Challenges in estimating the counterfactual placebo HIV incidence rate from a registration cohort: The PrEPVacc trial.

Background: There is increasing recognition that the interpretation of active-controlled HIV prevention trials should consider the counterfactual placebo HIV incidence rate, that is, the rate that would have been observed if the trial had included a placebo control arm. The PrEPVacc HIV vaccine and pre-exposure prophylaxis trial (NCT04066881) incorporated a pre-trial registration cohort partly for this purpose. In this article, we describe our attempts to model the counterfactual placebo HIV incidence rate from the registration cohort.

Methods: PrEPVacc was conducted at four study sites in three African countries. During the set up of the trial, potential participants were invited to join a registration cohort, which included HIV testing every 3 months. The trial included a non-inferiority comparison of two daily, oral pre-exposure prophylaxis regimens (emtricitabine/tenofovir disoproxil fumarate, emtricitabine/tenofovir alafenamide fumarate), administered for a target duration of 26 weeks (until 2 weeks after the third of four vaccinations). We developed a multi-variable Poisson regression model to estimate associations in the registration cohort between HIV incidence and baseline predictors (socio-demographic and behavioural variables) and time-dependent predictors (calendar time, time in follow-up). We then used the estimated regression coefficients together with participant characteristics in the active-controlled pre-exposure prophylaxis trial to predict a counterfactual placebo incidence rate. Sensitivity analyses regarding the effect of calendar period were conducted.

Results: A total of 3255 participants were followed up in the registration cohort between July 2018 and October 2022, and 1512 participants were enrolled in the trial between December 2020 and March 2023. In the registration cohort, 106 participants were diagnosed with HIV over 3638 person-years of follow-up (incidence rate = 2.9/100 person-years of follow-up (95% confidence interval: 2.4-3.5)). The final statistical model included terms for study site, gender, age, occupation, sex after using recreational drugs, time in follow-up, and calendar period. The estimated effect of calendar period was very strong, an overall 37% (95% confidence interval: 19-51) decline per year in adjusted analyses, with evidence that this effect varied by study site. In sensitivity analyses investigating different assumptions about the precise effect of calendar period, the predicted counterfactual placebo incidence ranged between 1.2 and 3.7/100 person-years of follow-up.

Conclusion: In principle, the use of a registration cohort is one of the most straightforward and reliable methods for estimating the counterfactual placebo HIV incidence. However, the predictions in PrEPVacc are complicated by an implausibly large calendar time effect, with uncertainty as to whether this can be validly extrapolated over the period of trial follow-up. Other limitations are discussed, along with suggestions for mitigating these in future studies.