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Viral Hepatitis.ppt
- 5. Hepatocellular Necrosis Alanine Aminotransferase (ALT) & Aspartate Amino- transferase (AST) Serum Albumin Prothrombin Time Acute Chronic Biochemical Effects
- 6. Clinical Stages Incubation Period - the time from exposure to the onset of symptoms, virus shedding may precede symptoms Prodromal Period - symptoms preceding hepatitis signs such as jaundice Icteric Phase - clinically evident signs of variable duration, may recur Post-icteric Phase - clinical and biochemical recovery of variable duration
- 7. Clinical Spectrum Subclinical Infection – serologic and biochemical evidence of infection but asymptomatic. Clinical Infection – signs and symptoms of hepatitis, Acute fulminant – massive necrosis Acute self-limited – complete recovery Chronic carrier – usually non-progressive Chronic active – progressive damage +/- symptoms Cirrhosis and liver failure Hepatocellular carcinoma
- 8. Virus Genome Genome Envelope Family / genus size (kb) HAV RNA 7.5 - Picornaviridae positive sense, hepatovirus single stranded, linear HBV DNA 3.2 + Hepadnaviridae partially double stranded, circular HCV RNA 9.6 + Flaviviridae positive sense, hepacivirus single stranded, linear HDV RNA 1.7 + Unclassified positive sense, (viroid), delta virus single stranded, linear HEV RNA 7.5 - Unclassified, positive sense, single togavirus and stranded, linear alpha virus-like Human Hepatitis Viruses Human Hepatitis Viruses
- 9. Hepatitis C
- 10. Nucleic Acid: 9.6 kb ssRNA Classification: Flaviviridae, Hepacivirus Genotypes: 1 to 6 Enveloped In vitro model: primary hepatocyte and T cell cultures; replicon system In vivo replication: in cytoplasm, hepatocyte and lymphocyte; human and other primates 40-60 nm Hepatitis C Virus Hepatitis C Virus: Morphology and Characteristics
- 11. Prevalence HCV - Epidemiology United States Anti-HCV positive 3.9 million (1.8%) HCV RNA positive 2.7 million (1.4%) Worldwide 170 million ( 3%) Alter MJ et al., New Engl J Med 1999; 341:556 Lavanchy D & McMahon B, In: Liang TJ & Hoofnagle JH (eds.) Hepatitis C. New York: Academic Press, 2000:185 Prevalence
- 12. HCV - Epidemiology Terrault NA, Hepatology 2002 ;36(Suppl 1):S99 Roberts EA, Yeung L. Hepatology 2002 ;36(Suppl 1):S106 Current Likelihood of Transmission Transfusion ~ 1 in 1,000,000 Maternal-Infant Mother HIV-negative ~ 5% Mother HIV-positive 15 - 20% Heterosexual partner ~1 in 1,000 per yr Needlestick injury HCV-positive source ~ 5% HCV status unknown ~ 1% Current Likelihood of Transmission
- 13. HCV - Natural History Outcome Following Hepatitis C Infection Acute hepatitis C Chronic infection Chronic hepatitis Cirrhosis Time (yr) 55 - 85% 70% 20% 10 20 30 Decompensation HCC 1 - 4%/yr 4 - 5%/yr Outcome Following Hepatitis C Infection
- 14. Diagnostic Tests • Hepatitis C antibody tests • Qualitative HCV RNA tests • Quantitative HCV RNA tests • Genotyping HCV - Diagnosis Diagnostic Tests
- 15. Hoofnagle JH, Hepatology 1997; 26:15S HCV - Diagnosis Acute HCV Infection Time After Exposure 0 400 600 800 1000 ALT (IU/L) 0 2 4 6 8 10 12 24 1 2 3 4 5 6 Anti-HCV Symptoms Weeks Months HCV RNA positive 200 7 Normal ALT Acute hepatitis C infection
- 16. HCV Antibody Test • Indicates past or present infection • Inexpensive, sensitive and specific • Poor positive predictive value in low prevalence populations • Low sensitivity in immunosuppressed patients HCV - Diagnosis Antibody tests for hepatitis C
- 17. HCV - Diagnosis Qualitative HCV RNA (PCR) • Confirms diagnosis of HCV infection • Useful in the early diagnosis of acute hepatitis C • Demonstrates the presence of active infection • “Gold standard” for documenting response to treatment Qualitative tests for HCV RNA
- 18. Clinical Features of Hepatitis C Transmission Oral No Percutaneous Common Sexual Yes, rare Perinatal Yes, low frequency Incubation period 14 – 160 (days) Clinical Illness at 5 - 10% presentation
- 19. Clinical Features of Hepatitis C Jaundice 5 – 10% Fulminant Rare Diagnostic tests Acute infection HCV RNA (anti-HCV) Chronic infection HCV RNA (anti-HCV), >6 months Immunity Unknown Case-fatality rate 1 – 2% Chronic infection 60 – 85%
- 20. Hepatitis B
- 21. 42 nm 22 nm HBsAg HBV DNA HBcAg 42 nm Nucleic Acid: 3.2 kb DNA Classification: Hepadnaviridae Multiple serotypes and genotypes A-F Enveloped In vitro model: primary hepatocyte culture and transfection of cloned HBV DNA In vivo replication: in cytoplasm, cccDNA in nucleus; hepatocyte and other tissues, human and other primates Hepatitis B Virus Hepatitis B Virus: Morphology and Characteristics 4
- 22. HBV - Epidemiology Prevalence of HBsAg Carrier State WHO >8% 2-8% <2% Epidemiology of Hepatitis B
- 23. HBV - Epidemiology Risk factors for hepatitis B infection Risk Factors for Infection Percutaneous Injection drug use Transfusion or transplant Occupational exposure Parenteral practices Permucosal Perinatal Sexual Household contact
- 24. HBV - Natural History Acute Hepatitis Subclinical Hepatitis Fulminant Hepatitis Death Acute Infection Recovery Outcome of Acute HBV Infection Chronic Infection Clinical Outcome of Acute Hepatitis B
- 25. HBV - Epidemiology Risk of chronic infection Age at Infection 0 20 40 60 80 100 Neonates Infants Children Adults % Risk Risk of Chronic Infection
- 26. Outcome of Chronic HBV Infection HBV - Natural History Chronic HBV Infection Inactive Carrier State Chronic Hepatitis Cirrhosis HCC Clinical Outcome of Chronic Hepatitis B
- 27. Hepatitis B Virus Polymerase Terminal protein (priming) Reverse transcriptase, RNAse H Surface Envelope proteins Pre - S1 Receptor binding, Regulation of cccDNA, viral assembly Pre - S2 Viral assembly, fusion sequence S Primary structural component, major antigenic determinants Core HBeAg Secreted, immunomodulatory function Core Nucleocapsid component HBX Pleiotropic effects Gene Products and Functions Hepatitis B Virus: The Functions of Gene Products
- 28. HBV - Diagnosis Acute Infection 0 2 4 6 HBsAg Anti-HBs Anti-HBc Anti-HBc IgM Months Years HBeAg HBV DNA Anti-HBe Serological Markers of Acute HBV Infection
- 29. Chronic Infection HBV - Diagnosis HBV DNA HBeAg Months Years Anti-HBc IgM Anti-HBc IgG Anti-HBe HBsAg Serological Markers of Chronic HBV Infection
- 30. Serological Markers Clinical Significance HBsAg Acute/Chronic infection Anti-HBc IgM Acute infection HBeAg High infectivity Anti-HBe Low infectivity Anti-HBs Immunity Anti-HBc IgG and HBsAg Chronic infection Anti-HBc IgG and anti-HBs Resolved infection HBV - Diagnosis Clinical Significance of Serological Markers for HBV Infection
- 31. Clinical Features of Hepatitis B Transmission Oral Not likely Percutaneous Common Sexual Common Perinatal Common Incubation period 60-180 (days) Clinical Illness at 10 - 15% presentation
- 32. Clinical Features of Hepatitis B Jaundice 5 –20% Fulminant <1% Diagnostic tests Acute infection HBsAg, IgM anti-HBc Chronic infection HBsAg, IgG anti-HBc Immunity IgG anti-HBc, anti-HBs Case-fatality rate 1 – 3% Chronic infection >90% infants <5% adults
- 33. Hepatitis D
- 34. Nucleic Acid: 1.7 kb ssRNA Classification: unclassified, related to viroids; deltavirus HBV envelope One serotype, three genotypes In-vitro model: primary hepatocyte culture and transfection of cloned HDV DNA In-vivo replication: in nucleus, requires HBV for assembly and infection 35-37nm Hepatitis D Virus Hepatitis D Virus: Morphology and Characteristics
- 35. Pattern Distribution Modes of transmission Endemic Mediterranean Intra-familial Middle East Sexual Central & South America Africa Non-endemic North America Injection drug use Northern Europe Transfusion of clotting factor concentrates HDV Epidemiologic Patterns Transmission of hepatitis D virus (HDV)
- 36. Coinfection Superinfection B B D D HDV Modes of HDV infection
- 37. HDV - Coinfection HDV Months HDV RNA IgM anti-HDV IgG anti-HDV HDAg IgG anti-HBc ALT HBsAg anti-HBs IgM anti-HBc HDV Co-infection
- 38. HDV - Superinfection HDV ALT HDV RNA IgM anti-HDV IgG anti-HDV HDAg HBV DNA Years HBsAg, IgG anti-HBc HDV Superinfection
- 39. Clinical Sequelae HDV Acute hepatitis Acute exacerbation Fulminant hepatitis Cirrhosis and HCC Coinfection Superinfection Chronic hepatitis Uneventful recovery Clinical sequelae of HDV infection
- 40. Clinical Features of Hepatitis D Transmission Oral No Percutaneous Common Sexual Yes, rare Perinatal No Incubation period 21 – 45 (days) Clinical Illness at 10%, higher with presentation superinfection
- 41. Clinical Features of Hepatitis D Jaundice Unknown Fulminant 2 – 7.5% Diagnostic tests Acute infection IgM anti-HDV Chronic infection IgG anti-HDV, HBsAg + Immunity Not applicable Case-fatality rate 1 – 2% Chronic infection Superinfection – 80% Coinfection < 5%
- 42. Hepatitis A
- 43. 27 nm Nucleic Acid: 7.5 kb ssRNA Classification: Picornaviridae, Hepatovirus One serotype and multiple genotypes Nonenveloped, acid and heat stable In vitro model: monkey and human cell cultures In vivo replication: in cytoplasm of hepatocyte; human and other higher primates Hepatitis A Virus Hepatitis A Virus: Morphology and Characteristics
- 44. HAV - Epidemiology Global Prevalence of Hepatitis A HAV Prevalence High Intermediate Low Very Low Global Prevalence of Hepatitis A Infection
- 45. < 5 5 - 10 10 - 20 >20 cases per 100,000 population Prevalence of Hepatitis A in the United States Prevalence of Hepatitis A in the United States CDC
- 46. Routes of Hepatitis A Transmission • Close personal contact Household or sexual contact Daycare centers • Fecal-oral contamination of food or water Food handlers Raw shellfish Travel to endemic areas • Blood-borne (rare) Injecting drug users Hepatitis A Transmission
- 47. Typical Serologic Course of Acute Hepatitis A Virus Infection HAV Fecal HAV ALT IgM anti-HAV Months after exposure Symptoms 0 1 2 3 4 5 6 12 24 Total anti-HAV Serological Course of Acute Hepatitis A
- 48. Age-specific Incidence of Hepatitis A • Asymptomatic (anicteric) disease Children under 6 years of age, > 90% Children from 6-14 years old, 40-50% • Symptomatic (icteric) disease Adults and children over 14, 70-80% Clinical Variants of Hepatitis A Infection
- 49. Hepatitis A Prevention - Immune Globulin HAV Hepatitis A Prevention: Immune Globulin Preexposure – Travelers to high HAV-prevalence regions Postexposure (within 14 days) – Routine • Household and other intimate contacts – Selected situations • Institutions (e.g. daycare centers) • Common source exposure (e.g. food prepared by infected food handler)
- 50. ACIP Recommendations MMWR 1999; 48(RR12):1 HAV Hepatitis A: Pre-exposure Vaccination Hepatitis A Vaccination: Preexposure Vaccination Persons at increased risk or danger of infection – Travelers to intermediate and high HAV prevalence areas – Men having sex with men – Injecting drug users – Persons with chronic liver disease Communities with high rates of hepatitis A (e.g., Alaskan Natives, Native-Americans) Routine pre-school childhood vaccination
- 51. Clinical Features of Hepatitis A Transmission Oral Common Percutaneous Rare Sexual No Perinatal No Incubation period 15 – 49 days (average 25) Clinical Illness at 5% Children presentation 70-80% Adults
- 52. Clinical Features of Hepatitis A Jaundice Adults-30% Children-<5% Fulminant <1% Diagnostic tests Acute infection IgM anti-HAV Chronic infection Not applicable Immunity IgG anti-HAV Case-fatality rate 0.1 – 2.7% Chronic infection None
- 53. Hepatitis E
- 54. Nucleic Acid: 7.5 kb ssRNA Classification: unclassified, togavirus, and alphavirus-like One serotype with genetic heterogeneity Non-enveloped, acid stable Invitro model, no cell culture system Invivo replication: in cytoplasm of hepatocyte; human and other primates 32 nm Hepatitis E Virus Hepatitis E Virus: Morphology and Characteristics
- 55. Hepatitis E Suspected from study of waterborne hepatitis in India in 1980 Confirmed by transmission to chimp and human in 1983 Probably accounts for many historical outbreaks of hepatitis Endemic mainly in Asia, Middle East, North Africa Epidemiology Epidemiology
- 56. Hepatitis E Fecal-oral transmission (human to human) Contaminated water supplies in tropical or subtropical developing countries Mainly young adults Can infect primates, swine, sheep, rats Swine may be reservoir of infection in North America (attenuated virus) Maternal-infant transmission occurs and is often fatal Epidemiology Epidemiology
- 57. Hepatitis E Similar to hepatitis A Can cause severe acute hepatitis Subclinical infection is common Attenuated virus from animal reservoirs Low-dose infections often asymptomatic No chronic infection Up to 20% mortality among pregnant women (esp. third trimester) Clinical Characteristics Clinical Characteristics
- 58. Hepatitis E Course of Acute Infection Course of Acute Infection 0 10 20 30 40 50 60 Time After Infection (days) 1 2 Viral Replication IgM Antibody IgG Antibody Viremia ALT Virus in Stool (years) Symptoms
- 59. Hepatitis E Passive (Immune serum globulin) Does not prevent infection May ameliorate hepatitis Active (Vaccine) Anti-ORF2 prevents infection in chimps and humans Clinical trials in progress Prevention Prevention
- 60. Clinical Features of Hepatitis E Transmission Oral Common Percutaneous Unknown Sexual No Perinatal Yes, unknown frequency Incubation period 15 – 60 (days) Clinical Illness at 70 – 80% in adults presentation Jaundice Common
- 61. Clinical Features of Hepatitis E Fulminant <1%, in pregnancy up to 30% Diagnostic tests Acute infection IgG anti-HEV (sero- conversion) Chronic infection Not applicable Immunity Not applicable Case-fatality rate 0.5 – 4% 1.5 – 21% in pregnant women Chronic infection None
- 63. Additional Hepatitis Agents 12% of post transfusion hepatitis unrelated to A-E 18% of acute hepatitis unrelated to A-E Up to 40% of fulminant hepatitis no etiology is present Cases of acute hepatitis followed by aplastic anemia Alter H, AASLD Postgraduate course syllabus. 2002; 68-75 Additional Hepatitis Agents
- 66. Hepatitis A Vaccine Efficacy JAMA 1994; 271:1363; N Engl J Med 1992; 327:453 HAV Vaccine Site/Age Efficacy Vaccine Group N (95% CI) HAVRIX Thailand 38,157 94% 1-16 yrs (79%-99%) 2 doses 360 EL.U. VAQTA New York 1,037 100% 2-16 yrs (85%-100%) 1 dose 25 units Hepatitis A Vaccine Efficacy Studies
- 67. Hepatitis E Hepatitis E vs. Hepatitis A HEV HAV Fecal-oral transmission Yes Yes Transmission in family No Yes Distribution Developing Worldwide countries Ages infected Young adults All Subclinical infection Yes Yes Chronic infection No No Hepatitis E vs. Hepatitis A
- 68. HCV - Epidemiology Prevalence In Groups at Risk Recipients of clotting factors before 1987 75 - 90% Injection drug users 70 - 85% Long-term hemodialysis patients 10% Individuals with > 50 sexual partners 10% Recipients of blood prior to 1990 5% Infants born to infected mothers 5% Long-term sexual partners of HCV positive 1 - 5% Health workers after random needlesticks 1 - 2% CDC, MMWR 1998;47(No. RR-19):1 Prevalence In Groups at Risk
- 69. HCV - Treatment Evolution of treatment for chronic hepatitis C 6 15 30 46 55 0 20 40 60 IFN 24wk IFN 48wk PEG IFN INF/R PEGINF/R Evolution of Treatment for Chronic Hepatitis C
- 70. Indications in Adults Sexual and household contacts of carriers Sexually active individuals with multiple sex partners and men who have sex with men Injection drug users Hemodialysis patients Recipients of clotting factor concentrates Families of adoptees from endemic areas HBV - Vaccine CDC and WHO Vaccination of selected high-risk groups in adults
- 71. Vaccine Indications HBIG and HB vaccine to infants of HBsAg+ mothers Routine vaccination of infants and adolescents Catch-up vaccination of children Vaccination of adults at risk of infection HBV Indications for HBV vaccination
- 72. HBV - Vaccine CDC and WHO Vaccination of selected high-risk groups in adults Indications in Adults (con’t.) Health care and public safety workers with occupational risks Persons in institutions for the developmentally disabled or in long-term correctional facilities Travelers to countries endemic for hepatitis B who plan to stay > 6 months Transplant candidates before transplantation Patients with chronic liver disease
- 73. HBV - Vaccine Neonates of HBsAg+ Mothers Vaccine HBIG 0 1 6 Birth Months Hepatitis B immune globulin for neonates born to HBsAg+ mothers
- 74. Dose Schedule HBV - Vaccine Vaccine Age Group Dose Volume # Doses (ug) (ml) Engerix-B 0-19 yr 10 0.5 3 (mo 0,1,6) 20 yr 20 1.0 3 (mo 0,1,6) Adults on hemodialysis 40 2.0 4 (mo 0,1,2,6) Recombivax HB 0-19 yr 5 0.5 3 (mo 0,1,6) 20 yr 10 1.0 3 (mo 0,1,6) (Optional 2-dose) 11-15 yr 10 1.0 2 (mo 0, 4-6) Adults on hemodialysis 40 1.0* 3 (mo 0,1,6) *Special Formulation Dose schedule of HBV vaccine
- 75. Twinrix Bivalent HAV and HBV vaccine 1ml contains 720 ELISA Units of inactivated HAV and 20 ug of recombinant HBsAg protein Dosage: 1 ml at 0, 1, 6 months Recommended for all susceptible persons 18 years at risk of exposure to both HAV and HBV, including travelers to areas of high/intermediate endemicity for both viruses Combined HAV and HBV - Vaccine Knoll A, Vaccine 2000; 18:2029 Combined hepatitis A and B vaccines
- 76. Immunogenicity of Twinrix Combined HAV and HBV - Vaccine Thoelen S, Vaccine 1999; 26:1657 0 25 50 75 100 0 7 24 36 48 Months Seroconversion (%) Anti-HAV Anti-HBs Twinrix vaccinations Immunogenicity of Twinrix
- 77. Management of Non-responders HBV - Vaccine Primary series No response Repeat 3-dose series Response No response 50% - 75% Immunocompetent adults Test for HBsAg 5-10% Management of non-responders
- 78. Therapeutic Agents HBV - Therapy Immune Modulators Nucleo(s)tide analog Interferon Lamivudine Thymosin Adefovir dipivoxil Therapeutic vaccines Emtricitabine Entecavir L-dT/ L-dC Clevudine Famciclovir Therapeutic agents for chronic hepatitis B
- 79. Treatment Indications Chronic infection HBsAg+, anti-HDV for > 6 months Replicative infection Serum HDV RNA+ Active liver disease Elevated ALT Chronic hepatitis cirrhosis Recommendations IFN 9 MU tiw for 12 months HDV - Therapy Treatment of chronic hepatitis D