Time-Varying Effects of Valacyclovir Prophylaxis in the Zoster Eye Disease Study

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Importance: The Zoster Eye Disease Study (ZEDS) supports consideration of suppressive valacyclovir for 1 year to reduce risk of recurrent keratitis or iritis in patients with herpes zoster ophthalmicus (HZO). Although the primary outcome did not show benefit of suppressive valacyclovir treatment, secondary study outcomes showed treatment superiority at the 18-month end point and reduced number of multiple episodes of keratitis or iritis at both 12 and 18 months; however, it is unknown if these possible protective effects vary over time. Objective: To assess for temporal patterns of potential benefit of suppressive valacyclovir treatment to reduce risk of new or worsening stromal keratitis (SK), endothelial keratitis (EK), iritis (IR), or dendriform epithelial keratitis (DEK). Design, Setting, and Participants: This is a post hoc exploratory analysis of a multicenter, double-masked, placebo-controlled randomized clinical trial conducted in 95 centers from November 2017 to January 2023. Immunocompetent, nonpregnant adults with history of HZO rash, documented active keratitis or IR within 1 year, and estimated glomerular filtration rate of 45 mL/min/1.73 m2 or greater were eligible. Data were analyzed from September 2025 through December 2025. Intervention: Twelve months of double-masked daily valacyclovir, 1000 mg, or placebo, with 6 months of observational follow-up. Main Outcomes and Measures: The primary outcome was the time from randomization to first occurrence of new or worsening SK, EK, IR, or DEK. Results: A total of 651 participants consented and 527 were randomized (stratified by age at onset and chronicity), while 490 participants completed 12 months and 460 completed 18 months. Median (IQR) participant age was 60 years (50-68), and 266 of 527 patients (50.5%) were female. Cox proportional hazards and restricted mean survival time analyses of ZEDS data suggested greater benefit of valacyclovir over placebo in early treatment and observational periods. Time-varying Cox analyses showed lower hazards for valacyclovir during the treatment interval (hazard ratio [HR], 0.77; 95% CI, 0.56-1.05; P = .09) for 0 to 12 months and the observation interval (HR, 0.57; 95% CI, 0.27-1.18; P = .12) for more than 12 to 18 months, with lower hazard from 0 to 6 months (HR, 0.71; 95% CI, 0.49-1.01; P = .06) than from more than 6 to 12 months (HR, 0.99; 95% CI, 0.52-1.86; P = .97). Conclusions and Relevance: In this post hoc exploratory analysis of the ZEDS randomized clinical trial, prophylactic valacyclovir decreased probability of subsequent zoster-related keratitis and IR, although statistical significance was not reached. Protective effects of valacyclovir prophylaxis were localized to early treatment and observation periods, supporting previously published recommendation of 1 year of prophylaxis. Trial Registration: ClinicalTrials.gov Identifier: NCT03134196.

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