Analysing direct effects in randomized trials with secondary interventions: An application to human immunodeficiency virus prevention trials
The 'Methods for improving reproductive health in Africa' trial is a recently completed randomized trial that investigated the effect of diaphragm and lubricant gel use in reducing infection by the human immunodeficiency virus (HIV) among susceptible women. 5045 women were randomly assigned to either the active treatment arm or not. Additionally, all subjects in both arms received intensive condom counselling and provision, the 'gold standard' HIV prevention barrier method. There was much lower reported use of condoms in the intervention arm than in the control arm, making it difficult to answer important public health questions based solely on the intention-to-treat analysis. We adapt an analysis technique from causal inference to estimate the 'direct effects' of assignment to the diaphragm arm, adjusting for use of condoms in an appropriate sense. Issues raised in the trial apply to other trials of HIV prevention methods, some of which are currently being conducted or designed.