Viral Hepatitis Prevention Board Meeting Rotterdam, The Netherlands, November 13-14, 2008 National Institute for Public Health and the Environment Epidemiology of hepatitis B in The Netherlands Mirjam Kretzschmar Centre for Infectious Disease Control, RIVM, and Julius Center for Health Sciences & Primary Care University Medical Centre Utrecht, The Netherlands
Outline Prevalence and incidence of notified cases by age and risk group Epidemiological studies - Seroprevalence studies - Modelling - Enhanced surveillance (BRON study) - Molecular epidemiology International dimensions - NL low endemic country, no universal vaccination Conclusions
Incidence of notified cases of acute and chronic HBV infection (1976-2007) 12,0 10,0 8,0 6,0 4,0 2,0 0,0 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 men acute women acute men chronic women chronic Source: Osiris notification system
Age distribution of notified cases incidence per 100000 6,0 5,0 4,0 3,0 2,0 1,0 men 2006 men 2007 women 2006 women 2007 0,0 0-4 5-9 10-14 15-19 20-24 25-34 35-44 45-54 55-64 65-74 >75 age
Geographical distribution Koedijk et al Inf Bull 2007
Numbers of notified cases of HBV infection 2003-2007 1800 1600 1400 1200 1000 800 600 400 200 0 2003 2004 2005 2006 2007 Acute Chronic Unknown
Acute HBV infections by risk group 120 100 80 60 40 20 0 2003 2004 2005 2006 2007 heterosexual MSM sexual, unknown IDU needle stick injury other route unknown 2007: sexual contact 65%, IDU 0,9%, needle stick injuries 1%, other 10%, unknown 23% 19% first generation migrants, 17% infected abroad Source: Osiris
Acute HBV infections by risk group 100% 80% 60% 40% 20% 0% 2003 2004 2005 2006 2007 heterosexual MSM sexual, unknown IDU needle stick injury other route unknown 2007: sexual contact 65%, IDU 0,9%, needle stick injuries 1%, other 10%, unknown 23% 19% first generation migrants, 17% infected abroad Source: Osiris
Chronic HBV infections by risk group 900 800 700 600 500 400 300 200 100 0 2003 2004 2005 2006 2007 MSM heterosexual IDU needle stick injury vertical other route unknown 2007: sexual 7%, IDU 0,6%, needle stick injury 0,6%, vertical 54%, other route 8%, unknown 29% 78% first generation migrants, 73% infected abroad Source: Osiris
Chronic HBV infections by risk group 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 2003 2004 2005 2006 2007 heterosexual MSM IDU needle stick injury vertical other route unknown 2007: sexual 7%, IDU 0,6%, needle stick injury 0,6%, vertical 54%, other route 8%, unknown 29% 78% first generation migrants, 73% infected abroad Source: Osiris
Fraction clinical infections Age Numbers infected Fraction clinical infections (%) McMahon et al. JID 1985 0-4 21 9.5 5-9 61 9.8 10-19 58 10.3 20-29 22 13.6 30 27 33.3 Underreporting? 1600 1400 1200 reported acute infections McMahon fractions mean logistic estimate 75% of symptomatic cases reported in England (Ramsay et al. Vaccine 1998) number (1996-2000) 1000 800 600 400 200 0 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 age
Seroprevalence study in representative population sample, PIENTER study 1995 12,0% 10,0% 8,0% prevalence 6,0% 4,0% 2,0% 0,0% Van Marrewijk et al 1999 0-5 5-10 10-15 15-20 20-25 25-30 30-35 35-40 40-45 45-50 50-55 55-60 60-65 65-70 70-74 75-79 age (years) HBsAg+ antihbc+ Overall prevalence: 0.2% HBsAg+ and 2.1% antihbc+ New seroprevalence study with oversampling of migrant populations conducted in 2007, results to come soon.
Insights from mathematical modelling Development of dynamic transmission model with - stratified by age and sexual activity - sexual, vertical, and horizontal transmission - hetero- and MSM populations - Age dependent probability of becoming chronic carrier Model used to assess effects of vaccination Analysis of basic reproduction number and transmission dynamics in risk groups Williams et al. Epidemiol Infect 1996; Kretzschmar et al Epidemiol Infect 2002; Kretzschmar & de Wit Lancet Inf Dis 2008
birth birth high infectivity susceptible latent infection acute infection vaccinated chronic carrier immune birth low infectivity 0,2 0,15 maximum likelihood estimate R0 minimal in 95% confidence region R0 maximal in 95% confidence region probability 0,1 Model features 0,05 0 10 20 30 40 50 60 age (years) probability of chronic infection
Estimates for R 0 for the heterosexual population 1 constant age-dependent R0 0 1,11 0,79 0,69 0,53 estimates UK estimates NL
Implications for epidemiology? Homosexual men R 0 >1: - Infection persists; - Import of infected persons has small impact. Heterosexual population R 0 <1: - short transmission chains; - Import von infected persons determines prevalence.
Molecular epidemiology Origin of hepatitis B virus in Dutch blood donors No indigenous heterosexual strain Koppelman & Zaaijer J Med Virol 2004
IDU cluster has disappeared Effect of vaccination? van Houdt et al Vaccine 2007
Surveillance Enhanced surveillance of acute hepatitis B 1999/2000 (Veldhuijzen et al. 2005) - 18.8% of male, 34.3% of female patients are of non-dutch ethnicity - Non-Dutch ethnicity of source: hetero men 65%, women 57%, MSM 30% Surveillance of chronic hepatitis B 2001-2003: 54%-76% of patients born in high or medium endemic countries (Koedijk et al. 2005) Chronic carriers with Dutch ethnicity mostly infected sexually, chronic carriers with non-dutch ethnicity mostly infected perinatally (Toy et al 2008) Prevalence estimate based on analysis of literature data: population prevalence is between 0.36% and 0.55% (Marschall et al 2008)
Global immunization coverage will impact on epidemiology of low endemic countries
Conclusions Netherlands is a low endemic country Incidence of acute infections in MSM and other high risk groups Persistent circulation of virus in MSM but not in general heterosexual population Prevalence of chronic infections strongly determined by migration from high and medium endemic areas Epidemiology of HBV in the Netherlands will change with increasing global vaccination coverage Targetted screening required to increase treatment uptake of persons with chronic infection
Acknowledgements CIb/RIVM: Susan Hahné Jim van Steenbergen Ardine de Wit Femke Koedijk Erasmus Medical Centre, LiverDoc: Mehlika Toy Irene Veldhuijzen Solko Schalm University of Bielefeld, Germany: Tanja Marschall National Institute for Public Health and the Environment