Tenofovir diphosphate (TFV-DP) concentrations measured with dried blood spots (DBS) can be used to classify adherence to emtricitabine/tenofovir disoproxil fumarate (F/TDF) for HIV pre-exposure prophylaxis (PrEP). A TFV-DP of 700 fmol/punch was previously associated with high PrEP efficacy, and was estimated to represent ≥4 doses/week on average. However, interindividual variability in TFV-DP concentrations may lead to adherence misclassification and decrease the precision of adherence–efficacy relationships. The purpose of this analysis was to evaluate sources of TFV-DP variability to improve the precision of TFV-DP for adherence assessments by incorporating individual characteristics. Data and samples from a 36-week study of TFV-DP in DBS, collected biweekly, among 48 HIV-negative volunteers (25 Females/26 Caucasian/10 African American/14 Hispanic) receiving F/TDF at 33%, 67%, and 100% of daily dosing under directly observed therapy were used for analysis. The simplest pharmacokinetic model to describe TFV-DP accumulation with acceptable performance was a one-compartment constant input model. Covariates, including laboratory values and demographics were ranked in importance of their association with post hoc pharmacokinetic (PK) parameters using random forest analyses. Weight and platelet count were included in the final model and simulations were conducted to generate benchmarks for <2, 2–3, 4–5, and 6–7 doses/week. Based on these simulations, the previously established protective TFV-DP concentration of ≥700 fmol/punch was observed in those taking 2–3 (in individuals ≤110 kg) and ≥4 (in individuals >110 kg) doses/week, amounting to a much lower rate of misspecification (17% vs. 30%) with this individualized model versus previous interpretations. Incorporating body weight and platelet count improved the precision of TFV-DP concentrations for adherence assessments. Previous benchmarks were conservative, indicating that the pharmacological forgiveness of F/TDF may be higher than currently recognized and supports continued investigation of intermittent PrEP dosing regimens.

中文翻译：

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HIV 暴露前预防的个体化依从性基准

用干血斑 (DBS) 测量的替诺福韦二磷酸 (TFV-DP) 浓度可用于对用于 HIV 暴露前预防 (PrEP) 的恩曲他滨/富马酸替诺福韦二吡呋酯 (F/TDF) 的依从性进行分类。700 fmol/punch 的 TFV-DP 先前与高 PrEP 疗效相关，据估计平均每周 ≥ 4 剂。然而，TFV-DP 浓度的个体差异可能导致依从性错误分类并降低依从性-效能关系的精确度。该分析的目的是评估 TFV-DP 变异性的来源，以通过结合个体特征来提高 TFV-DP 用于依从性评估的精度。来自 DBS 中为期 36 周的 TFV-DP 研究的数据和样本，每两周收集一次，在 48 名 HIV 阴性志愿者（25 名女性/26 名高加索人/10 名非洲裔美国人/14 名西班牙裔）中，在直接观察治疗下接受 F/TDF，每日剂量的 33%、67% 和 100% 用于分析。描述具有可接受性能的 TFV-DP 积累的最简单的药代动力学模型是单室恒定输入模型。协变量，包括实验室值和人口统计数据，根据它们与事后使用随机森林分析的药代动力学 (PK) 参数。体重和血小板计数包含在最终模型中，并进行模拟以生成<2、2-3、4-5 和 6-7 剂/周的基准。基于这些模拟，先前确定的保护性 TFV-DP 浓度≥700 fmol/punch 在每周服用 2-3 次（≤110 公斤的个体）和≥4 次（>110 公斤的个体）剂量/周的人群中观察到，总计与以前的解释相比，这种个性化模型的错误指定率要低得多（17% 对 30%）。结合体重和血小板计数提高了用于依从性评估的 TFV-DP 浓度的精确度。以前的基准是保守的，