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

Abstract

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.

Figure 1.

Sensitivity analysis of averted infections ratio (AIR) in Partners PrEP Study supposing there was no placebo arm. The estimated AIR and corresponding lower 5% CL are plotted as a function of (A) the assumed placebo incidence rate and (B) the assumed effectiveness of TDF-FTC. Footnote Dashed line shows the actual values observed in Partners PrEP Study. In actual applications of this approach this information would not be available. Dotted line shows unobserved value corresponding to AIR of 50%.

Figure 1.

Sensitivity analysis of averted infections ratio (AIR) in Partners PrEP Study supposing there was no placebo arm. The estimated AIR and corresponding lower 5% CL are plotted as a function of (A) the assumed placebo incidence rate and (B) the assumed effectiveness of TDF-FTC. Footnote Dashed line shows the actual values observed in Partners PrEP Study. In actual applications of this approach this information would not be available. Dotted line shows unobserved value corresponding to AIR of 50%.

Figure 2.

Ratio of sample sizes required under the standard analytical approach compared to using the AIR, for non-inferiority trials. Footnote See Appendix for mathematical derivation.