1. Viral Hepatitis Medicine Student Lecture David R Nelson, M.D. Associate Professor of Medicine Director, Hepatology and Liver Transplantation University of Florida

3. Causes of Acute Hepatitis Acute Hepatitis Viral Hepatitis A, B/D, C, E EBV CMV & HSV Drugs Ethanol Tylenol Halothane Toxins Jamaica Bush Tea Mushrooms Vascular Hypotension Budd-Chiari Autoimmune Hepatitis Metabolic Wilson's Disease A1AT

5. Causes of Chronic Hepatitis Abbreviations: NAFLD: nonalcoholic fatty liver disease; AIH: autoimmune hepatitis; PBC: primary biliary cirrhosis PSC: primary sclerosing cholangitis, A1AT: alpha-1 antitrypsin deficiency, HHC:hereditary hemochromotosis Chronic Hepatitis Viral Hepatitis Hep B Hep C Drugs MTX INH Amiodarone Alcohol NAFLD Autoimmune AIH PBC PSC Metabolic A1AT HHC Wilson's

6. 47% 34% 16% 3% Hepatitis A Hepatitis B Hepatitis C Hepatitis Non-ABC Source: CDC Sentinel Counties Study on Viral Hepatitis Acute Viral Hepatitis by Type, USA: 1982-1993

8. HAV Prevalence High Intermediate Low Very Low Global Prevalence of Hepatitis A Infection

15. Geographic Distribution of Chronic HBV Infection HBsAg Prevalence  8% - High 2-7% - Intermediate <2% - Low > 350 million carriers (HBsAg + > 6 months) 10th cause of death (1 million / year) Cirrhosis in 20% (75 - 100 million) HCC in 5 - 10% (20 - 40 million)

17. HBV Sources of Infection Household, 3% Other, 23% IDU, 20% Multiple sex partners, 24% Sex contact, 23% MSM, 23% Centers for Disease Control and Prevention. Hepatitis B. In: Atkinson W et al, eds. Epidemiology & Prevention of Vaccine-Preventable Diseases . 8th ed Washington DC: Public Health Foundation; 2005:191-212. Many patients do not reveal IDU as source of infection

19. Hepatitis B - Clinical Features Incubation period Average: 60 – 90 days Range: 45 – 180 days Clinical illness (jaundice) < 5 yrs of age: <10%  5 yrs of age: 30 – 50% Acute case-fatality rate 0.5 – 1% Chronic infection < 5 yrs of age: 30 – 90%  5 yrs of age: 2 – 10% Mortality from chronic liver disease 15 – 25%

20. Progression to Chronic Hepatitis B Virus Infection Typical Serologic Course Weeks after Exposure Titer IgM anti-HBc Total anti-HBc HBsAg Acute (6 months) HBeAg Chronic (Years) anti-HBe 0 4 8 12 16 20 24 28 32 36 52 Years HBV DNA

21. Interpretation of Serologic Markers Acute hepatitis B Recovery from acute hepatitis B Chronic HBeAg + disease Chronic HBeAG – disease Successful Vaccination Resistance to antiviral agents HBsAg  (may clear)   Anti-HBs   Anti-HBc IgM  Anti-HBc     HBeAg   Anti-HBe  (in some cases)  DNA (PCR if required)  (may be only marker during window period)    (sequence pol region)

22. Hepatitis B: Disease Progression Acute Infection Chronic Infection Cirrhosis Death 1. Torresi J et al. Gastroenterology . 2000. 2. Fattovich G et al. Hepatology . 1995. 3. Moyer LA et al. Am J Prev Med . 1994. 4. Perrillo R et al. Hepatology . 2001. 5%-10% 1 10-30% 1 23% within 5 years Liver Cancer (HCC) Chronic HBV is the 6th leading cause of liver transplantation in the US 4 Liver Transplantation Liver Failure (Decompensation) 2-6% 90% in perinatal 30-90% in children<5yrs old 5% in healthy adults Higher in HIV, immune suppressed

26. Approved Treatments Lok AND McMahon. .Hepatology , Vol. 45, No. 2, 2007

28. Modes of HDV infection Coinfection Superinfection B B D D

29. HCV Life-Cycle and Pathogenesis Cell Binding and Infection Replication Immune Response CD4 CD8 NK DC HSC Fibrosis Immune Recognition Cytokines Viral Packaging and Release Effector HCV

30. Course of Acute HCV Infection Time After Exposure Symptoms 0 400 600 800 1000 ALT (IU/L) 0 2 4 6 8 10 12 24 1 2 3 4 5 6 Anti-HCV Weeks Months HCV RNA positive 200 7 Normal ALT Hoofnagle JH. Hepatology. 1997;26:15S. Carithers RL Jr, et al. Semin Liver Dis. 2000;20:159-171. Pawlosky JM. Hepatology. 2002;36(suppl 1):S65-S73. NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002. Available at: http://consensus.nih.gov/2002/2002HepatitisC2002116html. Accessed April 10, 2007.

31. Symptoms, or Lack of, in Chronic HCV Infection Symptomatic 37% Cirrhosis 7% 56% Asymptomatic 0 20 40 60 80 100 Fatigue Patients (%) 80

32. ALT Elevations Are Not Indicative of Chronic HCV Infection Inglesby TV, et al. Hepatology. 1999;29:590-596. 42 43 15 0 20 40 60 80 100 Persistently Normal ALT Intermittently Elevated ALT Persistently Elevated ALT Patients* With HCV infection (%)

33. Diagnostic Tests for HCV Infection CDC Morbidity Mortality Weekly Report. 1998;16(RR-19):1-33. NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002. Available at: http://consensus.nih.gov/2002/2002HepatitisC2002116html. Accessed April 10, 2007. Diagnostic Test Type Specifications Serologic Virologic Mode of detection Antibodies Virus Sensitivity > 95% > 98% Specificity Variable > 98% Detection postexposure 2-6 mos 2-6 wks Use Screening Confirmation

34. Molecular Virologic Assays Quantitative assays Detection cutoff > qualitative How much HCV is present? Qualitative assays High sensitivity (  50 IU/mL) Is HCV present? Genotype assays What type of HCV is present?

37. Prevalence of HCV Infection: United States Alter et al. N Engl J Med . 1999;341:556-562. Anti-HCV+ (%) 0 1 2 3 4 5 6 7 Age (yr) Mexican American Caucasian 3.5% 1.1% African American 3.2% 6–11 12–19 20–29 30–39 40–49 50–59 70+ 60–69

38. HCV: Disease Progression 1. NIH Consensus Development Conference Statement; March 24-26, 1997. 2. Davis GL et al. Gastroenterol Clin North Am . 1994;23:603-613. 3. Koretz RL et al. Ann Intern Med . 1993;119:110-115. 4. Takahashi M et al. Am J Gastroenterol . 1993;88:240-243. HCV infection Chronic HCV Cirrhosis Hepatic Failure Liver Cancer Liver Transplant Candidates 60-85% 1 ~20% 4 ~ 20% 3 20%-50% 2 Time: 20-30 years

41. Improvements in Therapy of HCV Sustained Virologic Response (%) IFN 6m IFN/RBV 6m Peg-IFN/ RBV 12m IFN 12m IFN/RBV 12m Peg-IFN 12m Strader DB et al. Hepatology 2004;39:1147-1171 1991 1998 2001 2002

42. Current standard treatment duration is 48 or 24 weeks according to genotype HCV genotyping HCV-1 (4,5,6) Quantitative HCV RNA HCV-2,3 Peg-IFN + RBV 800 mg/day for 24 weeks Peg-IFN+ RBV 1000/1200 mg/day Quantitative HCV RNA at week 12 <2 log decline Stop or re-evaluate therapy  2 log decline or HCV RNA (–) 48 weeks