Causal indirect effect of an HIV curative treatment: mediators subject to an assay limit and measurement error

Abstract

Causal mediation analysis decomposes the total effect of a treatment on an outcome into the indirect effect, operating through the mediator, and the direct effect, operating through other pathways. One can estimate only the pure indirect effect/indirect effect relative to no treatment, rather than the total effect by combining a hypothesized treatment effect on the mediator with outcome data without treatment. Furthermore, the mediation formula holds for the pure indirect effect (or the organic indirect effect relative to no treatment) regardless of whether there is an interaction between the treatment and mediator in the outcome model. This methodology holds significant promise in selecting prospective treatments based on their indirect effect for further evaluation in randomized clinical trials. We apply this methodology to assess which of two measures of HIV persistence is a more promising target for future HIV curative treatments. We combine a hypothesized treatment effect on two mediators, and outcome data without treatment, to compare the indirect effect of treatments targeting these mediators. Some HIV persistence measurements fall below the assay limit, leading to left-censored mediators. We address this by assuming the outcome model extends to mediators below the assay limit and use maximum likelihood estimation. To address measurement error in the mediators, we adjust our estimates. Using data from completed ACTG studies, we estimate the pure or organic indirect effect of potential curative HIV treatments on viral suppression through weeks 4 and 8 after HIV medication interruption, mediated by HIV persistence measures.