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：替诺福韦、拉米夫定和度鲁特韦（dolutegravir）已成为主要的一线治疗药物 抗逆转录病毒疗法（ART）方案在撒哈拉以南非洲（SSA）。虽然病毒学上的失败相对 随着时间的推移，发病率将不可避免地上升，威胁到该地区的流行病控制。最优 目前尚不清楚如何管理病毒学上的失败，并且SSA的政策差异很大。创新：我们 提出第一个随机临床试验，以确定病毒学失败的最佳管理策略， 在南苏丹。该试验将评估一种新的个性化护理策略，旨在解决不同的患者- 病毒学失败的水平决定因素，包括依从性挑战、药丸负担、患者偏好、治疗方案 耐受性和耐药性。个性化护理策略包括即时尿液替诺福韦 检测，以及基因型耐药性测试，目的是挽救个人每天一次的方案 病毒学上的失败研究者：我们的临床流行病学专家团队（Suzanne McCendarkey）， 实施科学家和临床试验专家（Mark Siedner、Monica Gandhi）、全球合作伙伴（温妮 Muyindike，Richard Lessells，Mahomed Yunus Moosa），生物统计学家（Susanne Hoeppner），以及决定 科学家（艾米丽海尔），由一个早期阶段的调查员（麦克拉伦基）领导，是独特的定位，以提供政策， 指导性数据，以应对这一具有重大公共卫生意义的问题。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NIH R 01资助的随机试验 在乌干达姆巴拉拉和南非德班，完成以下具体目标：目标1）我们将 进行RESOLVE试验，这是一项在六家公共部门诊所进行的开放、平行组、随机临床试验， 确定SSA一线治疗中病毒学失败管理的最佳策略。我们会随机 a）维持口服降糖药，改用蛋白酶抑制剂（PI）- 如果病毒学失败持续超过6个月，则使用基于二线的ART，类似于南非目前的指南; B）个体化护理，根据基因型耐药试验和尿替诺福韦结果选择方案 c）立即转换为基于PI的二线ART，类似于乌干达的现行指南。的 主要结果将是在入组后48周时的病毒抑制（<50拷贝/mL）。目标2）我们将 通过临床试验填充预防艾滋病并发症的成本效益-国际模型 目标1中的数据，以预测长期临床结局和累积寿命成本。我们将使用模拟 建立模型，以检查改善病毒感染的临床影响、成本和成本效益 病毒学失败后的抑制作用。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战略，指导全球艾滋病毒政策 病毒学上的失败在这样做时，该提案直接响应了NIH HIV研究的优先事项，以改善 病毒抑制，并确保实现最佳治疗反应。