Hepatitis B Virus Dr R V S N Sarma., M.D., [SLIDE 1] Title Slide This slide set presents an overview of the clinical and epidemiologic features for viral hepatitis A, B, C, D, and E and prevention measures for these infections. More detailed information regarding the epidemiologic features and prevention measures can be found on-line at http://www.cdc.gov/MMWR/MMWR.html: for hepatitis A read the MMWR, Prevention of Hepatitis A Through Active or Passive Immunization: Recommendations of the Advisory Committee on Immunization Practices, Vol. 48, No RR12;1, 10/01/1999; for hepatitis B read the MMWR, Recommendations to Prevent Hepatitis B Virus Transmission – US, Vol.44, No 30;574, 08/04/1995, Updated; for hepatitis C read the MMWR, Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCV-Related Chronic Disease, Vol. 47, No RR19;1, 10/16/1998. Dr R V S N Sarma., M.D.,

Geographic Distribution of Chronic HBV Infection [SLIDE 41, SLIDE 42] Global Patterns of Chronic HBV Infection, Geographic Distribution of Chronic HBV infection* Approximately 45% of the global population live in areas with a high prevalence of chronic HBV infection (> 8% of the population is HBsAg‑positive); 43% in areas with a moderate prevalence (2%‑7% of the population is HBsAg‑positive); and 12% in areas with a low prevalence (< 2% of the population is HBsAg‑positive). In high prevalence areas, the lifetime risk of HBV infection is >60%, and most infections are acquired at birth or during early childhood when the risk of developing chronic infection is greatest. In these areas, because most infections in children are asymptomatic, very little acute disease related to HBV occurs, but rates of chronic liver disease and liver cancer in adults are very high. In moderate prevalence areas, the lifetime risk of being infected is 20%‑60% and infections occur in all age groups. Acute disease related to HBV is common in these areas because many infections occur in adolescents and adults; however, the high rates of chronic infection are maintained mostly by infections occurring in infants and children. In low prevalence areas, the lifetime risk of infection is <20%. Most HBV infections in these areas occur in adults in relatively well defined risk groups. *(Note: The map of HBsAg prevalence generalizes available data and patterns may vary within countries.) HBsAg Prevalence ³8% - High 2-7% - Intermediate <2% - Low

Global Patterns of Chronic HBV Infection High (>8%): 45% of global population lifetime risk of infection >60% early childhood infections common Intermediate (2%-7%): 43% of global population lifetime risk of infection 20%-60% infections occur in all age groups Low (<2%): 12% of global population lifetime risk of infection <20% most infections occur in adult risk groups [SLIDE 41, SLIDE 42] Global Patterns of Chronic HBV Infection, Geographic Distribution of Chronic HBV infection* Approximately 45% of the global population live in areas with a high prevalence of chronic HBV infection (> 8% of the population is HBsAg‑positive); 43% in areas with a moderate prevalence (2%‑7% of the population is HBsAg‑positive); and 12% in areas with a low prevalence (< 2% of the population is HBsAg‑positive). In high prevalence areas, the lifetime risk of HBV infection is >60%, and most infections are acquired at birth or during early childhood when the risk of developing chronic infection is greatest. In these areas, because most infections in children are asymptomatic, very little acute disease related to HBV occurs, but rates of chronic liver disease and liver cancer in adults are very high. In moderate prevalence areas, the lifetime risk of being infected is 20%‑60% and infections occur in all age groups. Acute disease related to HBV is common in these areas because many infections occur in adolescents and adults; however, the high rates of chronic infection are maintained mostly by infections occurring in infants and children. In low prevalence areas, the lifetime risk of infection is <20%. Most HBV infections in these areas occur in adults in relatively well defined risk groups. *(Note: The map of HBsAg prevalence generalizes available data and patterns may vary within countries.)

Hepatitis B by Year, United States, 1966 - 2000 HBsAg screening of pregnant women recommended Infant Immunization recommended Vaccine licensed OSHA Rule enacted Adolescent Immunization recommended [SLIDE 15] Hepatitis B by year, United States, 1966 – 2000 Since hepatitis B vaccine was licensed for use in the United States in 1981, the incidence of acute hepatitis B has changed dramatically. During the 1980s, use of hepatitis B vaccine had little impact on disease incidence, which actually increased during the early 1980s. The incidence declined between 1985 and 1988, and between 1988 and 1991, when fewer cases were reported among men who have sex with men and among injecting drug users, respectively. In both of these groups the decline in incidence was likely related to behavioral changes in response to the epidemic of acquired immunodeficiency syndrome (AIDS) rather than to vaccine use. The incidence has continued to decline during the first half of the 1990s; a likely contributing factor for this most recent decline is the widespread use of hepatitis B vaccine in response to regulations issued by the Occupational Safety and Health Administration. Future declines in incidence are expected to occur as a result of the implementation of routine infant and routine adolescent vaccination, which have been recommended in the 1990s. Decline among injecting drug users Decline among MSM & HCWs Source: NNDSS

Hepatitis B – Clinical Features Incubation period Average 60-90 days Range 45-180 days Clinical illness <5 yrs, <10% (jaundice) >5 yrs, 30%-50% Acute case-fatality rate 0.5%-1% Chronic infection <5 yrs, 30%-90% >5 yrs, 2%-10% Premature mortality from chronic liver disease 15%-25% 29

Natural History of Hepatitis B Infection Asymptomatic Resolved Immune Chronic infection Cirrhosis Liver cancer Symptomatic acute hepatitis B Chronic infection

Serological Markers of HBV HBsAg Screening test Anti HBsAb Vaccinated or Infected. Anti HBcAb Remote past Infection HBeAg Active Multiplication Viral DNA Quantitative evidence AST/ALT Acute Liver Injury Serological Markers of HBV

HEPATITIS B TESTING HBsAg HBeAg HBeAb Viral DNA AST/ALT Neg Positive Normal > 2 fold HBeAb Negative Viral DNA <105 copies > 105 copies

Hepatitis Clinical Stages Chronic Active Hepatitis B HbsAg +ve for > 6 months Serum HBV DNA > 105 copies Persistent ↑ AST /ALT Necro inflammatory score 4 Inactive Carrier of B HBsAg + for > 6 months HBeAg - and anti HBeAb + Serum HBV DNA < 105 copies Persistent normal AST /ALT Resolved Hepatitis B Presence of antiHBc and anti HBs HBsAg- and undetectable HBV DNA load Normal AST and ALT

Chronic Hepatitis B HBeAg Positve HBeAg Negative HBeAg Seroconversion HBeAg Clearnace HBeAg Reversion HBsAg carrier state

Acute Hepatitis B Virus Infection with Recovery Typical Serologic Course Weeks after Exposure Symptoms HBeAg anti-HBe Total anti-HBc IgM anti-HBc anti-HBs HBsAg 4 8 12 16 20 24 28 32 36 52 100 Titer [SLIDE 34] Acute Hepatitis B Virus Infection with Recovery: Typical Serologic Course Serologic markers of HBV infection vary depending on whether the infection is acute or chronic. The first serologic marker to appear following acute infection is HBsAg, which can be detected as early as 1 or 2 weeks and as late as 11 or 12 weeks (mode, 30‑60 days) after exposure to HBV. In persons who recover, HBsAg is no longer detectable in serum after an average period of about 3 months. HBeAg is generally detectable in patients with acute infection; the presence of HBeAg in serum correlates with higher titers of HBV and greater infectivity. A diagnosis of acute HBV infection can be made on the basis of the detection of IgM class antibody to hepatitis B core antigen (IgM anti‑HBc) in serum; IgM anti‑HBc is generally detectable at the time of clinical onset and declines to subdetectable levels within 6 months. IgG anti‑HBc persists indefinitely as a marker of past infection. Anti‑HBs becomes detectable during convalescence after the disappearance of HBsAg in patients who do not progress to chronic infection. The presence of anti‑HBs following acute infection generally indicates recovery and immunity from reinfection.

Progression to Chronic Hepatitis B Virus Infection Typical Serologic Course IgM anti-HBc Total anti-HBc HBsAg Acute (6 months) HBeAg Chronic (Years) anti-HBe 4 8 12 16 20 24 28 32 36 52 Weeks after Exposure Titer [SLIDE 35] Progression to Chronic Hepatitis B Virus Infection: Typical Serologic Course In patients with chronic HBV infection, both HBsAg and IgG anti‑HBc remain persistently detectable, generally for life. HBeAg is variably present in these patients. The presence of HBsAg for 6 months or more is generally indicative of chronic infection. In addition, a negative test for IgM anti‑HBc together with a positive test for HBsAg in a single serum specimen usually indicates that an individual has chronic HBV infection.

HBV Modes of Transmission Sexual Parenteral Perinatal 2 2 2

Low / not High Moderate Detectable Concentration of HBV in Various Body Fluids Low / not High Moderate Detectable Semen Serum Vaginal fluid Blood Wound exudates Saliva Urine Feces Sweat Tears Breast milk 1 1 1

Risk Factors Associated with Reported Hepatitis B, 1990-2000 [Slide 8] Risk Factors Associated with Reported Hepatitis B, 1990-2000, United States Of persons with acute hepatitis B reported in the National Notifiable Diseases Surveillance System and the Viral Hepatitis Surveillance Program from 1990‑2000, 36% had a sexual risk factor (>1 sex partner during the previous 6 months, sex contact with a person with hepatitis, or men who have sex with men), 14% reported injecting drug use, and 18% had other risk factors (e.g., household contact with a hepatitis patient, health care employment). No risk factor could be identified for 32% of reported cases. *Other: Surgery, dental surgery, acupuncture, tattoo, other percutaneous injury Source: NNDSS/VHSP

Elimination of HBV Transmission Strategy Prevent perinatal HBV transmission Routine vaccination of all infants Vaccination of children in high-risk groups Vaccination of adolescents all children up through age 18 Vaccination of adults in high-risk groups [SLIDE 47] Elimination of Hepatitis B Virus Transmission, United States: Strategy The hepatitis B elimination strategy includes the following components: 1) preventing perinatal HBV transmission by screening all pregnant women for hepatitis B surface antigen (HBsAg) and providing hepatitis B immune globulin (HBIG) and hepatitis B vaccine to infants of HBsAg‑positive mothers; 2) providing hepatitis B vaccine to all infants as part of the routine childhood vaccination schedule; 3) making special efforts to provide catch‑up vaccination for children in high risk groups, including Alaska Natives, Pacific Islanders and infants of immigrants from countries with a high prevalence of chronic HBV infection; 4) providing hepatitis B vaccine to adolescents, including a) all previously unvaccinated children at 11‑12 years of age and b) adolescents of all ages who are at high risk for infection (see adult high‑risk groups below); and 5) vaccinating adults in high‑risk groups including a) men and women with a history of other sexually transmitted diseases and persons who have a history of multiple sex partners (>1 partner/6 months), b) household contacts and sex partners of persons with chronic HBV infection and health care and public safety workers who have exposure to blood in the workplace, d) clients and staff of institutions for the developmentally disabled, e) international travelers who plan to spend >6 months in countries with high rates of HBV infection and who will have close contact with the local population, f) injecting drug users, g) sexually active homosexual and bisexual men, and h) recipients of clotting‑factor concentrates.

Hepatitis B Vaccine Licensed in 1982; currently recombinant 3 dose series, typical schedule 0, 1-2, 4-6 months - no maximum time between doses (no need to repeat missed doses or restart) 2 dose series (adult dose) licensed by FDA for 11-15 year olds (Merck) Protection ~30-50% dose 1; 75% - 2; 96% - 3; lower in older, immunosuppressive illnesses (e.g., HIV, chronic liver diseases, diabetes), obese, smokers Vaccine advisory groups that have endorsed this strategy include the Immunization Practices Advisory Committee to the U.S. Public Health Service (ACIP), the American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the American College of Physicians (ACP).

Hepatitis B Vaccine Safety Administered to over 12 million infants and children in the United States – side effects rare Anaphylaxis estimated to occur in 1/600,000 doses given No scientific data to link hepatitis B vaccine with multiple sclerosis (MS), other autoimmune diseases, autism Vaccine advisory groups that have endorsed this strategy include the Immunization Practices Advisory Committee to the U.S. Public Health Service (ACIP), the American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the American College of Physicians (ACP).

Hepatitis B Vaccination ACIP Recommendations Routine infant Ages 11-15 “catch up”, and through age 18(VFC eligible) Over 18 – high risk Occupational risk (HCWs) Hemodyalisis patients All STD clinic clients Multiple sex partners or prior STD Inmates in Correctional settings MSM IDU Institution for developmental disability Pre-vaccination testing – if cost effective Post-vaccination testing – 1-2 months after last shot, if establishing response critical (HCW)