CRONIC HEPATITIS, CIRRHOSIS, HEPATIC FAILURE

1. CRONIC HEPATITIS, CIRRHOSIS, HEPATIC FAILURE ASSOC. PROF. DR. INGRID MIRON

2. What is Viral Hepatitis ? • Viral hepatitis is a systemic disease with primary inflammation of the liver by any one of a heterogenous group of hepatotropic viruses

3. Hepatitis Terms • Acute Hepatitis: Short-term hepatitis. • Body’s immune system clears the virus from the body within 6 months • Chronic Hepatitis: Long-term hepatitis. • Infection lasts longer than 6 months because the body’s immune system cannot clear the virus from the body

4. HEPATITIS VIRUSES • Hepatitis A (HAV) Picornaviridae (1973) • Hepatitis B (HBV) Hepadnaviridae (1970) • Hepatitis C (HCV) Flaviviridae (1988) • Hepatitis D (HDV) ? (1977) • Hepatitis E (HEV) (Caliciviridae) (1983), Hepeviridae • Hepatitis F – Not separate entity – Mutant of B Virus. • Hepatitis G (HGV) Flaviviridae (1995)

5. Viral Hepatitis - Historical Perspectives A E Enterically transmitted “Infectious” Viral hepatitis NA:NB Parenterally transmitted C B D “Serum” F- Mutant Of B G

6. Type of Hepatitis

7. Hepatitis B Virus

8. 4、Epidemiology • 350,000,000 carriers worldwide • 120,000,000 carriers in China - the carrier rate can exceed 10% -15 to 25% of chronically infected patients will die from chronic liver disease • 500,000 deaths/year in China • 50% of children born from mothers with chronic HBV in the US are Asian American

9. Geographic Distribution of Chronic HBV Infection HBsAg Prevalence 8% - High 2-7% - Intermediate <2% - Low

10. Whom to screen • Patients with elevated liver enzymes • Patients with HCC, Cirrhosis ,liver fibrosis • Immigrants from areas of high HBV prevalence • Families , household members and sexual contacts of HBV + person • Patients in psychiatric institutions, residents of welfare institutions and mentally disabled • Homo/Bisexuals and person having multiple sexual partners • Active and ex drug user • Dialysis patients

11. HBV: Modes of Transmission • Parenteral -IV drug abusers, health workers are at increased risk. • Sexual - sex workers and homosexuals are particular at risk. • Perinatal (Vertical) –mother (HBeAg+)→infant.

12. Properties of HBV • a member of the hepadnavirus group • Circular partiallydouble-stranded DNA viruses • Replication involves a reverse transcriptase.

13. HBV: Structure • Virion also referred to as Dane particle (d-stranded DNA) • 42nm enveloped virus • Core antigens located in the center (nucleocapsid) * Core antigen (HBcAg) * e antigen (HBeAg)- an indicator of transmissibility (minor component of the core- antigenically distinct from HBcAg) • 22nm spheres and filaments other forms- no DNA in these forms so they are not infectious (composed of surface antigen)- these forms outnumber the actual virions

14. HBV Structure & Antigens Dane particle HBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr) HBcAg = inner core protein (a single serotype) HBeAg = secreted protein; function unknown

15. Serology • Antigen Detection- HBsAg,HBcAg,HBeAg • Antibody Detection-Anti HBc, Anti-HBe, Anti-HBs • DNA Detection- HBV DNA

16. Diagnosis

17. Clinical Features Incubation period: Average 60-90 days Range 45-180 days Insidious onset of symptoms. Tends to cause a more severe disease than Hepatitis A. Clinical illness (jaundice): <5 yrs, <10% ≥ 5 yrs, 30%-50% 1/3 adults-no symptoms Clinical Illness at presentation 10 - 15% Acute case-fatality rate: 0.5%-1% Chronic infection: < 5 yrs, 30%-90% ≥ 5 yrs, 2%-10% More likely in asymptomaticinfections Premature mortality fromchronic liver disease: 15%-25%

18. Hepatitis B-SignsandSymptoms Dark urine Pale stool Jaundice Stomach pain Side pain Itchyskin Hepatitis B virus has been linked to the development of Membranous glomerulonephritis (MGN). • Nausea • Loss of appetite • Vomiting • Fatigue • Fever

19. 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-HBcIgM - 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.

20. Interpretation of Hepatitis B Panel HBsAg negative antiHBc negative susceptible antiHBs negative HBsAg negative antiHBc positive immune due to natural infection antiHBs positive HBsAg negative antiHBc negative immune due to vaccine antiHBs positive HBsAg positive antiHBc ( total ) positive acutely infected IgM antiHBc positive antiHBs negative HBsAg positive antiHBc ( IgG) positive chronically IgM antiHBc negative infected antiHBs negative HBsAg negative antiHBc ( IgG) positive antiHBs negative 1.resolution of chronic infection 2. “window period” infection 3. false-positive anti-HBc 4. active infection with waning HBsAg

21. Differential diagnosis • - Acute icteric hepatitis • The jaundice caused by another disease • Hemolytic jaundice • Extrahepatic obstructive jaundice • Hepatitis caused by another reasons • Toxic hepatitis • Infective toxic hepatitis • Mononucleosis • Alcohol hepatic disease • Schistosomiosis • Wilson disease

22. Phases of Chronic HBV Infection

23. Immune tolerant • HBsAgandHBeAgdetectable • Biopsynotgenerallyindicated • HBV DNA >20,000 IU/mL (>105 copies/mL) • Antiviral therapies are generallyineffective • ALT normal Risk of drug resistanceiftreatedwithnucleos(t)ide analogs • Absent or minimal liver inflammationand fibrosis • Continuedmonitoring recommended

24. HBeAg+immune active • HBsAgand HBeAg remain detectable Most children still show no signs or symptoms of disease • HBV DNA >20,000 IU/mL (>105 copies/mL) Biopsy indicated • ALT persistently elevated:Appropriate testing should be considered to rule outother liver diseases • Liver inflammationand fibrosiscandevelopTreatmentshouldbeconsidered

25. Inactive HBsAg‘‘carrier’’ • HBsAgpresent • Ageat seroconversionappearstobe influencedby HBV genotype • HBeAgundetectable, anti-HBepresent. Riskof developingcirrhosisdeclines • HBV DNA <2000 IU/mL (<104 copies/mL) • or undetectable . Riskof developing HCC • ALT normal . Biopsygenerallynotindicated • Absent or minimal liver inflammation, fibrosiswillregress over time. Continued monitoring recommended

26. Reactivation or HBeAg-negativeimmune active • HBsAgpresentoccursin 20-30% of patients • HBeAgremains negative andanti-HBepositiveCalled ‘‘e-antigen-negative’’ hepatitis B • HBV DNA levels >2000 IU/mL (>104 copies/mL) Usuallyduetobasalcorepromoter or precoremutation • ALT normal or elevatedLiverbiopsyindicated, especiallyif ALT abnormal • Active liver inflammationandfibrosis:Treatmentshouldbeconsideredif moderate or severe inflammationor fibrosispresent.Treatmentwithnucleos(t)ide analogsmaybelong-term

27. Possible Outcomes of HBV Infection Acutehepatitis B infection 3-5% of adult-acquiredinfections 95% of infant-acquired infections Chronic HBV infection Chronic hepatitis 12-25% in 5 years Cirrhosis 20-23% in 5 years 6-15% in 5 years Hepatocellularcarcinoma Liver failure Liver transplant Death Death

28. A liver biopsy is indicated in the following scenarios: • HBeAg-negative and HBV DNA ≥ 20,000 IU/ml and ALT < 2x ULN • HBeAg-negative and HBV DNA = 2,000–19,999 IU/ml • HBeAg-positive and HBV DNA ≥ 20,000 IU/ml and ALT < 2x ULN and age ≥ 40

29. Treatment

30. Goals of HBV Therapy • HBV infection cannot eliminated or “cured” • The clinical goal of HBV treatment (primary goal ) Prevention or reversal of complications /deaths suppress HBV replication and achieve a target HBV DNA <10-15 IU/mL Can allow biochemical remission and prevent further liver injury

31. Goals of HBV Therapy In HBeAg-positive patients (cont) HBeAg loss and seroconversion In HBeAg-positive and HBeAg-negative patients HBsAg loss and seroconversion is ultimate form of HBV treatment success Best predictor of durable viral suppression Strongest indicator of best longterm outcome, lowest risk of cirrhosis and liver cancer Not achieved by the majority of patients Histological Improvement

32. Options in treatment

33. Evolution of Approved HBV Therapy Over Time Peginterferon alfa-2a Entecavir Lamivudine Tenofovir 1990 2006 1998 2002 2005 2008 1990 1998 2002 2005 2006 2008 Interferon alfa-2b Telbivudine Adefovir

34. Treatment • Interferon - for HBeAg +ve carriers with chronic active hepatitis. Response rate is 30 to 40%. • alpha-interferon 2b (original) • alpha-interferon 2a (newer, claims to be more efficacious and efficient) • 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. • Adefovir– less likely to develop resistance than Lamivudine and may be used to treat Lamivudine resistance HBV. However more expensive and toxic • Entecavir – most powerful antiviral known, similar to Adefovir • Successful response to treatment will result in the disappearance of HBsAg, HBV-DNA, and seroconversion to HBeAg.

35. Interferon-Alfa • IFN-alfa-2b has been used for the treatment ofchronic HBV infection in children for more than a decade. • Lamivudine is now considered first-line therapy. Lamivudine is labeled for treatmentof chronic HBV infection in children of age 3 andolder.Discontinue lamivudine only when repeated assays demonstrateHBeAgloss or seroconversion to HBeAb • AdefovirDipivoxil. Adefovir is labeled for use inchildren age 12 years and older, and is the preferredoral treatment option for children ages 12-15 • EntecavirandTenofovir-adolescent

36. 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.

37. Hepatitis B Vaccine • Infants: several options that depend on status of the mother • If mother HBsAg negative: birth, 1-2m,6-18m • If mother HBsAg positive: vaccine and Hep B immune globulin within 12 hours of birth, 1-2m, <6m • Adults * 0,1, 6 months • Vaccine recommended in • All those aged 0-18 • Those at high risk

38. Recommendations for Treatment Initiation in HBeAg-Positive Patients • Criteria for HBV DNA, ALT and disease stage/grade must all be met • If not, guidelines recommend monitoring and consideration of treatment based on individual’s age, health status, and stage of infection/disease 1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 3. EASL HBV Guidelines. J Hepatology. 2009;50:227-242.

39. Recommendations for Treatment Initiation in HBeAg-Negative Patients • Criteria for HBV DNA, ALT and disease stage/grade must all be met • If not, guidelines recommend monitoring and consideration of treatment based on individual’s age, health status, and stage of infection/disease 1. Lok A, et al. Hepatology. 2007;45:507-539. 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 3. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227-242.

40. Selecting an Interferon-Based Initial HBV Treatment

41. Factors Associated With Choosing Interferon for Initial Therapy Favorable predictors of response Genotype A or B > C or D Low HBV DNA (baseline and on treatment) High ALT (baseline) Specific patient demographics Younger people Young woman wanting future pregnancy Patient preference No coinfection with HIV Concomitant HCV infection

42. PegIFN Treatment-Associated Adverse Effects Patients should be carefully monitored for adverse events Most common adverse events: flu-like symptoms (fever, chills, headache, malaise, and myalgia) as well as psychological impairment Depression Increase in Incidence/Severity Fatigue Anxiety Flu-like symptoms 0 1 2 3 4 Months Keeffe EB, et al. Clin GastroenterolHepatol. 2008;6:1315-1341.

43. On interferon alpha therapy: • Primary non-response is defined as • less than 1 log10 IU/ml decrease in HBV DNA level from • baseline at 3 months of therapy. • Virological response is defined as an HBV DNA concentration of less than 2000 IU/ml at 24 weeks of therapy. • Serological response is defined by HBeseroconversion in patients with HBeAg-positive CHB.

45. Monitor HBV patients who are not in treatment • HBeAg(+) and treatment not indicated: •  ALT every 3–6 months if WNL; ALT every 1–3 months if 1–2x ULN. •  HBV DNA viral load every 6–12 months. •  Liver biopsy if ALT ≥ 2x ULN for 6 months, or if ALT 1–2x ULN for 6 months and age ≥ 40 • HBeAg(–) and treatment not indicated: •  ALT every 3 months for 1 year; then every 6–12 months. •  HBV DNA viral load if ALT > 1–2x ULN. •  Liver biopsy if persistent ALT elevation or HBV DNA ≥ 2,000 IU/ml.

46. Monitor patients on treatment . Monitoring schedule for Nucleos(t)ide Analogues:  ALT and AST levels every 3–6 months  HBeAg every 3–6 months (in patients who are HBeAg(+) at start of treatment)  HBsAg every 6–12 months (in patients who are HBeAg(–) at start of treatment)  HBV DNA viral load every 3 months during first year of therapy; then every 6 months  Serum creatinine every 12 weeks while taking adefovir or tenofovir Monitoring schedule for Interferon alfa:

47. Monitor patients on treatment • Monitoring schedule for Nucleos(t)ide Analogues: • ALT and AST levels every 3–6 months • HBeAgevery 3–6 months (in patients who are HBeAg(+) at start of treatment) • HBsAgevery 6–12 months (in patients who are HBeAg(–) at start of treatment) • HBV DNA viral load every 3 months during first year of therapy; then every 6 months • Serum creatinine every 12 weeks while taking adefovir or tenofovir • Monitoring schedule for Interferon alfa:

48. Hepatitis C

49. HEPATITIS C VIRION: spherical, icosahedral, NUCLEIC ACID: ss (+) RNA

50. Hepatitis C Virus capsid envelope protein protease/ helicase RNA-dependent RNA polymerase c22 c-100 33c 5’ 3’ NS3 NS5 core E1 E2 NS2 NS4 hypervariable region