Predicting HIV Incidence in the SEARCH Trial: A Mathematical Modeling Study

Abstract

Background: The SEARCH study provided community-based HIV and multidisease testing and antiretroviral therapy (ART) to 32 communities in East Africa and reported no statistically significant difference in 3-year HIV incidence. We used mathematical modeling to estimate the effect of control arm viral suppression and community mixing on SEARCH trial outcomes.

Setting: Uganda and Kenya.

Methods: Using the individual-based HIV modeling software EMOD-HIV, we configured a new model of SEARCH communities. The model was parameterized using demographic, HIV prevalence, male circumcision, and viral suppression data and calibrated to HIV prevalence, ART coverage, and population size. Using assumptions about ART scale-up in the control arm, degree of community mixing, and effect of baseline testing, we estimated comparative HIV incidence under multiple scenarios.

Results: Before the trial results, we predicted that SEARCH would report a 4%-40% reduction between arms, depending on control arm ART linkage rates and community mixing. With universal baseline testing followed by rapidly expanded ART eligibility and uptake, modeled effect sizes were smaller than the study was powered to detect. Using interim viral suppression data, we estimated 3-year cumulative incidence would have been reduced by up to 27% in the control arm and 43% in the intervention arm compared with a counterfactual without universal baseline testing.

Conclusions: Our model suggests that the active control arm substantially reduced expected effect size and power of the SEARCH study. However, compared with a counterfactual "true control" without increased ART linkage because of baseline testing, SEARCH reduced HIV incidence by up to 43%.

Conflict of interest statement

B.L.J., L.B.B., T.D.C, E.D.C., D.K., M.R.K., D.V.H., and M.L.P. have received grant funding paid to her institution from the NIH. Research reported in this article was supported by the Division of AIDS, NIAID of the National Institutes of Health under award numbers U01A1099959 and UM1AI068636 and in part by the President's Emergency Plan for AIDS Relief, the Bill and Melinda Gates Foundation, and Gilead Sciences. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the article. The remaining author has no funding or conflicts of interest to disclose.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Figures

Figure 1:

Modeled HIV prevalence among adults (aged 15-49) over time for six nodes (A) and sex- and age-specific HIV prevalence at SEARCH baseline in 2013 (B). Each orange line represents one of 250 selected model trajectories; black dots and bars represent data. In (A), data prior to 2013.5 is taken from regional DHS survey data that corresponds with the respective region of nodes of the SEARCH communities, but does not match the boundaries of the communities directly.

Figure 2:

Cumulative 3-year incidence in the control and intervention arms of the SEARCH study, based on different assumptions of mixing between SEARCH and non-SEARCH community members and ART scale-up in the control arm. In 2A, we assumed no external mixing and no additional linkage (i.e., a closed cohort with no active control); in 2B, we assumed no external mixing and maximum ART linkage due to the baseline testing campaign; in 2C, we assumed equivalent mixing between SEARCH residents and non-residents and no additional linkage; in 2D, we assumed equivalent mixing and maximum additional ART linkage.

Figure 3:

Modeled annual incidence (per 100 person-years) over time in the control (dashed lines) and intervention (solid lines) arms of the SEARCH trial, under three different scenarios: a counterfactual “true control” with no SEARCH baseline testing or interventions in either arm of the trial (gray), year 3 viral suppression in both arms of the trial but no mixing (purple), and “precision estimate” assumptions informed by baseline mobility and year 3 viral suppression in both arms of the trial (orange). Solid lines represent the intervention arm and dashed lines represent the control arm.