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Hepatitis Viruses

Hepatitis Viruses. A*. B**. C*. D*. E*. Viral Hepatitis overview. Source of. feces. blood/. blood/. blood/. feces. virus. blood-derived. blood-derived. blood-derived. body fluids. body fluids. body fluids. Route of. fecal-oral. percutaneous. percutaneous. percutaneous.

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Hepatitis Viruses

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  1. Hepatitis Viruses

  2. A* B** C* D* E* Viral Hepatitis overview Source of feces blood/ blood/ blood/ feces virus blood-derived blood-derived blood-derived body fluids body fluids body fluids Route of fecal-oral percutaneous percutaneous percutaneous fecal-oral transmission permucosal permucosal permucosal Chronic no yes yes yes no infection Prevention pre/post- pre/post- blood donor pre/post- ensure safe exposure exposure screening; exposure drinking immunization immunization risk behavior immunization; water modification risk behavior modification *RNA virus **DNA virus

  3. Epidemiologic risk groupsHAV

  4. Clinical and laboratory manifestations of acute hepatitis A

  5. Hepatitis A: a public health burden • Millions of cases annually worldwide • Billions of people have been infected globally during their life time • Adult infections - 75-90% of cases are symptomatic • Historically- fulminant hepatitis is rare (<1%) but with 1.75-2.1% mortality rate after age >40 years of age • Rising(?) incidence of fulminant hepatitis in distinct regions

  6. Proportion of susceptibles among older children and adults risk for clinically significant outbreaks childhood exposure to virus The hepatitis A paradox Improved socio-economic conditions Proportion of symptomatic disease increase with age Adapted from Dagan.R Jama, July 13, 2005 p.202 and WHO/CDS/CSR/EDC/2000.7 p.20-217

  7. % anti-HAV IgG +

  8. Hepatitis B Virus(HBV)

  9. Prevalence of HBV: Global Estimates HBsAg Prevalence High (≥ 8%) Intermediate (2% to 8%) Low (< 2%) Mast EE, et al. MMWR Recomm Rep. 2006;55:1-33.Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S158-S168.

  10. > 2 billion have been infected[1] 4 million acute cases per year[1] 1 million deaths per year[1] 350-400 million chronic carriers[1] 25% of carriers die from chronic hepatitis, cirrhosis, or liver cancer[1] Nearly 75% of chronic carriers are Asian[2] Second most important carcinogen behind tobacco[3] Causes 60% to 80% of all primary liver cancer[1] HBV is 100 times more contagious than HIV[4] HBV: A Significant Cause of Worldwide Morbidity and Mortality 1. WHO. Hepatitis B. 2002. 2. Maynard JE, et al. In: Viral Hepatitis and Liver Disease. New York: Alan R. Liss, Inc. 1988. 3. CDC. Epidemiology & prevention of vaccine-preventable diseases. The Pink Book. 8th ed. 4. CDC. MMWR. 2001;50:RR-11.

  11. Chronic Hepatitis BLong-term Consequences HBeAg-positive CHB HBeAg-negative CHB 15-20% develop cirrhosis in 5 yrs Cirrhosis Decompensation* Death Hepatocellular carcinoma (HCC) Lok et al NEJM 2002 *5-yr survival 55% Weissberg et al Ann Intern Med 1984, Beasley Lancet 1981

  12. Outcome of HBV Infection According to Age at Time of Infection % of infections with outcome Chronic infection Symptomatic acute infection Birth 1–6 months 7–12 months 1–4 years Older children and adults Age at infection WHO 2001

  13. Risk Factors Associated With Acute HBV Infection: US (2006) MMWR: Surveillance Summary March 21, 2008 / Vol. 57 / No. SS—2.

  14. Acute Hepatitis B With Recovery Serologic Course …..HBV-DNA Symptoms anti-HBe HBeAg Total anti-HBc Titer anti-HBs IgM anti-HBc HBsAg 0 4 8 12 16 24 28 32 52 100 20 36 Weeks after exposure

  15. Progression to Chronic HBV Infection Evolution of Persitent Infection HBV-DNA Acute (6 months) Chronic (Years) HBeAg anti-HBe HBsAg Total anti-HBc Titer IgM anti-HBc Years 0 4 8 16 20 24 28 36 12 32 52 Weeks of Exposure Source: CDC and Prevention

  16. Virology of HBV: A Primer

  17. Life Cycle of HBV in the Hepatocyte Subviralparticles InfectiousHBV virion Viral polymeraseconverts pregenomic RNAto partially ds DNA ER Cytoplasm PartiallydsDNA HBeAg Minus strand DNA Encapsulated pregenomic mRNA HBsAg HBcAg cccDNA mRNA Precore/core Nucleus Hepatocyte Adapted from Lai CL, et al. J Med Virol.2000;61:367-373.

  18. Global Distribution of the 8 HBV Genotypes A D G A, B, C, D, G B, C D A, D, E H, F F A, B, C, D Arauz-Ruiz P, et al. J Gen Virol. 2002;83:2059-2073. Bell SJ, et al. J Clin Virol. 2005;32:122-127. Chu CJ, et al. Gastroenterology. 2003;125:444-451. Kidd-Ljunggren K, et al. J Gen Virol. 2002;83:1267-1280. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.

  19. Phases of Disease

  20. Phases of Chronic HBV Infection Immune Immune Low Replicative Reactivation Tolerance Clearance Phase Phase HBeAg-/anti-HBe+ (precore/core promoter variants) HBeAg+ > < < > > 2000 IU/mL HBV DNA < 2000 IU/mL 2 x 108 - 2 x 1011 IU/mL 200,000 - 2 x 109 IU/mL Slide courtesy of A. S. F. Lok, MD.

  21. Phases of Chronic HBV Infection Immune Immune Low Replicative Reactivation Tolerance Clearance Phase Phase HBeAg-/anti-HBe+ (precore/core promoter variants) HBeAg+ > < < > > 2000 IU/mL HBV DNA < 2000 IU/mL 2 x 108 - 2 x 1011 IU/mL 200,000 - 2 x 109 IU/mL ALT Slide courtesy of A. S. F. Lok, MD.

  22. Phases of Chronic HBV Infection Immune Immune Low Replicative Reactivation Tolerance Clearance Phase Phase HBeAg-/anti-HBe+ (precore/core promoter variants) HBeAg+ > < < > > 2000 IU/mL HBV DNA < 2000 IU/mL 2 x 108 - 2 x 1011 IU/mL 200,000 - 2 x 109 IU/mL ALT Normal/mild CH Moderate/severe CH Normal/mild CH Moderate/severe CH Cirrhosis Inactive cirrhosis Cirrhosis Slide courtesy of A. S. F. Lok, MD.

  23. Phases of Chronic HBV Infection Immune Immune Low Replicative Reactivation Tolerance Clearance Phase Phase HBeAg-/anti-HBe+ (precore/core promoter variants) HBeAg+ > < < > > 2000 IU/mL HBV DNA < 2000 IU/mL 2 x 108 - 2 x 1011 IU/mL 200,000 - 2 x 109 IU/mL ALT Normal/mild CH Moderate/severe CH Normal/mild CH Moderate/severe CH Cirrhosis Inactive cirrhosis Cirrhosis HBeAg+ chronic hepatitis Inactive-carrier state HBeAg- chronic hepatitis Slide courtesy of A. S. F. Lok, MD.

  24. Natural History of HBV Infection > 95% Immune Tolerance Adulthood Early Childhood < 5% HBeAg-ChronicHepatitis B HBeAg+ChronicHepatitis B Cirrhosis Inactive Carrier Courtesy of W. Ray Kim, MD.Chen DS, et al. J Gastroenterol Hep. 1993;8:470-475.Seeff L, et al. N Engl J Med. 1987;316:965-970.

  25. Natural History of HBV Infection > 95% Immune Tolerance Adulthood Early Childhood < 5% HBeAg-ChronicHepatitis B HBeAg+ChronicHepatitis B HCC Inactive Carrier Courtesy of W. Ray Kim, MD.Chen DS, et al. J Gastroenterol Hep. 1993;8:470-475.Seeff L, et al. N Engl J Med. 1987;316:965-970.

  26. Current Methods of Determining the Risk of HCC: HBV DNA Level

  27. HBV DNA Associated With Increased Risk of HCC 3.9-fold greaterrisk of HCC in individuals with detectable HBV DNA vs those with undetectable HBV DNA Risk associated with increasing HBV DNA levels These data support possibility of reducing long-term risk of HCC by inducing sustained suppression of HBV replication Yang HI, et al. N Engl J Med. 2002;347:168-174.

  28. Diagnostic Criteria andPatient Evaluation

  29. Can HBV Infection Be Cured? HBV is not curable but it is controllable HBsAg seroconversion is the ultimate form of viral control

  30. Presence of Occult HBV Among Patients Without Liver Disease Occult HBV infection defined by presence of HBV DNA in liver of HBsAg-negative individuals These individuals may be at increased risk of liver fibrosis progression and development of HCC if other causes of liver damage are present[1] Immunosuppression may reactivate occult HBV Individuals may transmit HBV infection to others 1. Squadrito G, et al. Cancer. 2006;106:1326-30. 2. Raimondo G et al. J Hepatol. 2008;48:743-746.

  31. Goals of Hepatitis B Treatment Prevention of long-term negative clinical outcomes (eg, cirrhosis, HCC, death) by durable suppression of HBV DNA Primary treatment endpoint Sustained decrease in serum HBV DNA level to low or undetectable Secondary treatment endpoints Decrease or normalize serum ALT Improve liver histology Induce HBeAg loss or seroconversion Induce HBsAg loss or seroconversion

  32. HBV Treatment Landscape Peginterferon alfa-2a Entecavir Lamivudine Tenofovir 1990 1998 2002 2005 2006 2008 Interferon alfa-2b Telbivudine Adefovir

  33. Factors Driving Selection of Initial Therapy Nucleos(t)ide Analogues Peginterferon Safety & tolerability Efficacy(potency) Efficacy(potency) Safety & tolerability Barrier to resistance (durability)

  34. Undetectable* HBV DNA in HBV Patients After 1 Year of Treatment Not head-to-head trials; different patient populations and trial designs HBeAg Positive HBeAg Negative 100 100 90 93 88 76 80 80 67 63 60-73 60 60 60 51-63 Undetectable* HBV DNA (%) 40-44 40 40 25 20 20 13-21 0 0 Peg-IFN Peg-IFN LAM ADV TBV ETV TDF LAM ADV TBV ETV TDF *By PCR-based assay (LLD ~ 50 IU/mL) except for some LAM studies. Lok AS, et al. Hepatology. 2007;45:507-539. Lok AS, et al. Hepatology. 2009;50:661-662.

  35. HBeAg Loss and Seroconversion in HBeAg+ Patients After 1 Year of Treatment Not head-to-head trials; different patient populations and trial designs HBeAg Loss HBeAg Seroconversion 100 100 80 80 60 60 Outcome (%) 40 40 30 26 24 23 22 22 21 22 22-27 17-32 20 20 12-18 NA 0 0 Peg-IFN Peg-IFN LAM ADV TBV ETV TDF LAM ADV TBV ETV TDF Lok AS, et al. Hepatology. 2007;45:507-539. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2003;348:808-816. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Lai CL, et al. N Engl J Med. 2007;357:2576-2588. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Janssen HL, et al, Lancet. 2005;365;123-129. Heathcote J, et al. AASLD 2009. Abstract 483.

  36. Cumulative Rates of Resistance With Oral Agents in Nucleos(t)ide-Naive Patients Not head-to-head trials; different patient populations and trial designs Yr 6 Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Drug Generation 1st LAM 24% 49% 67% 38% 70% ADV 29% 0% 3% 11% 18% 2nd TBV 4% 17% ETV 0.2% 0.5% 1.2% 1.2% 1.2% 1.2% 3rd TDF 0% 0% 0% EASL HBV Guidelines. J Hepatol. 2009;50:227-242. Tenny DJ, et al. EASL 2009. Abstract 20. Marcellin P, et al. AASLD 2009. Abstract 481. Heathcote E, et al. Abstract 483.

  37. Tolerability and Safety: Nucleos(t)ide Analogues vs Peginterferon Nucleos(t)ide Analogues Safe at all stages of disease, including decompensated cirrhosis Safe in immunocompromised populations Selected drugs probably safe in pregnancy Reported toxicities are rare Peginterferon Contraindications Decompensated cirrhosis Pregnancy Significant cardiopulmonary disease Uncontrolled seizures, psychiatric disease Autoimmune diseases Not recommended Cirrhosis Adverse effects common Lok AS, et al. Hepatology. 2007;45:507-539. Lok AS, et al. Hepatology. 2009;50:661-662.

  38. The First Branch Point in Choosing Treatment for Hepatitis B Decision to treat PegIFN Nucleos(t)ide analogues

  39. “Undesirable” Virologic Responses to Oral Therapy 1.0 Antiviral Drug Primary nonresponse 0 Virologic breakthrough -1.0 Change in HBV DNA(log10 IU/mL) Suboptimal response -2.0 -3.0 1 log Nadir -4.0 0 6 12 18 Mo Lok AS, et al. Hepatology. 2007;45:507-539.

  40. Hepatitis C:Epidemiology

  41. Hepatitis C Virus InfectionMagnitude of the Problem • Nearly 4 million persons in United States infected • Approximately 35,000 new cases yearly • 85% of new cases become chronic • Leading cause of • Chronic liver disease • Cirrhosis • Liver cancer • Liver transplantation Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm. Accessed February 1, 2006.

  42. Worldwide Prevalence of Hepatitis C(~170 million HCV carriers) WHO. Wkly Epidemiol Rec. 2000.

  43. Hepatitis C VirusFate of Acute Infection Spontaneous resolution 15% Chronic 85% Alter MJ, et al. N Eng J Med. 1999;341:556-562.

  44. Course of Acute HCV Infection HCV RNA positive 1000 Anti-HCV 800 Symptoms 600 ALT (IU/L) 400 200 Normal ALT 0 0 2 4 6 8 10 12 24 1 2 3 4 5 6 7 Weeks Months Time After Exposure 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.

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