 如果病毒学失败持续六个月，则基于二线抗逆转录病毒治疗，类似于南非目前的指导方针； B)个体化护理，根据基因耐药试验和尿替诺福韦的结果选择方案 或c)立即改用以PI为基础的二线抗逆转录病毒治疗，类似于乌干达目前的指导方针。这个 主要结果将是在注册后48周内病毒抑制(&lt；50拷贝/毫升)。目标2)我们将 用临床试验推广预防艾滋病并发症的成本-效果-国际模式 来自AIM 1的数据，以预测长期临床结果和累积终生成本。我们将使用模拟 用于检查改善病毒策略的临床影响、成本和成本效益的建模 病毒学失败后对TLD的抑制。影响：我们将用数据来应对这一优先研究差距 通过确定最具临床效果和成本效益的管理策略来指导全球艾滋病毒政策 TLD上的病毒学故障。在这样做时，这项建议直接回应了NIH艾滋病毒研究的优先事项，以改进 抑制病毒，并确保实现最佳的治疗反应。

PROJECT SUMMARY Significance: Tenofovir, lamivudine, and dolutegravir (TLD) has become the predominant first-line antiretroviral therapy (ART) regimen in sub-Saharan Africa (SSA). While virologic failure on TLD is relatively rare currently, rates will inevitably increase over time, threatening epidemic control in the region. The optimal management of virologic failure on TLD is currently unknown, and policies vary widely in SSA. Innovation: We propose the first randomized clinical trial to determine the optimal management strategy for virologic failure on TLD in SSA. The trial will evaluate a novel individualized care strategy, which seeks to address diverse patient- level determinants of virologic failure, including adherence challenges, pill burden, patient preference, regimen tolerability, and drug resistance. The individualized care strategy incorporates a point-of-care urine tenofovir assay, as well as genotypic resistance tests, with a goal of salvaging once-daily regimens among individuals with virologic failure on TLD. Investigators: Our expert team of clinical epidemiologists (Suzanne McCluskey), implementation scientists and clinical trialists (Mark Siedner, Monica Gandhi), global partners (Winnie Muyindike, Richard Lessells, Mahomed Yunus Moosa), biostatisticians (Susanne Hoeppner), and decision scientists (Emily Hyle), led by an early-stage investigator (McCluskey), is uniquely positioned to provide policy- guiding data in response to this question of great public health significance. Approach: We will leverage an established pragmatic clinical trial infrastructure which recently completed an NIH R01-funded randomized trial in Mbarara, Uganda and Durban, South Africa to complete the following Specific Aims: Aim 1) We will conduct the RESOLVE trial, an open, parallel arm, randomized clinical trial in six public sector clinics to determine the optimal strategy for management of virologic failure on first-line TLD in SSA. We will randomize participants to one of the following strategies: a) Maintenance on TLD with switch to protease inhibitor (PI)- based second-line ART if virologic failure persists past six months, similar to current guidelines in South Africa; b) Individualized Care, with regimen choice based on results of genotypic resistance tests and urine tenofovir assays; or c) Immediate Switch to PI-based second-line ART, similar to current guidelines in Uganda. The primary outcome will be viral suppression (<50 copies/mL) at 48-weeks post-enrollment. Aim 2) We will populate the Cost-Effectiveness of Preventing AIDS Complications-International model with the clinical trial data from Aim 1 to project long-term clinical outcomes and cumulative lifetime costs. We will use simulation modeling to examine the clinical impact, costs, and cost-effectiveness of strategies to improve viral suppression after virologic failure on TLD. Impact: We will respond to this priority research gap with data to guide global HIV policy by determining the most clinically effective and cost-effective strategy for management of virologic failure on TLD. In doing so, this proposal directly responds to NIH HIV research priorities to improve viral suppression and to ensure that optimal treatment responses are achieved.