1. An Overview Terry Kotrla, MS, MT(ASCPBB Unit 4 Part 5 Hepatitis A-E Viruses

2. Background Viral hepatitis caused by infection by any of at least five distinct viruses. Hepatitis A, B and C most common ones identified in US. Produce acute illness characterized by: Nausea Malaise Abdominal pain Dark urine Jaundice HBV and HCV can become chronic, associated with increased risk of chronic liver disease and hepatocellular carcinoma.

3. A “Infectious” “Serum” Viral hepatitis Enterically transmitted Parenterall y transmitted F, G, TTV ? other E NANB BD C Viral Hepatitis - Historical Perspectives

4. Source of virus fecesblood/ blood-derived body fluids blood/ blood-derived body fluids blood/ blood-derived body fluids feces Route of transmission fecal-oralpercutaneous permucosal percutaneous permucosal percutaneous permucosal fecal-oral Chronic infection noyes no Preventionpre/post- exposure immunization pre/post- exposure immunization blood donor screening; risk behavior modification pre/post- exposure immunization; risk behavior modification ensure safe drinking water Summary of Viral Hepatitis ABCDE

5. Hepatitis A Virus

6. RNA virus Humans only natural host Can be stable in environment for months. Children younger than 6 years of age may have asymptomatic infection (70%). Older children and adults usually symptomatic, jaundice occurring in 70%.

7. Transmitted by close personal contact (e.g., household contact, sex contact, child day care centers) Contaminated food, water (e.g., infected food handlers, raw shellfish) Blood exposure (rare) (e.g., injecting drug use, transfusion) Hepatitis A Virus Transmission

8. Incubation period:Average 28 days Range 15-50 days Jaundice by age group: 14 yrs, 70%-80% Complications:Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis Chronic sequelae:None Hepatitis A - Clinical Features

9. Fecal HAV Symptoms 0123 4561212 2424 Hepatitis A Infection Total anti-HAV TitreALT IgM anti-HAV Months after exposure Typical Serological Course

11. Endemicity Disease Rate Peak Age of InfectionTransmission Patterns HighLow to High Early childhood Person to person; outbreaks uncommon ModerateHighLate childhood/ young adults Person to person; food and waterborne outbreaks Low Young adultsPerson to person; food and waterborne outbreaks Very low AdultsTravelers; outbreaks uncommon Global Patterns of Hepatitis A Virus Transmission

12. Prevalence of Antibody to HAV 2006

13. Laboratory Diagnosis Acute infection is diagnosed by the detection of IgM anti- HAV in serum by EIA. Generally detectable 5-10 days before onset of symtpoms. May persist for up to 6 months. Past infection is determined by the detection of IgG anti- HAV by EIA. Appears during convalescence. Present in serum forever, confers lifelong immunity. PCR helpful during outbreaks to determine common source.

14. Many cases occur in community-wide outbreaks No risk factor identified for most cases Highest attack rates in 5-14 year olds Asymptomatic children serve as source of infection Persons at increased risk of infection Travelers Homosexual men Injecting drug users Hepatitis A Vaccination Strategies Epidemiologic Considerations

15. Pre-exposure Travelers to intermediate and high HAV-endemic regions Post-exposure (within 14 days) Routine Household and other intimate contacts Selected situations Institutions (e.g., day care centers) Common source exposure (e.g., food prepared by infected food handler) Hepatitis A Prevention - Immune Globulin

16. Hepatitis B Virus

17. Incubation period:Average 60-90 days Range 45-180 days  Clinical illness (jaundice):<5 yrs, <10% 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% Hepatitis B - Clinical Features

18. Spectrum of Chronic Hepatitis B Diseases Chronic Persistent Hepatitis – asymptomatic Chronic Active Hepatitis – symptomatic exacerbations of disease Cirrhosis of liver Hepatocellular Carcinoma Liver failure Death

19. Symptoms HBeAg anti-HBe Total anti-HBc IgM anti-HBc anti-HBs HBsAg 0481216 20 242832 36 52100 Acute HBV Infection with Recovery Typical Serologic Course Weeks after Exposure Titre

20. IgM anti-HBc Total anti-HBc HBsAg Acute (6 months) HBeAg Chronic (Years) anti-HBe 048 12 16202428 32 36 52 Years Weeks after Exposure Titre Progression to Chronic HBV Infection - Serology

21. Symptomatic Infection Chronic Infection Age at Infection Chronic Infection (%) Symptomatic Infection (%) Birth 1-6 months7-12 months 1-4 years Older Children and Adults 0 20 40 60 80 100 80 60 40 20 0 Outcome of Hepatitis B Virus Infection by Age at Infection Chronic Infection (%)

22. 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 Global Patterns of Chronic HBV Infection

24. Prevalence of Chronic HBV 2006

25. HighModerate Low/Not Detectable bloodsemenurine serumvaginal fluidfeces wound exudatessalivasweat tears breastmilk Concentration of Hepatitis B Virus in Various Body Fluids

26.  Sexual - sex workers and homosexuals are particular at risk.  Parenteral - IVDA, Health Workers are at increased risk.  Perinatal - Mothers who are HBeAg positive are much more likely to transmit to their offspring than those who are not. Perinatal transmission is the main means of transmission in high prevalence populations. Hepatitis B Virus Modes of Transmission

27. Diagnosis A battery of serological tests are used for the diagnosis of acute and chronic hepatitis B infection. HBsAg - used as a general marker of infection. HBsAb - used to document recovery and/or immunity to HBV infection. anti-HBc IgM - marker of acute infection. anti-HBcIgG - past or chronic infection. HBeAg - indicates active replication of virus and therefore infectiveness. Anti-Hbe - virus no longer replicating. However, the patient can still be positive for HBsAg which is made by integrated HBV. HBV-DNA - indicates active replication of virus, more accurate than HBeAg especially in cases of escape mutants. Used mainly for monitoring response to therapy.

28. Treatment Interferon - for HBeAg +ve carriers with chronic active hepatitis. Response rate is 30 to 40%. Lamivudine - a nucleoside analogue reverse transcriptase inhibitor. Well tolerated, most patients will respond favorably. However, tendency to relapse on cessation of treatment. Another problem is the rapid emergence of drug resistance. Successful response to treatment will result in the disappearance of HBsAg, HBV-DNA, and seroconversion to HBeAg.

29. Prevention Vaccination - highly effective recombinant vaccines are now available. Vaccine can be given to those who are at increased risk of HBV infection such as health care workers. It is also given routinely to neonates as universal vaccination in many countries. Hepatitis B Immunoglobulin - HBIG may be used to protect persons who are exposed to hepatitis B. It is particular efficacious within 48 hours of the incident. It may also be given to neonates who are at increased risk of contracting hepatitis B i.e. whose mothers are HBsAg and HBeAg positive. Other measures - screening of blood donors, blood and body fluid precautions.

30. hypervariable region capsidenvelop e protein protease/helica se RNA- dependent RNA polymerase c22 5’ cor e E1E2NS 2 NS 3 33c NS 4 c-100 NS 5 3’ Hepatitis C Virus

31. Incubation period:Average 6-7 wks Range 2-26 wks Clinical illness (jaundice):30-40% (20-30%) Chronic hepatitis:70% Persistent infection:85-100% Immunity:No protective antibody response identified Hepatitis C - Clinical Features

32. Chronic Hepatitis C Infection The spectrum of chronic hepatitis C infection is essentially the same as chronic hepatitis B infection. All the manifestations of chronic hepatitis B infection may be seen, albeit with a lower frequency i.e. chronic persistent hepatitis, chronic active hepatitis, cirrhosis, and hepatocellular carcinoma.

33. Symptoms anti- HCV ALT Normal 012345 61234 Hepatitis C Virus Infection Typical Serologic Course Titre Month s Years Time after Exposure

34.  Transfusion or transplant from infected donor  Injecting drug use  Hemodialysis (years on treatment)  Accidental injuries with needles/sharps  Sexual/household exposure to anti-HCV-positive contact  Multiple sex partners  Birth to HCV-infected mother Risk Factors Associated with Transmission of HCV

36. Prevalence of Hepatitis C Infection

37. Laboratory Diagnosis HCV antibody - generally used to diagnose hepatitis C infection. Not useful in the acute phase as it takes at least 4 weeks after infection before antibody appears. HCV-RNA - various techniques are available e.g. PCR and branched DNA. May be used to diagnose HCV infection in the acute phase. However, its main use is in monitoring the response to antiviral therapy. HCV-antigen - an EIA for HCV antigen is available. It is used in the same capacity as HCV-RNA tests but is much easier to carry out.

38. Treatment Interferon - may be considered for patients with chronic active hepatitis. The response rate is around 50% but 50% of responders will relapse upon withdrawal of treatment. Ribavirin - there is less experience with ribavirin than interferon. However, recent studies suggest that a combination of interferon and ribavirin is more effective than interferon alone.

39. Treatment for HCV Interferon May be considered for patients with chronic active hepatitis. Response rate is around 50% but 50% of responders will relapse upon withdrawal of treatment. Ribavirin Less experience than with interferon. Recent studies suggest combination of interferon and ribavirin.

40. Prevention of Hepatitis C Screening of blood, organ and tissue donors. High-risk behavior modification. Blood and body fluid precautions.

41. HBsAg RNA  antigen Hepatitis D (Delta) Virus

42. Hepatitis D Clinical Features Coinfection Severe, acute disease Low risk of chronic infection Super infection Usually develop chronic HDV infection High risk of severe chronic liver disease May present as an acute hepatitis.

43. Heptaitis D Virus Modes Transmission Percutaneous exposure Injecting (IV) drug use. Permucosal exposure Sexual contact

44. anti-HBs Symptoms ALT Elevated Total anti-HDV IgM anti-HDV HDV RNA HBsAg HBV - HDV Coinfection Typical Serologic Course Time after Exposure Titre

45. anti-HBs Symptoms ALT Elevated Total anti-HDV IgM anti-HDV HDV RNA HBsAg HBV - HDV Coinfection Serology Time after Exposure Titre

46. Jaundice Symptoms ALT Total anti-HDV IgM anti-HDV HDV RNA HBsAg HBV - HDV Superinfection Typical Serologic Course Time after Exposure Titre

48. Hepatitis D Prevention Because HDV requires HBV for replication pre- or postexposure prophylaxis to prevent HBV infection. No product exists to prevent HDV superinfection in persone with chronic HBV infection. Educate to reduce risk behaviors among persons with chronic HBV infecion.

49. Hepatitis E Virus

50. Incubation period:Average 40 days Range 15-60 days Case-fatality rate:Overall, 1%-3% Pregnant women, 15%-25% Illness severity:Increased with age Chronic sequelae:None identified Hepatitis E - Clinical Features

51. Symptoms ALT IgG anti-HEV IgM anti-HEV Virus in stool 012345678910101 1212 1313 Typical Serologic Course of HEV Infection Titer Weeks after Exposure

52. Most outbreaks associated with faecally contaminated drinking water. Several other large epidemics have occurred since in the Indian subcontinent and the USSR, China, Africa and Mexico. In the United States and other nonendemic areas, where outbreaks of hepatitis E have not been documented to occur, a low prevalence of anti- HEV (<2%) has been found in healthy populations. The source of infection for these persons is unknown. Minimal person-to-person transmission. Hepatitis E - Epidemiologic Features

53. HEV – Epidemiologic Features Most outbreaks associated with fecally contaminated drinking water. Large epidemics still occur

54. Prevention and Control Measures Travelers to HEV Endemic regions should use caution. Avoid drinking water and beverages with ice, uncooked shellfish and uncooked fruit or vegetables which are not peeled or prepared by traveler IG prepared from donors in Western countries does not prevent infection. Unknown efficacy of IG prepared from donors in endemic areas. Vaccine?

55. Distribution of HEV Infection, 2008