Incidence of Herpes Zoster and Postherpetic Neuralgia and Herpes Zoster Vaccination Uptake in a US Administrative Claims Database

Abstract Background The objective of this study was to estimate the annual incidence rates of herpes zoster (HZ) and postherpetic neuralgia (PHN) among individuals aged ≥19 years and the proportion who received HZ vaccination among those aged ≥50 years. Methods This observational cohort study was conducted with administrative claims data from HealthVerity and included insured individuals across the US. Crude and US age- and sex-standardized incidence rates of HZ and PHN were calculated from 1 January 2019 to 31 May 2022 by calendar year in persons aged ≥19 years. Outcomes were defined as ≥1 ICD-10 diagnosis code for HZ or PHN. Analyses were stratified by age, sex, and immunocompromised status. Among those aged ≥50 years, the proportion who received 1 or 2 doses of recombinant zoster vaccine (Shingrix) or 1 dose of Zostavax was calculated. Results Standardized annual incidence rates from 2019 to 2021 were 542 to 685 per 100 000 person-years for HZ and 35 to 38 per 100 000 person-years for PHN. Rates were highest among females, older adults, and individuals who were immunocompromised. From 1 January 2019 to 31 May 2022, 4.3% and 9.0% of persons aged ≥50 years received 1 and 2 doses of Shingrix, respectively, and 0.2% received 1 dose of Zostavax. Conclusions In this US claims database analysis, HZ and PHN were more frequent among older adults, females, and individuals who were immunocompromised. Between 1 January 2019 and 31 May 2022, 9% of persons aged ≥50 years received 2 doses of the Shingrix vaccine. Greater efforts are needed to increase vaccine uptake against HZ, especially for those at highest risk.


Study Sample and Follow-up
The study design is depicted in Supplementary Figure 1.The study included adults aged ≥19 years to capture the range of those at greatest risk for acquiring HZ.Age and sex were assessed on the index date; individuals were excluded if their data had missing or conflicting sex or missing age.The index date within the calendar year of interest (2019, 2020, or 2021) was the day following 180 days of continuous enrollment (no gaps allowed).The baseline period included the start of all available data for a patient in the database from 1 December 2017, or later, through the index date.Outcomes were assessed over the course of the calendar year of interest, following the index date.A washout for the outcome of interest was applied prior to the index date to capture incident cases of HZ and PHN only and to exclude patients with prior HZ or PHN diagnosis.The washout period was assessed from 1 December 2017 (start of data range) onward such that the minimum washout period for any individual was 13 months.
When HZ vaccination was assessed, the entire data range (1 January 2019-31 May 2022) was used to maximize capture of vaccine exposure; thus, individuals in that analysis were required to have continuous enrollment from 1 January 2019 to 31 May 2022.

Outcomes
HZ and PHN were separately defined as at least 1 ICD-10 diagnosis code for HZ or PHN (any position, inpatient or outpatient setting).HZ vaccinations were defined as ≥1 dose of zoster vaccine live (Zostavax) or 1 or 2 doses of recombinant zoster vaccine (Shingrix; second dose, 30 to 210 days after the first) and were defined by Current Procedural Terminology codes and brand names.The measurement approach for defining HZ vaccinations is illustrated in Supplementary Figure 2. The codes utilized to measure HZ, PHN, and HZ vaccinations are included in Supplementary Table 1.

Statistical Analyses
All analyses were conducted on Aetion Substantiate, a scientifically validated analytic platform.Baseline demographic and patient characteristics, including age, sex, and clinical conditions, were assessed.Summary statistics included mean and SD for continuous variables and counts and proportions for categorical variables.Baseline demographics and clinical characteristics are described for all individuals in 2019, 2020, and 2021.
Incidence rates of HZ and PHN were estimated separately for each calendar year and reported per 100 000 person-years.Crude estimates of incidence rates were calculated by dividing the number of patients meeting the case definition of incident HZ or PHN by the total number of person-years within the calendar year.Overall incidence rate estimates for HZ and PHN were age and sex standardized according to 2019 US Census distributions.Analyses were stratified by age, sex, and immunocompromised categories.Immunocompromised status was based on claims indicating at least 1 of the following (relative to index): blood/stem cell transplant in the prior 2 years, history of organ transplant and immunosuppressive therapy in the prior 60 days, active cancer treatment on cohort entry with an active cancer diagnosis in the prior year, any history of primary immunodeficiency, or any history of HIV infection [8].
The count and percentage of HZ vaccinations (1 dose of Zostavax, 1 dose of Shingrix, or 2 doses of Shingrix) from 1 January 2019 to 31 May 2022 were reported overall and by age categories.The entire data range was used for assessing vaccine uptake to maximize outcome ascertainment.

Incidence Rates of HZ and PHN
The HZ analytic cohorts in 2019, 2020, and 2 and 3).In 2019, the mean (SD) age was 56.0 (15.7) years for those with HZ and 63.1 (15.0) years for those with PHN.When compared with those without HZ or PHN, those with HZ or PHN were older and more likely to be female, have comorbidities, and be immunocompromised.Distributions of baseline characteristics were similar in the 2020 and 2021 cohorts.
A total of 188 244 HZ cases were observed in 2019, 155 668 in 2020, and 141 490 in 2021 (Supplementary Table 4).The crude and standardized incidence rates of HZ per 100 000 personyears, respectively, were 674.58 4, Supplementary Table 6).Among the immunocompromised cohort, the highest incidence rates were observed in those with a history of blood/stem cell transplantation.
A total of 9649 PHN cases were observed in 2019, 8904 in 2020, and 8778 in 2021 (Supplementary Table 4).Crude and standardized incidence rates of PHN per 100 000 person-years, respectively, were 34.37 (95% CI, 33.78 4, Supplementary Table 6).Among those who were immunocompromised, the highest incidence rates were observed in those with a history of blood/stem cell transplantation.

DISCUSSION
In this observational cohort study from 2019 to 2021, the standardized annual incidence rates of HZ ranged from 542 to 685 per 100 000 person-years, and the standardized annual incidence rates of PHN ranged from 35 to 38 per 100 000 person-years.For HZ and PHN, a gradual increase in the incidence rate was observed with increasing age, and incidence rates were highest among females, older adults, and individuals who were immunocompromised.In addition, HZ vaccine uptake from 2019 to 2022 was low overall.These results provide contemporary claims-based evidence on the disease burden of HZ and PHN and HZ vaccine uptake in the United States.Our results should be interpreted in the context of published literature.Using the Optum database from 1994 to 2018, Thompson et al reported a crude incidence rate of HZ of 503 per 100 000 person-years overall, 413 per 100 000 person-years for males, and 589 per 100 000 person-years for females [5].In addition, a population-based study of adults from 1 January 1996 to 15 October 2005 based on medical record review to define HZ reported a crude incidence rate of 340 per 100 000 person-years overall, 280 per 100 000 person-years for males, and 390 per 100 000 person-years in females [3].In our claims-based study from 2019 to 2021, we found a slightly higher crude incidence rate of HZ.Moreover, Thompson et al estimated the crude incidence rate of PHN to be 65 per 100 000

Table 1 .
[8]tinued The Quan-Charlson Comorbidity Index score includes the following clinical conditions: myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, rheumatologic disease, peptic ulcer disease, mild liver disease, diabetes, diabetes with chronic complications, hemiplegia or paraplegia, renal disease, any malignancy (including leukemia or lymphoma), moderate or severe liver disease, metastatic solid tumor, and AIDS.Comorbidity weights were taken from the original Charlson Comorbidity Index by Charlson et al[8].
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