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头发样品来监测HIV感染中对抗逆转录病毒（ARV）治疗的依从性。我们已经证明，监测长期暴露的ARV的头发浓度比自我报告的依从性或血浆ARV水平在大量的HIV感染患者中更强。来自最近的HIV暴露前预防（PREP）试验的数据表明，对预防性ARV的依从性并不总是与自我报告一致，因此将药物暴露措施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％，但是在血浆中仅从8％的血清抗体中检测到药物，而匹配的活跃臂对照中有54％的药物未感染。在非洲妇女的两项大型预备试验中，通过自我报告的依从性也很高（FEM-PREP和声音），但是在不到三分之一的参与者中观察到血浆中的药物浓度足够。由于疗效结果可以通过低依从性研究产物来实质性地抑制或掩盖，因此纳入了评估HIV预防试验中依从性的药理学指标已变得越来越常规。尽管在所有临床试验中自我报告的依从性可能尤其不正确，但使用药物水平来监测艾滋病毒治疗试验的依从性，但远远落后于 预防试验设置。单个血浆ARV水平（如单葡萄糖测量）预测长期治疗结果的能力有限，因为它们仅反映了一小段 暴露持续时间，表现出明显的日常变化和“白涂层”的影响。以类似于糖基化的血红蛋白A1C（HBA1C）的方式，在长期内提供了平均葡萄糖水平的信息，头发中的药物浓度反映了几周到几个月的全身循环中药物的吸收。该提案旨在扩展我们使用头发ARV水平来监测从队列和HIV预防设置的依从性到HIV治疗试验设置的方法，并与AIDS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研究是一项三个非核苷逆转录酶抑制剂（NNRTI）的随机比较研究，用于治疗不接受HIV-1感染的患者。该审判于2009年5月开放了入学；头发采样于2010年8月启动，并继续于2013年6月完成研究。该提案寻求资金来分析A5257收集的头发样品中相关的ARV，并使用头发测量方法为进一步的数据分析提供资金。将头发量度纳入A5257，将其随机分配给固定治疗方案并进行了频繁的病毒负荷监测，将为头发水平提供额外的功率，以预测即将来临的病毒学衰竭。因此，该提案的目的可能为在现实世界中的早期和治疗过程中的早期和后期提供有用的依从性干预措施提供了有用的算法。 AIM 1具有描述性，将评估A5257三个臂中每个臂中每个臂的头发浓度与使用标准化问卷进行量化的自我报告的依从性之间的关系。 ARV的头发水平与自我报告的依从性测量之间的比较将在临床试验中首次通过该提案进行。 AIM 2将表征头发中抗逆转录病毒浓度的关系，依从性的自我报告的措施以及A5257三个臂中每个臂的治疗功效和耐受性。我们旨在评估头发中ARV的浓度如何预测和解释A5257的治疗结果，包括病毒学衰竭，由于毒性而导致的失败，病毒学抑制速率，CD4+ T细胞计数轨迹，耐药性的发展，不良反应，不良影响以及与纵向型的远程代理综合症相关的参数，以评估其预测性的潜力。在研究完成时，我们预计将在大型HIV临床试验中验证头发中的ARV浓度，并且是依从性的一种新颖和实用的生物标志物，并且是治疗结果的有用预测指标。这些发现将为实施项目铺平道路，旨在评估将头发浓度措施纳入临床实践的可行性，以此作为增强依从性干预和结果的工具。