Nancy S. Padian

HIV prevention transformed: the new prevention research agenda

We have entered a new era in HIV prevention whereby priorities have expanded from biomedical discovery to include implementation, effectiveness, and the effect of combination prevention at the population level. However, gaps in knowledge and implementation challenges remain. In this Review we analyse trends in the rapidly changing landscape of HIV prevention, and chart a new path for HIV prevention research that focuses on the implementation of effective and efficient combination prevention strategies to turn the tide on the HIV pandemic.

Implementation science for the US President's Emergency Plan for AIDS Relief (PEPFAR).

Working with implementing organizations and governments in over 32 countries, the US President’s Emergency Plan for AIDS Relief (PEPFAR) has contributed to the rapid acceleration of HIV treatment access, availability of care and support services, and HIV prevention interventions. In the first phase of PEPFAR, these activities were appropriately carried out in an emergency fashion with the goal of using available interventions to reduce mortality and alleviate suffering from HIV disease as quickly and effectively as possible. Many lessons have been learned through examination of programs, including simple evaluations and operations research. Commensurate with the emergency response, however, state-of-the-art monitoring, evaluation, and research methodologies were not fully integrated or systematically performed. In the second phase of PEPFAR, characterized by an increased emphasis on sustainability, programs must demonstrate value and impact to be prioritized within complex and resource-constrained environments. In this context, there is a greater demand to causally attribute outcomes to programs. Better attribution can be used to inform midcourse corrections in the scale-up of new interventions (eg, male circumcision) or to reevaluate investments in programs for which impact is less clear. To meet these demands, PEPFAR is adopting an implementation science (IS) framework to improve the development and effectiveness of its programs at all levels. IS is the study of methods to improve the uptake, implementation, and translation of research findings into routine and common practices (the ‘‘know-do’’ or ‘‘evidence to program’’ gap). For example, IS was used to evaluate the routine operational effectiveness of the South African National Prevention of Mother-to-Child Transmission Programme. Investigators explored the survival of HIV-free infants across program sites and identified specific sources of variation such as health system factors (eg, limited antenatal visits and lack of syphilis screening) and individual behaviors (eg, breastfeeding practices). By framing the problem through IS, the study revealed opportunities for improving program performance that could be translated into immediate solutions (eg, improving quality of care, infant feeding counseling). In this way, IS proved to be a valuable tool that was used not only to improve program effectiveness, but also to explain what worked, why, and under what circumstances. Although no less rigorous than biomedical research dictated by a static protocol with robust internal validity (ie, ‘‘proof-of-concept’’ research with a precisely defined and narrow objective), an IS approach represents a paradigmatic shift in emphasis to greater external validity. The IS scope is also broader, seeking to improve program effectiveness and optimize efficiency, including the effective transfer of interventions from one setting to another. The methods of IS facilitate making evidence-based choices between competing or combined interventions and improving the delivery of effective and costeffective programs.

HIV Treatment as Prevention: Considerations in the Design, Conduct, and Analysis of Cluster Randomized Controlled Trials of Combination HIV Prevention

The rigorous evaluation of the impact of combination HIV prevention packages at the population level will be critical for the future of HIV prevention. In this review, we discuss important considerations for the design and interpretation of cluster randomized controlled trials (C-RCTs) of combination prevention interventions. We focus on three large C-RCTs that will start soon and are designed to test the hypothesis that combination prevention packages, including expanded access to antiretroviral therapy, can substantially reduce HIV incidence. Using a general framework to integrate mathematical modelling analysis into the design, conduct, and analysis of C-RCTs will complement traditional statistical analyses and strengthen the evaluation of the interventions. Importantly, even with combination interventions, it may be challenging to substantially reduce HIV incidence over the 2- to 3-y duration of a C-RCT, unless interventions are scaled up rapidly and key populations are reached. Thus, we propose the innovative use of mathematical modelling to conduct interim analyses, when interim HIV incidence data are not available, to allow the ongoing trials to be modified or adapted to reduce the likelihood of inconclusive outcomes. The preplanned, interactive use of mathematical models during C-RCTs will also provide a valuable opportunity to validate and refine model projections.