  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.
