Ongoing Vaccine and Monoclonal Antibody HIV Prevention Efficacy Trials and Considerations for Sequel Efficacy Trial Designs

Abstract

Four randomized placebo-controlled efficacy trials of a candidate vaccine or passively infused monoclonal antibody for prevention of HIV-1 infection are underway (HVTN 702 in South African men and women; HVTN 705 in sub-Saharan African women; HVTN 703/HPTN 081 in sub-Saharan African women; HVTN 704/HPTN 085 in U.S., Peruvian, Brazilian, and Swiss men or transgender persons who have sex with men). Several challenges are posed to the optimal design of the sequel efficacy trials, including: (1) how to account for the evolving mosaic of effective prevention interventions that may be part of the trial design or standard of prevention; (2) how to define viable and optimal sequel trial designs depending on the primary efficacy results and secondary "correlates of protection" results of each of the ongoing trials; and (3) how to define the primary objective of sequel efficacy trials if HIV-1 incidence is expected to be very low in all study arms such that a standard trial design has a steep opportunity cost. After summarizing the ongoing trials, I discuss statistical science considerations for sequel efficacy trial designs, both generally and specifically to each trial listed above. One conclusion is that the results of "correlates of protection" analyses, which ascertain how different host immunological markers and HIV-1 viral features impact HIV-1 risk and prevention efficacy, have an important influence on sequel trial design. This influence is especially relevant for the monoclonal antibody trials because of the focused pre-trial hypothesis that potency and coverage of serum neutralization constitutes a surrogate endpoint for HIV-1 infection. Another conclusion is that while assessing prevention efficacy against a counterfactual placebo group is fraught with risks for bias, such analysis is nonetheless important and study designs coupled with analysis methods should be developed to optimize such inferences. I draw a parallel with non-inferiority designs, which are fraught with risks given the necessity of making unverifiable assumptions for interpreting results, but nevertheless have been accepted when a superiority design is not possible and a rigorous/conservative non-inferiority margin is used. In a similar way, counterfactual placebo group efficacy analysis should use rigorous/conservative inference techniques that formally build in a rigorous/conservative margin to potential biases that could occur due to departures from unverifiable assumptions. Because reliability of this approach would require new techniques for verifying that the study cohort experienced substantial exposure to HIV-1, currently it may be appropriate as a secondary objective but not as a primary objective.

Application of the SLAPNAP statistical learning tool to broadly neutralizing antibody HIV prevention research

“…Gilbert61 considered this design as a potential sequel phase 2b design to the AMP trials. These baseline hazards imply sample sizes (see Table 2 in Gilbert 61 ).…”

Contribution to HIV Prevention and Treatment by Antibody-Mediated Effector Function and Advances in Broadly Neutralizing Antibody Delivery by Vectored Immunoprophylaxis

“…Given the potential for bNAb-mediated protection in HIV prevention and viral clearance, the question of implementation has come to the forefront. The AMP clinical trials utilized passive transfer of VRC01, a CD4bs bNAb, to measure HIV prevention in different populations, including HIV-uninfected men who have sex with men (MSM), transgender men who have sex with men, and sexually active women in sub-Saharan Africa (17,(84)(85)(86) ClinicalTrials.gov: NCT02716675 (17,(84)(85)(86). The results from these trials have been promising, with excellent safety and tolerability to bNAb administration and reduced transmission of sensitive strains.…”

“…AAVs are non-enveloped viruses that belong to the Parvoviridae family (85,86). AAVs are unable to replicate on their own, and as such require a helper virus, such as an adenovirus or herpesvirus to productively replicate within cells (87)(88)(89)(90).…”

Counterfactual estimation of efficacy against placebo for novel PrEP agents using external trial data: example of injectable cabotegravir and oral PrEP in women

“…After clinically meaningful prevention efficacy and safety is established in an RCT with a placebo arm, subsequent randomized efficacy trials compare two active agents (novel vs. proven) in an active‐control trial, typically using a non‐inferiority design [ 14 ]. A challenge in HIV prevention is that fully powered non‐inferiority designs of active‐controlled trials will not be feasible when the risk of infection is reduced to rates well below 1/100 person‐years (PYs) through the use of prevention agents with proven efficacy >90%.…”