2. Viral Hepatitis Paul Martin M.D. Medical Director, Liver Transplant Cedars-Sinai Professor of Medicine, UCLA

3. Viral Hepatitis 5 major hepatitis viruses A-E “Hepatitis” indicates biochemical hepatic dysfunction, not necessarily due to a virus Hepatitis can also occur as part of multisystem viral disorder

4. 95 % of viral hepatitis due to the 5 major hepatitis Other viruses ( EBV, CMV, HSV, etc.,) cause hepatitis as part of systemic illness “Hepatitis” like picture can also result from other etiologies e.g. drugs, autoimmune process

5. Older terms such as “infectious hepatitis” (fecal-oral spread) and “serum hepatitis” are becoming obsolete as diagnostic testing readily identifies specific virus

6. Acute Hepatitis Malaise, nausea, abdominal discomfort, jaundice typical but not invariable Acute hepatitis can occur with any of the 5 major viruses Recovery usual in acute hepatitis Fulminant course with liver failure a concern

7. Acute Viral Hepatitis Source: CDC

8. Chronic Hepatitis Implied by persistence of hepatitis > 6 mos Occurs with hepatitis B, C and D Hepatitis A and E do not become chronic Spectrum of findings from mild biochemical dysfunction to advanced cirrhosis

9. Hepatocellular Carcinoma Secondary to Childhood-acquired HBV Infection

10. Diagnosis of viral hepatitis Based on serological workup Liver biopsy does not distinguish one type from another, mainly used in chronic hepatitis to assess prognosis Biochemical tests, ALT and AST, reflect hepatic necrosis

11. Role of Liver Biopsy Confirm clinical diagnosis Assess severity of necro- inflammation Evaluate possible concomitant disease processes Assess therapeutic intervention Assess fibrosis

12. Hepatitis A Virus Transmission 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)

14. Hepatitis A Virus Transmission 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)

15. Rate >20/100,000 Rate 10-20/100,000 Rate <10/100,000 Average Hepatitis A Rates by State 1987-1997 Adapted from Advisory Committee on Immunization Practices MMWR 1999:48(RR12);1-37.

16. Fecal HAV Symptoms ALT IgM anti-HAV Total anti- HAV Months after Exposure Titer Typical Serologic Course 0123 4561212 2424 Hepatitis A Virus Infection

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

21. Most outbreaks associated with fecally contaminated drinking water Minimal person-to-person transmission U.S. cases usually have history of travel to HEV-endemic areas Hepatitis E - Epidemiologic Features Hepatitis E - Epidemiologic Features

22. HBsAg Prevalence (%)  8:High 2-7:Intermediate <2:Low Global Distribution of Chronic HBV Infection 350 million chronic carriers worldwide350 million chronic carriers worldwide Ninth leading cause of deathNinth leading cause of death Nearly 75% of HBV chronic carriers are AsianNearly 75% of HBV chronic carriers are Asian

23. Transfusion and transplant recipients Individuals with multiple sexual partners Healthcare workers Newborns of long-term carriers Intravenous drug users Prisoners and other institutionalised people Transmission of Hepatitis B Infection

24. Estimated Incidence of Acute Hepatitis B United States, 1978-1995 Vaccine licensed HBsAg screening of pregnant women recommended OSHA rule enacted Infant immunization recommended * Provisional date * Adolescent immunization recommended Decline among homosexual men & HCWs † Decline among injecting drug users Cases per 100,000 Population †Health Care Workers http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_b/slide_15.htm. Accessed 11-02-02.

25. Risk of Developing Chronic Hepatitis B by Age at Infection

26. Acute Hepatitis B Virus Infection with Recovery Typical Serologic Course Weeks after Exposure Titer Symptoms HBeAg anti-HBe Total anti-HBc IgM anti-HBc anti-HBs HBsAg 0481216 20 242832 36 52100

27. 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 048 12 16202428 32 36 52 Years

28. Coinfection –severe acute disease –low risk of chronic infection Superinfection –usually develop chronic HDV infection –high risk of severe chronic liver disease Hepatitis D - Clinical Features

29. Percutanous exposures –injecting drug use Permucosal exposures –sex contact Hepatitis D Virus Modes of Transmission Hepatitis D Virus Modes of Transmission

30. Hepatitis D (Delta) Incidence declining worldwide due to vaccination and clean needle programs Only found in HBV infected patients, consider when liver disease unusually severe

31. Epidemiology of HCV –In United States: 3.9 million people have been infected, nearly 3 million are chronically infected –Incidence Most common blood-borne infection Worldwide,170 million persons have been HCV-infected

32. HCV Prevalence by Selected Groups in the United States 0102030405060708090 Hemophilia Injection-drug users Surgeons, other HCWs Hemodialysis Anti-HCV Positive General population adults Military personnel STD patients Pregnant women Centers for Disease Control and Prevention. MMWR. 1998;47(RR-18):1-39.

33. Natural History of HCV Infection Exposure (Acute phase (Acute phase) Resolved Chronic Cirrhosis Stable SlowlyProgressive HCC,Transplant,Death 20% (17) 15% (15) 85% (85) 25% (4) 80% (68) 75% (13) HIV and alcohol Alter, MJ. Epidemiology of Hepatitis C in the West. Semin Liver Dis. 1995; 15: 5-14. Management of Hepatitis C. NIH Consensus Statement. 1997; March 24-26: 15(3).

34. Future Disease Burden Related to HCV: 2008 Davis GL. Hepatology. 1998;28(4 pt 2):390a. 61% 68% 223% 279% 528% 0%100%200%300%400%500%600% Cirrhosis HCC Liver-related Deaths Decompensation Need for Liver Transplantation Estimated Increase by the Year 2008

35. Viral Hepatitis Acute hepatitis can be caused by A-E viruses Presentation non-specific Chronic hepatitis and cirrhosis caused by B,C and D Specific diagnosis is by serology

36. Outcome of HAV Superinfection in Patients With Chronic Viral Hepatitis Vento S et al. N Engl J Med. 1998;338:286. 6/7 died Underlying Disease

37. HAV Vaccination in CLD Seroconversion Rate Keeffe EB, et al. Hepatology 1998;27:881-886.

38. HAV:Summary Higher Mortality in older patients and those with preexisting liver disease Vaccine increasingly recommended for patients with liver disease

39. Hepatitis B—Reported Cases per 100,000 Population, 1998 MMWR. 1998; 47:No.53:44. 2.4-3.9 1.5-2.3 0.0-1.4 >4.0 NYC DC PR VI GUAM AM SAMOA CNMI NA

40. Childhood Acquired HBV Lok 1990 010203040506070 HBeAg+ HBeAg/anti-HBe+ Anti-HBe+ HBV-DNA ALT Years CPHCAH Immune tolerance to HBV Residual Integrated HBV Immune clearance of HBV CirrhosisHCC

41. Hepatitis B Mortality About 1/3 of chronic HBV infections in the United States start in perinatal and early childhood Except flu and pneumococcal infections, HBV kills more people/year than any other vaccine- preventable disease (VPD) (>5,000 HBV deaths/year) HBV causes hepatocellular carcinoma that kills about 1,000 Americans annually

42. Estimated HBV Infections among US Born Children (aged <10 years) of HBsAg-Negative Mothers, 1990 7280605120,298Asian/ Pacific Islander 867723.73,656,618White/Black/ Hispanic # of Annual Infections Annual Incidence/ 100,000 Births/ year Race/Ethnicity

43. Prevent perinatal HBV transmission Routine vaccination of all infants Vaccination of children in high-risk groups Vaccination of adolescents –all unvaccinated children at 11-12 years of age –“high-risk” adolescents at all ages Vaccination of adults in high-risk groups Elimination of Hepatitis B Virus Transmission United States Strategy

44. HBV: who to treat Patients with chronic HBV Hepatic Inflammation: ALT > 2 upper limit of normal Active HBV replication: HBV DNA +/- HBeAG Symptoms not a factor

45. Asia-Pacific Guidelines for Management of Hepatitis B APASL/JGH – JGH 2000; 15:825–841 Indications for treatment –Those with normal ALT should not be treated Patients with ALT >2 x ULN should be considered for treatment Liver biopsy is recommended prior to antiviral therapy (especially if ALT 1–2 x ULN)

46. Asia-Pacific Guidelines A PASL/JGH – JGH 2000; 15:825–841 Patients with ALT >5 x ULN should be treated with lamivudine Patients with ALT 2–5 x ULN can be treated with lamivudine or interferon: inform patients about adverse effects, treatment duration, possible emergence of drug-resistant HBV No firm recommendation on ALT 1–2 x ULN: consider severity, HBeAg; monitor if don’t treat

47. Implications of HBeAg Seroconversion l Usually (>80%) permanent suppression of HBV replication ( HBV DNA not detectable in serum) l Loss of HBsAg possible (10–30% with IFN) l Normalisation ALT; reduced necroinflammatory change l Functional improvement; abolishes risk of liver failure or transplantation l Effect on HCC risk less clearcut; ~50% reduction

48. HBeAg Seroconversion Over 4 Years Treatment in Patients with Elevated ALT Seroconversion = HBeAg-ve and anti-HBe+ve ALT>1 X ULN (n=41) ALT>2 X ULN (n=26) 27 37 49 59 38 42 65 73 0 10 20 30 40 50 60 70 80 1234 Duration of therapy (years) Patients (%)

49. HBV:Summary Most commonly diagnosed in patients with early acquisition HBsAg to diagnose infection, HBeAg and HBV DNA to assess replication IgM anti-HBc is absent in chronic infection

50. HBV:Summary Therapy indicated for chronically infected patients with elevated ALT Lamivudine limited by viral resistance, adevofir has recently received FDA approval

51. Hepatitis C: Transmission Factors Recipients of clotting factors made before 1987 (85% transmission rate) Injection drug use/intranasal drug use (80% transmission rate) Long term hemodialysis patients (10% - 20% transmission rate) Persons with multiple sex partners (5% transmission rate) Recipients of blood transfusions prior to July 1992 ( 5% transmission rate) Alter MJ, Kruszon-Moran D, Nainan O, et al. The prevalence of hepatitis C virus in the United States, 1988-1994. New Engl Jour of Med.1999; 341:556-562. Ohto H, Terazawa S, Sasaki N, et al. Transmission of hepatitis C from mothers to infants. New Engl Jour of Med. 1994: 330:744-750. Carithers RL. Am J Med. 1999;107:90S-94S.

52. Centers for Disease Control and Prevention. MMWR. 1998;47:11. HCV Infection: Utility of Diagnostic Tests AssessPredict treatment responseresponse and Method Screen Confirmation to therapy length of therapy ALT/AST x x Enzyme x immunoassay Recombinant x immunoblot assay HCV RNA x x qualitative assay HCV RNA x xx quantitative assay Genotypex

53. HCV Genotypes Genotypes are viral sequences Utilized for estimating potential for response to treatment; not used to determine eligibility for treatment Genotype 1 & 4: least responsive to therapy Genotype 2 & 3: more responsive to therapy

54. Factors Influencing HCV Progression Heavy alcohol intake Male gender Obesity Coinfection with HIV Coinfection with HBV Iron in the liver, as detected via liver biopsy >40 years of age at time of infection, particularly if contracted via blood transfusion Thomas DL, Astemborski J, Rai RM. et al The national history of hepatitis C Virus Infection: Host, viral, and environmental factors. American Journal of Medicine. 2000; 284(4): 450-456. Note: HCV progression has NOT been demonstrated to be influenced by viral load, serum ALT, or mode of transmission.

55. Role of Liver Biopsy Confirm clinical diagnosis. Brunt EM. Hepatology. 2000;31:241-246. Assess severity of necro- inflammation Evaluate possible concomitant disease processes Assess therapeutic intervention Assess fibrosis Diagnosis of HCV: Role of Liver Biopsy

56. Future Disease Burden Related to HCV: 2008 Davis GL. Hepatology. 1998;28(4 pt 2):390a. 61% 68% 223% 279% 528% 0%100%200%300%400%500%600% Cirrhosis HCC Liver-related Deaths Decompensation Need for Liver Transplantation Estimated Increase by the Year 2008

57. HCV Clinical Manifestations Present only 20 – 40% of time Frequently no symptoms until development of advanced liver disease Frequently nonspecific, mild, and intermittent Most common symptoms: Malaise, weakness, anorexia (25 – 35% of cases) RUQ abdominal discomfort and pruritus Less common symptoms: Jaundice Intermittent nausea Vomiting Management of Hepatitis C. NIH Consensus Statement, March 24-26, 1997;16(3): 1-41.

59. HIV-HCV Coinfection in the USA 0 10 20 30 40 X100,000 Hepatitis CHIV Coinfected Mono-infected

60. 1999 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections HCV di sease specific recommendations – HIV-infected persons should be screened for HCV by EIA – Patients should be advised on alcohol use – Screen for HAV IgG. If negative, vaccinate – Patients should be evaluated for liver disease and possible need for treatment – Monitor liver enzymes after initiation of HAART MMWR Vol. 48 / No. RR10 (http://www.cdc.gov)

61. Risk of Transmission by Single Needle Stick to Susceptible Healthcare Workers 0 10 20 30 40 HBVHCVHIV Percent ~30% 3% 0.3% Alter MJ. N Engl J Med. 1999;341:556 (NHANES III, 1988–1994). HCV and Healthcare Workers: Transmission Rate after Needle Stick

62. HCV:Antiviral therapy Eradicate virus-negative PCR Arrest Progression of liver disease Improve Quality of Life

63. Treatment Responses Biochemical Virologic Biochemical Virologic End of treatment response (ETR) End of treatment Normal ALTHCV RNA response (ETR) negative Sustained virologic response (SVR) Sustained virologic Normal ALT HCV RNA response (SVR) negative Lindsay KL. Hepatology. 1997;26(suppl 1):72S. (6 mos post- treatment)

64. Clinical Significance of Sustained Virologic Response >90% of those with 6 months post treatment SVR maintain response during 1-6 years of follow-up Liver histology improves or stabilizes Lindsay KL. Hepatology. 1997;26(suppl 1):75S.

65. Time Serum IFN  Levels (U/mL) Higher- Dose IFN  Pegylated IFN  Optimizing Interferon  Kinetics 1 week

66. Pegylated IFNs PEG IFN alfa-2b –Molecular weight 12 kDa –Linear –1.0 ug/kg QW subcutaneous (SC) injection with monotherapy –1.5 ug/kg SC when given in combination with ribavirin  PEG IFN alfa-2a  Molecular weight 40 kDa, linear structure   180 ug QW subcutaneous injection

67. Who Should Be Treated? Persistently elevated ALT levels Detectable HCV RNA levels Liver biopsy (not required) indicating portal or bridging fibrosis or at least moderate degrees of inflammation and necrosis No active autoimmune disease No hepatic encephalopathy, variceal bleeding, ascites, or other clinical decompensation Consider –Co-morbid conditions –Symptomatic cryoglobulinemia –Continuing substance abuse

68. Who Should Not Be Treated? Pregnant or nursing mothers Current substance abusers –CDC recommends patient be alcohol/drug free for >6 months prior to undergoing treatment Centers for Disease Control and Prevention, MMWR. 1998; 47:24 Caution in patients with:  Decompensated cirrhosis  Prior history of psychiatric disorders  Persistent ALT elevations, with less severe histological changes  Patients aged 60 years

69. IFN alfa-2b/RBV: Summary of Predictive Factors for a SVR Increasing usefulness in predicting sustained response 2040 6 80 % Sustained Virologic Response Weight > 75 kg Weight  75 kg Advanced Fibrosis Minimal Fibrosis Male Female Age > 40 Age  40 High HCV RNA Low HCV RNA Genotype 1 Genotype 2 or 3 Adapted with permission from McHutchison JG et al. Semin Liver Dis. 1999;19(suppl 1):63. 6

70. PEG-IFN alfa-2b (12 kDa)/RBV vs. IFN alfa-2b/RBV IFN/RBV 1000 -1200 mg/d (n=505) PEG (12 kDa) 0.5 qw /RBV 1000-1200 mg/d (n=514) PEG (12 kDa) 1.5 qw /RBV 800 mg/d (n=511) Sustained viral response* Manns MP et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. The Lancet (358): 958-965. * End-of-treatment not reported † P=0.01 vs IFN/RBV ‡ Not approved dosing for PEG-IFN alfa-2b § P=0.02 vs IFN/RBV 47% 47% ‡ 54% †‡ 42% ‡§ 34% ‡ 33% 79% 80%82%

71. SVR Genotype 1 0 10 20 30 40 50 60 24 weeks 48 weeks SVR (%) 29% 41%40% 51% n=101n=118n=250n=271 RBV 800 RBV 1000/1200RBV 800RBV 1000/1200 Hadziyannis SJ et al., EASL. 2002. PEG-IFN  -2a (40 KD) 180 µg

72. SVR Genotype Non-1 0 10 20 30 40 50 60 70 80 90 78% 73% 77% n=106n=162n=111n=165 SVR (%) Hadziyannis SJ et al., EASL. 2002. 24 weeks 48 weeks RBV 800 RBV 1000/1200RBV 800RBV 1000/1200 PEG-IFN  -2a (40 KD) 180 µg

73. HCV Genotype 1 Commonest genotype Less responsive to therapy than genotype 2,3 80% of genotype 1 are high viral load 56% of all US patients are genotype1, high viral load

74. SVR Genotype 1 Low Viral Load 0 10 20 30 40 50 60 70 SVR (%) 41% 51% 53% 61% n=51n=71n=60n=85 Hadziyannis SJ et al., EASL. 2002. 24 weeks 48 weeks RBV 800 RBV 1000/1200RBV 800RBV 1000/1200 PEG-IFN  -2a (40 KD) 180 µg

75. SVR Genotype 1 High Viral Load 0 5 10 15 20 25 30 35 40 45 50 16% 26% 35% 46% n=50n=47n=190n=186 SVR (%) Hadziyannis SJ et al., EASL. 2002. 24 weeks 48 weeks RBV 800 RBV 1000/1200RBV 800RBV 1000/1200 PEG-IFN  -2a (40 KD) 180 µg

76. Viral Hepatitis:initial tests IgM anti-HAV HBsAg, IgM anti-HBc Anti-HCV

77. Viral Hepatis:management Vaccinate Educate (alcohol etc.,) Evaluate for therapy

79. Hepatitis A - Clinical Features Incubation period:Average 30 days Range 15-50 days Jaundice by 14 yrs, 70%-80% Complications:Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis Chronic sequelae:None