Control groups for HIV prevention efficacy trials: what does the future hold?

Abstract

Purpose of review: Ending the HIV epidemic will require the development of additional effective immune-mediated and nonimmune-mediated means of HIV prevention. Evaluating novel interventions requires large, controlled trials demonstrating efficacy. Recent advances in the field of HIV prevention necessitate new approaches to efficacy trial design.

Recent findings: Three classes of efficacy trial designs are possible: standard of prevention-controlled trials, active-controlled trials, and active-controlled trials augmented with external control data. Recent experience with these approaches provides lessons on considerations around and success of the designs. Additional experience and development is needed for the augmented active-controlled trial design.

Summary: Efficacy trials of new HIV prevention interventions are feasible but require careful consideration, given the complexity and dynamic state of the prevention field. While standard of prevention-controlled efficacy trials are reasonable approaches for HIV vaccine and monoclonal antibody efficacy trials, trials of new antiretroviral agents may require active-controlled designs.

Figure 1.

Main study design options for future HIV prevention efficacy trials

Figure 2.

Historical placebo-arm HIV incidence for HIV prevention efficacy trials in women in SSA, 2011 to 2020 spanning eSwatini, Kenya, Malawi, South Africa, Uganda, Zambia, Zimbabwe, and a counterfactual placebo HIV incidence estimate based on the historical incidence data. The placebo-arm HIV incidence for HVTN 703/HPTN 081 (2016–2020; Botswana, Kenya, Malawi, Mozambique, South Africa, Tanzania, and Zimbabwe) is shown for comparison. FACTS 001 (ClinicalTrials.gov #NCT01386294) ASPIRE (ClinicalTrials.gov #NCT01617096) HVTN 703 (ClinicalTrials.gov #NCT02568215) Ring Study (IPM 027) (ClinicalTrials.gov #NCT01539226 ECHO (ClinicalTrials.gov #NCT02550067) HVTN 702 (ClinicalTrials.gov #NCT02968849)

Figure 3.

Historical placebo-arm HIV incidence for HIV prevention efficacy trials in men who have sex with men (MSM), 2004 to 2014 spanning Australia, Brazil, Canada, Dominican Republic, Ecuador, England, France, Haiti, Jamaica, Peru, Puerto Rico, South Africa, Thailand, United States, and a counterfactual placebo HIV incidence estimate based on the historical incidence data. The placebo-arm HIV incidence for HVTN 704/HPTN 085 (2016–2020; United States, Peru, Switzerland, Brazil) is shown for comparison. HPTN 039 (ClinicalTrials.gov #NCT00076232) HVTN 502 (ClinicalTrials.gov #NCT00865566) HVTN 704 (ClinicalTrials.gov #NCT02716675)iPrEx (ClinicalTrials.gov #NCT00458393) Ipergay (ClinicalTrials.gov #NCT01473472) PROUD (ClinicalTrials.gov #NCT02065986)