Inverse probability-of-censoring weights for the correction of time-varying noncompliance in the effect of randomized highly active antiretroviral therapy on incident AIDS or death

Abstract

In 1996-1997, the AIDS Clinical Trial Group 320 study randomized 1156 HIV-infected U.S. patients to combination antiretroviral therapy (ART) or highly active ART with equal probability. Ninety-six patients incurred AIDS or died, 51 (4 per cent) dropped out, and 290 (= 51 + 239, 25 per cent) dropped out or stopped their assigned therapy for reasons other than toxicity during a 52-week follow-up. Such noncompliance likely results in null-biased estimates of intent-to-treat hazard ratios (HR) of AIDS or death comparing highly active ART with combination ART, which were 0.75 (95 per cent confidence limits [CL]: 0.43, 1.31), 0.30 (95 per cent CL: 0.15, 0.60), and 0.51 (95 per cent CL: 0.33, 0.77) for follow-up within 15 weeks, beyond 15 weeks, and overall, respectively. Noncompliance correction using Robins and Finkelstein's (RF) inverse probability-of-censoring weights (where participants are censored at dropout or when first noncompliant) yielded estimated HR of 0.46 (95 per cent CL: 0.25, 0.85), 0.43 (95 per cent CL: 0.19, 0.96), and 0.45 (95 per cent CL: 0.27, 0.74) for follow-up within 15 weeks, beyond 15 weeks, and overall, respectively. Weights were estimated conditional on measured age, sex, race, ethnicity, prior Zidovudine use, randomized arm, baseline and time-varying CD4 cell count, and time-varying HIV-related symptoms. Noncompliance corrected results were 63 and 13 per cent farther from the null value of one than intent-to-treat results within 15 weeks and overall, respectively, and resolve the apparent non-proportionality in intent-to-treat results. Inverse probability-of-censoring weighted methods could help to resolve discrepancies between compliant and noncompliant randomized evidence, as well as between randomized and observational evidence, in a variety of biomedical fields.