Hair measures to assess adherence and explain outcomes in an HIV clinical trial

用于评估依从性并解释 HIV 临床试验结果的毛发测量

• 批准号: 8730255
• 负责人: Monica Gandhi
• 金额: $ 18.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-05 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8730255
• 关键词: AIDS clinical trial group; AIDS prevention; Adherence; Adult; Adverse effects; African; Algorithms; Anti-Retroviral Agents; Atazanavir; Biological Markers; Blood; Blood Circulation; CD4 Positive T Lymphocytes; Cell Count; Chronic Disease; Clinical; Clinical Trials; Clinical Trials Cooperative Group; Comparative Study; Data; Data Analyses; Development; Drug Exposure; Drug resistance; Drug usage; Enrollment; Failure; Funding; Glucose; Glycosylated Hemoglobin; Gold; HIV; HIV Infections; HIV Seropositivity; HIV prevention trial; HIV-1; Hair; Individual; Intervention; Life; Masks; Measurement; Measures; Metabolic syndrome; Methodology; Modeling; Monitor; Outcome; Outcome Study; Painless; Participant; Patient Self-Report; Patients; Pharmaceutical Preparations; Phase; Plasma; Prevention; Prophylactic treatment; Questionnaires; Randomized; Research Personnel; Rest; Ritonavir; Sampling; Scalp structure; Tenofovir; Testing; Therapeutic; Time; Toxic effect; Treatment Efficacy; Treatment Failure; Treatment Protocols; Treatment outcome; Variant; Viral Load result; Woman; antiretroviral therapy; arm; clinical practice; cohort; cost effective; design; emtricitabine; improved; innovation; non-nucleoside reverse transcriptase inhibitors; novel; primary outcome; prophylactic; prospective; public health relevance; secondary outcome; success; tool; treatment trial; uptake

DESCRIPTION (provided by applicant): Our group has pioneered the use of small hair samples to monitor adherence to antiretroviral (ARV) therapy in HIV infection. We have demonstrated that hair concentrations of ARVs, which monitor long-term exposure, are stronger predictors of treatment success than self-reported adherence or plasma ARV levels in large cohorts of HIV-infected patients. Data from recent HIV pre-exposure prophylaxis (PrEP) trials indicate that adherence to prophylactic ARVs is not always concordant with self report, so the incorporation of drug exposure measures as biomarkers of adherence has been crucial to trial interpretation. In iPrEx, mean self-reported adherence was 95%, but drug was detected in plasma from only 8% of seroconverters compared with 54% of matched active-arm controls who remained uninfected. Adherence via self-report was similarly high in two large PrEP trials in African women (FEM-PrEP and VOICE), but adequate drug concentrations in plasma were observed in fewer than one-third of participants. Since efficacy results can be substantially dampened or masked by low adherence to study product, the incorporation of pharmacologic measures to assess adherence in HIV prevention trials has become increasingly routine. The use of drug levels to monitor adherence in HIV treatment trials, despite the fact that self-reported adherence may be particularly inaccurate in all clinical trials, has lagged far behind the prevention trial setting. Single plasma levels of ARVs, like single glucose measurements, are limited in their ability to predict long-term treatment outcomes, because they reflect only a short duration of exposure, demonstrating significant day-to- day variation and "white-coat" effects. In a manner analogous to glycosylated hemoglobin A1C (HbA1C) providing information on average glucose levels over prolonged periods, the concentration of medications in hair reflects drug uptake from the systemic circulation over weeks to months. This proposal seeks to extend our approach of using hair ARV levels to monitor adherence from the cohort and HIV prevention setting to the HIV treatment trial setting, partnering with the AIDS Clinical Trials Group (ACTG) to further test our methodology in a cost-effective manner. The ACTG A5257 study is a phase III randomized comparative study of three non-nucleoside reverse transcriptase inhibitor (NNRTI)-sparing combination regimens for treatment-naive HIV-1-infected patients. The trial was opened to enrollment in May 2009; hair sampling was initiated in August 2010 and continued to the completion of the study in June 2013. This proposal seeks funds to analyze the relevant ARV(s) in the collected hair samples from A5257 and to fund further data analyses using the hair measures. Incorporating hair measures into A5257, which randomized participants to fixed treatment regimens and performed frequent viral load monitoring, will provide additional power over the cohort setting for hair levels to predict impending virologic failure. This proposal's aim may therefore provide useful algorithms for adherence interventions, both early on and later in the treatment course, in the real-world setting. Aim 1 is descriptive and will assess the relationship between hair concentrations of the target ARV in each of the 3 arms of A5257 and self-reported adherence as quantified using standardized questionnaires. This comparison between hair levels of ARVs and self-reported adherence measures will be performed for the first time in a clinical trial via this proposal. Aim 2 will characterize relationships between antiretroviral concentrations in hair, as well as self-reported measures of adherence, and treatment efficacy and tolerability in each of the 3 arms of A5257. We aim to evaluate how concentrations of ARVs in hair predict and explain treatment outcomes in A5257, including virologic failure, failure due to toxicity, rates of virologic suppression, CD4+ T-cell count trajectories, the development of drug resistance, adverse effects, and parameters associated with the metabolic syndrome in a longitudinal fashion to assess their predictive and explanatory potential. At study completion, we expect to have validated ARV concentrations in hair as a novel and practical biomarker of adherence and a useful predictor of treatment outcomes in a large HIV clinical trial. These findings will pave the way for an implementation project designed to assess the feasibility of incorporating hair concentration measures into clinical practice as a tool to enhance adherence interventions and outcomes.

描述（由申请人提供）：我们的小组率先使用小毛发样本来监测 HIV 感染者抗逆转录病毒 (ARV) 治疗的依从性。我们已经证明，在大量艾滋病毒感染者中，监测长期暴露的抗逆转录病毒药物的头发浓度比自我报告的依从性或血浆抗逆转录病毒药物水平更能预测治疗成功。最近的 HIV 暴露前预防 (PrEP) 试验数据表明，预防性抗逆转录病毒药物的依从性并不总是与自我报告一致，因此将药物暴露指标纳入依从性的生物标志物对于试验解释至关重要。在 iPrEx 中，平均自我报告的依从性为 95%，但只有 8% 的血清转化者在血浆中检测到药物，而未感染的匹配主动臂对照中有 54% 的检测到药物。在非洲女性的两项大型 PrEP 试验（FEM-PrEP 和 VOICE）中，自我报告的依从性也同样较高，但只有不到三分之一的参与者观察到血浆中药物浓度足够。由于对研究产品的低依从性可能会大大削弱或掩盖功效结果，因此在艾滋病毒预防试验中纳入药理学措施来评估依从性已变得越来越常规。尽管自我报告的依从性在所有临床试验中可能特别不准确，但在艾滋病毒治疗试验中使用药物水平来监测依从性仍远远落后于实际情况。 预防试验设置。与单次血糖测量一样，单次抗逆转录病毒药物血浆水平在预测长期治疗结果方面受到限制，因为它们仅反映短期治疗结果。 暴露持续时间，表现出显着的日常变化和“白大衣”效应。与提供长期平均血糖水平信息的糖化血红蛋白 A1C (HbA1C) 类似，头发中的药物浓度反映了数周至数月内体循环的药物摄取情况。该提案旨在将我们使用头发抗逆转录病毒水平来监测从队列和艾滋病毒预防环境到艾滋病毒治疗试验环境的依从性的方法扩展，与艾滋病临床试验组（ACTG）合作，以具有成本效益的方式进一步测试我们的方法。 ACTG A5257 研究是针对初治 HIV-1 感染患者的三种非核苷逆转录酶抑制剂 (NNRTI) 保留联合方案的 III 期随机比较研究。该试验于 2009 年 5 月开始招募；头发采样于 2010 年 8 月开始，并持续到 2013 年 6 月完成研究。该提案寻求资金来分析从 A5257 收集的头发样本中的相关抗逆转录病毒药物，并资助使用头发测量进行进一步的数据分析。将头发测量纳入 A5257 中，将参与者随机分配到固定的治疗方案并进行频繁的病毒载量监测，这将为头发水平的队列设置提供额外的能力，以预测即将发生的病毒学失败。因此，该提案的目的可能为现实环境中治疗过程的早期和后期的依从性干预提供有用的算法。目标 1 是描述性的，将评估 A5257 3 个臂中每个臂中目标 ARV 的毛发浓度与使用标准化问卷量化的自我报告的依从性之间的关系。通过该提案，将首次在临床试验中对头发中的抗逆转录病毒药物水平与自我报告的依从性测量进行比较。目标 2 将描述头发中抗逆转录病毒浓度之间的关系，以及 A5257 3 个臂中每个臂的自我报告的依从性、治疗效果和耐受性之间的关系。我们的目的是评估头发中抗逆转录病毒药物的浓度如何预测和解释 A5257 的治疗结果，包括病毒学失败、毒性导致的失败、病毒学抑制率、CD4+ T 细胞计数轨迹、耐药性的发展、不良反应和参数以纵向方式与代谢综合征相关联，以评估其预测和解释潜力。研究完成后，我们希望在大型艾滋病毒临床试验中验证头发中的抗逆转录病毒药物浓度，作为一种新颖实用的依从性生物标志物和治疗结果的有用预测因子。这些发现将为实施项目铺平道路，该项目旨在评估将头发浓度测量纳入临床实践作为增强依从性干预措施和结果的工具的可行性。