Abstract：
Standard-of-care HIV pre-exposure prophylaxis (PrEP) is highly efficacious, but uptake of and persistence on a daily oral pill is low in many settings. Evaluation of alternate PrEP products will require innovation to avoid the unpractically large sample sizes in noninferiority trials. We propose estimating HIV incidence in people not on PrEP as an external counterfactual to which on-PrEP incidence in trial subjects can be compared. HIV recent infection testing algorithms (RITAs), such as the limiting antigen avidity assay plus viral load used on specimens from untreated HIV positive people identified during screening, is one possible approach. Its feasibility is partly dependent on the sample size needed to ensure adequate power, which is impacted by RITA performance, the number of recent infections identified, the expected efficacy of the intervention, and other factors. Screening sample sizes to support detection of an 80% reduction in incidence for 3 key populations are more modest, and comparable to the number of participants in recent phase III PrEP trials. Sample sizes would be significantly larger in populations with lower incidence, where the false recency rate is higher or if PrEP efficacy is expected to be lower. Our proposed counterfactual approach appears to be feasible, offers high statistical power, and is nearly contemporaneous with the on-PrEP population. It will be important to monitor the performance of this approach during new product development for HIV prevention. If successful, it could be a model for preventive HIV vaccines and prevention of other infectious diseases.
摘要：
标准护理HIV暴露前预防（PrEP）非常有效，但是在许多情况下，每日口服药丸的摄取和持久性都很低。替代PrEP产品的评估将需要创新，以避免非劣效性试验中不切实际的大样本量。我们建议估算未使用PrEP的人群中的HIV发病率，作为可以与试验对象中的PrEP发病率进行比较的外部反事实。最近的HIV感染测试算法（RITAs），例如限制性抗原亲和力测定加上病毒载量，用于未处理的标本，在筛查过程中确定的HIV阳性人群是一种可能的方法。其可行性部分取决于确保足够功率所需的样本量，这受到RITA绩效的影响，最近发现的感染数量，干预的预期疗效，和其他因素。支持检测三个关键人群发病率降低80%的筛查样本量较为适度，与最近3期PrEP试验的参与者数量相当.在发病率较低的人群中，样本量会明显更大，假新率较高或预期PrEP疗效较低。我们提出的反事实方法似乎是可行的，提供高统计能力，几乎与PrEP人群同时发生。在艾滋病毒预防新产品开发过程中，必须监测这种方法的性能。如果成功,它可能是预防艾滋病毒疫苗和预防其他传染病的典范。
