Objective measures of adherence for later-stage ART failure in resource limited settings

在资源有限的环境中对后期 ART 失败的依从性进行客观测量

• 批准号: 10012880
• 负责人: Monica Gandhi
• 金额: $ 8.05万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-14 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012880
• 关键词: AIDS clinical trial group; Adherence; Age; Anti-Retroviral Agents; Biological Assay; Blood; CD4 Lymphocyte Count; Clinical; Counseling; Data; Exposure to; Failure; Funding; Genetic; Genotype; Growth; HIV; Hair; Ingestion; Intervention Studies; Measures; Methodology; Modeling; Monitor; New Agents; Outcome; Participant; Patient Self-Report; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Pharmacy facility; Plasma; Protease Inhibitor; Recommendation; Regimen; Research Design; Resistance; Resources; Sampling; Scalp structure; Social Desirability; Specimen; Spottings; Subgroup; Tenofovir; Testing; Time; Treatment Failure; United States National Institutes of Health; Urine; Viral; Viral Load result; antiretroviral therapy; base; clinical application; cohort; cost; data format; design; experience; improved; improved outcome; innovation; low and middle-income countries; monitoring device; novel; pill; point of care; prospective; public health relevance; response; sex; success; therapy adherence; viral resistance; virology

PROJECT SUMMARY/ ABSTRACT Strategies to prolong the durability of ART in low-and-middle income countries (LMICs) are important. With the new recommendation for dolutegravir to be used for all people living with HIV (PLHIV) globally, first-line ART now contains an agent with a high genetic barrier to resistance for the first time. Second-line ART still includes protease inhibitors (PIs) which have high genetic barriers to resistance like dolutegravir. First-line ART failure in the current era triggers enhanced adherence counseling, more frequent viral loads, and a switch to second- line ART if unsuccessful. Second-line ART failure in LMIC then requires expensive and difficult-to-access resistance testing and/or third-line ART and, therefore, unraveling the contribution of inadequate adherence to ART failure in LMICs, especially in the era of regimens with high genetic barriers to resistance, is critical. The AIDS Clinical Trials Group (ACTG) A5288 (MULTI-OCTAVE) study is an unprecedented prospective interventional study that evaluated strategies to treat PLHIV experiencing virologic failure on second-line regimens in LMIC. Self-reported adherence was not associated with virologic failure in the study, likely revealing the limitations of self-report. Importantly, A5288 chose to integrate an objective adherence metric into their study design by collecting hair samples for antiretroviral (ARV) levels, a methodology we pioneered at UCSF. However, A5288 requires independent funding to assay the hair samples (as sought in this R03) collected in the study to retrospectively assess the contribution of adherence to failure. Moreover, although performing hair levels is not practical in routine clinical settings, our group and others have recently developed and validated a practical, low-cost, real-time urine-based objective adherence metric, which measures tenofovir use over the short-term. We plan in this proposal to exploit a novel application of hair analysis by segmenting one half of each sample collected in A5288 into a proximal short segment (reflecting 1 week of exposure) and the other half into a longer segment to reflect longer-term (6 weeks) of exposure to examine both short-term and long-term metrics of adherence in relationship to virologic outcomes and resistance in LMIC. We will also examine the relationship between short-and long-term hair measures to determine if “white coat” adherence occurred in this study. The use of objective adherence metrics in this large and well-characterized cohort of ART failure in LMIC will define the degree of adherence required to maintain virologic success on regimens with high genetic barriers to resistance (of particular import now that the new agent for first-line therapy globally is dolutegravir). Moreover, the novel design of this relatively low-cost proposal, leveraging data and samples already collected in an NIH-funded study, along with segmental hair analysis, will provide formative data on how to inform the use of practical short-term urine-based point-of-care adherence assays (which will be widely available within the year) to improve outcomes in resource-limited settings.

项目摘要/摘要 延长低和中间收入国家（LMIC）艺术耐用性的策略很重要。与 DoluteGravir的新建议将用于全球艾滋病毒（PLHIV）的所有人一线艺术 现在，首次包含具有高遗传障碍的试剂。二线艺术仍然包括 蛋白酶抑制剂（PIS）具有高遗传障碍，例如DoluteGravir。一线艺术失败 在当前时代，触发了增强的依从性咨询，更频繁的病毒载荷以及转换为第二 线艺术如果不成功。然后，LMIC的二线艺术失败需要昂贵且难以访问 抵抗测试和/或三线艺术，因此，揭示了遵守不足的贡献 LMIC中的艺术失败，尤其是在具有抗药性遗传障碍的方案时代，至关重要。 AIDS临床试验组（ACTG）A5288（多核）研究是前所未有的 预期介入的研究评估了治疗PLHIV经历病毒学衰竭的策略 LMIC的二线方案。自我报告的依从性与病毒学衰竭无关 研究，可能揭示了自我报告的局限性。重要的是，A5288选择整合目标 通过收集抗逆转录病毒（ARV）水平的头发样品（A）的遵守指标 我们在UCSF开创性的方法。但是，A5288需要独立资金来主张头发 在研究中收集的样品（如本R03中所示），以回顾性评估依从性的贡献 失败。而且，尽管在常规临床环境中，我们的小组和 其他人最近开发并验证了实用，低成本，基于尿液的目标 依从性度量，可在短期内测量替诺福韦的使用。 我们计划在此提案中通过分割每个的一半来利用头发分析的新颖应用 在A5288中收集到近端短段（反映1周的暴露），另一半中收集的样品 更长的细分市场以反映长期和长期检查长期（6周）的暴露 LMIC中与病毒学结局和抗性关系的依从性指标。我们还将检查 短期和长期头发措施之间的关系，以确定在此中是否发生了“白色外套” 学习。在这个大型且特征良好的艺术失败中，客观依从性指标在 LMIC将定义维持较高方案的病毒学成功所需的依从性程度 抗抵抗的遗传障碍（尤其是进口，现在全球一线治疗的新药物是 DoluteGravir）。此外，这个相对低成本的提案的新设计，利用数据和样品 已经在NIH资助的研究中收集的以及分段的头发分析将提供有关 如何告知使用实用的短期尿液点依从性测定法（这将是广泛的 在一年内提供），以改善资源有限设置的结果。