Correcting for Noncompliance and Dependent Censoring in an AIDS Clinical Trial with Inverse Probability of Censoring Weighted (IPCW) Log‐Rank Tests

TLDR

The study demonstrates that bactrim improves survival, but intent‑to‑treat analysis missed this benefit due to high crossover and discontinuation. The authors used ACTG 021, a randomized trial comparing bactrim to aerosolized pentamidine, and applied inverse probability of censoring weighted Kaplan–Meier and Cox estimators treating therapy discontinuation or switching as dependent censoring, adjusting for time‑dependent prognostic factors. Patients on bactrim had a delayed time to POP, yet overall survival did not differ significantly between arms (p = 0.32), but the weighted analysis revealed a survival benefit for bactrim. Summary.

Abstract

Summary. AIDS Clinical Trial Group (ACTG) randomized trial 021 compared the effect of bactrim versus aerosolized pentamidine (AP) as prophylaxis therapy for pneumocystis pneumonia (POP) in AIDS patients. Although patients randomized to the bactrim arm experienced a significant delay in time to POP, the survival experience in the two arms was not significantly different ( p = .32). In this paper, we present evidence that bactrim therapy improves survival but that the standard intent‐to‐treat comparison failed to detect this survival advantage because a large fraction of the subjects either crossed over to the other therapy or stopped therapy altogether. We obtain our evidence of a beneficial bactrim effect on survival by artificially regarding the subjects as dependently censored at the first time the subject either stops or switches therapy; we then analyze the data with the inverse probability of censoring weighted Kaplan‐Meier and Cox partial likelihood estimators of Robins (1993, Proceedings of the Biopharmaceutical Section, American Statistical Association , pp. 24–33) that adjust for dependent censoring by utilizing data collected on time‐dependent prognostic factors.