Cross-Sectional and Longitudinal Associations Between Treatment for Herpes Virus Infection and the Dispensing of Antidementia Medicines: An Analysis of the Australian Pharmaceutical Benefits Scheme Database

Abstract

Background:

Evidence from previous observational studies suggest that infection by herpes simplex virus (HSV) and varicella zoster virus (VZV) increase the risk of dementia.

Objective:

To investigate if older adults exposed to HSV treatment have lower risk of dementia than the rest of the population.

Methods:

We used the 10% Australian Pharmaceutical Benefits Scheme (PBS) database from 2013 to 2022 to ascertain the cross-sectional, time-series and longitudinal association between exposure to HSV treatment and the dispensing of antidementia medicines. Participants were men and women aged 60 years or older. We used Anatomical Therapeutic Chemical (ATC) codes to identify medicines dispensed for the treatment of HSV and dementia.

Results:

During the year 2022 6,868 (1.2%) of 559,561 of participants aged 60 years or over were dispensed antidementia agent. The odds ratio (OR) of being dispensed an antidementia agent among individuals dispensed treatment for HSV was 0.73 (99% CI = 0.56–0.95). Multilevel logistic regression for the 2013–2022 period for those dispensed HSV treatment was 0.87 (99% CI = 0.75–1.00). Split-time span series from 2013 was associated with hazard ratio of 0.98 (99% CI = 0.89–1.07) for individuals dispensed relative to those not dispensed HSV treatment. All analyses were adjusted for age, sex, and the dispensing of medicines for the treatment of diabetes, hyperlipidemia, hypertension, and ischemic heart disease.

Conclusions:

The dispensing of antiviral medicines for the treatment of HSV and VZV is consistently, but not conclusively, associated with decreased dispensing of antidementia medicines. This suggests that treatment of HSV and VZV infections may contribute to reduce the risk of dementia.

Keywords

Keywords: Alzheimer’s disease dementia herpes simplex virus varicella zoster virus

INTRODUCTION

Dementia, a complex clinical syndrome characterized by various physiological and neuropathological changes, significantly impacts both higher cortical abilities and functional capacity [1]. The global prevalence of dementia is projected to surge from 57.4 million cases worldwide in 2019 to 152.8 million cases by 2050 [2]. This trajectory brings forth substantial associated costs and health burdens, and highlights the urgent need for effective action in the coming years [3].

Despite comprehensive research into potential medications for dementia, existing symptomatic treatments are limited in both scope and effectiveness [4]. This underscores the importance of targeting risk-modifying interventions to reduce the prevalence of dementia worldwide. The 2020 report for Dementia Prevention, Intervention and Care emphasized various risk factors for dementia including: lower educational achievement, hearing loss, hypertension, alcohol use, obesity, social isolation, physical inactivity, diabetes, air pollution and depression [1]. Promisingly, studies have indicated the potential efficacy of such interventions [5].

Herpes simplex virus (HSV) types 1 and 2 are neurotropic viruses shown to have associations with dementia [6, 7]. HSV-1, in particular, has been strongly linked to Alzheimer’s disease (AD) [8]. Similarly, varicella zoster virus (VZV), another neurotropic member within the Herpesviridae family, has also been implicated in dementia development [9]. While a recent meta-analysis failed to confirm the association between VZV and the incidence of AD [10], population based cohort studies have suggested a 10% increase in the risk of dementia with VZV infection [9]. Additionally, herpes zoster ophthalmicus (HZO), affecting the trigeminal nerve, has been associated with a 3-fold increased risk of dementia [10].

Notably, the treatment of HSV shows promise in reducing dementia risk [11, 12]. Registry-based studies in Taiwan, Sweden and Korea have reported reduced dementia risk associated with antiviral treatment for both symptomatic HSV and herpes zoster infections [13, 14]. However, this association has not been consistent across studies [15, 16], possibly because of sampling issues, confounding and differences in study design. Emerging research has also suggested that shingles vaccination against Herpes Zoster may reduce the incidence of dementia [17, 18]. Drugs currently approved for the treatment of HSV/VZV-associated diseases in Australia include acyclovir, its oral pro-drug valacyclovir, and famciclovir.

Due to the high prevalence of HSV/VZV infections in the adult population [19, 20], emphasizing antiviral management and vaccination may play a significant role in decreasing the risk of AD. We used data from the Pharmaceutical Benefits Scheme (PBS) to investigate if antiviral treatment of HSV/VZV is associated with a reduction in the prevalence and incidence of dementia in the Australian Population as measured by the dispensing of anti-dementia medicines.

METHODS

Study design, participants, and setting

The study included cross-sectional, time-series and retrospective cohort designs. Participants were men and women aged 60 years and older who were dispensed a PBS listed medicine between 2013 and 2022 (inclusively) and were captured in the PBS 10% sample. The structure and content of the PBS database have been described in detail elsewhere [21]. Briefly, the PBS 10% sample is a de-identified random sample of medications dispensed under the PBS for the entire Australian population. The PBS was implemented by the Australian government to subsidize the cost of approved medicines dispensed to Australian citizens, residents, and eligible foreign nationals.

Study measures

Individuals with dementia were identified from the dispensing of antidementia medicines indicated for the treatment of AD: donepezil, rivastigmine, galantamine, and memantine at any point during each calendar year between 2013 to 2022 using the Anatomical Therapeutic Chemical (ATC) codes N06DA and N06DX (primary outcome of interest).

The ATC code J05AB was used to identify individuals dispensed antiviral medicines for the treatment of HSV infections, and this was supplemented by an additional string search for the following agents: aciclovir (or acyclovir), famciclovir, valaciclovir (or valacyclovir) (exposure). Individuals were deemed to have been exposed to HSV treatment if they were dispensed any of these agents during each of the calendar years between 2013 and 2022.

Age was stratified into 5-year groups: 60–64, 65–69, 70–74, 75–79, and ≥85 years. Sex was recorded as male or female. We used the Rx-Risk Comorbidity Index as an indicator of comorbidity by identifying dispensed medications for the management of diabetes [A10AA01–A10BX99], hypertension [C03AA01–C03BA11, C03DB01, C03DB99, C03EA01, C09BA02–C09BA09, C09DA02–C09DA08, C02AB01–C02AC05, C02DB02–C02DB99 (C03CA01–C03CCO1 or C09CA01–C09CX99)], hyperlipidemia [A10BH03‡, C10AA01–C10BX09], and ischemic heart disease [C01DA02–C01DA14, C01DX16, C08EX02] [22, 23]. These measures were included in the analyses as possible confounding factors of the association between the dispensing of medicines for HSV and AD.

Statistical analysis

The characteristics of participants dispensed and not dispensed antidementia drugs (age, sex, and comorbidities) were summarized and compared using Pearson chi-squared tests. We investigated the association between the dispensing of pharmacological treatments for herpes, and for dementia, using four different approaches: (1) logistic regression to examine the cross-sectional association between the dispensing of these medicines during the year 2022 (odds ratio (OR)), (2) multilevel logit models examining the association between the dispensing of HSV treatment and dementia between 2013 and 2022 (OR), (3) Cox proportional hazards model examining the incidence of the dispensing of antidementia medicines among individuals dispensed HSV treatment in 2013 (hazard ratio, HR), (4) Cox proportional hazards model examining the incidence of the dispensing of antidementia medicines following the dispensing of HSV treatment (split time span series). The latter models considered participants as non-exposed until the time of exposure to antiviral treatment, and as exposed once they were dispensed HSV antiviral medicines. All analyses were adjusted for age group and sex, and for the dispensing of medicines to manage diabetes, hyperlipidemia, hypertension, and ischemic heart disease. We also completed two additional analyses that excluded individuals dispensed antidementia medicines within 2 and 5 years after the start of the follow up period to examine if the associations were consistent over time. We used t-test to examine the age difference between individuals dispensed and not dispensed HSV medicines at the time they were dispensed antidementia drugs. Due to the large sample size and complementary approaches to address the research question, alpha was set at 1% and the confidence intervals at 99%. All probability tests were two-tailed. Analyses were carried out using Stata-MP version 18.0.

Ethical considerations

The study was approved by Services Australia and the University of Western Australia Human Research Ethics Committee (2022/ET000372).

RESULTS

The 2013–2022 10% PBS sample contained 4,891,920 records related to 723,151 men and women aged 60 years or over. In 2022 6,868 (1.2%) of 559,561 individuals were dispensed an antidementia medicine. Table 1 shows their distribution by age, sex, and the dispensing of medicines for the management of diabetes, hyperlipidemia, hypertension, ischemic heart disease, and herpes. The odds ratio of being dispensed antidementia medicines among those dispensed pharmacological treatment for herpes (OR 0.73, 99% CI = 0.56–0.95) after adjustments were made for age group, sex, and the dispensing of medicines to treat diabetes, hyperlipidemia, hypertension, and ischemic heart disease. Individuals who were dispensed antiherpetic medications were more likely to be female, and have medical comorbidities such as diabetes, hyperlipidemia, and hypertension (Supplementary Table 1).

Table 1

Cross-sectional associations between the dispensing of antidementia medicines by age, sex, and the dispensing of medicines for the management of diabetes, dyslipidemia, hypertension, ischemic heart disease, and herpes during the year 2022

	No antidementia medicines	Antidementia medicines	p
	N = 552,693	N = 6,868
	n (%)	n (%)
Age, y			<0.01
60–64	126,299 (22.8)	145 (2.1)
65–69	117,465 (21.2)	334 (4.9)
70–74	107,455 (19.4)	704 (10.2)
75–79	86,801 (15.7)	1,431 (20.8)
80–84	56,939 (10.3)	1,786 (26.0)
≥85	57,734 (10.4)	2,468 (35.9)
Female sex	292,945 (53.0)	3,960 (57.7)	<0.01
Diabetes	98,019 (17.7)	1,228 (17.9)	0.754
Hyperlipidemia	246,761 (44.6)	3,298 (48.0)	<0.01
Hypertension	268,449 (48.6)	3,496 (50.9)	<0.01
Ischemic heart disease	22,707 (4.1)	366 (5.3)	<0.01
Herpes	13,064 (2.4)	103 (1.5)	<0.01

A multilevel logit model using all data available between 2013 and 2022 for the 723,151 individuals aged ≥60 years in the 10% PBS sample showed that the dispensing of HSV medicines was associated with decreased odds of dispensing of medicines for dementia (OR = 0.87, 99% CI = 0.75–1.00), adjusted for age group, sex, and the dispensing of medicines to treat diabetes, hyperlipidemia, hypertension, and ischemic heart disease. Longitudinal analysis of the data using split time span series showed an adjusted HR of 0.98 (99% CI = 0.89–1.07), which remained largely unchanged when we excluded participants dispensed antidementia medicines within the first 3 and 5 years of follow up (Table 2). Among participants dispensed antidementia agents between 2014–2022, those who had been dispensed HSV treatment beforehand were older when they were first dispensed antidementia medicines than those not dispensed HSV treatment (80.5±6.8 versus 79.8±7.4, p < 0.01).

Table 2

Longitudinal associations between the dispensing of medicines for the treatment of HSV from 2013 and the future dispensing of antidementia drugs up to 2022

Year dispensed HSV treatment	Dispensed antidementia medicines during:^*
	2014–2022	2015–2022	2018–2022
	N = 416,647	N = 394,279	N = 336,387
	HR (99% CI)	HR (99% CI)	HR (99% CI)
2013	0.95 (0.79–1.13)	0.95 (0.79–1.15)	0.92 (0.72–1.18)
Split time span series from 2013	0.98 (0.89–1.07)	0.98 (0.89–1.07)	0.95 (0.86–1.06)

^*The analyses excluded individuals dispensed antidementia medicines outside the respective range of years (i.e., year 2013 for the 2014–2022 column, years 2013–2014 for the 2015–2022 column, and years 2013–2017 for the 2018–2022 column). HR (99% CI): hazard ratio and respective 99% confidence interval (99% CI). All analyses adjusted for age group, sex, and dispensing of medicines used for treatment of diabetes, hyperlipidemia, hypertension, and ischemic heart disease.

DISCUSSION

Our study found suggestive, but inconclusive evidence that use of antiviral medications for HSV and VZV is associated with a decreased risk of dementia. Time-series analyses spanning from 2013 to 2022 indicated that older Australians aged over 60 years, who were dispensed antiherpetic medications, were 13% less likely to be dispensed antidementia medications. Based on cross-sectional data, individuals dispensed antiherpetic medications were 27% less likely to also receive antidementia drugs compared to those not dispensed antiherpetic medicines, although the direction of the association was unclear. A time-series analysis covering a 10-year period showed that older individuals exposed to HSV treatment were 13% less likely to be dispensed medicines for the management of AD. The findings of our longitudinal analyses could not dismiss the null hypothesis regarding the association between exposure to HSV medicines and the dispensing of anti-dementia agents.

Our findings are generally consistent with those of previous population-based studies conducted across various administrative databases, investigating the impact of antiherpetic medications on dementia risk. Tzeng and colleagues, using a Taiwanese administrative database, reported a 90% reduction in dementia risk with the use of anti-herpetic medications [14]. Other population studies utilizing administrative databases from South Korea and Sweden described similar results, with individuals treated at least once with antiherpetic medications having 10% –24% lower risk of dementia compared to untreated individuals [13 , 24]. A Swedish nested case-control study of people infected with HSV-1 (confirmed by positive IgG), found that individuals treated with antiherpetic agents had 71% lower odds of AD compared with controls [25]. Ongoing research in Sweden, involving a clinical trial of valacyclovir for early AD, is expected to provide further insights into dementia treatment and prevention [26].

The underlying mechanisms of the association between HSV infections and dementia remain unclear. Early research by Libikova et al. in 1975 provided initial insight, after noting an increased incidence of HSV 1 serum antibodies in cerebrospinal fluid of individuals with dementia [27]. Subsequent efforts were made to establish a link between herpes infection and AD using neuronal and glial cell cultures. Wozniak et al observed a direct induction of amyloid-β production by HSV1 in both cell cultures and mice, a characteristic feature of AD [28]. Subsequently, in 2008, Zambrano et al. demonstrated that HSV-1 infection of mouse neuronal cultures led to tau hyperphosphorylation, another hallmark feature of AD [29]. Expanding on these findings, in 2009, Wozniak et al. revealed the presence of HSV-1 DNA in 90% of amyloid-β plaques in postmortem brains from AD patients [30]. Moreover, they found that 72% of HSV1 DNA in the brain was concentrated within these plaques. Despite this compelling evidence, the mechanistic links between viral infection, AD genetic risk factors such as APOE4, and the etiology of AD remains elusive.

Strengths and limitations

Strengths of our study include that it was based on a large, nationally representative sample of older Australians dispensed medicines [31]. This provided sufficient power to investigate the association between the dispensing of antiherpetic medications and antidementia medications both cross-sectionally and longitudinally. Utilizing the 10% PBS dispensing dataset, offers an indirect but validated approach to estimate medication usage [21, 32]. Furthermore, the utilization of various study designs, including longitudinal, time-series and cross-sectional approaches, allowed us to analyze the relationship between the use of antiherpetic medications and anti-dementia medications both over time and concurrently.

However, we acknowledge that while the dispensing of antidementia and antiherpetic medications is an acceptable proxy marker for the diagnosis of AD and HSV/HZV respectively, these medications can also be used to manage other conditions [33]. Additionally, other medications not covered in our 10% PBS sample search may be used to treat these conditions [34]. Determining the exact prevalence of AD within the community is difficult [35], however, approximately 8.4% of individuals aged over 65 have a diagnosis of dementia [36] with AD typically representing 60–80% of dementia diagnoses [37]. Our results indicated that only 1.2% of Australians aged 60 and over were dispensed at least one antidementia prescription in 2022. Hence, a significant proportion of individuals living with AD were either untreated or treated with other medications. Consequently, this may have biased the results by including individuals with dementia among those not dispensed antidementia medicines. The consequence of such bias would be decreased effect of the association. Another limitation is the relatively brief observation period of our study, given that the time between exposure to HSV/VZV infection and the clinical expression of dementia could be much longer.

Unmeasured factors should also be considered. Obesity, smoking, physical inactivity, socioeconomic status and immunodeficiencies, among various others, may mediate or modulate the risk of AD and the risk of HSV/HZV [1, 38]. Hence, residual error and confounding by unmeasured factors could potentially explain some of the observed associations.

Conclusion

The dispensing of antiviral medications for HSV and VZV is associated with decreased risk of the dispensing of medicines to treat dementia over a 10-year period in cross-sectional and time-series analysis, but not longitudinally. If the observed associations are proven to be causal, antiherpetic treatment of individuals at high risk could contribute to decrease the incidence of dementia in later life. We await the results of well-designed and sufficiently powered randomized controlled trials to confirm or reject this hypothesis.

AUTHOR CONTRIBUTIONS

Stephanie Tan (Conceptualization; Writing – original draft; Writing – review & editing); Erin Kelty (Conceptualization; Data curation; Writing – review & editing); Amy Page (Data curation; Project administration; Writing – review & editing); Christopher Etherton-Beer (Data curation; Writing – review & editing); Frank Sanfilippo (Data curation; Writing – review & editing); Osvaldo P. Almeida (Conceptualization; Data curation; Formal analysis; Writing – review & editing).

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgements to report.

FUNDING

Access to the PBS database was made possible through infrastructure grants from the Western Australian Department of Health to CEB and OPA. EK is partly supported by an Investigator Grant from the National Health & Medical Research Council of Australia (NHMRC).

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

DATA AVAILABILITY

Access to the 10% PBS database is available upon approved request from Services Australia ().

The supplementary material is available in the electronic version of this article: .

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