Methodological considerations for indirect treatment comparisons of HIV incidence for long-acting injectable pre-exposure prophylaxis

Background: Given the effectiveness of pre-exposure prophylaxis (PrEP), the HIV prevention landscape is expanding rapidly – including recently approved injectable options which have shown high efficacy in clinical trials. As head-to-head trials of injectable PrEPs are not feasible, indirect treatment comparisons (ITCs) are of value to generate comparative estimates of efficacy and safety. However, several methodological challenges must be carefully considered when conducting these ITCs. This review outlines these complexities to support informed decision-making. Main text: We identified methodological considerations through a narrative review of available literature (including leveraging published systematic reviews), evidence from PrEP trials and, where applicable, reference to methodological guidelines. Our review suggests treatment effect modifiers (TEMs) for PrEP are poorly defined in the HIV PrEP literature and, due to the high efficacy of injectable compared with oral PrEP, encompass potential prognostic factors (such as background HIV incidence). Challenges in comparing potential TEMs across trials were also noted due to, for example, differences in measurement methodology and reporting timepoint for adherence. Accounting for variation in follow-up across studies within potential ITCs is critical as HIV acquisition is a rare, time-dependent event. Additionally, zero or few events occur within injectable PrEP trials in HIV, challenging variance estimation and necessitating alternative statistical approaches. Population-adjustment methods are similarly complicated. Conclusions: This review outlines key considerations and offers practical recommendations to inform robust conduct of ITCs of PrEP, and support the interpretation of results. Areas of further research to strengthen future comparative evidence are also highlighted.