Medical Research Council Clinical Trials Unit, University College London, London, UK; Institute for Global Health, University College London, London, UK.
Division of Biostatistics, University of California, San Francisco, CA, USA.
Lancet HIV. 2018 Jun;5(6):e329-e334. doi: 10.1016/S2352-3018(18)30045-6.
Tenofovir disoproxil fumarate combined with emtricitabine is a highly effective oral pre-exposure prophylaxis (PrEP) agent for preventing the acquisition of HIV. This effectiveness has consequences for the design and analysis of trials assessing experimental PrEP regimens, which now generally include an active-control tenofovir disoproxil fumarate plus emtricitabine group, rather than a placebo group, as a comparator. Herein, we describe major problems in the interpretation of the primary measure of effectiveness proposed for these trials, namely the ratio of HIV incidence in the experimental agent group to that in the active-control group. We argue that valid interpretation requires an assumption about one of two parameters: either the incidence among trial participants had they not received PrEP or the effectiveness of tenofovir disoproxil fumarate plus emtricitabine within the trial. However, neither parameter is directly observed because of the absence of a no-treatment group, thus requiring the use of external evidence or subjective judgment. We propose an alternative measure of effectiveness based on the concept of averted infections, which incorporates one of these parameters. The measure is simple to interpret, has clinical and public health relevance, and is a natural preservation-of-effect criterion for assessing statistical non-inferiority. Its adoption could also allow the use of smaller sample sizes, currently a major barrier to the assessment of experimental PrEP regimens.
富马酸替诺福韦二吡呋酯联合恩曲他滨是一种高效的口服暴露前预防（PrEP）药物，可预防 HIV 的感染。这种有效性对评估实验性 PrEP 方案的试验设计和分析产生了影响，这些试验现在通常包括一个活性对照富马酸替诺福韦二吡呋酯联合恩曲他滨组，而不是安慰剂组作为对照。在此，我们描述了这些试验中提出的主要有效性指标（即实验药物组与活性对照组相比 HIV 发病率的比值）的解释存在的主要问题。我们认为，有效的解释需要对两个参数之一做出假设：要么是参与者未接受 PrEP 的情况下的发病率，要么是试验中富马酸替诺福韦二吡呋酯联合恩曲他滨的有效性。然而，由于缺乏无治疗组，这两个参数都无法直接观察到，因此需要使用外部证据或主观判断。我们提出了一种基于预防感染概念的替代有效性衡量标准，该标准包含了这两个参数之一。该衡量标准易于解释，具有临床和公共卫生相关性，是评估统计学非劣效性的自然效果保持标准。它的采用还可以允许使用更小的样本量，这目前是评估实验性 PrEP 方案的主要障碍。
