Introduction to chronic hepatitis B infection 1 23/09/2018 Introduction to chronic hepatitis B infection

2 23/09/2018 Epidemiology

Hepatitis B virus infection Virus discovered in 1966 Infects 350–400 million people worldwide Affects 1.25 million people in the US1 >1 million people die annually of HBV-related chronic liver disease Approximately 15-40% who develop CHB progress to cirrhosis, end-stage liver disease or HCC 1Maddrey, J Med Virol 2000; 61: 362

Global distribution of CHB carriers: 350 million Source: World Health Organization / Centers for Disease Control and Prevention

Chronic hepatitis B: Epidemiology

Epidemiology of chronic hepatitis B infection

Epidemiology of HBV: United States 1.25 million in US have chronic HBV infection; highest incidence is in Alaska (6.4%) Local factors influence incidence and prevalence ethnicity immigration patterns IVDA high-risk sexual activity Increased incidence of infection in first generation children of families from high risk area

Transmission of the hepatitis B virus 8 23/09/2018 Transmission of the hepatitis B virus

Transmission of hepatitis B virus Perinatal – with risk of transmission affected by HBeAg status of the mother Sexual transmission Non-sexual person-to-person contact, e.g., household contact Present in blood, saliva, vaginal secretions, menstrual blood less so in perspiration, tears, breast milk Percutaneous blood / blood products, needlestick, injection drug use, tattoo, acupuncture Lavanchy, J Viral Hepat 2004; 11: 97

Risk of persistence after initial HBV infection At birth and infants <1 yr 90% Children 1–5 yrs 30% Older children, adults 2%

Hepatitis B infection: Transmission prevention Universal vaccination Education regarding alterations in sexual behavior Screening of high risk populations Screening of blood products Needle exchange programs Cultural outreach and education

Components of Strategies to Prevent HBV Transmission Hepatitis B immunization Universal infant immunization Prevent perinatal transmission Catch-up immunization Prevent nosocomial HBV transmission The priority for incorporation of strategies to prevent perinatal HBV transmission in a particular country should take into account several factors, including: relative contribution of perinatal transmission to the overall disease burden B vaccine feasibilty of delivering hepatitis B vaccine at birth.

Hepatitis B Vaccination Targets 45th World Health Assembly, 1992 Integrate hepatitis B vaccine into national childhood vaccination programs By 1995 in countries with HBsAg prevalence 8% By 1997 in all countries Routine infant hepatitis B vaccination is the primary essential element of hepatitis B prevention strategies in all countries. In 1992, the 45th World Health Assembly established global hepatitis B vaccination targets

Impact of Hepatitis B Immunization Reduces prevalence of chronic HBV infection in immunized cohorts <1% in areas with low rate of perinatal transmission <2% in areas with high rate of perinatal transmission Reduces infection "pressure" Unvaccinated persons with chronic infection lose HBeAg and become less infectious Results in greater than expected impact on transmission Reduces liver cancer

Chronic HBV infection Age Vaccine Before After (yrs) Coverage Program Effect of Routine Infant Immunization on the Prevalence of Chronic HBV Infection Chronic HBV infection No. Age Vaccine Before After Study Year Tested (yrs) Coverage Program Program Alaska 1995 268 1-10 96% 16% 0% Taiwan 1994 424 7-10 73% 10% 1.1% Samoa 1996 435 7-8 87% 7% 0.5% Lombok 1994 2519 4 > 90% 6.2% 1.9% Saipan 1994 200 3-4 94% 9% 0.5% Ponape 1994 364 3-4 82% NA 1.0% Micronesia 1992 544 2 40% 12% 3.0%

Impact of vaccination schedules in the US 1991 CDC published guidelines recommending universal vaccination of infants and children In period from 1990–2002, incidence of acute HBV decreased 67% in all age groups 89% in children < 20 years of age MMWR 2004: 52; 1252

Age of Acquisition of Chronic HBV Infections in High Endemic Countries % of Chronic Infections Perinatal 10-30 Young children 65-80 The most important factor in determining the critical ages for vaccination to interrupt HBV transmission is the proportion of chronic infections that are acquired in each age group. In countries with a high endemicty of infection, virtually all chronic infections are acquired either perinatally or from transmission among young childre -- so vaccination programs in these countries should pimarily target these age groups for vaccination. Preventing perinatal and early childhood transmission is also important in low-endemic countriesbecause about 1/3 of chronic infections are acquired in these age groups. In addition , vaccination programs targeted to adolescents and adults at high risk of infection are needed in these countries, because the majority of chronic infections are acquired among adolescents and adults. Adolescents/Adults <5

Strategies to Prevent Perinatal HBV Transmission (1) Selective Immunoprophylaxis Screen pregnant women for HBsAg Give prophylaxis to infants of HBsAg+ mothers prophylaxis targeted to infants that need it can administer both HBIG/HepB vaccine Issues Requires extensive resources to screen pregnant women/track infants of HBsAg+ mothers Few successful programmes Two different strategies can be used to prevent perinatal HBV transmission. First, perinatal hepatitis B prevention can be integrated as a component of routine infant vaccination by beginning vaccination of all infants at birth and assuring infants complete the 3-dose vaccine series by 6 months of age. This strategy is desirable for countries where it is feasible to deliver the first dose of vaccine to all infants soon after birth. Second, all pregnant women can be screened for HBsAg and immunoprophylaxis provided to infants of HBsAg-positive mothers. This strategy is desirable in countries where all infants are not vaccinated at birth; however, extensive resources are required to screen all pregnant women and to track infants of HBsAg positive mothers to assure delivery of post-exposure prophylaxis.

Strategies to Prevent Perinatal HBV Transmission (2) Integrate as Component of Routine Infant Vaccination Vaccinate all infants beginning at birth No need to screen pregnant women Very feasible to implement if a high proportion of infants are born in health care facilities Issues Need to assure effective HepB vaccine delivery for all infants Two different strategies can be used to prevent perinatal HBV transmission. First, perinatal hepatitis B prevention can be integrated as a component of routine infant vaccination by beginning vaccination of all infants at birth and assuring infants complete the 3-dose vaccine series by 6 months of age. This strategy is desirable for countries where it is feasible to deliver the first dose of vaccine to all infants soon after birth. Second, all pregnant women can be screened for HBsAg and immunoprophylaxis provided to infants of HBsAg-positive mothers. This strategy is desirable in countries where all infants are not vaccinated at birth; however, extensive resources are required to screen all pregnant women and to track infants of HBsAg positive mothers to assure delivery of post-exposure prophylaxis.

Priority of Perinatal Hepatitis B Prevention High proportion of chronic infections acquired perinatally (e.g., SE Asia) A birth dose should be given when feasible (e.g., in birthing hospitals) Efforts should be made to administer HepB vaccine to infants who deliver at home Low proportion of chronic infections acquired perinatally (e.g., Africa) A birth dose may be considered after evaluating disease burden, cost-effectiveness, and feasibility

Priority of Catch-up Immunization High endemicity of HBV infection Catch-up immunization not generally needed Most chronic infections acquired before age 5 years Immunizing infants will rapidly reduce transmission

Priority of Catch-up Immunization II Lower endemicity of HBV infection May be large disease burden from infections acquired in older age groups Immunizing infants alone may not substantially lower disease incidence for decades Catch-up immunization may be desirable: single-age cohorts (e.g., routine adolescent immunization) high risk groups (e.g., MSM, IDUs, persons w/STDs) STD clinics, correctional facilities, drug treatment

Potential factors affecting the natural history of chronic hepatitis B Age of patient at infection Host factors gender age immune status Viral factors HBV genotype viral mutation level of HBV replication External factors concurrent infection with HCV, HDV, HIV immune suppression – transplantation, chemotherapy alcohol Adapted from Fattovich, Semin Liver Dis 2003; 23: 47

HBV Transmission in Healthcare Settings Patient Patient Unsafe injection practices Reuse of contaminated medical equipment Blood transfusion Use safe injection practices Use sterile equipment Screen blood supply Patient Provider Use standard precautions Vaccinate HCW Needlestick/sharps injuries Provider Patient Invasive surgical procedures Use standard precautions

Vaccination strategy for the prevention of HBV infection MMWR 1991; 40: 1

Chronic Hepatitis B: Counseling Vaccinate against hepatitis A Non-pharmacologic supportive diet, rest, fluid balance Reduce risk for spreading HBV no needle sharing, notify partner etc. condoms, vaccinate sexual partner(s) vaccinate household members against hepatitis B Avoid alcohol and other hepatotoxins

Natural history of hepatitis B infection 30 23/09/2018 Natural history of hepatitis B infection

Natural history of chronic hepatitis B infection Lee, N Engl J Med 1997; 337: 1733

Natural history of hepatitis B virus infection and mechanism of disease progression Slowly progressive disease Complications of cirrhosis develop after 5–50+ years Progression of disease influenced by the phase of viral replication and the incidence of hepatitis (ALT) flares A recent liver biopsy is usually required for assessment of disease stage

A model of the natural history of chronic viral hepatitis

Factors affecting the course of the disease 34 23/09/2018 Factors affecting the course of the disease

Effect of timing of infection: Birth or early childhood Asian, Africans, some Mediterraneans, South Pacific Islanders Prolonged immune tolerance and immune clearance phases Respond less well to immunomodulatory therapy Disease continues to progress in a proportion of anti- HBe patients Hoofnagle et al, Hepatology 1987; 7: 758

Effect of timing of infection: Adolescence and adulthood Majority of Caucasian patients No immune tolerance phase Active hepatitis of shorter duration Responds better to immunomodulatory therapy Disease in many non-progressive after HBeAg seroconversion, with low HBV-DNA levels undetectable by hybridization assays – “HBsAg carriers”1 Some may develop anti-HBe chronic hepatitis 1Hoofnagle et al, Hepatology 1987; 7: 758

The impact of gender Males higher risk1,2 male : female ratio for HCC >5:1 male : female crude mortality rate in Haiman City per 100,000 person-year3 207:42.5 1Lai et al, Cancer 1981; 47:2746-55 2Yuen et al, Hepatology 2000; 31:330 3Evans et al, Cancer Epidemiol Biomarkers Prev 2001; 11:369

Hepatitis B virus genome

The impact of viral load on the progression of hepatocellular damage Viral load probably significant factor in natural history both for disease and HCC prolonged immune destruction of antigen-presenting liver cells results in cirrhosis prolonged low-level viremia may influence progression in CHB HCC develops through: cirrhotic necroinflammation and regeneration direct viral effect through replication and/or random integration

Hepatitis B virus genotypes 8 HBV genotypes (based on complete HBV genome) A D B C A B C D D F A E G H F A,B,C,D US Lindh et al, J Infect Dis 1997; 175: 1285 Norder et al, J Gen Virol 1993; 74: 1341

Association of HBV genotype with long-term sequelae A: Potentially less cirrhosis, but hepatocellular carcinoma does occur B: When compared to genotype C younger age at HBeAg seroconversion lower risk of chronic hepatitis increased risk of icteric and fulminant acute hepatitis increased risk of HCC, but higher proportion of patients with HCC in the absence of cirrhosis C: Increased risk of hepatitis and HCC D: Increased risk of anti-HBe hepatitis and HCC; associated with vasculitis in Alaska natives E, G, H: Limited information available F: HCC reported in young Alaska natives Kao, Intervirology 2003; 46: 400 Nakayoshi et al, J Med Virol 2003; 70: 350

HBeAg and precore mutation

Viral factors: HBeAg-negative disease Late phase in the natural history of chronic HBV infection More common in subjects infected during childhood and in those with B or D genotype HBeAg-negative variants have mutations in the core promotor and / or the pre-core region of the HBV genome abolishes HBeAg production but high level of viral replication occurs May develop severe disease with cirrhosis or HCC Responds to antiviral medications but relapses after withdrawal Hadziyannis et al, Semin Liv Dis 2003; 23: 81

HBeAg-negative disease demonstrates frequent fluctuations in ALT and HBV DNA levels Hadziyannis et al, Hepatology 2001; 34: 617

The impact of age on the development of HCC Peak incidence for cirrhosis complication / HCC 50–60 years of age Prospective study of 684 Taiwan patients (509 HBeAg+; 175 anti-HBe+) median follow-up 35.3 months cirrhosis incidence increased with age at entry (p<0.001) Liaw et al, Hepatology 1988; 8:493

Summary CHB significant public health concern worldwide Natural history and outcome dependent on number of factors Persons infected with CHB at increased risk of developing cirrhosis and/or HCC These risks can likely be reduced by effective treatment interventions Prevention is a central strategy to reduce the future impact of the disease

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