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Peer Reviewed

From Trials to Public Health Impact: Transportability of Causal Effects to Inform Implementation of HIV Pre-exposure Prophylaxis

Mehrotra, Megha Lynne
Advisor(s): Glidden, David V.

UC San Francisco Electronic Theses and Dissertations (2019)

With the support of several successful randomized placebo-controlled trials, the FDA approved Truvada for daily oral pre-exposure prophylaxis of HIV (PrEP) in the United States in 2012, and shortly thereafter the CDC and WHO released guidelines for widespread PrEP use by all at-risk individuals around the world. However, PrEP rollout is still is infancy, and there are several important questions regarding PrEP implementation that cannot be addressed by randomized trials. The causal transportability theory developed by Pearl and Bareinboim is a mathematically-grounded framework used to consider how effects observed in one setting might be applied to another. This dissertation proposes novel ways transportability can be applied to improve how trial results are used to inform implementation of PrEP. applies transportability to address some of these lingering questions about PrEP implementation.

The first chapter uses transportability to better understand why randomization to PrEP was effective in preventing HIV among cisgender men but not effective among transgender women in the iPrEx study. We find that after transporting the results of the trial from cisgender men to transgender women, differences in measured baseline characteristics between the populations were sufficient to explain the observed effect heterogeneity in the trial. The second chapter demonstrates how transportability can be applied to subgroup analyses of randomized controlled trials to produce target-specific guidance for how to most efficiently implement new interventions. To illustrate this approach, we transport subgroup analyses of the iPrEx trial to two hypothetical target populations and show that the subgroups with the lowest number needed to treat differs depending on the composition of the target population. The third and final chapter addresses a common practical challenge faced in applying transportability theory to real-world data: how to decide which variables to include in a transport estimator. In this chapter, we discuss the various types of unnecessary variables that may inadvertently be included in transport estimators. We use a Monte Carlo simulation study to identify what types of variables should be included to maximize the performance (with respect to mean-squared error) of the parametric g-computation transport estimator.

Together these projects highlight how transportability theory can be applied to improve translation of study results to real-world populations.

Cover page: From Trials to Public Health Impact: Transportability of Causal Effects to Inform Implementation of HIV Pre-exposure Prophylaxis

Article
Peer Reviewed

Understanding HIV Program Effects: A Structural Approach to Context Using the Transportability Framework.

UC Berkeley Previously Published Works (2019)

Background

Implementation science focuses on evaluating strategies for delivering evidence-based interventions to improve HIV prevention and treatment. The effectiveness of these implementation strategies is often context-dependent and reconciling the desire to produce generalizable knowledge in the face of these contextual interventions is a central challenge for implementation science researchers.

Methods

We provide an overview of the causal transportability theory and conceptualize context under this framework. We review how causal graphs can be used to illustrate the assumptions necessary to apply the results of a study to a new context, and we illustrate this approach using an example of a community adherence group intervention that aims to improve retention in HIV care. Finally, we discuss several key insights highlighted by the transportability theory that are relevant to implementation science researchers.

Results

By adopting causal transportability to consider how context may affect the success of an implementation strategy, researchers can formally diagnose when the results of a study are likely to generalize to a given setting. Moreover, selection diagrams can highlight what additional measurements would be needed in a target population to estimate the effect of an implementation strategy in that target population without having to repeat the initial study.

Conclusions

Transportability translates intuition about context-dependent interventions and external validity into actionable and testable insight.

Cover page: Understanding HIV Program Effects: A Structural Approach to Context Using the Transportability Framework.

Article
Peer Reviewed

Mosaic effectiveness: measuring the impact of novel PrEP methods

UC San Francisco Previously Published Works (2019)

Various ongoing trials seek to evaluate long-acting pre-exposure prophylaxis (PrEP) agents by showing that they are non-inferior to daily oral tenofovir disoproxil fumarate and emtricitabine. Trials comparing oral PrEP to new methods examine effectiveness in a setting where only one or the other is provided; however, a new product will probably be delivered in a context where oral PrEP is also available. The effectiveness of a new PrEP product is best measured by its potential effect in a context that also includes oral tenofovir disoproxil fumarate and emtricitabine as an option. We offer an alternative standard for long-acting products-a measure of the effectiveness of the new product in addition to oral tenofovir disoproxil fumarate and emtricitabine as compared with oral PrEP alone. We term this measure mosaic effectiveness. We illustrate scenarios where a novel product can fail to show non-inferiority but show substantial mosaic effectiveness, thus implying the public health value of the novel product even if it is less effective than oral PrEP. Regulatory standards should consider mosaic effectiveness, not just comparative effectiveness. We assert that measurements that combine rigor with public health relevance can accelerate progress against the HIV epidemic.

Cover page: Mosaic effectiveness: measuring the impact of novel PrEP methods

Article
Peer Reviewed

Transporting Subgroup Analyses of Randomized Controlled Trials for Planning Implementation of New Interventions.

UC San Francisco Previously Published Works (2021)

Subgroup analyses of randomized controlled trials guide resource allocation and implementation of new interventions by identifying groups of individuals who are likely to benefit most from the intervention. Unfortunately, trial populations are rarely representative of the target populations of public health or clinical interest. Unless the relevant differences between trial and target populations are accounted for, subgroup results from trials might not reflect which groups in the target population will benefit most from the intervention. Transportability provides a rigorous framework for applying results derived in potentially highly selected study populations to external target populations. The method requires that researchers measure and adjust for all variables that 1) modify the effect of interest and 2) differ between the target and trial populations. To date, applications of transportability have focused on the external validity of overall study results and understanding within-trial heterogeneity; however, this approach has not yet been used for subgroup analyses of trials. Through an example from the Iniciativa Profilaxis Pre-Exposición (iPrEx) study (multiple countries, 2007-2010) of preexposure prophylaxis for human immunodeficiency virus, we illustrate how transporting subgroup analyses can produce target-specific subgroup effect estimates and numbers needed to treat. This approach could lead to more tailored and accurate guidance for resource allocation and cost-effectiveness analyses.

Cover page: Transporting Subgroup Analyses of Randomized Controlled Trials for Planning Implementation of New Interventions.

Article
Peer Reviewed

The Role of Social Relationships in PrEP Uptake and Use Among Transgender Women and Men Who Have Sex with Men

UC San Francisco Previously Published Works (2018)

Qualitative studies suggest that social relationships play an important role in HIV pre-exposure prophylaxis (PrEP) use, but there have been few quantitative assessments of the role of social relationships in PrEP uptake or adherence. We examined the association between disclosure of study participation or LGBT identity and PrEP use in the 1603 HIV-negative participants enrolled in the iPrEx OLE study. We also evaluated the association between LGBT social group involvement and PrEP use. Study participation disclosure to parents and LGBT identity disclosure to anyone in a participant's social network were associated with greater PrEP uptake. Study participation disclosure to partners was associated with higher probability of having protective PrEP drug concentrations compared [risk difference 0.15 95% CI (0.01, 0.30)]. For each additional type of LGBT organization a participant was involved in, the probability of PrEP uptake and having protective drug concentrations increased by 0.04 [95% CI (0.03, 0.06)] and 0.04 (95% CI (0.02, 0.07)] respectively. Overall, social context was associated with PrEP use in iPrEx OLE, and should be taken into consideration when designing future PrEP implementation programs.

Cover page: The Role of Social Relationships in PrEP Uptake and Use Among Transgender Women and Men Who Have Sex with Men

Article
Peer Reviewed

Brief Report

UC San Francisco Previously Published Works (2016)

Association of HIV-1-specific T-cell responses to infection risk in seronegative individuals is controversial. We quantified and phenotypically characterized gp120-specific T-cell responses in HIV-1 exposed, but uninfected subjects enrolled in the global Pre-exposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial. IFNγ ELISpot responses were detected in 24% of subjects irrespective of infection outcome. HIV-1 gp120 envelope-specific T-cell responses were more uniformly IFN-γ+TNF-α+Mip-1β+ in persistently seronegative subjects relative to subjects who later seroconverted (median frequency of 76.5% and 66.5%, respectively). IFNγ responses targeted the V2 loop for subjects who remained seronegative. HIV-1 gp120 envelope V2 loop-specific CD8 T-cell responses may help to protect against HIV-1 acquisition.

Article
Peer Reviewed

Persistent HIV Type 1 Seronegative Status Is Associated With Lower CD8+ T-Cell Activation

UC San Francisco Previously Published Works (2016)

We leveraged data from the Preexposure Prophylaxis Initiative (iPrEx), a global trial of preexposure chemoprophylaxis against human immunodeficiency virus type 1 (HIV-1) infection, to compare T-cell activation between those who remained negative for HIV-1 and those who became infected during the trial. The frequency of CD38(+)HLA-DR(+) CD8(+) T cells was greater in those who seroconverted, relative to the frequency in those who remained uninfected (1.30% vs 0.82%, respectively; P = .005). This translated to an odds ratio of 4.26 (95% confidence interval, 1.54-11.78) for the association between CD8(+) T-cell activation and infection with HIV-1. T-cell activation may be a biomarker for elevated HIV-1 infection risk.

Cover page: Persistent HIV Type 1 Seronegative Status Is Associated With Lower CD8+ T-Cell Activation

Article
Peer Reviewed

Skating on thin ice: stimulant use and sub‐optimal adherence to HIV pre‐exposure prophylaxis

UC San Francisco Previously Published Works (2018)

Introduction

Stimulant and heavy alcohol use are prevalent and associated with elevated risk for HIV seroconversion among men who have sex with men (MSM) and transgender women. In addition, each can pose difficulties for antiretroviral adherence among people living with HIV. Scant research has examined the associations of stimulant and heavy alcohol use with adherence to daily oral pre-exposure prophylaxis (PrEP) among MSM and transgender women. To address this gap in the literature, we evaluated the hypothesis that stimulant use and binge drinking are prospectively associated with sub-optimal PrEP adherence.