Estimating Counterfactual Placebo HIV Incidence in HIV Prevention Trials Without Placebo Arms Based on Markers of HIV Exposure

Abstract

SummaryGiven recent advances in HIV prevention, future trials of many experimental interventions are likely to be “active-controlled” designs, whereby HIV negative individuals are randomized to the experimental intervention or an active control known to be effective based on a historical trial. The efficacy of the experimental intervention to prevent HIV infection relative to placebo cannot be evaluated directly based on the trial data alone. One approach that has been proposed is to leverage an HIV exposure marker, such as incident rectal gonorrhea which is highly correlated with HIV infection in populations of men who have sex with men (MSM). Assuming we can fit a model associating HIV incidence and incidence of the exposure marker, based on data from multiple historical studies, incidence of the marker in the active-controlled trial population can be used to infer the HIV incidence that would have been observed had a placebo arm been included, i.e. a “counterfactual placebo”, and to evaluate efficacy of the experimental intervention relative to this counterfactual placebo. We formalize this approach and articulate the underlying assumptions, develop an estimation approach and evaluate its performance in finite samples, and discuss the implications of our findings for future development and application of the approach in HIV prevention. Improved HIV exposure markers and careful assessment of assumptions and study of their violation are needed before the approach is applied in practice.

Efficacy estimates of oral pre-exposure prophylaxis for HIV prevention in cisgender women with partial adherence

“…The preventive e cacy of these new products can only be derived from counterfactual estimates of placebo incidence. 28 Such counterfactual placebos often rely on baseline estimates of recent infection in the enrolled population, 29 markers of HIV exposure such as STIs, 30 or propensity scores. 31 For MSM/TGW, counterfactual estimates can also be constructed from the active placebo arm using the adherence-e cacy relationship with TFV-DP in DBS; 32 our work will allow that method to be extended to women's studies.…”

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

“…Another approach leverages the historical correlation between incidence of HIV and other sexually transmitted infections (STIs) to estimate counterfactual placebo HIV incidence [46][47][48]. The historical studies must have been conducted in contexts without HIV or STI biomedical interventions that would change their correlation, for example, without HIV PrEP or doxycycline postexposure prophylaxis (PEP) to prevent bacterial STIs.…”

“…The historical studies must have been conducted in contexts without HIV or STI biomedical interventions that would change their correlation, for example, without HIV PrEP or doxycycline postexposure prophylaxis (PEP) to prevent bacterial STIs. There are three other strong assumptions underlying the method [48]: (i) there is a common correlation between HIV incidence and STI incidence across the historical studies and the active-controlled trial; (ii) the common correlation can be estimated with historical data; and (iii) at least one intervention in the activecontrolled trial does not influence acquisition of the STI. This approach is applied to HVTN 704/HPTN 085, with results shown in Table 1 and methods described in Supplemental Materials, http://links.…”