, Volume 15, Issue 2, pp 417–429 | Cite as

Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections—a Nationwide, Population-Based Cohort Study in Taiwan

  • Nian-Sheng Tzeng
  • Chi-Hsiang Chung
  • Fu-Huang Lin
  • Chien-Ping Chiang
  • Chin-Bin Yeh
  • San-Yuan Huang
  • Ru-Band Lu
  • Hsin-An Chang
  • Yu-Chen Kao
  • Hui-Wen Yeh
  • Wei-Shan Chiang
  • Yu-Ching Chou
  • Chang-Huei Tsao
  • Yung-Fu Wu
  • Wu-Chien ChienEmail author
Original Article


This retrospective cohort study is to investigate the association between herpes simplex virus (HSV) infections and dementia, and the effects of anti-herpetic medications on the risk involved, using Taiwan’s National Health Insurance Research Database (NHIRD). We enrolled a total of 33,448 subjects, and identified 8362 with newly diagnosed HSV infections and 25,086 randomly selected sex- and age-matched controls without HSV infections in a ratio of 1:3, selected from January 1, to December 31, 2000. A multivariable Cox proportional hazards regression model was used to evaluate the risk of developing dementia in the HSV cohort. This analysis revealed an adjusted hazard ratio of 2.564 (95% CI: 2.351-2.795, P < 0.001) for the development of dementia in the HSV-infected cohort relative to the non-HSV cohort. Thus, patients with HSV infections may have a 2.56-fold increased risk of developing dementia. A risk reduction of dementia development in patients affected by HSV infections was found upon treatment with anti-herpetic medications (adjusted HR = 0.092 [95% CI 0.079-0.108], P < 0.001). The usage of anti-herpetic medications in the treatment of HSV infections was associated with a decreased risk of dementia. These findings could be a signal to clinicians caring for patients with HSV infections. Further research is, therefore, necessary to explore the underlying mechanism(s) of these associations.

Key Words

Herpes simplex virus Dementia National Health Insurance Research Database Anti-herpetic medications Cohort study 



This study was supported by grants from Tri-Service Hospital Research Foundation (TSGH-C105-130, TSGH-C106-002, and TSGH-C107-004), and the sponsor has no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

13311_2018_611_MOESM1_ESM.pdf (1.2 mb)
ESM 1 (PDF 1224 kb)
13311_2018_611_MOESM2_ESM.docx (20 kb)
Supplementary Table 1 (DOCX 20 kb)


  1. 1.
    Liu CK, Lai CL, Tai CT, et al. Incidence and Subtypes of Dementia in Southern Taiwan: Impact of Socio-Demographic Factors. Neurology. 1998;506:1572–1579.CrossRefGoogle Scholar
  2. 2.
    Sun Y, Lee HJ, Yang SC, et al. A Nationwide Survey of Mild Cognitive Impairment and Dementia, Including Very Mild Dementia, in Taiwan. PLoS One. 2014;96:e100303.CrossRefGoogle Scholar
  3. 3.
    World Health Organization. Dementia Cases Set to Triple by 2050 but Still Largely Ignored. Available from: Accesed 17 Feb 2018.
  4. 4.
    Tzeng NS, Chang CW, Hsu JY, et al. Caregiver Burden for Patients with Dementia with or without Hiring Foreign Health Aides: A Cross-Sectional Study in a Northern Taiwan Memory Clinic. J Med Sci 2015;356:239–247CrossRefGoogle Scholar
  5. 5.
    Tzeng NS, Chiang WS, Chen SY, et al. The Impact of Pharmacological Treatments on Cognitive Function and Severity of Behavioral Symptoms in Geriatric Elder Patients with Dementia: Pharmacological Treatments on in Elder Patients with Dementia. Taiwanese J Psychiatry. 2017;311:69–79.Google Scholar
  6. 6.
    Wang HY, Chen JH, Huang SY, et al. Forensic Evaluations for Offenders with Dementia in Taiwan’s Criminal Courts. J Am Acad Psychiatry Law. in press.Google Scholar
  7. 7.
    Gupta R, Warren T, Wald A. Genital Herpes. Lancet. 2007;3709605:2127–2137.CrossRefGoogle Scholar
  8. 8.
    Gilbert S, Corey L, Cunningham A, et al. An Update on Short-Course Intermittent and Prevention Therapies for Herpes Labialis. Herpes. 2007;14 Suppl 1:13A-18A.PubMedGoogle Scholar
  9. 9.
    Harris SA, Harris EA. Herpes Simplex Virus Type 1 and Other Pathogens Are Key Causative Factors in Sporadic Alzheimer’s Disease. J Alzheimers Dis. 2015;482:319–353.CrossRefGoogle Scholar
  10. 10.
    Itzhaki RF, Lathe R, Balin BJ, et al. Microbes and Alzheimer’s Disease. Journal of Alzheimer’s disease : JAD. 2016;514:979–984.CrossRefGoogle Scholar
  11. 11.
    Itzhaki RF. Herpes and Alzheimer’s Disease: Subversion in the Central Nervous System and How It Might Be Halted. J Alzheimers Dis. 2016;544:1273–1281.CrossRefGoogle Scholar
  12. 12.
    Ho Chan WS. Taiwan’s Healthcare Report 2010. EPMA J. 2010;14:563–585.CrossRefGoogle Scholar
  13. 13.
    Kang JH, Ho JD, Chen YH, Lin HC. Increased Risk of Stroke after a Herpes Zoster Attack: A Population-Based Follow-up Study. Stroke. 2009;4011:3443–3448.CrossRefGoogle Scholar
  14. 14.
    Chiang CH, Huang CC, Chan WL, et al. Herpes Simplex Virus Infection and Risk of Atrial Fibrillation: A Nationwide Study. Int J Cardiol. 2013;1642:201–204.Google Scholar
  15. 15.
    Huang CC, Chan WL, Chen YC, et al. Herpes Simplex Virus Infection and Erectile Dysfunction: A Nationwide Population-Based Study. Andrology. 2013;12:240–244.CrossRefGoogle Scholar
  16. 16.
    Ministry of Justice. National Health Insurance Reimbursement Regulations. 2014 Available from: Accesed 17 Feb 2018.
  17. 17.
    Chao PC, Chien WC, Chung CH, et al. Cognitive Enhancers Associated with Decreased Risk of Injury in Patients with Dementia: A Nationwide Cohort Study in Taiwan. J Investig Med. 2017;
  18. 18.
    Tzeng NS, Chung CH, Lin FH, et al. Magnesium Oxide Use and Reduced Risk of Dementia: A Retrospective, Nationwide Cohort Study in Taiwan. Curr Med Res Opin. 2018;341:163–169.CrossRefGoogle Scholar
  19. 19.
    Tai SY, Chien CY, Chang YH, Yang YH. Cilostazol Use Is Associated with Reduced Risk of Dementia: A Nationwide Cohort Study. Neurotherapeutics. 2017;143:784–791.CrossRefGoogle Scholar
  20. 20.
    Chang CY, Chen WL, Liou YF, et al. Increased Risk of Major Depression in the Three Years Following a Femoral Neck Fracture--a National Population-Based Follow-up Study. PLoS One. 2014;93:e89867.CrossRefGoogle Scholar
  21. 21.
    Charlson ME, Pompei P, Ales KL, MacKenzie CR. A New Method of Classifying Prognostic Comorbidity in Longitudinal Studies: Development and Validation. J Chronic Dis. 1987;405:373–383.CrossRefGoogle Scholar
  22. 22.
    de Groot V, Beckerman H, Lankhorst GJ, Bouter LM. How to Measure Comorbidity. A Critical Review of Available Methods. J Clin Epidemiol. 2003;563:221–229.Google Scholar
  23. 23.
    Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a Combined Comorbidity Index. J Clin Epidemiol. 1994;4711:1245–1251.CrossRefGoogle Scholar
  24. 24.
    Mayeux R, Stern Y. Epidemiology of Alzheimer Disease. Cold Spring Harb Perspect Med. 2012;28.Google Scholar
  25. 25.
    Needham DM, Scales DC, Laupacis A, Pronovost PJ. A Systematic Review of the Charlson Comorbidity Index Using Canadian Administrative Databases: A Perspective on Risk Adjustment in Critical Care Research. Journal of Critical Care. 2005;201:12–19.CrossRefGoogle Scholar
  26. 26.
    Lovheim H, Gilthorpe J, Johansson A, et al. Herpes Simplex Infection and the Risk of Alzheimer’s Disease: A Nested Case-Control Study. Alzheimers Dement. 2015;116:587–592.CrossRefGoogle Scholar
  27. 27.
    Letenneur L, Peres K, Fleury H, et al. Seropositivity to Herpes Simplex Virus Antibodies and Risk of Alzheimer’s Disease: A Population-Based Cohort Study. PLoS One. 2008;311:e3637.CrossRefGoogle Scholar
  28. 28.
    Daulatzai MA. Fundamental Role of Pan-Inflammation and Oxidative-Nitrosative Pathways in Neuropathogenesis of Alzheimer’s Disease. Am J Neurodegener Dis. 2016;51:1–28.Google Scholar
  29. 29.
    Stefaniak J, O'Brien J. Imaging of Neuroinflammation in Dementia: A Review. J Neurol Neurosurg Psychiatry. 2016;871:21–28.Google Scholar
  30. 30.
    Kao LT, Sheu JJ, Lin HC, Tsai MC, Chung SD. Association between Sepsis and Dementia. J Clin Neurosci. 2015;229:1430–1433.CrossRefGoogle Scholar
  31. 31.
    Chiu WC, Tsan YT, Tsai SL, et al. Hepatitis C Viral Infection and the Risk of Dementia. Eur J Neurol. 2014;218:1068-e1059.CrossRefGoogle Scholar
  32. 32.
    Huang WS, Yang TY, Shen WC, et al. Association between Helicobacter Pylori Infection and Dementia. J Clin Neurosci. 2014;218:1355–1358.CrossRefGoogle Scholar
  33. 33.
    Tseng CH, Huang WS, Muo CH, Kao CH. Increased Risk of Dementia among Chronic Osteomyelitis Patients. Eur J Clin Microbiol Infect Dis. 2015;341:153–159.CrossRefGoogle Scholar
  34. 34.
    Barnes LL, Capuano AW, Aiello AE, et al. Cytomegalovirus Infection and Risk of Alzheimer Disease in Older Black and White Individuals. J Infect Dis. 2015;2112:230–237.CrossRefGoogle Scholar
  35. 35.
    Ball MJ. Limbic Predilection in Alzheimer Dementia: Is Reactivated Herpesvirus Involved?. Can J Neurol Sci. 1982;93:303–306.CrossRefGoogle Scholar
  36. 36.
    Lathe R, Haas JG. Distribution of Cellular Hsv-1 Receptor Expression in Human Brain. J Neurovirol. 2017;233:376–384.CrossRefGoogle Scholar
  37. 37.
    Itzhaki RF, Lin WR, Shang D, et al. Herpes Simplex Virus Type 1 in Brain and Risk of Alzheimer’s Disease. Lancet. 1997;3499047:241–244.CrossRefGoogle Scholar
  38. 38.
    Strandberg TE, Pitkala K, Eerola J, Tilvis R, Tienari PJ. Interaction of Herpesviridae, Apoe Gene, and Education in Cognitive Impairment. Neurobiol Aging. 2005;267:1001–1004.CrossRefGoogle Scholar
  39. 39.
    Feart C, Helmer C, Fleury H, et al. Association between Igm Anti-Herpes Simplex Virus and Plasma Amyloid-Beta Levels. PLoS One. 2011;612:e29480.CrossRefGoogle Scholar
  40. 40.
    Bourgade K, Le Page A, Bocti C, et al. Protective Effect of Amyloid-Beta Peptides against Herpes Simplex Virus-1 Infection in a Neuronal Cell Culture Model. J Alzheimers Dis. 2016;504:1227–1241.CrossRefGoogle Scholar
  41. 41.
    Wozniak MA, Itzhaki RF, Shipley SJ, Dobson CB. Herpes Simplex Virus Infection Causes Cellular Beta-Amyloid Accumulation and Secretase Upregulation. Neurosci Lett. 2007;4292-3:95–100.CrossRefGoogle Scholar
  42. 42.
    Zambrano A, Solis L, Salvadores N, et al. Neuronal Cytoskeletal Dynamic Modification and Neurodegeneration Induced by Infection with Herpes Simplex Virus Type 1. J Alzheimers Dis. 2008;143:259–269.CrossRefGoogle Scholar
  43. 43.
    Civitelli L, Marcocci ME, Celestino I, et al. Herpes Simplex Virus Type 1 Infection in Neurons Leads to Production and Nuclear Localization of App Intracellular Domain (Aicd): Implications for Alzheimer’s Disease Pathogenesis. J Neurovirol. 2015;215:480–490.CrossRefGoogle Scholar
  44. 44.
    Soscia SJ, Kirby JE, Washicosky KJ, et al. The Alzheimer's Disease-Associated Amyloid Beta-Protein Is an Antimicrobial Peptide. PLoS One. 2010;53:e9505.CrossRefGoogle Scholar
  45. 45.
    Wozniak MA, Mee AP, Itzhaki RF. Herpes Simplex Virus Type 1 DNA Is Located within Alzheimer’s Disease Amyloid Plaques. J Pathol. 2009;2171:131–138.CrossRefGoogle Scholar
  46. 46.
    Piacentini R, Li Puma DD, Ripoli C, et al. Herpes Simplex Virus Type-1 Infection Induces Synaptic Dysfunction in Cultured Cortical Neurons Via Gsk-3 Activation and Intraneuronal Amyloid-Beta Protein Accumulation. Sci Rep. 2015;5:15444.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Wozniak MA, Shipley SJ, Combrinck M, Wilcock GK, Itzhaki RF. Productive Herpes Simplex Virus in Brain of Elderly Normal Subjects and Alzheimer’s Disease Patients. J Med Virol. 2005;752:300–306.CrossRefGoogle Scholar
  48. 48.
    Tzeng NS, Chung CH, Yeh CB, et al. Are Chronic Periodontitis and Gingivitis Associated with Dementia? A Nationwide, Retrospective, Matched-Cohort Study in Taiwan. Neuroepidemiology. 2016;472:82–93.CrossRefGoogle Scholar
  49. 49.
    Shen JH, Huang KY, Chao-Yu C, et al. Seroprevalence of Herpes Simplex Virus Type 1 and 2 in Taiwan and Risk Factor Analysis, 2007. PLoS One. 2015;108:e0134178.CrossRefGoogle Scholar
  50. 50.
    Itzhaki RF. Herpes Simplex Virus Type 1 and Alzheimer's Disease: Increasing Evidence for a Major Role of the Virus. Front Aging Neurosci. 2014;6:202.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Prasad KM, Eack SM, Keshavan MS, et al. Antiherpes Virus-Specific Treatment and Cognition in Schizophrenia: A Test-of-Concept Randomized Double-Blind Placebo-Controlled Trial. Schizophr Bull. 2013;394:857–866.CrossRefGoogle Scholar
  52. 52.
    Lovheim H. Feasibility and Effects of Valaciclovir Treatment in Persons with Early Alzheimer’s Disease (Valz-Pilot). Available from: Accesed 21 Feb 2018.
  53. 53.
    Derby CA, Katz MJ, Lipton RB, Hall CB. Trends in Dementia Incidence in a Birth Cohort Analysis of the Einstein Aging Study. JAMA Neurol. 2017;7411:1345–1351.CrossRefGoogle Scholar
  54. 54.
    Gao M, Kuang W, Qiu P, et al. The Time Trends of Cognitive Impairment Incidence among Older Chinese People in the Community: Based on the Clhls Cohorts from 1998 to 2014. Age Ageing. 2017;465:787–793.CrossRefGoogle Scholar
  55. 55.
    Langa KM. Is the Risk of Alzheimer's Disease and Dementia Declining? Alzheimers Res Ther. 2015;71:34.CrossRefGoogle Scholar
  56. 56.
    Lee Y. The Recent Decline in Prevalence of Dementia in Developed Countries: Implications for Prevention in the Republic of Korea. J Korean Med Sci. 2014;297:913–918.CrossRefGoogle Scholar
  57. 57.
    Wu YT, Fratiglioni L, Matthews FE, et al. Dementia in Western Europe: Epidemiological Evidence and Implications for Policy Making. Lancet Neurol. 2016;151:116–124.CrossRefGoogle Scholar
  58. 58.
    Brigden D, Fiddian P, Rosling AE, Ravenscroft T. Acyclovir - a Review of the Preclinical and Early Clinical Data of a New Antiherpes Drug. Antiviral Res. 1981;14:203–212.CrossRefGoogle Scholar
  59. 59.
    Pebody RG, Andrews N, Brown D, et al. The Seroepidemiology of Herpes Simplex Virus Type 1 and 2 in Europe. Sex Transm Infect. 2004;803:185–191.CrossRefGoogle Scholar
  60. 60.
    Bradley H, Markowitz LE, Gibson T, McQuillan GM. Seroprevalence of Herpes Simplex Virus Types 1 and 2--United States, 1999-2010. J Infect Dis. 2014;2093:325–333.CrossRefGoogle Scholar
  61. 61.
    Liu HC, Lin KN, Teng EL, et al. Prevalence and Subtypes of Dementia in Taiwan: A Community Survey of 5297 Individuals. J Am Geriatr Soc. 1995;432:144–149.CrossRefGoogle Scholar
  62. 62.
    Lin RT, Lai CL, Tai CT, et al. Prevalence and Subtypes of Dementia in Southern Taiwan: Impact of Age, Sex, Education, and Urbanization. J Neurol Sci. 1998;1601:67–75.Google Scholar
  63. 63.
    Chuang WL, Hsieh YC, Wang CY, Kuo HC, Huang CC. Association of Apolipoproteins E4 and C1 with Onset Age and Memory: A Study of Sporadic Alzheimer Disease in Taiwan. J Geriatr Psychiatry Neurol. 2010;231:42–48.CrossRefGoogle Scholar
  64. 64.
    Kamboh MI. Apolipoprotein E Polymorphism and Susceptibility to Alzheimer’s Disease. Hum Biol. 1995;672:195–215.Google Scholar
  65. 65.
    Ward A, Crean S, Mercaldi CJ, et al. Prevalence of Apolipoprotein E4 Genotype and Homozygotes (Apoe E4/4) among Patients Diagnosed with Alzheimer’s Disease: A Systematic Review and Meta-Analysis. Neuroepidemiology. 2012;381:1–17.CrossRefGoogle Scholar
  66. 66.
    Koelle DM, Magaret A, Warren T, Schellenberg GD, Wald A. Apoe Genotype Is Associated with Oral Herpetic Lesions but Not Genital or Oral Herpes Simplex Virus Shedding. Sex Transm Infect. 2010;863:202–206.CrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2018

Authors and Affiliations

  • Nian-Sheng Tzeng
    • 1
    • 2
  • Chi-Hsiang Chung
    • 3
    • 4
    • 5
  • Fu-Huang Lin
    • 4
  • Chien-Ping Chiang
    • 6
  • Chin-Bin Yeh
    • 1
    • 7
  • San-Yuan Huang
    • 1
    • 7
  • Ru-Band Lu
    • 1
    • 8
    • 9
    • 10
    • 11
    • 12
  • Hsin-An Chang
    • 1
    • 2
  • Yu-Chen Kao
    • 1
    • 13
  • Hui-Wen Yeh
    • 1
  • Wei-Shan Chiang
    • 1
    • 14
  • Yu-Ching Chou
    • 4
  • Chang-Huei Tsao
    • 5
  • Yung-Fu Wu
    • 5
  • Wu-Chien Chien
    • 4
    • 5
    Email author return OK on get
  1. 1.Department of Psychiatry, Tri-Service General Hospital, School of MedicineNational Defense Medical CenterTaipeiRepublic of China
  2. 2.Student Counseling CenterNational Defense Medical CenterTaipeiRepublic of China
  3. 3.Taiwanese Injury Prevention and Safety Promotion AssociationTaipeiRepublic of China
  4. 4.School of Public HealthNational Defense Medical CenterTaipeiRepublic of China
  5. 5.Department of Medical Research, Tri-Service General HospitalNational Defense Medical CenterTaipei CityRepublic of China
  6. 6.Department of Dermatology, Tri-Service General Hospital, School of MedicineNational Defense Medical CenterTaipeiRepublic of China
  7. 7.Graduate Institute of Medical SciencesNational Defense Medical CenterTaipeiRepublic of China
  8. 8.Division of Clinical Psychology, Institute of Allied Health Sciences, College of MedicineNational Cheng Kung UniversityTainanRepublic of China
  9. 9.Department of Psychiatry, College of MedicineNational Cheng Kung UniversityTainanRepublic of China
  10. 10.Institute of Behavioral Medicine, College of MedicineNational Cheng Kung UniversityTainanRepublic of China
  11. 11.Department of PsychiatryNational Cheng Kung University HospitalTainanRepublic of China
  12. 12.Center for Neuropsychiatric ResearchNational Health Research InstituteMiaoli CountyRepublic of China
  13. 13.Department of Psychiatry, Tri-Service General Hospital, Song-Shan BranchNational Defense Medical CenterTaipeiRepublic of China
  14. 14.Department and Institute of MathematicsTamkang UniversityNew Taipei CityRepublic of China

Personalised recommendations