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Clinical Trial
. 2025 Apr 1;143(4):269-276.
doi: 10.1001/jamaophthalmol.2024.6114.

Low-Dose Valacyclovir in Herpes Zoster Ophthalmicus: The Zoster Eye Disease Randomized Clinical Trial

Elisabeth J Cohen  1 , Andrea B Troxel  2 , Mengling Liu  2 , Judith S Hochman  3 , Keith H Baratz  4 , Shahzad I Mian  5 , Mazen Y Choulakian  6 , David B Warner  7 , Ying Lu  2 , Alberta Twi-Yeboah  2 , Ting-Fang Lee  2 , Jiyu Kim  2 , Carlos Lopez-Jimenez  8 , Sarah C Laury  8 , Bennie H Jeng  9 ; ZEDS Trial Research Group
Collaborators, Affiliations
Clinical Trial

Low-Dose Valacyclovir in Herpes Zoster Ophthalmicus: The Zoster Eye Disease Randomized Clinical Trial

Elisabeth J Cohen et al. JAMA Ophthalmol. .

Abstract

Importance: High-quality evidence regarding suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) is necessary to guide care.

Objective: To determine whether suppressive valacyclovir compared with placebo delays the occurrence of new or worsening stromal keratitis (SK), endothelial keratitis (EK), iritis, or dendriform epithelial keratitis (DEK) during 12 months of treatment and if treatment benefit persisted at 18 months (secondary end point).

Design, setting, and participants: The Zoster Eye Disease Study (ZEDS) was a randomized clinical trial conducted in 95 sites from November 2017 to June 2024. Immunocompetent, nonpregnant adults with a history of an HZO rash, documented active keratitis or iritis within 1 year, and an estimated glomerular filtration rate of 45 mL/min/1.73 m2 or greater were eligible. After determined to be eligible, participants were randomized in 4 strata: age at onset (<60 years vs ≥60 years) and disease duration (<6 months vs ≥6 months).

Interventions: A total of 12 months of double-masked daily valacyclovir, 1000 mg, or placebo.

Main outcomes and measures: The primary outcome was time to first occurrence within 12 months of new or worsening SK, EK, iritis, or DEK.

Results: A total of 527 participants (median [IQR] age, 60 [50-68] years; 266 female [50.5%]; 266 in the valacyclovir group; 261 in the placebo group) were randomized in 4 strata; 481 completed 12 months, and 460 completed 18 months. Data were analyzed by intention to treat. At 12 months, primary end points occurred in 86 participants (33%) assigned to placebo and 74 (28%) assigned to valacyclovir, and at 18 months in 104 participants (40%) assigned to placebo and 86 (32%) assigned to valacyclovir. The hazard ratio (HR) of the primary end point at 12 months was 0.77 for participants taking valacyclovir vs placebo (HR, 0.77; adjusted 95% CI, 0.56-1.05; P = .09) and 0.73 at the secondary end point at 18 months (HR, 0.73; adjusted 95% CI, 0.55-0.97; P = .03). There was a reduction of multiple other secondary end points at 12 months (HR, 0.70; 95% CI, 0.52-0.95; P = .02) and 18 months (HR, 0.72; 95% CI, 0.55-0.95; P = .02).

Conclusions and relevance: Although the primary outcome did not show a 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. These results support consideration of 1 year of suppressive valacyclovir treatment for HZO.

Trial registration: ClinicalTrials.gov Identifier: NCT03134196.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Hochman reported receiving grants from the National Institutes of Health (NIH)/National Eye Institute (NEI) during the conduct of the study. Dr Baratz reported receiving grants from the NIH during the conduct of the study. Dr Mian reported grants from the NEI during the conduct of the study. Dr Warner reported receiving grants from New York University/NIH during the conduct of the study. Dr Lee reported receiving consulting fees from Wills Eye Hospital. Dr Jeng reported receiving personal fees from GSK and stock options from Kiora outside the submitted work. No other disclosures were reported.

Comment on

  • Zoster Eye Disease Study.
    Jabs DA. Jabs DA. JAMA Ophthalmol. 2025 Apr 1;143(4):285-286. doi: 10.1001/jamaophthalmol.2025.0204. JAMA Ophthalmol. 2025. PMID: 40048156 No abstract available.

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