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Viral Hepatitis for the Generalist

Viral Hepatitis for the Generalist. Thursday 20 th May Dr Allister Grant Leicester Liver Unit. Viral Hepatitis- Objectives. Name the common viral infections affecting the liver

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Viral Hepatitis for the Generalist

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  1. Viral Hepatitis for the Generalist Thursday 20th May Dr Allister Grant Leicester Liver Unit

  2. Viral Hepatitis- Objectives • Name the common viral infections affecting the liver • Understand the epidemiology, natural history, investigation and treatment of the chronic viral infection of the liver • Hepatitis B • Hepatitis C • Gain an insight of the role of Hepatitis B in patients undergoing immunosupression

  3. Viral Infections and Abnormal LFT’s • Herpes Viruses • CMV • EBV • But also • VZV • Herpes Simplex virus • HHV 6,7,8….. • Adenovirus • Influenza • Hepatitis Viruses • Acute • Hepatitis A • Hepatitis E • Hepatitis B • Chronic • Hepatitis B • Hepatitis C • Delta Virus • HIV } “Infectious”

  4. Type of Hepatitis A B C D E 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

  5. Hepatitis A - Clinical Features • Incubation period: Average 30 days Range 15-50 days • Jaundice by <6 yrs, <10%age group: 6-14 yrs, 40%-50% >14 yrs, 70%-80% • Complications: Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis • Chronic sequelae: None

  6. Hepatitis A Infection Typical Serological Course Total anti-HAV Symptoms Titre ALT Faecal HAV IgM anti-HAV 4 5 6 12 24 0 1 2 3 Months after exposure

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

  8. Hepatitis E Virus Infection Typical Serologic Course Symptoms IgG anti-HEV ALT Titer IgM anti-HEV Virus in stool 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Weeks after Exposure

  9. Viral Infections and Abnormal LFT’s • Herpes Viruses • CMV • EBV • But also • VZV • Herpes Simplex virus • HHV 6,7,8….. • Adenovirus • Influenza • Hepatitis Viruses • Acute • Hepatitis A • Hepatitis E • Hepatitis B • Chronic • Hepatitis B • Hepatitis C • Delta Virus • HIV } “Infectious”

  10. World HepatitisDayMay 19th World Hepatitis Alliance

  11. Did You Know? 500 million people worldwide are infected with Hepatitis B or C Hepatitis B and C kills 1.5 million people/year One in 3 peopleon the planet have been exposed to one or both Viruses Most of the 500 million infected do not know

  12. Acute HBV= cIgM+ Immunity= sAb+ Previous exposure= cAb+ Chronic infection= sAg+ HBV Infection

  13. 2 Billion Infected with HBV Worldwide • Almost half of the world’s population lives in an area with high HBV prevalence 15–25% die of cirrhosis or liver cancer 2 billion with evidence of HBV infection 350 million with chronic HBV World population 6 billion • 500,000 -1,200,000 deaths yearly due to HBV complications Lavanchy D. J Viral Hepatitis 2004; 11: 97-107

  14. HBeAg Anti-HBe HBV-DNA ALT immunetolerance immuneclearance inactivecarrier reactivation The Stages of Chronic HBV Infection

  15. Inactive carrier? HBeAg(-) CHB Detection limit HBV DNA HBeAg(-) Inactive carrier Detection limit 0 3mo 6mo 9mo 12mo

  16. 1010 HBeAg (+) CHB 109 108 HBeAg (-) CHB 107 106 Serum HBV DNA (IU/ml) 105 104 103 Inactive Carrier State 102 10 HBV DNA Thresholds

  17. Management of eAg Negative Hepatitis B HBsAg +ve, HBeAg -ve HBV DNA < 2000 IU/ml Normal ALT Possible chronic inactive state s-seroconversion 1-3%/yr HBV DNA > 2000 IU/ml and ALT > 2 x ULN (or persistently 1-2 x ULN) ALT abnormal Measure HBV DNA • Monitor • ALT/ HBV DNA 3 monthly for 12/12 then if normal ALT every 6-12/12 Liver biopsy (unless clinical evidence of cirrhosis or contraindication) Advanced fibrosis/ Cirrhosis (F5-6) Moderate or severe necroinflammation (Metavir ≥ A2, Ishak grade ≥ 5) and/or fibrosis (Metavir ≥ F2, Ishak stage ≥ F2) Mild inflammation (Metavir A0/1, Ishak grade <5) and/or No/ Mild Fibrosis (Metavir/Ishak 0 or 1) • Monitor • 3-6/12 ALT/ HBV DNA • If ALT remains abnormal + HBV DNA > 2000 IU/ml repeat biopsy after 2-5 yrs (or annual fibroscan if available) Start indefinite NUC therapy (ETV* or TDF) Consider combination therapy (TDF/ ETV or TDF/LAM) Start indefinite NUC monotherapy (ETV* or TDF) unless s seroconversion (then consider discontinuing after 6-12/12) Draft EM Guidelines based on EASL Guidelines 2009

  18. Prevalence of HBeAg Negative Chronic HBV in Italy HBeAg positive HBeAg negative 1975-85: 539 patients 2001: 837 patients 10% 58% 42% 90% Giusti et al, 1991 Gaeta et al, 2003

  19. Where do carriers come from? Acute infection <5% risk Chronic infection “carrier”

  20. Where do carriers come from? “carrier” from abroad Acute infection ~5% risk Chronic infection “carrier”

  21. Transmission of HBV in England & WalesHahné et al J Clin Virol 2004;29:211-220. New chronic infections in England & Wales (per annum) • Arising in E & W • n = 216 (3%) • Coming from abroad • n = 6,571 (97%)

  22. QE Hepatitis Database 2005/6Ethnicity of HBV Patients

  23. HBV Notifications in England & Wales

  24. .4 Baseline HBV DNA Level, copies/mL .3 Cumulative Incidence of Liver CirrhosisREVEAL HBV Study 37.1% 1.0 x 106 n=627 1.0-9.9x105 n=344 1.0-9.9x104 n=649 300-9.9x103 n=1210 <300 n=944 n=3,774 23.0% Cumulative incidence of liver cirrhosis .2 .1 10.0% 6.3% 5.2% 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Year of follow-up P value for log-rank test, <0.001 Uchenna H. I, et al. Gastroenterology 2006; 130:678-686

  25. High Serum HBV DNA Levels are Associated with Increased Risk of HCC Mortality HBV DNA Negative HBV DNA Low < 105copies/mL RR = 1.7 (0.5-5.7) HBV DNA High > 105copies/mL RR = 11.2 (3.6-35.0) p< 0.001 across viral categories Chen G, et al. J Hepatology 2005; 42 (suppl 2):477A. Chen G, et al. Hepatology 2005; 40 (suppl 1):594A.

  26. 20 Clear the HCV 80 Develop Chronic Hepatitis 20 No Harmful Effects 60 Signs/symptoms Age Gender Alcohol 20% at 20yrs 50% at 30yrs Liver Failure CIRRHOSIS 3.9% pa Liver Cancer 1.4% pa HCV- Natural History 100 Infected HCV Ab pos HCV Ab pos PCR neg HCV Ab pos & PCR pos Transplantation

  27. Prevalence of Hepatitis C virus 2001 WHO

  28. UK HCV Prevalence <1% IV Drug Use Screening1991 Blood Donation 2-400,000 Migration

  29. QE Hepatitis Database 2005/6Hepatitis C

  30. Natural Hx of HCV Cirrhosis

  31. liver fibrosis score (degree of scarring) cirrhosis 6 3 0 10 60 20 30 years

  32. liver fibrosis score (degree of scarring) HCV-pos (median time 38 years) cirrhosis 6 3 0 10 60 20 30 years

  33. liver fibrosis score (degree of scarring) end-stage renal disease immune suppression cirrhosis 6 ? 3 0 10 60 20 30 years

  34. HBV Aim is suppression of replication rarely elimination HIV treatment paradigm suppression prevents disease Indefinite treatment ? lifelong Treatment well tolerated Antiviral Therapy

  35. HBV Aim is suppression of replication rarely elimination HIV treatment paradigm suppression prevents disease Indefinite treatment ? lifelong Treatment well tolerated HCV Aim is viral eradication Treatment of finite duration Treatment is poorly tolerated Antiviral Therapy

  36. Pegylated IFN in HBV Advantages Mainly used for eAg positive disease • Finite duration of Rx • Stopping rule at 12 weeks • Can seroconvert to eAg negative disease (30%) • But some do sAg seroconvert (3%) + some late Disadvantages • Cant use in Cirrhosis • Side effects ++ • 48 week course of Rx • Not good for all genotypes AB>CD

  37. HBV Genotypes F D A A B C D C Bj D D C D D Ba E F F A Fung & Lok, Hepatology 2004;40:790-2

  38. Pegylated Interferon • Neuropsychiatric (aggression, anxiety, depression) • Lethargy • Flu-like symptoms • Neutropenia • Rashes • Anorexia and weight loss • Alopecia • Thyroid dysfunction • Nephrotoxic • Cardiac disturbance (high/low BP or arrhythmia) • Ocular effects

  39. Therapy For HBV is Rapidly Evolving • Approved Drugs • Conventional Interferons (IFNs) • Pegylated Interferon a-2a (PEG-IFN) • Lamivudine (LMV) • Adefovir (ADV) • Entecavir (ETV) -NICE 2009 • Tenofovir (TDF) -NICE 2009 • Future Options • X Telbivudine (LdT)- turned down by NICE 2009 • Clevudine • Pradefovir • Emtricitabine (Truvada= TDF+Emtricitabine) • Valtorcitabine • …………

  40. Rebound of serum HBV DNA >1 log10 cpm

  41. 80% 70% 70% 70% 60% 53% 50% 42% Incidence of Resistance 40% 29% 30% 24% 18% 20% 11% 10% 3% 0% 0% year 1 year 2 year 3 year 4 year 5 Incidence of HBV Resistance Lamivudine resistance (rtL180M+rtM204V/I) Adefovir resistance (rtN236T/rtA181V) Lai CL, Clin Infect Dis 2003;36:687.Locarnini et al., EASL 2005.

  42. Nucleoside analogue Anti-HBV drugs Nucleotide analogue ETV TDF LdT LAM FTC Potency ADV IFN Genetic Barrier

  43. UK Transplantation for Viral Hepatitis recipients Total HCV Total HBV

  44. Hepatitis C Treatment • Aim is viral eradication • Treatment of finite duration

  45. HCV Genotypes • 6 main genotypes • Nucleotide diversity > 20% • Little effect on natural history • Geographical variation • Most important determinant of response to treatment

  46. Ribavirin- adverse effects Haemolytic anaemia Thrombocytopenia Headache GI disturbance Alopecia Anxiety, depression, memory loss, irritability, insomnia Chest pain Cough Gout

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