The averted infections ratio: a novel measure of effectiveness of experimental HIV pre-exposure prophylaxis agents

摘要

There is clear evidence that tenofovir disoproxil fumarate combined with emtricitabine (TDF-FTC) is a highly efficacious oral pre-exposure prophylaxis agent for preventing the acquisition of HIV. This has consequences for the design and analysis of trials evaluating experimental pre-exposure prophylaxis regimens, which now generally include an active-control TDF-FTC arm rather than a placebo arm as a comparator. We point out major problems in the interpretation of the primary measure of effectiveness proposed for these trials, namely the ratio of the HIV incidence rates in the experimental agent and TDF-FTC arms. We argue that valid interpretation requires an assumption about one of two parameters: either the incidence rate that trial participants would have experienced had they not received pre-exposure prophylaxis or the effectiveness of the TDF-FTC within the trial. However, neither parameter is directly observed due to the absence of a no-treatment arm, requiring the use of external evidence or subjective judgement. 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 would also allow the use of smaller sample sizes, currently a major barrier to the evaluation of experimental pre-exposure prophylaxis regimens.