Baxi Sanjiv M, Liu Albert, Bacchetti Peter, Mutua Gaudensia, Sanders Eduard J, Kibengo Freddie M, Haberer Jessica E, Rooney James, Hendrix Craig W, Anderson Peter L, Huang Yong, Priddy Frances, Gandhi Monica
*Divisions of HIV/AIDS and Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, CA; †Bridge HIV, San Francisco Department of Public Health, San Francisco, CA; ‡Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA; §Kenya AIDS Vaccine Initiative, Nairobi, Kenya; ‖Centre for Geographic Medicine Research Coast, Kenya Medical Research Institute, Kilifi, Kenya; ¶Nuffield Department of Clinical Medicine, University of Oxford, Headington, United Kingdom; #MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda; **Center for Global Health, Massachusetts General Hospital, Boston, MA; ††Gilead Sciences, Foster City, CA; ‡‡Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; §§Department of Pharmaceutical Sciences, University of Colorado, Aurora, CO; ‖‖Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA; and ¶¶International AIDS Vaccine Initiative, New York, NY.
J Acquir Immune Defic Syndr. 2015 Jan 1;68(1):13-20. doi: 10.1097/QAI.0000000000000386.
OBJECTIVE: The efficacy of pre-exposure prophylaxis (PrEP) in HIV will diminish with poor adherence; pharmacologic measures of drug exposure have proven critical to PrEP trial interpretation. We assessed drug exposure in hair against other pharmacologic and more routinely used measures to assess pill-taking. DESIGN: Participants were randomized to placebo, daily PrEP, or intermittent PrEP to evaluate safety and tolerability of daily versus intermittent tenofovir/emtricitabine (TFV/FTC) in 2 phase II PrEP clinical trials conducted in Africa. Different measures of drug exposure, including self-report, medication event monitoring system (MEMS)-caps openings, and TFV/FTC levels in hair and other biomatrices were compared. METHODS: At weeks 8 and 16, self-reported pill-taking, MEMS-caps openings, and TFV/FTC levels in hair, plasma, and peripheral blood mononuclear cells (PBMCs) were measured. Regression models evaluated predictors of TFV/FTC concentrations in the 3 biomatrices; correlation coefficients between pharmacologic and nonpharmacologic measures were calculated. Both trials were registered on ClinicalTrials.gov (NCT00931346/NCT00971230). RESULTS: Hair collection was highly feasible and acceptable (100% in week 8; 96% in week 16). In multivariate analysis, strong associations were seen between pharmacologic measures and MEMS-caps openings (all P < 0.001); self-report was only weakly associated with pharmacologic measures. TFV/FTC hair concentrations were significantly correlated with levels in plasma and PBMCs (correlation coefficients, 0.41-0.86, all P < 0.001). CONCLUSIONS: Measuring TFV/FTC exposure in small hair samples in African PrEP trials was feasible and acceptable. Hair levels correlated strongly with PBMC, plasma concentrations, and MEMS-caps openings. As in other PrEP trials, self-report was the weakest measure of exposure. Further study of hair TFV/FTC levels in PrEP trials and demonstration projects to assess adherence/exposure is warranted.
目的：暴露前预防（PrEP）对HIV的疗效会因依从性差而降低；药物暴露的药理学测量方法已被证明对PrEP试验的解读至关重要。我们评估了头发中的药物暴露情况，并将其与其他药理学及更常用的服药评估方法进行比较。 设计：在非洲进行的2项II期PrEP临床试验中，参与者被随机分配至安慰剂组、每日PrEP组或间歇性PrEP组，以评估每日与间歇性替诺福韦/恩曲他滨（TFV/FTC）的安全性和耐受性。比较了不同的药物暴露测量方法，包括自我报告、药物事件监测系统（MEMS）瓶盖开启情况以及头发和其他生物基质中的TFV/FTC水平。 方法：在第8周和第16周，测量自我报告的服药情况、MEMS瓶盖开启情况以及头发、血浆和外周血单核细胞（PBMC）中的TFV/FTC水平。回归模型评估了3种生物基质中TFV/FTC浓度的预测因素；计算了药理学和非药理学测量方法之间的相关系数。两项试验均已在ClinicalTrials.gov上注册（NCT00931346/NCT00971230）。 结果：采集头发非常可行且可接受（第8周为100%；第16周为96%）。在多变量分析中，药理学测量方法与MEMS瓶盖开启情况之间存在强关联（所有P<0.001）；自我报告与药理学测量方法仅存在弱关联。TFV/FTC头发浓度与血浆和PBMC中的水平显著相关（相关系数为0.41 - 0.86，所有P<0.001）。 结论：在非洲PrEP试验中，测量小份头发样本中的TFV/FTC暴露情况是可行且可接受的。头发中的水平与PBMC、血浆浓度以及MEMS瓶盖开启情况密切相关。与其他PrEP试验一样，自我报告是最弱的暴露测量方法。有必要在PrEP试验和示范项目中进一步研究头发中的TFV/FTC水平，以评估依从性/暴露情况。
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