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

描述（由申请人提供）：我们的小组率先使用小头发样本来监测艾滋病毒感染者是否坚持抗逆转录病毒（ARV）治疗。我们已经证明，在大量HIV感染患者中，与自我报告的依从性或血浆ARV水平相比，监测长期暴露的ARV头发浓度是治疗成功的更强预测因子。最近的HIV暴露前预防（PrEP）试验数据表明，预防性ARV的依从性并不总是与自我报告一致，因此将药物暴露指标作为依从性的生物标志物对试验解释至关重要。在iPrEx中，平均自我报告的依从性为95%，但仅8%的血清转换者的血浆中检测到药物，而未感染的匹配活性组对照为54%。在非洲妇女的两项大型PrEP试验（FEM-PrEP和VOICE）中，通过自我报告的依从性同样高，但在不到三分之一的参与者中观察到足够的血浆药物浓度。由于疗效结果可能会因对研究产品的低依从性而受到实质性抑制或掩盖，因此在HIV预防试验中纳入药理学措施以评估依从性已变得越来越常规。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， 预防试验设置。抗逆转录病毒药物的单一血浆水平，如单一葡萄糖测量，在预测长期治疗结果的能力方面是有限的，因为它们只能反映短期的治疗结果。 暴露的持续时间，表现出显着的日常变化和“白大衣”的影响。以类似于糖化血红蛋白A1 C（HbA 1C）提供长期平均葡萄糖水平信息的方式，头发中药物的浓度反映了数周至数月内从体循环中的药物吸收。该提案旨在将我们使用头发ARV水平来监测从队列和HIV预防环境到HIV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研究是一项III期随机对照研究，在未经治疗的HIV-1感染患者中评价三种非核苷类逆转录酶抑制剂（NNRTI）保留联合方案。本试验于2009年5月开放入组;毛发采样于2010年8月开始，并持续至2013年6月研究完成。该提案寻求资金，以分析从A5257收集的头发样本中的相关抗逆转录病毒药物，并资助使用头发措施进行进一步的数据分析。将毛发测量结果纳入A5257，将参与者随机分配至固定的治疗方案并进行频繁的病毒载量监测，将为毛发水平预测即将发生的病毒学失败提供额外的力量。因此，该提案的目的可能会提供有用的算法，坚持干预，早期和后期的治疗过程中，在现实世界的设置。目的1是描述性的，将评估A5257 3组中每一组的靶向ARV毛发浓度与使用标准化问卷量化的自我报告依从性之间的关系。通过这项提议，将首次在临床试验中对抗逆转录病毒药物的毛发水平和自我报告的依从性指标进行比较。目标2将描述头发中抗逆转录病毒药物浓度之间的关系，以及自我报告的依从性指标，以及A5257 3个治疗组中的治疗疗效和耐受性。我们的目的是评估头发中ARV的浓度如何预测和解释A5257的治疗结果，包括病毒学失败、毒性导致的失败、病毒学抑制率、CD 4 + T细胞计数轨迹、耐药性的发展、不良反应以及与代谢综合征相关的参数，以纵向方式评估其预测和解释潜力。在研究完成时，我们希望在一项大型HIV临床试验中验证头发中的ARV浓度作为一种新的实用的依从性生物标志物和治疗结果的有用预测因子。这些发现将为一个实施项目铺平道路，该项目旨在评估将毛发浓度测量纳入临床实践的可行性，作为增强依从性干预措施和结果的工具。

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.