Hendrix Craig W, Andrade Adriana, Bumpus Namandjé N, Kashuba Angela D, Marzinke Mark A, Moore Ayana, Anderson Peter L, Bushman Lane R, Fuchs Edward J, Wiggins Ilene, Radebaugh Christine, Prince Heather A, Bakshi Rahul P, Wang Ruili, Richardson Paul, Shieh Eugenie, McKinstry Laura, Li Xin, Donnell Deborah, Elharrar Vanessa, Mayer Kenneth H, Patterson Kristine B
1 Johns Hopkins University , Baltimore, Maryland.
2 University of North Carolina-Chapel Hill , Chapel Hill, North Carolina.
AIDS Res Hum Retroviruses. 2016 Jan;32(1):32-43. doi: 10.1089/AID.2015.0182. Epub 2015 Oct 15.
Oral preexposure prophylaxis (PrEP) trials report disparate efficacy attributed to variable adherence. HPTN 066 was conducted to establish objective, quantitative benchmarks for discrete, regular levels of adherence using directly observed dosing of tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC). Healthy, HIV-uninfected men and women were randomized to one of four oral regimens of fixed-dose TDF 300 mg/FTC 200 mg tablet for 5 weeks with all doses observed: one tablet weekly (one/week), one tablet twice weekly (two/week), two tablets twice weekly (four/week), or one tablet daily (seven/week). Trough serum TFV and FTC, peripheral blood mononuclear cell (PBMC), and CD4(+) TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) concentrations were determined throughout dosing and 2 weeks after the last dose. Rectosigmoidal, semen, and cervicovaginal samples were collected for drug assessment at end of dosing and 2 weeks later in a subset of participants. The 49 enrolled participants tolerated the regimens well. All regimens achieved steady-state concentrations by the second dose for serum TFV/FTC and by 7 days for PBMC TFV-DP/FTC-TP. Steady-state median TFV-DP predose concentrations demonstrated dose proportionality: one/week 1.6 fmol/10(6) PBMCs, two/week 9.1, four/week 18.8, seven/week, 36.3. Further, TFV-DP was consistently quantifiable 2 weeks after the last dose for the ≥4/week regimens. Adherence benchmarks were identified using receiver operating characteristic curves, which had areas under the curve ≥0.93 for all analytes in serum and PBMCs. Intersubject and intrasubject coefficients of variation (%CV) ranged from 33% to 63% and 14% to 34%, respectively, for all analytes in serum and PBMCs. Steady-state PBMC TFV-DP was established earlier and at lower concentrations than predicted and was the only analyte demonstrating predose concentration dose proportionality. Steady-state daily dosing serum TFV and PBMC TFV-DP was consistent with highly effective PrEP clinical trials. HPTN 066 provides adherence benchmarks for oral TFV/FTC regimens to assist interpreting study outcomes.
口服暴露前预防（PrEP）试验报告称，由于依从性不同，疗效存在差异。开展HPTN 066研究是为了使用直接观察法给予替诺福韦（TFV）富马酸替诺福韦二吡呋酯（TDF）/恩曲他滨（FTC），为不同的、规律的依从水平建立客观、定量的基准。健康的未感染HIV的男性和女性被随机分配至四种固定剂量的口服方案之一，即服用300毫克TDF/200毫克FTC片剂，为期5周，所有剂量均在观察之下：每周一片（每周一次）、每周两片（每周两次）、每周四片（每周两次）或每日一片（每周七天）。在整个给药期间以及最后一剂后的2周内，测定血清中TFV和FTC的谷浓度、外周血单核细胞（PBMC）以及CD4(+) 二磷酸替诺福韦（TFV-DP）和三磷酸恩曲他滨（FTC-TP）的浓度。在给药结束时以及2周后，在一部分参与者中采集直肠乙状结肠、精液和宫颈阴道样本进行药物评估。49名入组参与者对这些方案耐受性良好。所有方案在第二次给药时血清TFV/FTC达到稳态浓度，PBMC TFV-DP/FTC-TP则在7天时达到稳态浓度。稳态下TFV-DP给药前的中位浓度呈剂量比例关系：每周一次为1.6飞摩尔/10(6) 个PBMC，每周两次为9.1，每周四次为18.8，每日一次为36.3。此外，对于每周≥4次的方案，在最后一剂后的2周内，TFV-DP始终可定量。使用受试者工作特征曲线确定了依从性基准，血清和PBMC中所有分析物的曲线下面积均≥0.93。血清和PBMC中所有分析物的受试者间和受试者内变异系数（%CV）分别为33%至63%和14%至34%。稳态下PBMC TFV-DP的建立时间早于预期且浓度低于预期，是唯一显示给药前浓度呈剂量比例关系的分析物。稳态下每日给药血清TFV和PBMC TFV-DP与高效PrEP临床试验结果一致。HPTN 066为口服TFV/FTC方案提供了依从性基准，以帮助解释研究结果。
