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

评估撒哈拉以南非洲 TLD 个体病毒学失败管理解决方案的随机临床试验

• 批准号: 10548105
• 负责人: Suzanne McCluskey
• 金额: $ 69.42万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548105
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adherence; Adolescent; Adult; Africa South of the Sahara; Attention; Biological Assay; Caring; Clinic; Clinical; Clinical Data; Clinical Trials; Data; Dose; Drug resistance; Enrollment; Ensure; Epidemic; Epidemiologist; Failure; Fumarates; Funding; Genotype; Goals; Guidelines; HIV; Health system; Individual; Infrastructure; International; Knowledge; Lamivudine; Lead; Leadership; Maintenance; Modeling; Outcome; Participant; Patient Preferences; Patients; Persons; Policies; Positioning Attribute; Pragmatic clinical trial; Protease Inhibitor; Public Health; Public Sector; Randomized; Randomized Clinical Trials; Regimen; Reporting; Research Personnel; Research Priority; Resistance; Scientist; South Africa; South African; Technology; Tenofovir; Testing; Time; Treatment Failure; Uganda; United States National Institutes of Health; Urine; Viral; Viral Load result; antiretroviral therapy; arm; base; comparative cost effectiveness; cost; cost effective; cost effectiveness; drug intolerance; experience; improved; innovation; life time cost; models and simulation; non-nucleoside reverse transcriptase inhibitors; novel; optimal treatments; patient oriented; personalized approach; personalized care; personalized management; pill; point of care; prevent; primary outcome; randomized trial; recruit; response; treatment response

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.

项目摘要 意义：Tenofovir，Lamivudine和Dolutegravir（TLD）已成为主要的第一线 撒哈拉以南非洲（SSA）的抗逆转录病毒疗法（ART）方案。虽然在TLD上的病毒衰竭相对 目前，罕见的速度将不可避免地随着时间的流逝而增加，从而威胁到该地区的流行病控制。最佳 目前未知的TLD病毒性衰竭管理，而政策在SSA中差异很大。创新：我们 提出第一个随机临床试验，以确定病毒学衰竭的最佳管理策略 SSA中的TLD。该试验将评估一种新型的个性化护理策略，该策略旨在解决多样化的患者 - 病毒学衰竭的水平决定因素，包括依从性挑战，药丸负担，患者偏好，方案 耐受性和耐药性。个性化的护理策略结合了护理点尿替诺福韦 测定以及基因型抗性测试，其目标是每天一次挽救一次疗法 与TLD的病毒衰竭。调查人员：我们的临床流行病学家（Suzanne McCluskey）的专家团队， 实施科学家和临床试验员（马克·西德纳（Mark Siedner），莫妮卡·甘地（Monica Gandhi）），全球合作伙伴（Winnie Muyindike，Richard Lessells，Mahomed Yunus Moosa），生物统计学家（Susanne Hoeppner）和决定 由早期调查员（McCluskey）领导的科学家（艾米丽·希勒（Emily Hyle））的独特位置可以提供政策 - 指导数据，以回应这个具有巨大公共健康意义的问题。方法：我们将利用 建立的实用临床试验基础设施，该试验最近完成了NIH R01资助的随机试验 在穆巴拉，乌干达和南非的德班以完成以下具体目标：目标1）我们将 在六个公共部门诊所进行解决试验，这是一个开放的，平行的，随机的临床试验 确定SSA中一线TLD的病毒学衰竭管理的最佳策略。我们将随机化 参与者的以下策略之一：a）在TLD上进行维护，并切换到蛋白酶抑制剂（PI） - 基于二线艺术如果在过去的六个月中持续了病毒学衰竭，类似于南非目前的准则； b）个性化护理，基于基因型耐药性测试和尿液替诺福韦的结果进行方案选择 测定；或c）立即切换到基于PI的二线艺术，类似于乌干达当前的准则。这 主要结果将是在注册后48周抑制病毒抑制（<50份/mL）。目标2）我们将 通过临床试验，可以填充预防艾滋病并发症模型的成本效益 来自AIM 1到长期临床结果和累积终身成本的数据。我们将使用模拟 建模以检查策略改善病毒的临床影响，成本和成本效益 病毒学衰竭后TLD抑制。影响：我们将对这个优先研究的差距以及数据回应 通过确定最有效和成本效益的管理战略来指导全球艾滋病毒政策 在TLD上的病毒衰竭。为此，该提案直接应对NIH HIV研究的重点以改善 病毒抑制并确保实现最佳治疗反应。