Revisiting trial design considerations to improve efficiency of HIV-1 vertical transmission prevention efficacy trials in infants

INTRODUCTION: While the global incidence of HIV-1 vertical transmission has reduced greatly, a persistent and unacceptable number of new infant infections continue to occur through breastfeeding. Long-acting antiretroviral agents, including injectable drugs and broadly neutralizing monoclonal antibodies, given as prophylaxis to infants hold great potential to eliminate HIV-1 transmission. However, given the low frequency of HIV-1 vertical transmission during breastfeeding in trial settings, efficient and innovative study designs will be necessary to evaluate the efficacy of agents administered to infants as prophylaxis.Key Design Considerations:We provide an overview of study design considerations and assess alternative specifications that may improve the efficiency of future trials to evaluate the efficacy of a novel agent administered to infants in preventing breastfeeding acquisition of HIV-1. We highlight key attributes of the study estimand (intervention, target population, outcomes and endpoints, intercurrent events, and population-level summaries) and discuss nuances in their specification with respect to improving efficiency. We explore alternatives to the classic randomized clinical trial framework, including augmented clinical trials that incorporate external data to supplement clinical trial data. We also provide an overview of Bayesian and transportability-based statistical analysis approaches for analyzing such augmented clinical trials. Modifications to the study design in the context of the estimand framework alone will not be sufficient to address challenges introduced by the low frequency of transmission events. Alternative study designs that incorporate external data are becoming increasingly acceptable and may help alleviate resource constraints. CONCLUSION: A multi-faceted approach will be required to design efficacy trials for postnatal prophylaxis. This work provides a guide for thinking through key study design decisions.