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 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

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”

Source of virus fecesblood/ blood-derived body fluids blood/ blood-derived body fluids blood/ blood-derived body fluids feces Route of transmission fecal-oralpercutaneous permucosal percutaneous permucosal percutaneous permucosal fecal-oral Chronic infection noyes no Preventionpre/post- exposure immunization pre/post- exposure immunization blood donor screening; risk behavior modification pre/post- exposure immunization; risk behavior modification ensure safe drinking water Type of Hepatitis ABCDE

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

Faecal HAV Symptoms Hepatitis A Infection Total anti-HAV TitreALT IgM anti-HAV Months after exposure Typical Serological Course

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

Symptoms ALT IgG anti-HEV IgM anti-HEV Virus in stool Hepatitis E Virus Infection Typical Serologic Course Titer Weeks after Exposure

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”

World Hepatitis Day May 19th World Hepatitis Alliance

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 people on the planet have been exposed to one or both Viruses Most of the 500 million infected do not know

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

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

The Stages of Chronic HBV Infection immune tolerance immune clearance inactive carrier reactivation HBeAg Anti-HBe HBV-DNA ALT

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

HBV DNA Thresholds Inactive Carrier State HBeAg (+) CHB Serum HBV DNA (IU/ml) HBeAg (-) CHB

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 Monitor ALT/ HBV DNA 3 monthly for 12/12 then if normal ALT every 6-12/12 HBV DNA > 2000 IU/ml and ALT > 2 x ULN (or persistently 1-2 x ULN) Liver biopsy (unless clinical evidence of cirrhosis or contraindication) ALT abnormal Measure HBV DNA 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) 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) 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) Draft EM Guidelines based on EASL Guidelines 2009

HBeAg positive HBeAg negative Giusti et al, Giusti et al, : 539 patients Prevalence of HBeAg Negative Chronic HBV in Italy 58% 42% Gaeta et al, : 837 patients 10% 90%

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

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

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

QE Hepatitis Database 2005/6 Ethnicity of HBV Patients

HBV Notifications in England & Wales

Uchenna H. I, et al. Gastroenterology 2006; 130: Year of follow-up Cumulative incidence of liver cirrhosis Baseline HBV DNA Level, copies/mL P value for log-rank test, <0.001 n=3, x 10 6 n= x10 5 n= x10 4 n= x10 3 n=1210 <300 n= % 6.3% 10.0% 23.0% 37.1% Cumulative Incidence of Liver Cirrhosis REVEAL HBV Study

High Serum HBV DNA Levels are Associated with Increased Risk of HCC Mortality HBV DNA Negative HBV DNA Low copies/mL < 10 5 copies/mL RR = 1.7 ( ) HBV DNA High copies/mL > 10 5 copies/mL RR = 11.2 ( ) p < across viral categories Chen G, et al. J Hepatology 2005; 42 (suppl 2):477A. Chen G, et al. Hepatology 2005; 40 (suppl 1):594A.

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

Prevalence of Hepatitis C virus 2001 WHO

UK HCV Prevalence <1% IV Drug Use Migration Blood Donation 2-400,000 Screening 1991

QE Hepatitis Database 2005/6 Hepatitis C

Natural Hx of HCV Cirrhosis

liver fibrosis score (degree of scarring) years cirrhosis

liver fibrosis score (degree of scarring) years cirrhosis HCV-pos (median time 38 years)

liver fibrosis score (degree of scarring) years cirrhosis end-stage renal disease ? immune suppression

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

Antiviral Therapy 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

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 week course of Rx Not good for all genotypes AB>CD

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

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

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 –…………

Rebound of serum HBV DNA >1 log 10 cpm

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 % 10% 20% 30% 40% 50% 60% 70%80% year 1 year 2 year 2 year 3 year 4 0% 24% 3% 42% 11% 53% 70% Incidence of Resistance 18% 29% 70% year 5

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

UK Transplantation for Viral Hepatitis Total HCV recipients Total HBV

Hepatitis C Treatment Aim is viral eradication Treatment of finite duration

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

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

HCV Antiviral Treatment IFN Pegylated IFN IFN & ribavirin Peg-IFN & ribavirin efficacy tolerability

Treatment of Chronic Hepatitis C ´90 IFN  3x3 MU x 24 Wk. Davis et al., NEJM 1989 ´96 IFN  3x3 MU x 48 Wk. Poynard et al., NEJM 1995 Poynard et al., Hepatology 1996 ´98 IFN  + Ribavirin McHutchison et al., NEJM 1998 Poynard et al., Lancet 1998 ´00 PEG-IFN  2a Zeuzem et al., NEJM 2000 ´01 PEG-IFN  2b + RBV Manns et al., Lancet 2001 ´01 PEG-IFN  2a + RBV Fried et al., NEJM 2002 ´02 PEG-IFN  2a + RBV Hadzyannis et al Ann Intern Med 2004 sustained virologic response (%) 6% 16% 40% 39% 54-63% Protease Inhibitors-Telapravir and Bocepravir Trials awaited

Peg-IFN & Ribavirin (normal renal function)

Caucasian QE Hepatitis Database 2005/6 Hepatitis C genotype

Asian QE Hepatitis Database 2005/6 Hepatitis C genotype

Chemotherapy and HBV HBV reactivation is common among patients receiving chemotherapy haematological malignancy > solid malignant tumors. 21% to 53% of patients who are HBsAg positive will have a flare with chemotherapy. HBsAg-positive patients are at the highest risk.

Chemotherapy and HBV Patients with resolved HBV infection (ie, HBsAg-neg, HBcAb pos and HBsAb-pos) may have reactivation with immunosuppression. Worse if –HBeAg-positivity –High pretreatment HBV load –Male sex –Young age –High pretreatment serum ALT The risk for hepatic decompensation is greatest during recovery from immunosuppression

Current Advice All patients undergoing chemotherapy should be screened for HBV Infection. (Flares have been seen with the use of immunomodulatory drugs such as infliximab / rituximab) Consider Rx in Hepatitis B cAb+ve patients sAg positive patients should be started on Lamivudine 3 weeks before treatment Patients should have Lamivudine for 3 months after the completion of chemotherapy