Effect of acyclovir on herpetic ocular recurrence using a structural nested model

Noncompliance with assigned therapies is ubiquitous in randomized clinical trials. Treatment effects may be corrected for noncompliance using Robins' structural nested models, but few examples have been published. The Herpetic Eye Disease Study randomized 703 ocular herpes patients to 365 days of acyclovir or placebo between 1992 and 1996, and achieved over 90% compliance in both arms. The hazard of recurrence in the acyclovir arm was 0.55 times the hazard in the placebo arm using an intent-to-treat approach (95% confidence interval [CI]: 0.41, 0.75). Assuming a structural nested model with a Weibull distribution, the hazard of recurrence under constant exposure to acyclovir was 0.41 times that of the non-exposed (test-based 95% CI: 0.28, 0.72), or 34% larger than the intent-to-treat estimate. Notwithstanding excellent compliance, intent-to-treat estimates may notably undervalue the causal effect of a treatment.