Balzer Laura, Staples Patrick, Onnela Jukka-Pekka, DeGruttola Victor
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Clin Trials. 2017 Apr;14(2):201-210. doi: 10.1177/1740774516679666. Epub 2017 Jan 26.
Several cluster-randomized trials are underway to investigate the implementation and effectiveness of a universal test-and-treat strategy on the HIV epidemic in sub-Saharan Africa. We consider nesting studies of pre-exposure prophylaxis within these trials. Pre-exposure prophylaxis is a general strategy where high-risk HIV- persons take antiretrovirals daily to reduce their risk of infection from exposure to HIV. We address how to target pre-exposure prophylaxis to high-risk groups and how to maximize power to detect the individual and combined effects of universal test-and-treat and pre-exposure prophylaxis strategies.
We simulated 1000 trials, each consisting of 32 villages with 200 individuals per village. At baseline, we randomized the universal test-and-treat strategy. Then, after 3 years of follow-up, we considered four strategies for targeting pre-exposure prophylaxis: (1) all HIV- individuals who self-identify as high risk, (2) all HIV- individuals who are identified by their HIV+ partner (serodiscordant couples), (3) highly connected HIV- individuals, and (4) the HIV- contacts of a newly diagnosed HIV+ individual (a ring-based strategy). We explored two possible trial designs, and all villages were followed for a total of 7 years. For each village in a trial, we used a stochastic block model to generate bipartite (male-female) networks and simulated an agent-based epidemic process on these networks. We estimated the individual and combined intervention effects with a novel targeted maximum likelihood estimator, which used cross-validation to data-adaptively select from a pre-specified library the candidate estimator that maximized the efficiency of the analysis.
The universal test-and-treat strategy reduced the 3-year cumulative HIV incidence by 4.0% on average. The impact of each pre-exposure prophylaxis strategy on the 4-year cumulative HIV incidence varied by the coverage of the universal test-and-treat strategy with lower coverage resulting in a larger impact of pre-exposure prophylaxis. Offering pre-exposure prophylaxis to serodiscordant couples resulted in the largest reductions in HIV incidence (2% reduction), and the ring-based strategy had little impact (0% reduction). The joint effect was larger than either individual effect with reductions in the 7-year incidence ranging from 4.5% to 8.8%. Targeted maximum likelihood estimation, data-adaptively adjusting for baseline covariates, substantially improved power over the unadjusted analysis, while maintaining nominal confidence interval coverage.
Our simulation study suggests that nesting a pre-exposure prophylaxis study within an ongoing trial can lead to combined intervention effects greater than those of universal test-and-treat alone and can provide information about the efficacy of pre-exposure prophylaxis in the presence of high coverage of treatment for HIV+ persons.
多项整群随机试验正在进行，以调查普遍检测与治疗策略在撒哈拉以南非洲地区艾滋病毒疫情防控中的实施情况及效果。我们考虑在这些试验中嵌套暴露前预防研究。暴露前预防是一项总体策略，即高危未感染艾滋病毒者每天服用抗逆转录病毒药物以降低因接触艾滋病毒而感染的风险。我们探讨了如何将暴露前预防措施靶向应用于高危人群，以及如何最大限度地提高检测普遍检测与治疗策略及暴露前预防策略的个体和联合效果的效能。
我们模拟了1000项试验，每项试验由32个村庄组成，每个村庄有200人。在基线时，我们对普遍检测与治疗策略进行随机分组。然后，在3年的随访期后，我们考虑了四种靶向暴露前预防的策略：（1）所有自我认定为高危的未感染艾滋病毒者；（2）所有被其感染艾滋病毒的伴侣（血清学不一致的夫妻）认定为高危的未感染艾滋病毒者；（3）社交网络高度关联的未感染艾滋病毒者；（4）新诊断出的感染艾滋病毒个体的未感染艾滋病毒的性伴（基于环的策略）。我们探索了两种可能的试验设计，所有村庄的随访期共计7年。对于试验中的每个村庄，我们使用随机块模型生成二分（男性 - 女性）网络，并在这些网络上模拟基于主体的疫情传播过程。我们使用一种新颖的靶向最大似然估计器来估计个体和联合干预效果，该估计器通过交叉验证从预先指定的库中数据自适应地选择能使分析效率最大化的候选估计器。
普遍检测与治疗策略平均将3年累积艾滋病毒发病率降低了4.0%。每种暴露前预防策略对4年累积艾滋病毒发病率的影响因普遍检测与治疗策略的覆盖率而异，覆盖率较低时暴露前预防的影响更大。为血清学不一致的夫妻提供暴露前预防措施导致艾滋病毒发病率降低幅度最大（降低2%），而基于环的策略几乎没有影响（降低0%）。联合效果大于任何一种个体效果，7年发病率降低幅度在4.5%至8.8%之间。靶向最大似然估计在对基线协变量进行数据自适应调整后，与未调整分析相比，显著提高了效能，同时保持了名义置信区间覆盖率。
我们的模拟研究表明，在正在进行的试验中嵌套暴露前预防研究可能会带来比单独的普遍检测与治疗更大的联合干预效果，并能在艾滋病毒感染者治疗覆盖率较高的情况下提供有关暴露前预防效果的信息。
