Viral Hepatitis for the Generalist

Thursday 20th May

Dr Allister GrantLeicester 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 ofvirus

feces blood/blood-derived

body fluids

blood/blood-derived

body fluids

blood/blood-derived

body fluids

feces

Route oftransmission

fecal-oral percutaneouspermucosal

percutaneouspermucosal

percutaneouspermucosal

fecal-oral

Chronicinfection

no yes yes yes no

Prevention pre/post-exposure

immunization

pre/post-exposure

immunization

blood donorscreening;

risk behaviormodification

pre/post-exposure

immunization;risk behaviormodification

ensure safedrinking

water

Type of HepatitisA B C D E

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 hepatitisCholestatic

hepatitisRelapsing hepatitis

Chronic sequelae: None

Hepatitis A - Clinical Features

FaecalHAV

Symptoms

0 1 2 3 4 5 6 12 24

Hepatitis A Infection

Total anti-HAV

Titre ALT

IgM anti-HAV

Months after exposure

Typical Serological Course

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

Hepatitis E - Clinical Features

Symptoms

ALTIgG anti-HEV

IgM anti-HEVVirus in

stool

0 1 2 3 4 5 6 7 8 9 10 11 1213

Hepatitis E Virus InfectionTypical 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

DayMay 19th

World HepatitisAlliance

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 millioninfected 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 500,000 -1,200,000 deaths yearly due to HBV yearly due to HBV complicationscomplications

• 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: 97-107

The Stages of Chronic HBV Infection

immunetolerance

immuneclearance

inactivecarrier

reactivation

HBeAgAnti-HBe

HBV-DNA

ALT

Inactive carrier?

Detection limit

Detection limit

HBeAg(-)CHB

HBeAg(-)Inactivecarrier

HBV DNA

0 3mo 6mo 9mo 12mo

HBV DNA Thresholds

InactiveCarrierState

HBeAg (+)CHB

Ser

um

HB

V D

NA

(IU

/ml)

HBeAg (-)CHB

102

103

106

107

108

109

1010

104

105

10

Management of eAg Negative Hepatitis B

HBsAg +ve, HBeAg -ve

HBV DNA < 2000 IU/mlNormal ALT

Possible chronic inactive states-seroconversion 1-3%/yr

MonitorALT/ HBV DNA 3 monthly for 12/12 then if normal ALT every 6-12/12

HBV DNA > 2000 IU/mland ALT > 2 x ULN

(or persistently 1-2 x ULN)

Liver biopsy (unless clinical evidence of cirrhosis or

contraindication)

ALT abnormalMeasure 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)

Monitor3-6/12 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, 1991

1975-85: 539 patients

Prevalence of HBeAg Negative Chronic HBV in Italy

58%42%

Gaeta et al, 2003Gaeta et al, 2003

2001: 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 & WalesHahné et al J Clin Virol 2004;29:211-220.

QE Hepatitis Database 2005/6Ethnicity of HBV Patients

HBV Notifications in England & Wales

Uchenna H. I, et al. Gastroenterology 2006; 130:678-686

Year of follow-up

Cu

mu

lati

ve in

cid

ence

of

liver

ci

rrh

osi

s

.2

.1

0 1 2 3 4 5 6 7 8 9 10 11 12 13

0

.4

.3

Baseline HBV DNA Level, copies/mL

P value for log-rank test, <0.001

n=3,774

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

5.2%6.3%

10.0%

23.0%

37.1%

Cumulative Incidence of Liver CirrhosisREVEAL HBV Study

High Serum HBV DNA Levels are Associated with Increased Risk of HCC Mortality

HBV DNA Negative

HBV DNA LowHBV DNA Low< 105 copies/mL copies/mL RR = 1.7 (0.5-5.7)RR = 1.7 (0.5-5.7)

HBV DNA HighHBV DNA High> 105 copies/mL copies/mL

RR = 11.2 (3.6-35.0)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.

60 Signs/symptoms

CIRRHOSIS

HCV- Natural History

20% at 20yrs50% at 30yrs

AgeGenderAlcohol

20 No Harmful Effects

TransplantationLiver Failure

Liver Cancer

3.9% pa

1.4% pa

20 Clear the HCV

80 Develop Chronic Hepatitis

HCV Ab pos & PCR pos

HCV Ab posPCR 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 2005/6Hepatitis C

Natural Hx of HCV Cirrhosis

liver fibrosis score(degree of scarring)

0

6

3

years10 20 30 60

cirrhosis

liver fibrosis score(degree of scarring)

0

6

3

years10 20 30 60

cirrhosis

HCV-pos(median time 38 years)

liver fibrosis score(degree of scarring)

0

6

3

years10 20 30 60

cirrhosisend-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 ++

• 48 week course of Rx

• Not good for all genotypes

AB>CD

HBV Genotypes

AD

D

DD Ba

CC

Bj

F

D

E

AD

BC

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 log10

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 2005.

0%0%

10%10%

20%20%

30%30%

40%40%

50%50%

60%60%

70%70%

80%80%

year 1year 1 year 2year 2 year 3year 3 year 4year 4

0%0%

24%24%

3%3%

42%42%

11%11%

53%53%

70%70%

Inci

den

ce o

f R

esis

tan

ceIn

cid

ence

of

Res

ista

nce

18%18%

29%29%

70%70%

year 5year 5

TDF

ADV

ETV

LAM FTC

Genetic Barrier

Pot

ency

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 anaemiaThrombocytopeniaHeadacheGI disturbance AlopeciaAnxiety, depression, memory loss, irritability, insomniaChest painCoughGout

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 1998Poynard et al., Lancet 1998

• ´00 PEG-IFN2a Zeuzem et al., NEJM 2000

• ´01 PEG-IFN2b + RBV Manns et al., Lancet 2001

• ´01 PEG-IFN2a + RBV Fried et al., NEJM 2002

• ´02 PEG-IFN2a + RBV Hadzyannis et al Ann Intern Med 2004

s us t

a in

e d v

i ro

log

i cre

s po

n se

(%

)

6%16%

40% 39%

54-63%

Protease Inhibitors-Telapravir and Bocepravir Trials awaited

1990 2005

Peg-IFN & Ribavirin(normal renal function)

Caucasian

QE Hepatitis Database 2005/6Hepatitis C genotype

Asian

QE Hepatitis Database 2005/6Hepatitis 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

0116 258 6630

Allister.J.Grant@uhl-tr.nhs.uk

http://hepatologist.eu