Quantifying an Adherence Path-Specific Effect of Antiretroviral Therapy in the Nigeria PEPFAR Program

TL;DR

This paper develops a new method to quantify how adherence specifically influences the effectiveness of antiretroviral therapy, accounting for confounding factors like drug toxicity, with application to Nigerian HIV treatment data.

Contribution

It introduces a novel estimator for adherence-specific effects in mediation analysis that relaxes traditional assumptions, applicable to real-world HIV treatment data.

Findings

Adherence significantly mediates ART effectiveness.

The proposed method remains valid despite drug toxicity confounding.

Application to Nigerian data reveals key adherence effects.

Abstract

Since the early 2000s, evidence has accumulated for a significant differential effect of first-line antiretroviral therapy (ART) regimens on human immunodeficiency virus (HIV) viral load suppression. This finding was replicated in our data from the Harvard President's Emergency Plan for AIDS Relief (PEPFAR) program in Nigeria. Investigators were interested in finding the source of these differences, i.e., understanding the mechanisms through which one regimen outperforms another, particularly via adherence. This question can be naturally formulated via mediation analysis with adherence playing the role of a mediator. Existing mediation analysis results, however, have relied on an assumption of no exposure-induced confounding of the intermediate variable, and generally require an assumption of no unmeasured confounding for nonparametric identification. Both assumptions are violated by the presence of drug toxicity. In this paper, we relax these assumptions and show that certain path-specific effects remain identified under weaker conditions. We focus on the path-specific effect solely mediated by adherence and not by toxicity and propose an estimator for this effect. We illustrate with simulations and present results from a study applying the methodology to the Harvard PEPFAR data. Supplementary materials are available online.