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.

项目总结/摘要 在低收入和中等收入国家，延长抗逆转录病毒疗法持久性的战略十分重要。与 多替拉韦用于全球所有艾滋病毒感染者（PLHIV）的新建议，一线ART 现在首次包含了一种具有高遗传抗性屏障的药剂。二线ART仍包括 蛋白酶抑制剂（PI），其具有高遗传抗性屏障，如度鲁特韦。一线ART失败 在当前的时代触发加强坚持咨询，更频繁的病毒载量，并切换到第二- 如果不成功，则行ART。LMIC的二线ART失败则需要昂贵且难以获得的 耐药性测试和/或三线ART，因此，揭示了对 在中低收入国家，特别是在耐药基因屏障高的时代，ART失败是至关重要的。 艾滋病临床试验组（ACTG）A5288（MULTI-OCTAVE）研究是一项前所未有的 一项前瞻性干预性研究，评估了治疗病毒学失败的PLHIV的策略， 二线治疗方案。自我报告的依从性与病毒学失败无关。 研究，可能揭示了自我报告的局限性。重要的是，A5288选择将物镜 通过收集头发样本进行抗逆转录病毒（ARV）水平检测， 我们在加州大学旧金山分校开创的方法。然而，A5288需要独立的资金来分析头发， 研究中采集的样本（如本R 03所述），以回顾性评估依从性的贡献 要失败的此外，尽管在常规临床环境中进行毛发水平测定是不实际的，但我们的小组和 其他人最近开发并验证了一种实用的、低成本的、实时的基于尿液的目标 依从性指标，衡量短期内替诺福韦的使用情况。 我们计划在这个建议，以开拓一个新的应用程序的头发分析分割一半，每个 在A5288中采集的样本分为近端短节段（反映1周暴露），另一半分为 反映长期（6周）暴露的较长部分，以检查短期和长期 与病毒学结果和LMIC耐药性相关的依从性指标。我们亦会研究 短期和长期毛发测量之间的关系，以确定“白色被毛”粘附是否发生在这个 study.在这个大型且特征良好的ART失败队列中使用客观依从性指标， LMIC将定义维持高风险方案的病毒学成功所需的依从性程度。 耐药性的遗传障碍（特别重要的是，现在全球一线治疗的新药物是 dolutegravir）。此外，这种设计新颖的相对低成本的建议，利用数据和样本， 已经在NIH资助的一项研究中收集的数据，沿着部分毛发分析，将提供以下方面的形成性数据： 如何通知使用实际的短期基于尿液的护理点依从性测定（这将被广泛 年内提供），以改善资源有限情况下的成果。