School of Medicine, University of California San Francisco, San Francisco, CA, USA.
Department of Epidemiology and Biostatistics, San Francisco, CA, USA.
J Int AIDS Soc. 2021 May;24(5):e25744. doi: 10.1002/jia2.25744.
Randomized trials of new agents for HIV pre-exposure prophylaxis (PrEP) compare against emtricitabine and tenofovir disoproxil fumarate (F/TDF), without a placebo group. We used the well-characterized adherence-efficacy relationship for F/TDF to back-calculate the (non-PrEP) counterfactual background HIV incidence (bHIV) in a randomized trial of a novel PrEP agent and estimate comparative efficacy (to counterfactual bHIV).
The DISCOVER trial (ClinicalTrials.gov: NCT02842086) randomized 5387 men who have sex with men (MSM) and transgender women who have sex with men and demonstrated non-inferiority of emtricitabine and tenofovir alafenamide (F/TAF) to F/TDF (HIV incidence rate ratio [IRR] 0·47, 95% CI: 0·19 to 1.15). Tenofovir diphosphate (TFV-DP) levels in dried blood spots (DBS) were assessed for all diagnosed with HIV and in a random 10% of the cohort. We used a Bayesian model with a diffuse prior distribution, derived from established data relating tenofovir diphosphate levels to HIV prevention efficacy. This prior, combined with the F/TDF seroconversion rate and tenofovir diphosphate levels in DISCOVER, yielded Bayesian inferences on the counterfactual bHIV.
There were six versus 11 postbaseline HIV infections (0.14 vs. 0.25/100 person-years [PY]) on F/TAF and F/TDF respectively. Of the 11 on F/TDF, 10 had low, none had medium and one had high tenofovir diphosphate levels; among HIV-negative controls, 5% of the person-time years had low, 9% had medium and 86% had high TFV-DP levels. A non-informative prior distribution for counterfactual bHIV, combined with the prior for TFV-DP level-efficacy relationship, yielded a posterior counterfactual bHIV of 3·4 infections/100 PY (0.80 Bayesian credible interval [CrI] 1·9 to 5·9), which suggests a median HIV efficacy of 96% (0.95 CrI [88% to 99%]) for F/TAF and 93% (0.95 CrI [87% to 96%]) for F/TDF compared to bHIV.
Based on the established connection of drug concentrations to PrEP prevention efficacy, a Bayesian framework can be used to estimate a synthetic non-PrEP control group in randomized, active-controlled PrEP trials that include a F/TDF-comparator group.
针对 HIV 暴露前预防 (PrEP) 的新药物的随机试验将与恩曲他滨和替诺福韦富马酸酯（F/TDF）进行比较，而没有安慰剂组。我们利用 F/TDF 的良好特征化的依从性-疗效关系，对一种新型 PrEP 药物的随机试验中的（非 PrEP）反事实背景 HIV 发病率（bHIV）进行回溯计算，并估计比较疗效（针对反事实 bHIV）。
DISCOVER 试验（ClinicalTrials.gov：NCT02842086）随机分配了 5387 名男男性行为者（MSM）和与男性发生性关系的跨性别女性，并证明了恩曲他滨和替诺福韦艾拉酚胺（F/TAF）与 F/TDF 相比非劣效性（HIV 发病率比[IRR]0.47，95%CI：0.19 至 1.15）。对所有诊断出 HIV 的患者和队列中随机的 10%患者进行了干血斑（DBS）中替诺福韦二磷酸盐（TFV-DP）水平的评估。我们使用了一种贝叶斯模型，该模型具有从与替诺福韦二磷酸盐水平与 HIV 预防疗效相关的既定数据中得出的弥散先验分布。该先验与 F/TDF 血清转换率和 DISCOVER 中的替诺福韦二磷酸盐水平相结合，对反事实 bHIV 进行了贝叶斯推断。
F/TAF 和 F/TDF 组分别有 6 例和 11 例（0.14 与 0.25/100 人年[PY]）在基线后发生 HIV 感染。在 F/TDF 组的 11 例中，1 例的替诺福韦二磷酸盐水平低，1 例的替诺福韦二磷酸盐水平中，1 例的替诺福韦二磷酸盐水平高；在 HIV 阴性对照组中，5%的人年时间有低水平的 TFV-DP 水平，9%的人年时间有中水平的 TFV-DP 水平，86%的人年时间有高水平的 TFV-DP 水平。对反事实 bHIV 的非信息先验分布，与 TFV-DP 水平-疗效关系的先验分布相结合，得出反事实 bHIV 为 3.4 例/100 PY（0.80 贝叶斯可信区间[CrI]1.9 至 5.9），这表明 F/TAF 的 HIV 疗效中位数为 96%（0.95 CrI[88%至 99%]），F/TDF 为 93%（0.95 CrI[87%至 96%]），与 bHIV 相比。
基于药物浓度与 PrEP 预防疗效的既定联系，可以使用贝叶斯框架在包括 F/TDF 对照的随机、活性对照的 PrEP 试验中估计合成非 PrEP 对照组，这些试验包含了 F/TDF 对照。
