Estimating Risks of Central Nervous System Disturbance Associated with Medications for Herpes Zoster: Findings from a Regional Population-Based Cohort Study Using the Shizuoka Kokuho Database.

Background: Herpes zoster commonly occurs in older adults, whose renal function often declines, necessitating careful dosing of antivirals such as acyclovir, valacyclovir, and famciclovir. Insufficient dose adjustment can increase central nervous system (CNS) disturbance risk. Although previous reports show varying neurotoxic risk among these drugs, the safety profiles of these drugs remain underexplored. CNS disturbance significantly impacts quality of life, but it is rare and primarily documented through case reports, with little thorough investigation or comparison across drugs.

Objective: This study aims to evaluate the potential risks of CNS disturbance associated with acyclovir and valacyclovir compared with famciclovir in patients with herpes zoster, highlighting the potential influence of renal function and dose adjustments.

Methods: We conducted a population-based cohort study using data from the National Health Insurance and the Late-Stage Medical Care System for the Elderly in Japan, including patients diagnosed with herpes zoster and newly prescribed oral or intravenous antiviral drugs between April 2012 and September 2021. The outcome was defined as the occurrence of CNS disturbance within 1 month from the index date. Patients with neurological, infectious or psychiatric disorders during the 1-year baseline period were excluded. The incidence of CNS disturbance with 95% confidence intervals (CIs) was compared between dialysis and nondialysis patients, owing to incomplete renal function data. In addition, we compared the incidence of CNS disturbance among groups using propensity score matching to adjust for confounders, with famciclovir users as the control group. Postmatching, risk differences with 95% CIs, and number needed to harm (NNH) were calculated.

Results: The final cohort consisted of 82,646 patients (8646 acyclovir, 46,643 valacyclovir, and 27,357 famciclovir users). Severe renal dysfunction was associated with CNS disturbance. The CNS disturbance incidence was 0.33% in nondialysis and 2.29% (risk difference 1.96%, 95% CI [0.39-3.53]) in dialysis patients using acyclovir/valacyclovir versus 0.18% and 0.60% (risk difference 0.42%, 95% CI [- 0.76 to 1.6]) for famciclovir, respectively. After propensity score matching, CNS disturbances were observed in 0.50% of patients in the acyclovir group versus 0.17% in the famciclovir group and in 0.29% of patients in the valacyclovir group versus 0.17% in the famciclovir group. The risk of CNS disturbance remained higher in both the acyclovir group (risk difference 0.33%, 95% CI [0.16-0.51], NNH 278) and the valacyclovir group (0.12%, [0.04-0.19], 833) compared with the famciclovir group.

Conclusions: Acyclovir and valacyclovir, when compared with famciclovir, are associated with an increased risk of CNS disturbance in patients with herpes zoster, particularly among those with severe renal dysfunction. These findings highlight the importance of careful consideration of renal function when determining antiviral dosing and support the development of clinical guidelines to enhance the safety of antiviral treatments, though further investigation into additional kidney function stages is needed.