Abstract
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.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40801-025-00500-2.
Key Points
| Acyclovir and valacyclovir pose higher neurotoxic risk compared with famciclovir. |
| Consideration for renal function may be crucial for reducing central nervous system disturbance. |
| Updated clinical guidelines are needed for safer antiviral therapy. |
Introduction
Herpes zoster, commonly known as shingles, is a viral infection characterized by a painful rash and blisters resulting from the reactivation of the varicella zoster virus. Antiviral medications, such as acyclovir, valacyclovir, and famciclovir [1], are commonly prescribed to reduce the severity and duration of herpes zoster symptoms. The incidence of herpes zoster increases with advancing age [2], particularly in individuals over 50 years old. As age increases, renal function often declines [3], which makes proper dose adjustment essential for drugs excreted primarily through the kidneys. Central nervous system (CNS) disturbances, such as confusion, seizures, or encephalopathy, have also emerged in this population. These events may arise from both inadequate antiviral drug dosages and CNS involvement by the herpes zoster virus, and these etiologies are often clinically indistinguishable.
Previous studies have reported varying incidences of neurotoxic events associated with acyclovir, valacyclovir, and famciclovir, particularly in patients with advanced age or compromised renal function [4–13]. Because drugs such as valacyclovir, acyclovir, and famciclovir are primarily excreted through the kidneys, they tend to accumulate in individuals with renal impairment, increasing the risk of CNS disturbance. To our knowledge, despite these concerns, few comparative studies have been conducted on the incidence of CNS disturbance among different antiviral drugs because it is a rare side effect. Moreover, it is unclear whether appropriate dose reductions are consistently applied in cohort-based studies, particularly in older adults who often have declining renal function. Without clearer evidence on the interplay between aging, renal dosing, and CNS outcomes, clinicians have limited guidance on balancing efficacy with safety when choosing an antiviral regimen for herpes zoster. Given the clinical significance of CNS disturbances associated with antiviral drugs, we believe this issue warrants careful consideration. However, distinguishing between CNS disturbances caused by antiviral drugs and those resulting from infection by the herpes zoster virus remains challenging. To address this, we designed our study to clarify the differences in the prevalence of such events among anti-herpes zoster drugs, aiming to account for CNS disturbances caused by the virus itself and to better identify agents that may increase patients’ susceptibility to CNS disturbances.
Therefore, the primary objective of this study is to determine whether the incidence of CNS disturbance is increased in patients with herpes zoster treated with acyclovir and valacyclovir compared with that in those treated with famciclovir using a large claims database-based cohort. We also aim to assess the role of renal function and dosage adjustments in modulating the risk of CNS disturbance, thereby providing more robust evidence for safer clinical practice.
Materials and Methods
Database Source and Japanese Medical Insurance
This study utilized the Shizuoka Kokuho Database (SKDB), which is compiled from a database offering linked data such as demographic and registration information and medical claims for National Health Insurance (NHI) and Late-Stage Medical Care System for the Elderly (LSMCSE) subscribers in the Shizuoka Prefecture [14]. The SKDB includes information on a regional population-based longitudinal cohort that includes 2,230,848 Japanese individuals (women, n = 1,211,161, 54.3%) living in Shizuoka Prefecture, near the center of Japan (population: approximately 3.6 million), and has been used as a data source in several studies [14–16]. Comprehensive, personally linked data—including medical checkup information obtained from annual health examinations conducted by 35 municipalities in Shizuoka Prefecture—were collected, and each individual was assigned a unique identifier.
The Japanese healthcare system operates on a comprehensive insurance model. For individuals under 75 years old, there are two types of health insurance: employee health insurance, which covers employees of government bodies and large corporations, and NHI, which covers small business owners and their employees. Health insurance for individuals aged 75 and older is provided by the LSMCSE. In this analysis, we utilized NHI and LSMCSE data, which include individuals both younger than 75 years and aged 75 years and older. The SKDB records information on prescribed drug name, prescription date, daily dosage, and number of prescription days.
Study Design and Analyzed Cohort
Figure 1 illustrates the study schema. This population-based cohort study was conducted using the 2023 version of the SKDB. The dataset included 9.5 years of longitudinal data from April 2012 to September 2021. All enrollees were investigated using the individually linked data in the databases for their insurance claims. Each enrollee’s data availability period was defined as the date of insurance registration or April 2012, whichever was later, to the date of insurance withdrawal or September 2021, whichever was earlier.
Fig. 1.
Study schema; cohort entry is defined as the date of registration with the health insurance provider or 1 April 2012, whichever occurred later. The index date is defined as the date diagnosed with herpes zoster and first prescribed an antiviral drug. The follow-up period is defined as the interval between the index date and (1) the end of the study (30 September 2021), (2) the withdrawal date from the health insurance system, or (3) the death date, whichever occurred first. SKDB, Shizuoka Kokuho Database
The study period spanned from 1 April 2012 to 30 September 2021. The entry date of analyzed cohort participation was defined as either the enrollment date in corresponding health insurance organizations or 1 April 2012, whichever was later. The follow-up end date was determined as the date of occurrence of CNS disturbance within 1 month from the index date, the study end date (30 September 2021), or withdrawal from the NHI or LSMCSE, whichever was earlier. If no CNS disturbance occurred by 1 month, the observation period ended at that time.
The inclusion criterion was patients with herpes zoster who were newly prescribed an oral or intravenous antiviral drug during the above-described study period (Supplementary Material Tables 1 and 2). The exclusion criteria were the occurrence of encephalitis, herpes zoster, or Hunt syndrome during the baseline period and patients with alcohol abuse, substance abuse, depression, psychosis, or dementia, which were used to maintain specificity (Supplementary Material Table 3). For a similar reason, cases including modified names of CNS disturbance, such as “prolonged, subacute, viral, post-operative, organic, steroid, autoimmune, hypertensive, diabetic, septic, alcoholic, cyclic, recurrent, post-cardiopulmonary arrest, post-cardiac arrest, pulmonary, febrile, sequela, persistent, chronic, pre-existing, or traumatic,” within 1 month from the index date were excluded.
Among the eligible patients, famciclovir users were classified as the control group because famciclovir is thought to have low transferability to the central nervous system [17]. The acyclovir and valacyclovir groups were defined as the interest exposure groups.
Outcome
The outcome of this study was the incidence of CNS disturbance, ascertained from claims data using International Classification of Diseases, tenth revision (ICD-10) codes (Supplementary Material Table 4, definition of CNS disturbance using ICD-10 codes: F058, F059, G92, G934, R400, R401, R402, R440, and R443) [18].
Potential Confounders
Age, sex, seasonal period of herpes zoster onset, the first-prescribed year for an antiviral drug, disease classified according to the Charlson and Elixhauser comorbidity index (using only selected representative chronic conditions likely to affect immunocompetence), and medications during 1 month from the index date were considered candidate confounders (Supplementary Material Tables 5 and 6) [4]. Seasonal period was included on the basis of prior findings from a Japanese study showing that herpes zoster incidence is higher in summer and lower in winter [19]. Given the potential for shifts in prescribing trends following the launch of amenamevir [1] in 2017, the first-prescribed year for an antiviral drug was included as a confounder. Disease classified according to the Charlson and Elixhauser comorbidity index was determined to be present if the disease was identified using the ICD-10 code in the claims data [20], with a search period of 1 year before the visit date, and several conditions, such as renal disease and renal failure, were merged into a single category. Medications potentially linked to the development of CNS disturbance and drug selection were defined.
Statistical Analysis
Frequencies and percentages were calculated for categorical variables, and the mean and standard deviation were determined for continuous variables. The incidence of CNS disturbance was compared between dialysis and nondialysis patients, and the risk differences (RDs) with 95% confidence intervals (CIs) were calculated, as obtaining estimated glomerular filtration rate (eGFR) values for all cases is challenging and chronic kidney disease (CKD) may be undercoded in claims data [21]. Those who underwent dialysis during the 1-year baseline were classified as the dialysis group, while the nondialysis group was defined as patients with normal kidney function as well as those with renal impairment, such as CKD stages 1–4 and stage 5, not on dialysis [22]. A logistic regression model was used to estimate propensity scores on the basis of all prespecified covariates, predicting the probability of allocation to the exposure group. Propensity score matching was conducted using the nearest-neighbor method (caliper: 0.2). For the acyclovir group, 1:3 matching against the famciclovir group was performed. Owing to the smaller sample size of the famciclovir group, we designated it as the matching reference group in EZR [23] and matched each famciclovir-treated patient with two valacyclovir-treated patients, thereby achieving balanced cohorts for analysis. The covariate balance between groups was assessed with standardized mean differences, using a cutoff value of 0.10. Postmatching, RDs, 95% CIs, and number needed to harm (NNH, defined as the inverse of the RDs) were calculated. Additionally, we performed a subgroup analysis to estimate the RD and 95% CI on the basis of renal impairment, sex, diabetes, hypertension, and age (≥ 75 or < 75 years). Diabetes and hypertension were included because of their potential to worsen systemic vascular function. We also analyzed a cohort of patients with herpes zoster without involvement of the face, head, and trigeminal regions (Supplementary Material Table 1) because herpes zoster-related aseptic meningitis may occur more frequently in patients with skin lesions in the craniocervical distribution [24]. Furthermore, we assessed whether the prescribed antiviral dosage was appropriate for renal function using eGFR values derived from medical checkup data within 6 months before the index date. Daily dosage was calculated on the basis of the total prescribed amount and drug content, as the database does not include dosing frequency or quantity per administration. Dosages exceeding the recommended level for the patient’s renal function were classified as overdoses. In addition, the eGFR was calculated using age, sex, height, body weight, and serum creatinine [25, 26]. Missing renal function data were expected because of the use of subgroup data with medical checkups. Therefore, we conducted our analysis using only the available data. As a sensitivity analysis, the E-value for the main outcome was estimated to assess unmeasured confounders [27, 28]. We also calculated the corresponding 95% CI. All statistical analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA), EZR version 1.55 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), and R statistical software version 4.4.0 (R Group for Statistical Computing) with the EValue library.
Ethics
All enrollee data were anonymized to ensure participant confidentiality [14]. The study received approval from the Medical Ethics Committee of Shizuoka Graduate School of Public Health in Shizuoka, Japan (no. SGUPH_2021_001_070). This committee waived the requirement for informed consent.
Results
Study Population
After applying the inclusion and exclusion criteria (Fig. 2), the final study cohort consisted of 8646 patients in the acyclovir group, 46,643 patients in the valacyclovir group, and 27,357 patients in the famciclovir group. Before propensity score matching, patients in the famciclovir group were generally older. A higher prevalence of comorbidities and concomitant medication use was noted as well (Supplementary Material Table 7).
Fig. 2.
Flow diagram of study cohort enrollment. PSM, propensity score matching. *We used the famciclovir group as the reference for matching, matching each famciclovir-treated subject with two valacyclovir-treated subjects, thereby achieving balanced cohorts for analysis
Incidence of CNS Disturbance in Relation to Chronic Kidney Disease Severity and Antiviral Medication Usage
Within 1 month from the index date, 47 patients (0.54%) in the acyclovir group, 143 patients (0.31%) in the valacyclovir group, and 50 patients (0.18%) in the famciclovir group developed CNS disturbance.
We explored the association between the severity of chronic kidney disease and CNS disturbance. In the acyclovir and valacyclovir groups, the incidences of CNS disturbance in patients without and with dialysis were 182 of 54,929 (0.33%) and 8 of 349 (2.29%, risk difference 1.96%, 95% CI [0.39–3.53]), respectively. In the famciclovir group, the incidences of CNS disturbance in patients without and with dialysis were 49 of 27,191 (0.18%) and 1 of 166 (0.60%, risk difference 0.42%, 95% CI [−0.76 to 1.6]), respectively.
Comparison of CNS Disturbance Risk Before and After Propensity Score Matching
Before propensity score matching, the acyclovir group had a higher risk of CNS disturbance than that in the famciclovir group (RD 0.36%; 95% CI 0.20–0.52) without adjustment for confounders. A similar trend was observed in the valacyclovir group compared with the famciclovir group (RD 0.12%; 95% CI 0.05–0.20).
After propensity score matching, all covariates were balanced between the two groups (Table 1). During the observation period, CNS disturbance developed in 34 of 6776 patients in the acyclovir group and in 34 of 20,328 patients in the famciclovir group (RD 0.33%; 95% CI 0.16–0.51, NNH, 278, Table 2). The valacyclovir group had a higher frequency of CNS disturbance, with 125 of 43,218 patients, than the famciclovir group, with 37 of 21,609 patients (RD 0.12%; 95% CI 0.04–0.19, NNH, 833).
Table 1.
Baseline characteristics of the famciclovir group, the acyclovir and valacyclovir groups after propensity score matching
| Variable | Category | Famciclovir group | Acyclovir group | SMD | Famciclovir group | Valacyclovir group | SMD |
|---|---|---|---|---|---|---|---|
| n = 20,328 | n = 6776 | n = 21,609 | n = 43,218 | ||||
| Age | < 40 years | 534 (2.6) | 178 (2.6) | < 0.001 | 878 (4.1) | 1756 (4.1) | < 0.001 |
| 40 to < 50 years | 426 (2.1) | 142 (2.1) | 660 (3.1) | 1320 (3.1) | |||
| 50 to < 60 years | 777 (3.8) | 259 (3.8) | 1177 (5.4) | 2354 (5.4) | |||
| 60 to < 70 years | 4947 (24.3) | 1649 (24.3) | 5918 (27.4) | 11836 (27.4) | |||
| 70 to < 80 years | 7233 (35.6) | 2411 (35.6) | 7330 (33.9) | 14660 (33.9) | |||
| 80 to < 90 years | 5469 (26.9) | 1823 (26.9) | 4767 (22.1) | 9534 (22.1) | |||
| ≥ 90 years | 942 (4.6) | 314 (4.6) | 879 (4.1) | 1758 (4.1) | |||
| Age | 72.79 (12.68) | 73.35 (12.80) | 0.044 | 70.94 (13.97) | 70.88 (13.94) | 0.004 | |
| Sex | Male | 7145 (35.1) | 2394 (35.3) | 0.004 | 7554 (35.0) | 15113 (35.0) | < 0.001 |
| Seasonal period of herpes zoster onset | July to September | 5721 (28.1) | 1923 (28.4) | 0.02 | 6198 (28.7) | 12119 (28.0) | 0.03 |
| October to December | 4667 (23.0) | 1509 (22.3) | 4737 (21.9) | 10018 (23.2) | |||
| January to March | 4365 (21.5) | 1497 (22.1) | 4850 (22.4) | 9578 (22.2) | |||
| April to June | 5575 (27.4) | 1847 (27.3) | 5824 (27.0) | 11503 (26.6) | |||
| First-prescribed year for an antiviral drug | 2013 | 2901 (14.3) | 967 (14.3) | < 0.001 | 2210 (10.2) | 4420 (10.2) | < 0.001 |
| 2014 | 3240 (15.9) | 1080 (15.9) | 3056 (14.1) | 6112 (14.1) | |||
| 2015 | 3075 (15.1) | 1025 (15.1) | 3070 (14.2) | 6140 (14.2) | |||
| 2016 | 2832 (13.9) | 944 (13.9) | 3077 (14.2) | 6154 (14.2) | |||
| 2017 | 2490 (12.2) | 830 (12.2) | 3014 (13.9) | 6028 (13.9) | |||
| 2018 | 1905 (9.4) | 635 (9.4) | 2319 (10.7) | 4638 (10.7) | |||
| 2019 | 1605 (7.9) | 535 (7.9) | 1980 (9.2) | 3960 (9.2) | |||
| 2020 | 1344 (6.6) | 448 (6.6) | 1723 (8.0) | 3446 (8.0) | |||
| 2021 | 936 (4.6) | 312 (4.6) | 1160 (5.4) | 2320 (5.4) | |||
| Comorbidity | |||||||
| Cancer | Presence | 2424 (11.9) | 874 (12.9) | 0.03 | 2290 (10.6) | 4584 (10.6) | < 0.001 |
| Cerebrovascular disease | Presence | 3555 (17.5) | 1225 (18.1) | 0.015 | 3513 (16.3) | 6845 (15.8) | 0.011 |
| Chronic pulmonary disease | Presence | 4590 (22.6) | 1588 (23.4) | 0.02 | 4728 (21.9) | 9332 (21.6) | 0.007 |
| Hypothyroidism | Presence | 545 (2.7) | 192 (2.8) | 0.009 | 496 (2.3) | 1041 (2.4) | 0.007 |
| Peptic ulcer disease excluding bleeding | Presence | 3556 (17.5) | 1258 (18.6) | 0.028 | 3477 (16.1) | 6977 (16.1) | 0.001 |
| Diabetes | Presence | 1470 (7.2) | 497 (7.3) | 0.004 | 1508 (7.0) | 2988 (6.9) | 0.003 |
| Heart disease | Presence | 5162 (25.4) | 1820 (26.9) | 0.033 | 5008 (23.2) | 9846 (22.8) | 0.009 |
| Hypertension | Presence | 11099 (54.6) | 3778 (55.8) | 0.023 | 11436 (52.9) | 22626 (52.4) | 0.011 |
| Renal disease | Presence | 917 (4.5) | 330 (4.9) | 0.017 | 859 (4.0) | 1641 (3.8) | 0.009 |
| Liver disease | Presence | 2956 (14.5) | 1040 (15.3) | 0.023 | 3032 (14.0) | 6044 (14.0) | 0.001 |
| Rheumatism | Presence | 1201 (5.9) | 426 (6.3) | 0.016 | 1133 (5.2) | 2287 (5.3) | 0.002 |
| Medication | |||||||
| Amitriptyline | Presence | 163 (0.8) | 55 (0.8) | 0.001 | 149 (0.7) | 299 (0.7) | < 0.001 |
| Duloxetine | Presence | 122 (0.6) | 46 (0.7) | 0.01 | 120 (0.6) | 240 (0.6) | < 0.001 |
| Gabapentin | Presence | 6 (0.0) | 3 (0.0) | 0.008 | 3 (0.0) | 5 (0.0) | 0.002 |
| Pregabalin | Presence | 2849 (14.0) | 1102 (16.3) | 0.063 | 2996 (13.9) | 6085 (14.1) | 0.006 |
| Nonsteroidal anti-inflammatory drugs | Presence | 9553 (47.0) | 3433 (50.7) | 0.073 | 10504 (48.6) | 20810 (48.2) | 0.009 |
| Opioid | Presence | 77 (0.4) | 36 (0.5) | 0.023 | 87 (0.4) | 182 (0.4) | 0.003 |
| Steroid | Presence | 2000 (9.8) | 766 (11.3) | 0.048 | 2045 (9.5) | 4049 (9.4) | 0.003 |
| Mirogabalin | Presence | 244 (1.2) | 64 (0.9) | 0.025 | 228 (1.1) | 385 (0.9) | 0.017 |
| Tramadol | Presence | 513 (2.5) | 216 (3.2) | 0.04 | 458 (2.1) | 903 (2.1) | 0.002 |
Categorical and continuous variables are presented as n (%) and the average ± standard deviation. Baseline characteristics before propensity score matching is described in Supplementary Material Information 7
SMD standardized mean difference
Table 2.
The number of events, incidence and risk difference between exposure and control group after propensity score matching
| Exposure (control) | Group | Number of patients in exposure group | Number of events in exposure group | Incidence of events in exposure group (%) | Number of patients in control group | Number of events in control group | Incidence of events in control group (%) | Risk difference (95% CI) | |
|---|---|---|---|---|---|---|---|---|---|
| Acyclovir (versus famciclovir) | Overall | 6776 | 34 | 0.50 | 20,328 | 34 | 0.17 | 0.33 (0.16–0.51) | |
| Age | < 75 years | 3499 | 9 | 0.26 | 10,497 | 6 | 0.06 | 0.20 (0.03–0.37) | |
| ≥ 75 years | 3205 | 23 | 0.72 | 9615 | 35 | 0.36 | 0.35 (0.04–0.67) | ||
| Sex | Male | 2255 | 18 | 0.80 | 6765 | 14 | 0.21 | 0.59 (0.21–0.97) | |
| Female | 4289 | 14 | 0.33 | 12,867 | 21 | 0.16 | 0.16 (− 0.02 to 0.35) | ||
| Renal disease | Absence | 6431 | 29 | 0.45 | 19,293 | 32 | 0.17 | 0.29 (0.11–0.46) | |
| Presence | 330 | 4 | 1.21 | 330 | 1 | 0.30 | 0.91 (− 0.41 to 2.23) | ||
| Diabetes | Absence | 6257 | 28 | 0.45 | 18,771 | 34 | 0.18 | 0.27 (0.09–0.44) | |
| Presence | 371 | 4 | 1.08 | 1113 | 5 | 0.45 | 0.63 (− 0.49 to 1.75) | ||
| Hypertension | Absence | 2918 | 9 | 0.31 | 8754 | 7 | 0.08 | 0.23 (0.02–0.44) | |
| Presence | 3608 | 23 | 0.64 | 10,824 | 29 | 0.27 | 0.37 (0.09–0.65) | ||
| Valacyclovir (versus famciclovir) | Overall | 43,218 | 125 | 0.29 | 21,609 | 37 | 0.17 | 0.12 (0.04–0.19) | |
| Age | < 75 years | 25,380 | 32 | 0.13 | 12,690 | 6 | 0.05 | 0.08 (0.02–0.14) | |
| ≥ 75 years | 17,786 | 92 | 0.52 | 8893 | 30 | 0.34 | 0.18 (0.02–0.34) | ||
| Sex | Male | 14,612 | 46 | 0.31 | 7306 | 15 | 0.21 | 0.11 (− 0.03 to 0.25) | |
| Female | 27,882 | 79 | 0.28 | 13,941 | 21 | 0.15 | 0.13 (0.04–0.22) | ||
| Renal disease | Absence | 41,402 | 113 | 0.27 | 20,701 | 30 | 0.14 | 0.13 (0.06–0.20) | |
| Presence | 1256 | 10 | 0.80 | 628 | 6 | 0.96 | − 0.16 (− 1.07 to 0.75) | ||
| Diabetes | Absence | 40,182 | 111 | 0.28 | 20,091 | 33 | 0.16 | 0.11 (0.04–0.19) | |
| Presence | 2578 | 10 | 0.39 | 1289 | 6 | 0.47 | − 0.08 (− 0.52 to 0.36) | ||
| Hypertension | Absence | 20,240 | 32 | 0.16 | 10,120 | 10 | 0.10 | 0.06 (− 0.02 to 0.14) | |
| Presence | 22,278 | 92 | 0.41 | 11,139 | 26 | 0.23 | 0.18 (0.06–0.30) | ||
CI confidence interval
Subgroup Analysis: Comparison of CNS Disturbance Risk Across Specific Patient Groups
In a prespecified subgroup analysis (Fig. 3), heterogeneity was not observed between the acyclovir and famciclovir groups. In the renal disease group, matching difficulties prompted us to match the acyclovir group with the famciclovir group at a 1:1 ratio. Similarly, heterogeneity was not observed between the valacyclovir and famciclovir groups.
Fig. 3.
Subgroup analysis results in terms of risk difference. CI confidence interval
In a cohort of patients with herpes zoster excluding those with face, head, and trigeminal involvement, a similar trend was observed to that in the group with a broader definition that include these regions (RD in the acyclovir cohort, 0.31%; 95% CI 0.12–0.50, RD in the valacyclovir cohort, 0.09%; 95% CI 0.01–0.17).
Assessment of Dosage According to Renal Function Using Medical Checkup Data
In this study, we assessed the relationship between antiviral drug dosage, renal function, and the occurrence of CNS disturbance using health checkup data. Retrospectively, over 6 months from the index date, the eGFR was calculated for 11,762 of 82,646 patients. Among these 11,762, 2 patients (0.18%) in the acyclovir group, 11 patients (0.16%) in the valacyclovir group, and 3 patients (0.08%) in the famciclovir group developed CNS disturbance within 1 month after starting antiviral drug administration.
We evaluated whether the prescribed daily dosages were appropriate relative to renal function according to the drug’s package insert guidelines and based on eGFR calculations. Of the 1087 patients in the acyclovir group, 1 (0.09%) received an overdose. In the valacyclovir group, among 6776 patients, 1227 (18.1%) received overdoses. Among the famciclovir group with 3899 patients, 1552 (39.8%) received an overdose of famciclovir.
Among those who received excessive dosages, only two patients (0.16%) in the valacyclovir group and one patient (0.06%) in the famciclovir group developed CNS disturbance.
Sensitivity Analysis: Estimation of the E-value to Assess Unmeasured Confounders
We estimated the E-value using the RD to evaluate the robustness of our findings with regard to potential unmeasured confounding factors (Fig. 4, citation: https://www.evalue-calculator.com/).
Fig. 4.
E-value used to assess unmeasured confounders as a sensitivity analysis
For the acyclovir group compared with the famciclovir group, the E-value was 5.45, with a minimum E-value of 3.05. In the case of the valacyclovir group compared with the famciclovir group, the E-value was 2.77, with a minimum E-value of 1.70.
Discussion
We found that the incidence of CNS disturbance was significantly higher in patients treated with acyclovir and valacyclovir than in those treated with famciclovir. The propensity score matching analysis confirmed that acyclovir and valacyclovir were associated with a higher risk of CNS disturbance, even after adjusting for various confounders such as age, sex, and comorbid conditions. The increased risk was particularly notable in patients with chronic kidney disease, suggesting that renal function plays a crucial role in the development of CNS disturbance.
The differential risk of CNS disturbance among these antiviral agents may be attributable to their distinct pharmacokinetic properties and metabolic pathways. Acyclovir and valacyclovir are primarily excreted unchanged in the urine, and their active metabolite, 9-carboxymethoxymethylguanine (CMMG), can accumulate in patients with impaired renal function, leading to neurotoxic effects [4, 29]. By contrast, famciclovir is converted to penciclovir, which has a lower propensity for CNS penetration than acyclovir and valacyclovir and does not produce CMMG, potentially explaining the lower incidence of CNS disturbance observed with famciclovir [12]. These pharmacokinetic differences underscore the importance of considering renal function when selecting antiviral therapy for patients with herpes zoster.
Moreover, calculated NNH values indicate that one additional CNS disturbance may occur for approximately every 278 patients treated with acyclovir and every 833 patients treated with valacyclovir, compared with famciclovir. These figures provide a quantifiable measure of the modestly increased neurotoxic risk associated with acyclovir and valacyclovir. It is important that clinical guidelines incorporate both efficacy and safety considerations when selecting antiviral agents.
Our findings highlight the need for vigilant monitoring of antiviral dosing, especially in the elderly and those with renal impairment. Despite existing guidelines recommending dose adjustments on the basis of renal function, our analysis revealed instances of overdoses with valacyclovir and famciclovir, albeit with a low incidence of CNS disturbance. This finding suggests that while overdose may not always result in neurotoxicity, it remains a significant risk factor that warrants attention. Implementing clinical decision support systems and educating healthcare providers about the importance of dosing adjustments could mitigate this risk [4]. Additionally, the routine assessment of renal function before and during antiviral therapy could facilitate timely dose modifications and reduce the likelihood of adverse neurological events [5]. Future research should focus on developing optimized dosing strategies and exploring the utility of therapeutic drug monitoring to enhance the safety profiles of these antiviral agents.
Studies have documented cases where acyclovir and valacyclovir lead to CNS disturbance, especially in patients with renal impairment. For instance, Ryan et al. reported valacyclovir neurotoxicity and its kinetics in a patient with impaired kidney function, highlighting the occurrence of neurotoxic symptoms because of drug accumulation [5]. Similarly, Wang et al. described cases of valacyclovir neurotoxicity in patients undergoing peritoneal dialysis and hemodialysis, emphasizing the risks in patients with end-stage renal disease [18]. These findings emphasize the importance of careful monitoring and dosage adjustments based on renal function to minimize neurotoxic risks.
While the low incidence of CNS disturbance even in overdose cases might suggest a weak association between dosage and its occurrence, CMMG accumulation in patients with impaired renal function could contribute significantly to neurotoxic effects [29]. Famciclovir, which inhibits viral replication by targeting DNA polymerase [1], has a lower risk of inducing CNS disturbance than acyclovir and valacyclovir because of its limited penetration of the CNS. However, this reduced CNS penetration may lead to insufficient efficacy in severe cases. Clinically, valacyclovir and acyclovir are often used in such cases to achieve therapeutic concentrations in the CNS, although they carry a higher risk of CNS disturbance. Therefore, while famciclovir’s safety profile is advantageous, it may not always be the optimal choice for severe herpes zoster infections with CNS involvement. In other words, clinical guidelines that prioritize both safety and efficacy are needed to support optimal antiviral selection for patients with herpes zoster, especially those at risk of CNS involvement.
Limitations
There are several limitations of this study. First, the observational design of this study cannot definitively establish causality, and residual confounding may still exist despite propensity score matching. For example, balancing the severity of herpes zoster may be challenging. Second, relying on claims data for CNS disturbance identification may lead to misclassification or underreporting because the accuracy of diagnosis codes and reporting practices vary across medical facilities. Third, the exclusion of patients with severe psychiatric conditions or substance abuse limits the generalizability of the findings, as the study population may not represent all patients with herpes zoster treated with antiviral drugs. Fourth, differentiation between herpes encephalitis or meningitis and encephalopathy is clinically difficult; however the use of propensity score matching and comparisons between groups helps mitigate this impact. Moreover, we observed consistent results in a cohort that excluded patients with herpes zoster involvement of the face, head, and trigeminal regions, even though herpes zoster (Supplementary Material Table 1, disease code: 0539013) may include these regions. Finally, the main analysis in this study did not consider the prescribed quantity for a dose, the dosing frequency, or the adherence to the antiviral regimen, which could impact the incidence of CNS disturbance, even though this study indicated a low association between overdose and its occurrence. Future studies should include detailed dosage and adherence data to perform a more comprehensive risk assessment. Despite these limitations, our study revealed a significantly increased risk of CNS disturbance associated with acyclovir and valacyclovir, particularly in patients with herpes zoster.
Conclusions
This study highlights the increased risk of CNS disturbance associated with acyclovir and valacyclovir in patients with herpes zoster. Our comprehensive analysis of a population-based cohort revealed that these antiviral drugs are associated with a significantly higher incidence of neurotoxic events than famciclovir. These findings underscore the necessity for careful consideration and monitoring when prescribing acyclovir and valacyclovir, emphasizing the importance of renal-function-based dose adjustments to minimize neurotoxic risks and the need to develop clinical guidelines for safer antiviral treatments, though further investigation across a broader range of kidney function stages is warranted.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors thank Lisa Kreiner, PhD, from Edanz (https://jp.edanz.com/ac), for editing the English text of a draft of this manuscript.
Declarations
Funding
The Shizuoka Graduate University of Public Health conducts contract research projects for public health in Shizuoka Prefecture, including the current study. Shizuoka Prefecture provided funding for this work. The funders had no role in the study design, data collection or analysis, publication decisions, or manuscript preparation.
Conflict of interest
The authors declare that no competing interests exist.
Ethics approval
The Ethics Committee of the Shizuoka Graduate University of Public Health approved the study protocol (no. SGUPH_2021_001_070).
Consent to participate
The Medical Ethics Committee of Shizuoka Graduate School of Public Health in Shizuoka Japan waived the requirement for informed consent.
Consent for publication
Not applicable.
Data availability
According to Shizuoka Prefecture’s data use agreement with local insurers, readers cannot access the data analyzed. Researchers interested in accessing this dataset may submit an application to Shizuoka Prefecture to request access. Please contact the staff of Shizuoka Graduate University of Public Health (email: info@s-sph.ac.jp).
Code availability
Not applicable.
Author contributions
R.H. performed the statistical analysis. R.H., E.N., and A.S. interpreted the data. R.H. wrote the draft of the manuscript. R.H., E.N., H.K., H.O., H.H., N.K., and A.S. contributed to the critical revision of the manuscript. All authors have read and approved the final version of the manuscript.
Contributor Information
Eiji Nakatani, Email: nakatani.eiji.int@gmail.com.
Akira Sugawara, Email: asugawara@s-sph.ac.jp.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
According to Shizuoka Prefecture’s data use agreement with local insurers, readers cannot access the data analyzed. Researchers interested in accessing this dataset may submit an application to Shizuoka Prefecture to request access. Please contact the staff of Shizuoka Graduate University of Public Health (email: info@s-sph.ac.jp).