How to interpret low-dose valacyclovir for postherpetic neuralgia in the Zoster Eye Disease Study—a randomized clinical trial

Herpes zoster (HZ) refers to the reactivation of the varicella-zoster virus (VZV) from its latent state within the human body. In the United States, approximately one million cases of HZ are reported each year, and an estimated 32% of the population will develop zoster at some point during their lifetime. Reported incident rates vary across studies, ranging from 3.2 to 4.2 cases per 1,000 persons per year (1). HZ ophthalmicus (HZO) is defined as HZ involving the ophthalmic division of the fifth cranial nerve and accounts for approximately 10–20% of all HZ cases (2).

Postherpetic neuralgia (PHN) represents the most common long-term complication resulting from reactivation of the VZV (3). PHN is a neuropathic pain disorder in which pain persists for months to years after the resolution of the HZ rash (4). Additionally, PHN is the most frequent and clinically challenging complication of HZ (5). Evidence from prospective cohort studies demonstrates that elderly individuals with HZ have a 20–30% risk of developing PHN (6).

The pathophysiology of PHN is not fully understood but can involve inflammation-induced peripheral and central sensitization, structural and functional brain abnormalities, and disruptions in afferent nerve signaling (7). Such symptoms most commonly begin during the healing phase of a skin lesion but have also been reported during the active phase and may persist for months to years (3). Because of its complex pathogenesis, PHN pain is often refractory to conventional pharmacological therapies, which are frequently associated with multiple drug-related adverse effects (8). Currently, no definitive treatment exists for PHN (7).

Three primary therapeutic strategies can be employed in the management of PHN. The first approach is prevention, which entails identifying populations at risk for HZ and providing vaccination. The second strategy involves early recognition and prompt treatment of acute HZ, as delays may increase the likelihood of developing PHN. The third approach focuses on the management of PHN symptoms through multimodal pharmacological regimens and interventional procedures (9).

The Zoster Eye Disease Study (ZEDS) was a double-masked, randomized clinical trial designed to compare low-dose valacyclovir (1,000 mg) versus placebo in the management of PHN. The study aimed to evaluate whether low dose valacyclovir could reduce the prevalence, severity, and duration of PHN at 12 and 18 months (9).

Warner et al. (9) included 527 immunocompetent, nonpregnant adults with history of HZO rash, documented keratitis or iritis within 1 year, and an estimated glomerular filtration rate (GFR) of 45 mL/min/1.73 m². The study design, eligibility criteria, and baseline characteristics at enrollment were previously described by Cohen et al. (10) and Prescott et al. (11). However, the inclusion and exclusion criteria were broad and poorly defined, which may limit the reliability of the study findings. For example, patients with systemic conditions such as diabetes and rheumatologic diseases were not excluded. These conditions may be associated with altered immune responses, and affected patients may be receiving treatments such as corticosteroids or immunomodulatory therapies, which could have acted as confounding factors in the study. Additionally, although patients were asked about classes of pain medications, it is unclear whether the two groups were matched with respect to these medications. Furthermore, the duration of treatment with these medications prior to study participation is not clearly reported. The medications may have also influenced the outcomes of the cohort.

Of the 527 participants, 490 completed 12 months of treatment, and 460 completed 18 months. Seventy-three patients (14%) had PHN and were analyzed according to age at HZO onset (<60 vs. ≥60 years) and disease duration (recent <6 months vs. chronic ≥6 months). At 12 months, the prevalence of PHN was not lower in the valacyclovir group [12/32 (38%)] compared to the placebo group [14/35 (40%)], with a between-group difference of 2.5% [95% confidence interval (CI): −20.8% to 25.8%; P>0.99]. Participants younger than 60 years at the onset of HZO with chronic disease duration exhibited lower pain scores in the valacyclovir group compared to the placebo group at 12 months {mean [standard deviation (SD)], 0.3 (0.9) vs. 0.8 (1.9); P=0.045} and 18 months [mean (SD), 0.2 (0.9) vs. 1.0 (2.3); P=0.02]. This information is invaluable; however, it would have been better to evaluate the incidence of PHN in the low dose valacyclovir group versus the placebo group as a prophylactic treatment for PHN. While prevalence partially reflects incidence, in diseases with immunological pathogenesis and epitope spreading associated with prolonged disease duration, incidence is likely a more suitable variable for evaluating treatment effectiveness (12).

The difference in prevalence of PHN in all participants at enrollment was not statistically significant between groups [2% (95% CI: −3.8% to 8.1%; P=0.56)]. The difference in prevalence of PHN at 12 and 18 months was not significantly reduced by valacyclovir compared to placebo at 12 months [2.5% (95% CI: −20.8% to 25.8%; P>0.99)] and 18 months [6.4% (95% CI: −16.8% to 29.6%; P=0.79)]. These findings should therefore be interpreted cautiously due to potential confounding factors explained earlier. However, in a post hoc analysis stratified by age at HZO onset, participants younger than 60 years showed a lower prevalence of PHN at 18 months in the valacyclovir group (2/11; 18%) compared to the placebo group (8/13; 62%), with a between-group difference of 43.4% (95% CI: 8.4–78.3%; P=0.047). This finding may reflect a type I (false-positive) error, as no Bonferroni correction was applied for multiple comparisons. Additionally, subgroup findings, especially the age-specific subgroup findings, including possible mechanisms and interpretation are not biologically and clinically explained.

Regarding pain outcomes, the magnitude of pain reduction from enrollment over time was not significantly different between groups. However, among participants younger than 60 years at the time of HZO onset, pain scores at 12 and 18 months were lower in the valacyclovir subgroup with chronic disease. Additionally, use of neuropathic medications was less frequent among patients treated with valacyclovir. These results should be interpreted cautiously, as they may represent a type I (false-positive) error due to the absence of Bonferroni correction for multiple comparisons. In our opinion, for the analysis of longitudinal randomized data with repeated measures and potential attrition, the use of linear mixed-effects models (LMMs) or generalized estimating equations (GEE) may provide a more robust approach.

In complementing ZEDS observations, long-term antiviral therapy has been explored as a strategy to reduce recurrences and chronic inflammation in patients with HZO. In a retrospective case series, Maleki et al. (1) reported outcomes in patients receiving prolonged antiviral therapy beyond the standard acute course. In this series of 17 patients with primary, recurrent, or chronic HZO, long-term antiviral monotherapy (acyclovir or valacyclovir) demonstrated a high response rate in primary HZO (≈90.9%) and moderate response in recurrent or chronic cases (~66.7%), with a subset requiring adjunctive immunomodulatory therapy. No significant systemic adverse effects were not reported over extended follow-up periods. These findings suggest that long-term antiviral prophylaxis may help maintain remission and prevent recurrences.

Although long-term use of valacyclovir is generally considered safe, potential risks can occur, including renal complications, neurological effects, hepatic inflammation, and, in rare cases, serious hematologic especially in older population. So, patients should be monitored closely during treatment (13,14).

The main weakness of this article is the discussion section, where the authors duplicate the results section and a literature review of PHN instead of interpreting the findings. The manuscript does not adequately address the apparent discrepancy between subgroup benefits and the lack of a significant overall treatment effect. Additionally, the ZEDS population was immunocompetent; however, prolonged low-dose antiviral therapy may carry distinct risks in immunocompromised patients, including antiviral resistance and breakthrough disease, limiting generalizability of the ZEDS study findings (15,16).

In conclusion, the results of the ZEDS trial should be interpreted with caution. Further robust studies that address the limitations of the present study are required to adequately evaluate this hypothesis. At present, although these limitations preclude definitive conclusions regarding the routine use of low-dose valacyclovir for chronic suppression in HZO with PHN, its favorable safety profile supports consideration of prophylactic use against HZO-related keratitis, iritis, and PHN in both clinical and research settings.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article has undergone external peer review.

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-2025-1-182/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-2025-1-182/coif). The authors have no conflicts of interest to declare.

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