Global burden of hbv

Global Burden of HBV

• 2 billion current or past infections

• 300-400 million with chronic HBV disease– 1.25 million in the US

• 25%-40% of persons with chronic HBV disease die from cirrhosis or HCC – Over 300,000 cases/year of HBV-related HCC– HBV is second most important carcinogen

behind tobaccoWorld Health Organization. Fact sheet. Available at: http://www.who.int. Accessed January 31, 2006. Centers for Disease Control. Fact sheet. Available at: http://www.cdc.gov. Accessed January 31, 2006. Lai CL, et al. Lancet. 2003;362:2089-2094.

Prevalence of Chronic Hepatitis B

HBsAg Prevalence

> 8% - High 2-8% - Intermediate< 2% - Low

Immigration numbers summed by continent from 1996-2002

~ 2 million Asians

~ 400,000

South Americans

~ 350,000 Africans

~ 930, 000 Europeans

350- 400 million chronically infected with Hepatitis B260-300 million in Asia1.25 million in the USHBV infection during Adolescence/adulthood for

Caucasians530,000 annual cases of HCC, 82% virus related

316,000 HBV related118,000 HCV related

Philippines Ranks Among the Philippines Ranks Among the Highest in HCC-related DeathsHighest in HCC-related Deaths

Age-adjusted Mortality Age-adjusted Mortality Rates due to HCC (per Rates due to HCC (per

100,000)100,000)

El-Serag & Rudolph. El-Serag & Rudolph. GastroenterologyGastroenterology 20072007

Life Cycle of HBV in the Life Cycle of HBV in the HepatocyteHepatocyte

Adapted from Lai CL, et al. J Med Virol. 2000;Adapted from Lai CL, et al. J Med Virol. 2000;

InfectiousInfectiousHBV virionHBV virion

Viral Viral polymerasepolymeraseconverts converts pregenomic RNApregenomic RNAto partially ds to partially ds DNADNA

PartiallyPartiallydsDNAdsDNA

SubviralSubviralparticlesparticles

HepatocyteHepatocyte

mRNAmRNA

CytoplasmCytoplasm

NucleusNucleusPrecore/corePrecore/core

HBeAgHBeAg

ERER

HBcAgHBcAg

HBsAgHBsAg

cccDNAcccDNA

Minus strand DNAMinus strand DNA

Encapsulated Encapsulated pregenomic mRNApregenomic mRNA

Complete viral packaging and release of complete virions or subviral Complete viral packaging and release of complete virions or subviral particles of e-Ag and core and surface antigen serves as decoy to the particles of e-Ag and core and surface antigen serves as decoy to the

immune system and modulates the immune system directlyimmune system and modulates the immune system directly

HBV-Triggered Immune Response

Ganem D, et al. N Engl J Med. 2004;350:1118-1129.

MHCclass II

CD4+T cell

HBVpeptides

HBV

MHCclass I

MHCclass I

TNF-αInterferon-gamma

Down-regulations

of viralreplication

HBV DNA

HBsAg

HBV peptides

CD8+T cell

Antigen-presenting cell

CD8+T cell

Infected hepatocyte

HBV cores

HBV RNA

HBVantigens

Immune and Immune and inflammatory inflammatory

responseresponse

Hepatitis B in the PhilippinesHepatitis B in the Philippines

• Prevalence of 12% (Lansang MA. Prevalence of 12% (Lansang MA. Gut 1996)Gut 1996)

• Prevalence of 16% (NNHeS/FNRI, Prevalence of 16% (NNHeS/FNRI, unpublished 2004)unpublished 2004)

HYPERENDEMICHYPERENDEMIC AREA AREA

14 million Filipinos14 million FilipinosAT RISKAT RISK

FeaturesFeatures C ( n=9 )C ( n=9 )Ba ( n=11)Ba ( n=11)Aa ( n=11 Aa ( n=11 ))

Mutations in the core promoterMutations in the core promoter

Mutations in the ATG initiator codon in the precore Mutations in the ATG initiator codon in the precore regionregion

T1809T1809 10/11 (91%)*10/11 (91%)* 0/0/9 (0%)9 (0%)0/0/11(0%)11(0%) < .0001< .0001

T1812T1812 11/11 11/11 (100%)*(100%)*

0/0/9 (0%)9 (0%)0/0/11 (0%)11 (0%) < .0001< .0001

Mutations in the precore Mutations in the precore regionregion

T1858T1858 1/11 (9%)*1/11 (9%)* 9/9 (100%)9/9 (100%)11/11 (100%)11/11 (100%) < .0001< .0001

T1862T186211/11(100%)11/11(100%)

**0/0/9 (0%)9 (0%)0/0/11 (0%)11 (0%) < .0001< .0001

H1888H18887/11 (86%)*7/11 (86%)* 0/0/9 (0%)9 (0%)0/0/11 (0%)11 (0%) < .0001< .0001

A1896A18960/0/11 (0%)11 (0%) 0/9 (0%)0/9 (0%)1/11 (9%)1/11 (9%)

T1762/T1762/A1764A1764

3/11 (27%)*3/11 (27%)* 8/9 (89%)8/9 (89%)10/11 (91%)10/11 (91%)< .0< .00505

HBeAgHBeAg 5/11 5/11 (45%)(45%)

7/11 (64%)7/11 (64%) 5/9 (56%)5/9 (56%)

Age (yr)Age (yr) 52.8 52.8 ±17.2±17.2

55.8 ±12.755.8 ±12.7 52.752.7 ±16.3±16.3

Characteristics of HBV genotypes among HCC Characteristics of HBV genotypes among HCC patientspatients

N.S.N.S.

N.S.N.S.

N.S.N.S.

Sollano, Quino, Mizokami, APASL 2005Sollano, Quino, Mizokami, APASL 2005

Subtype Ce (C2)

Subtype Cs (C1)

Subtype Cf (C5)

Subtype Cp (C3)

Subtype Ca (C4)

HBV Genotype C

10096

100

100

100 10076

100100 100

9788

N-ChinaKoreaJapan

S-ChinaVietnamMyanmar

PhilippineVietnam

PolynesiaMicronesiaAustralian Aborigine

HBV/C Should Be Classified into 5 Subtypes

Sollano, Quino, Muzokawi APASL, 2005

Hepatitis B Disease Hepatitis B Disease ProgressionProgression

Acute Acute InfectionInfection

ChronicChronic InfectionInfection CirrhosisCirrhosis DeathDeath

5%-10% of 5%-10% of chronic HBV-chronic HBV-infected infected individualsindividuals1 1

Liver FailureLiver Failure (Decompensation)(Decompensation)

>30% of >30% of CHB CHB

individualsindividuals11

•>90% of infected >90% of infected children progress children progress to chronic diseaseto chronic disease

•<5% of infected <5% of infected immunocompetenimmunocompetent adults progress t adults progress to chronic to chronic

diseasedisease1124% of patients 24% of patients decompensate decompensate within 5 years of within 5 years of developing developing cirrhosis cirrhosis 22

Liver Liver Cancer (HCC)Cancer (HCC)

Liver Liver TransplantatioTransplantatio

nn

• Torresi J, Locarnini. Gastroenterology 2000. Torresi J, Locarnini. Gastroenterology 2000. • Fattovich G et al. Hepatology 1995Fattovich G et al. Hepatology 1995

In 2007…In 2007…

Immune ToleranceImmune ToleranceImmune Immune ClearanceClearance

InactiveInactivecarriercarrier ReactivationReactivation

HBV DNAHBV DNA

ALTALT

HBeAg POSITIVEHBeAg POSITIVEAnti- HBe NEGATIVEAnti- HBe NEGATIVE

HBeAg NEGATIVEHBeAg NEGATIVEAnti- HBe POSITIVEAnti- HBe POSITIVE

Hepatitis B as a DYNAMIC DISEASEHepatitis B as a DYNAMIC DISEASEVARIABLE natural historyVARIABLE natural history

FLUCTUATIONS in disease activityFLUCTUATIONS in disease activity

Primary Goal of Hepatitis B Primary Goal of Hepatitis B Therapy: Preventing Cirrhosis, Therapy: Preventing Cirrhosis, HCC, and DeathHCC, and Death

Durable Suppression of HBV

Replication

HBV Seroprevalence Among Asian Americans

Guan R, et al. AASLD 2004. Abstract 1269.

• 5 large US cities (2001-2004)– Chinese– Korean– Vietnamese

• Median age– 43 yrs (12-80)

• HBsAg+, overall– 558/5341 (10.4%)

11%

14%

10%

11%

15%

11%

10.4%

0% 4% 8% 12% 16%

Philadelphia

San Francisco

Boston

Chicago

NY(1)

NY(2)

Overall

Proportion of Individuals HBsAg+

Clinical Consequences of HBV Acquisition

• Acute Infection– Major risk of death related to development of

fulminant liver failure (rare)

• Chronic Infection– Progressive liver disease– Risk of cirrhosis, liver failure, hepatocellular

carcinoma (HCC)– Rarely extrahepatic manifestations

Reducing the Burden of Chronic HBV Disease

• Prevention of infection– Vaccination!

• Prevention of liver-related complications– Modify lifestyle: weight control, limit alcohol– Anti-HBV therapies: interferon, lamivudine,

adefovir, entecavir– HCC surveillance

Incidence of Acute Hepatitis B:United States, 1978-1995

Vaccinelicensed HBsAg screening

of pregnant women

Infantimmunization

Adolescent immunization

80

70

60

50

40

30

20

10

078 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95

Cas

es/1

00,0

00

Safer Injection and Sexual Practices

Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/b/. Accessed February 5, 2006.

Year

http://www.cdc.gov/ncidod/diseases/hepatitis/b/

Hepatitis B Vaccine

• Vaccine licensed in 1982– Plasma-derived recombinant vaccine – 3-dose series, high efficacy, no boosters, safe

• Since licensing, adolescents and adults at high risk recommended to receive vaccine

• Comprehensive strategy to eliminate HBV transmission implemented in 1991– 1991: universal infant vaccination recommended– 1995: expansion to include vaccination of all adolescents ages 11-12

yrs– 1998: vaccination of all persons age 0-18 yrs not previously vaccinated

Achievements With HBV Vaccination• Decline in acute HBV in past decade by 67%

– Reflects effects of routine infant and childhood vaccination

• Vaccination rates high in this population but decline to ~ 60% in adolescents

– Slowest rate of decline in adults

• Some adult subgroups showing increase in incidence (men ≥ 19 yrs, women ≥ 40 yrs)

• Decline in risk of serious complications of chronic HBV

– Reduced rates of childhood HCC in countries of high endemnicity

Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2004;52:1252-1254.

Annual Incidence of Liver Cancer in Children Aged 6-15 Years

Age at Diagnosis

Before Program Cohort

(1974-1984),Incidence per

100,000

After Program Cohort (1984-1986),

Incidence per 100,000

6 0.46 0.00

7 0.53 0.15

8 0.48 0.31

9 0.61 0.00

Total 0.52 0.13*

Chang MH, et al. N Engl J Med. 1997;336:1855-1859.

*P < .001 for comparison between birth cohort.Vaccination program in effect since July 1984

Issues Related to HBV Vaccination• Poor or nonresponse to vaccination

– Strategies to maximize likelihood of response

• Durability of vaccine response– Need for booster vaccinations?

• Missed opportunities for vaccination– Especially among adults at risk

• During 1983-2000: ~ 110,000 adults acquired chronic HBV infection due to lack of adult hepatitis B immunization

Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2004;52:1252-1254.

Factors Associated with Reduced Vaccine ResponsesPatient-Related

• Older age (> 50 years)

• Male gender

• Smoking

• Obesity

• Immune deficiency

– HIV

– Transplant recipients

– Dialysis

• Compliance

Vaccine-Related

• Schedule (accelerated vs 0, 1, 2, 6 months)

• Double vs single dose

• Use of “adjuvants”

– GCSF, levamisole

• IM versus ID

HBV Vaccination Durability of Response• Durable immunity 15-18 years

– 84% of Alaskan natives at 15 years[1]

– 85% of MSM (some HIV+) at 7 years[2]

– > 50% of Chinese children at 15 years[3]

• Immunity preserved in anti-HBs-negative persons

– Amnestic response with booster dose

– Preserved T cell responses in PBMCs in vitro

1. McMahon BJ, et al. Ann Intern Med. 2005;142:333-341. 2. Hadler SC, et al. N Engl J Med. 1986;315:209-214. 3. Ni YH, et al. Ann Intern Med. 2001;135:796-800.

HBV Vaccination: Durability of Response

• Predictors of decline in anti-HBs titers over 15 yrs – Low initial antibody

response– Female gender– Younger age

(0-4 yrs greatest decline)

Vaccines With Specific Anti-HBs Titers

McMahon B, et al. Ann Intern Med. 2005;143:333-341.

0

10

20

30

40

< 2IU/L ≥ 2 IU/L ≥ 10 IU/L ≥ 100 IU/L

1618

38

28

Per

cen

tag

e o

f P

atie

nts

Hepatitis B Vaccination in Adults:Missed Opportunities

• Of all individuals with reported acute hepatitis B infection– 56% have been treated for an STD and/or were incarcerated

prior to their illness– 89% are IDUs– 35% are MSM– 70% are persons with multiple sexual partners

• Overlapping risks: IDU and sexual activities

Goldstein ST, et.al. JID. 2002;185:713-719. Khan A, et al. Antiviral Therapy. 2000:5(suppl 1):21.

Prevention of HBV InfectionPrevention of HBV InfectionSummarySummary• Vaccine is highly effective – HBV incidence is Vaccine is highly effective – HBV incidence is

decliningdeclining– Infants and children vaccination rates highInfants and children vaccination rates high– In countries endemic for HBV, infant In countries endemic for HBV, infant

vaccination has reduced rates of liver vaccination has reduced rates of liver complicationscomplications

• Missed opportunities among adultsMissed opportunities among adults– If sexually active, IDU If sexually active, IDU at risk at risk

• HBV-related HCC is vaccine-preventable HBV-related HCC is vaccine-preventable cancercancer

Outcomes of Acute HBV Infection

Recover

Subclinical Hepatitis

Fulminant Hepatitis

Acute Hepatitis

ACUTE INFECTION

Chronic InfectionDEATH

< 1% 0.1-2.7%

5-20%

Risk is Related to Age at Infection

Outcome Neonates, % Children, % Adults, %

Chronic carrier 90 20 < 5

Recover 10 80 > 95Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25.

Clinical-Epidemiologic CorrelationsHBV Endemicity

LocationAge of

InfectionMode of

TransmissionChronici

tyHCC Risk

High 10-15%Asia

Sub-Sahara Africa

BirthToddler

PerinatalHorizontal

Likely High

Low < 2%N. AmericaW. Europe

Scandinavia

EarlyAdulthoo

d

PercutaneousSexual

Rare Low

Available at: http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed February 6, 2006.Designed by Jules Dienstag, MD

http://www.who.int/mediacentre/factsheets/fs204/en/

Natural History of Chronic HBV Natural History of Chronic HBV InfectionInfection

0 10 20 30 40 50 60 70

Years

SerologyHBeAg Anti-HBe

ALT level

HBV DNA level

(viremia)

DiseaseChronic active

hepatitisCirrhosis/HCC

Immune tolerant (phase I)

Immune Active (phase II)

Non-Replicative (phase III)

Chronicity Stage

Minimal inflammation

Resolved

Normal to cirrhosis/HCC

HBsAg Anti-HBs

Possible Outcomes of HBeAg+ Possible Outcomes of HBeAg+ Chronic HBV InfectionChronic HBV Infection

24% HBeAg-24% HBeAg-negative CHB negative CHB

with with detectable detectable HBV DNAHBV DNA

5% 5% Undetermined Undetermined

causescauses

67% Sustained 67% Sustained remissionremission

Spontaneous Spontaneous seroconversioseroconversio

nn(n = 283)(n = 283)

33% ALT 33% ALT elevation elevation

(> 2 x ULN)(> 2 x ULN)

4% HBeAg 4% HBeAg reversionreversion

Hsu YS, et al. Hepatology. 2002;35:1522-1527.Hsu YS, et al. Hepatology. 2002;35:1522-1527.

Possible Outcomes of HBeAg+ Possible Outcomes of HBeAg+ Chronic HBV InfectionChronic HBV Infection

Patient Populations in Chronic Hepatitis BPatient Populations in Chronic Hepatitis B

MarkerMarker ImmuneImmuneTolerantTolerant

HBeAg+ HBeAg+ CHBCHB

Inactive Inactive HBsAg HBsAg CarrierCarrier

HBeAgHBeAg–– CHB CHB(Precore (Precore Mutant)Mutant)

HBsAgHBsAg ++ ++ ++ ++

HBeAgHBeAg ++ ++ –– ––

Anti-HBeAnti-HBe –– –– ++ ++

ALTALT NormalNormal NormalNormal

HBV DNA HBV DNA (copies/mL)(copies/mL) > 10> 1055 > 10> 1055 < 10< 1033 > 10> 1044

HistologyHistology Normal/Normal/MildMild ActiveActive NormalNormal ActiveActive

Lai CL, et al. Lancet. 2003:362:2089-2094. Lok AS, et al. Gastroenterology. Lai CL, et al. Lancet. 2003:362:2089-2094. Lok AS, et al. Gastroenterology. 2001;120:1828-1853.2001;120:1828-1853.

Natural Clearance of HBsAgNatural Clearance of HBsAg

• Occurs in ~ 0.5% of HBsAg Occurs in ~ 0.5% of HBsAg carriers/yearcarriers/year

• Duration of infection is primary Duration of infection is primary determinant of HBsAg lossdeterminant of HBsAg loss

• ~ 50% of carriers who clear HBsAg ~ 50% of carriers who clear HBsAg have HBV DNA present in sera in low have HBV DNA present in sera in low titer (1–2 logs)titer (1–2 logs)

McMahon BJ, et al. Ann Intern Med. 2001;135:759-768.McMahon BJ, et al. Ann Intern Med. 2001;135:759-768.

Annual Risk of HBV ProgressionAnnual Risk of HBV Progression

HBeAg+ chronic HBeAg+ chronic hepatitis Bhepatitis B

HBeAg-Neg chronic HBeAg-Neg chronic hepatitis Bhepatitis B

CirrhosisCirrhosis

DecompensationDecompensation HCCHCC

5.0%5.0%

1.0%-2.0%1.0%-2.0%

3.0%3.0% 2.0%2.0%

All HBsAg +All HBsAg +individualsindividuals

0.4%0.4%

Factors linked with Factors linked with progressionprogression

– Duration of “active”diseaseDuration of “active”disease– Heavy alcohol useHeavy alcohol use– Immune suppression (HIV)Immune suppression (HIV)

Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25.Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25.

Initial Evaluation of HBsAg+ Patient• History and PE• Assess risk factors

(coinfection)• Alcohol use• Family history of HBV

and HCC• Physical findings of

cirrhosisLok AS, et al. Hepatology 2001;34:1225-1241.Tsai NC. Sem Liver Dis. 2004;24(suppl 1):71-76.

Investigations

• Liver disease activity

• Serologic and virologic markers

• Screening for HCC (AFP and ultrasound)

Categorization of DiseaseCategorization of Disease

• HBeAg positive or negativeHBeAg positive or negative• Replication high or low (HBV DNA)Replication high or low (HBV DNA)• ALT elevated or normalALT elevated or normal• Liver histologyLiver histology

Role of Baseline Liver Biopsy

• Confirm diagnosis of chronic hepatitis BConfirm diagnosis of chronic hepatitis B• Establish baseline severityEstablish baseline severity

– Grade: severity of necroinflammationGrade: severity of necroinflammation– Stage: amount of fibrosisStage: amount of fibrosis

• Clarify diagnosis when ALT and HBV DNA levels are Clarify diagnosis when ALT and HBV DNA levels are discordantdiscordant

• Exclude other coexistent causes of liver disease Exclude other coexistent causes of liver disease (eg, fatty liver or alcoholic liver disease)(eg, fatty liver or alcoholic liver disease)

• Guide decision regarding initiation of treatmentGuide decision regarding initiation of treatment

Ferrell L, et al. in McSween, et al, editors. Pathology of the liver, 4th ed. London:Churchill Livingstone; 2002:313-362. Buckley A ,et al. Can J Gastroenterol 2000;14:481-82. Park A , et al. Minerva Gastroenterol Dietol. 2004;50:289-303.

Indications for Treatment ofIndications for Treatment ofChronic HBVChronic HBV

• Patients with active liver disease:Patients with active liver disease:– Abnormal liver function tests (AST, ALT)Abnormal liver function tests (AST, ALT)– HBeAg positive and > 10HBeAg positive and > 1055 HBV DNA HBV DNA– HBeAg negative and > 10HBeAg negative and > 1044 HBV DNA HBV DNA

• Biopsy if HBV DNA < 10Biopsy if HBV DNA < 1044 with with ALT ALT• Treat if active hepatitis (biochemical or Treat if active hepatitis (biochemical or

histologic)histologic)

Lok AS, et al. Hepatology. 2001;34:1225-1241.Lok AS, et al. Hepatology. 2001;34:1225-1241.

2 Distinct Patient Populations 2 Distinct Patient Populations With Chronic HBV With Chronic HBV

• HBeAg+ (wild-type), HBV DNA+HBeAg+ (wild-type), HBV DNA+– HBeAg lossHBeAg loss– Seroconversion to anti-HBe Seroconversion to anti-HBe – Durability of response ~ 80% Durability of response ~ 80%

• HBeAg-/anti-HBe+/HBV DNA+ HBeAg-/anti-HBe+/HBV DNA+ (precore mutant)(precore mutant)– HBeAg seroconversion not an endpointHBeAg seroconversion not an endpoint– Long-term therapy the ruleLong-term therapy the rule

Endpoints of TreatmentEndpoints of Treatment

• Sustained suppression of HBV DNA Sustained suppression of HBV DNA replicationreplication

• HBeAg seroconversionHBeAg seroconversion• Improvement in liver histologyImprovement in liver histology• Reduced rates of liver complicationsReduced rates of liver complications

Hepatitis C:Epidemiology, Diagnosis and Treatment

Mitchell L. Shiffman, MD

Professor of MedicineChief, Hepatology Section

Medical Director, Liver Transplant Program

Virginia Commonwealth University Health System

Richmond, Virginia

Hepatitis C Virus InfectionMagnitude of the Problem• Nearly 4 million persons in United States

infected• Approximately 35,000 new cases yearly• 85% of new cases become chronic• Leading cause of

Chronic liver disease Cirrhosis Liver cancer Liver transplantation

Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm. Accessed February 1, 2006.

Hepatitis C VirusFate of Acute Infection

15%

Chronic85%

Spontaneousresolution

Alter MJ, et al. N Eng J Med. 1999;341:556-562.

0

50

100

150

200

0 6 12 18 24

Month

AL

T (

IU/l)

Resolution

Chronic

HCV RNA+/- + -

Hepatitis C VirusResponse to Acute Infection

Illustration by Mitchell L. Shiffman, MD.

Hepatitis C Virus InfectionNatural History

Stable80%

(68%) HCCLiver failure25% (4%)

Slowlyprogressiv

e75% (13%)

Resolved15%

(15%)

Acute HCV

Cirrhosis20% (17%)

Chronic HCV85% (85%)

HCC, hepatocellular carcinoma

Hepatitis C Virus InfectionPopulation at Risk

• Transfusion of blood products before 1992

• Intravenous drug use

• Nasal inhalation of cocaine

• Chronic renal failure on dialysis

• Incarceration

• Occupational exposure to blood products

• Transplantation of an organ/tissue graft from an HCV-positive donor

• Body piercing and potentially tattoo

Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm. Accessed February 1, 2006.

Hepatitis C Virus InfectionPrevalence

SexB, Blacks; F, female; H, Hispanic; M, male; W, Whites.

0

1.0

2.0

3.0

4.0

All W B H M FRace

An

ti-H

CV

Po

siti

ve (

%)


1.8%

Hepatitis C Virus Infection Prevalence by Age

0

1.0

2.0

3.0

4.0

5.0

< 11 11-19 20-29 30-39 40-49 50-59 60-69 ≥ 70

Age Group

An

ti-H

CV

Po

siti

ve (

%)


Management of Chronic HCVTests Utilized

Disease Severity Response to Therapy

AST/ALT

Bilirubin

Albumin

Pro-time (INR)

Platelet count

Liver histology

ALT

HCV RNA

HCV genotype

Liver histology

LFTs

Viral HepatitisRole of Diagnostic Testing• Identify patients with viral hepatitis infection

– Previous exposure to hepatitis virus– Active infection– Inactive infection– Resolved infection

• Assess response to therapy– Prior to onset of treatment– During and following treatment

Hepatitis C VirusDiagnostic Testing

Diagnostic Test Type

Specifications Serologic Virologic

Mode of detection Antibodies Virus

Sensitivity > 95% > 98%

Specificity Variable > 98%

Detection postexposure 2-6 months 2-6 weeks

Use Screening Confirmation

Hepatitis C VirusHost Production of HCV Antibodies

• HCV infects cell• HCV proteins expressed

on surface of hepatocytes• Antibodies to HCV

proteins produced by host • HCV antibodies DO NOT

convey immunity

YY YYY YYY


Testing for Hepatitis C VirusTesting for Hepatitis C VirusAnti-HCV AntibodiesAnti-HCV Antibodies

• ELISA screening testELISA screening test– Sensitivity: 97%Sensitivity: 97%

– Detects circulating HCV antibodiesDetects circulating HCV antibodies

• False positive reactions may occurFalse positive reactions may occur– Cross-reacting circulating antibodiesCross-reacting circulating antibodies

– Nonspecific binding of anti-HCV antibodiesNonspecific binding of anti-HCV antibodies

• Positive predictive valuePositive predictive value– 95% with risk factors and elevated ALT 95% with risk factors and elevated ALT

– 50% without risk factors and normal ALT50% without risk factors and normal ALT

Illustration by Mitchell L. Shiffman, MD.Illustration by Mitchell L. Shiffman, MD.

• False positivesFalse positives– Autoimmune disordersAutoimmune disorders– Spontaneous resolution of viral infectionSpontaneous resolution of viral infection

• False negativesFalse negatives– Chronically immune suppressedChronically immune suppressed– Transplant recipientsTransplant recipients– Chronic renal failure on dialysisChronic renal failure on dialysis– HIV positiveHIV positive

HCV Antibody TestingHCV Antibody TestingLimitationsLimitations

Testing for Hepatitis C VirusRecombinant Immunoblot Assay

• Supplemental assay

• Detects circulating antibodies to 4 HCV proteins

• Antigen-antibody reaction

• More specific than anti-HCV enzyme immunoassay

• False positive reaction can still occur

• Largely replaced by HCV RNA testing

Positive≥ 2 bands

Indeterminate1 band

Control


Testing for Hepatitis C VirusIndications for HCV RNA• Confirm HCV infection

– Persistently normal serum ALT

– No risk factors

– HCV antibody positive

– Antinuclear antibodies

– Prior to initiating therapy

• Assess effectiveness of treatment

– Predict likelihood of response before and during therapy

– Confirm response after therapy completed

Testing for Hepatitis C VirusVirologic Assays

PCR TMA b-DNA

Polymerase chain reaction

Transcription mediated

amplificationBranched chain DNA

Amplifies target Amplifies target Amplifies probe

Qualitative

QuantitativeQualitative Quantitative

Quantitative HCV RNA AssaysInherent Variability• Normal variation of 1 log

unit in HCV RNA assays • Differences of < 1 log

between samples of probably NOT significant

• HCV RNA titer best reported in log units

1

10

100

1000

10,000

100,000

1,000,000

10,000,000

100,000,000

I II III IV V

Sample

HC

V R

NA

(IU

/mL

)

Nolte FS, et al. J Clin Microbiol. 2001;39:4005-4012.

Serum HCV RNA LevelStability Over Time

Patient

Limit of detection

0

2

4

6

8

Baseline 1 2 3 4

Time (Years)

Lo

g H

CV

RN

A

(IU

/mL

)

1

2

3

4

5

Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

HCV RNA and Liver HistologyFibrosis

Genotype

NoFibrosis

PortalFibrosis

BridgingFibrosis

Cirrhosis

Serum HCV RNA does not correlate with level of fibrosis

0

2

4

6

8

Lo

g H

CV

RN

A(c

op

ies/

mL

)

1

2

3

4


HCV RNA and Liver HistologyInflammation

Genotype

Serum HCV RNA does not correlate with level of inflammation

0

2

4

6

8

0 2 4 6 8 10 12

Inflammation Score

Lo

g H

CV

RN

A(c

op

ies/

mL

)

1

2

3

4


Hepatitis C VirusGenotypes in the USA

All others1%

Type 310%

Type 217%

Type 172%

McHutchinson JG, et al. N Engl J Med. 1998;339:1485-1492.

Determination of HCV GenotypeINNOLiPA Assay

• HCV genotype

– Best pretreatment predictor of response

– Determines duration of therapy

• All patients should have genotype determined prior to initiating therapy

PCR1a

1b

3a3b

4

2b

2a

5


Hepatitis C Virus InfectionLiver Biopsy• Only test that can accurately assess

– Severity of inflammation– Degree of fibrosis

• Determines the following– Risk for developing cirrhosis in future– Need for therapy– Need for ongoing therapy when initial

treatment has failed

Management of Chronic HCVIs Liver Biopsy Necessary?

NO

Patient wants treatment even if no fibrosis

Patient does not want treatment or treatment contraindicated even if advanced fibrosis

Labs and radiographic studies do not suggest cirrhosis

Patient achieves SVR

YES

Patient would only accept treatment if advanced fibrosis

Labs or radiographic studies suggest cirrhosis may be present

Patient fails to achieve SVR and no recent biopsy available

Assessment of Liver HistologyNoninvasive Serum Tests

0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4

Fibrosis Stage

FIB

RO

TE

ST

0

0.2

0.4

0.6

0.8

1.0

0 1 2 3

Activity Grade

AC

TIT

ES

T

Poynard T, et al. Hepatology. 2003;38:481-492.

Chronic HCV With Normal Serum ALTALT Patterns and Flares

ULN

0

20

40

60

80

100

120

0 3 6 9 12 15 18 21 24

Month

AL

T (

IU/l)

Single elevationsPeriodic elevationsAlways normal


Chronic HCV InfectionNormal Serum ALT

Normal ALT Elevated ALT

n = 37 n = 58

Race White, % Black, %

4829

5271

Serum ALT, IU/L 46.6 ± 5.2 76.7 ± 6.0

Log HCV RNA, copies/mL 5.42 ± 0.13 5.50 ± 0.07

Histology score Inflammation Fibrosis

4.2 ± 0.10.7 ± 0.2

5.3 ± 0.11.6 ± 0.2

Shiffman ML, et al. J Infect Dis. 2000;182:1595-1601.

Chronic HCV InfectionNormal vs Elevated Serum ALT

Normal ALT Elevated ALT

Portal26%

No fibrosis

23%

Mild39%

Cirrhosis6%

Bridging6%

Portal20%

No fibrosis

16% Mild33%

Cirrhosis18%

Bridging13%

Shiffman ML, et al. J Infect Dis. 2000;182:1595-1601.

Chronic HCV InfectionSymptoms

Asymptomatic

Symptomatic

Cirrhosis

0

20

40

60

80

100

Fatigue

Per

cen

tag

e o

f P

atie

nts

37%

7%

56%

Unpublished data from MCV Hepatitis Program, 1995.

Chronic HCV InfectionProgression to Cirrhosis

0

20

40

60

80

100

0 5 10 15 20Time (Years)

Bridging

Portal

None

Ap

pro

xim

ate

Pe

rce

nta

ge

of

Pa

tie

nts

Wit

h C

irrh

osi

s

Yano M, et al. Hepatology. 1996;23:1334-1340.

Proportion of Patients Developing Cirrhosis According to Initial Level of Fibrosis

Fibrosis Progression of HCVEffect of Inflammation

Change in Fibrosis Score According to Necrosis Score at Baseline

Piecemeal Necrosis Score at Baseline

0-1 3-2 > 4

Number of patients 30 66 27

Mean change in fibrosis score per year

.05 .19 .37

Ghany MG, et al. Gastroenterol. 2003;124:97-104.

Poynard T, et al. Lancet. 1997;349:825-832.

HCV Fibrosis Progression Effect of Alcohol

Alcohol intake> 50 g/day*< 50 g/day

*50 g is equal to approximately 3.5 drinks

< 10 11-20 21-30 31-40 > 40

Duration of Infection (Years)

4.0

3.0

2.0

1.0

0

Fib

rosi

s S

core

< 10 11-20 21-30 31-40 > 40


Fib

rosi

s S

core

4.0

3.0

2.0

1.0

0


HCV Fibrosis ProgressionEffect of Age

Age at time of infection

> 40 years< 40 years


HCV Fibrosis ProgressionEffect of Histology

< 10 11-20 21-30 31-40 > 40


Fibrosis

Inflammation

Gra

de

or

Sta

ge

4.0

3.0

2.0

1.0

0

HCV and AlcoholRisk of Cirrhosis

Excessive alcohol intake characterized as > 40 g/day for women and > 60 g/day for men.

0

20

40

60

80

100

10 20 30 40

Years Following Exposure

Cir

rho

sis

(%)

HCVHCV + alcohol

Wiley TE, et al. Hepatology. 1998:28:805-809.

Fibrosis Progression in HCVEffect of Steatosis

2% 4% 7%

18%

6%18%

30% 33%

0

20

40

60

80

100

< 5% 5%-10% 11%-30% > 30%

Percentage of Steatosis at Initial Biopsy

Cu

mu

lati

ve P

rob

abil

ity

of

Fib

rosi

s P

rog

ress

ion

(%

)

Year 4

Year 6

Fartoux L, et al. Hepatology. 2005;41:82-87.

Cumulative Probability of Fibrosis According to Level of Steatosis

Fattovich G, et al. Gastroenterology. 1997;112:463-472.

HCV in Patients With CirrhosisSurvival and Rate of Decompensation

0

20

40

60

80

100

Su

rviv

al (

%)

StableDecompensation

10-Year Cumulative Survival

0

10

20

30

40

50

0 2 4 6 8 10

Years

Pe

rce

nta

ge

of

Pa

tie

nts Decompensation

HCC

Cumulative Probability

Hepatocellular CarcinomaIncidence in the United States

0

2

4

6

8

10

12

1976-1980 1991-1995

Cas

es/1

00,0

00

Black male

White male

Black female

White female

El-Serag HB, et al. N Engl J Med. 1999;340:745-750.

Chronic Hepatitis C InfectionProgression to Cirrhosis

20%-33%

15%-33%

0 10 20 30 40 50

HCC

Cirrhosis C

Cirrhosis A

Severe

Moderate

Mild

Years

Shiffman ML. Viral Hepatitis Rev. 1999;5:27-43.

Armstrong GL, et al. Hepatology. 2000;31:777-782.

Hepatitis C Virus InfectionThe Burden of Disease

0

1.0

2.0

3.0

1960 1980 2000 2020

Year

All patients

Infection for> 20 years

An

ti-H

CV

Po

siti

ve (

%)

Hepatitis C Virus InfectionIdentification of Patients• Found to have elevated serum ALT during

– Routine physical examination– Routine blood testing after starting certain

medications

• Test positive for anti-HCV during– Volunteer blood donation– Health or life insurance applications

• Physician– Inquires about previous risk behaviors

Chronic Hepatitis C VirusExtrahepatic Manifestations• Nonspecific antibodies

• Essential mixed cryoglobulinemia

• Glomerulonephritis

• Porphyria cutanea tarda

• Leukocytoclastic vasculitis

• Mooren’s corneal ulcer

• Non-Hodgkin’s lymphoma

• Autoimmune thyroiditis

• Diabetes mellitus

• Sjögren’s syndrome

Pawlotsky JM, et al. Hepatology. 1994;19:841-848.

Chronic Hepatitis C VirusAutoantibodies

HCV, % Control, %

Rheumatoid factor 70 8

Cryoglobulins 36 < 1

ANA > 1:40 > 1:180

21

13

10

2

Antismooth muscle > 1:40 > 1:180

21

7

2

< 1

Anti–liver-kidney microsome 5 < 1

Antithyroid 7 2

Chronic Hepatitis C Virus Autoantibodies (cont’d)• No relationship between presence of autoantibodies and

– Severity of chronic HCV

– HCV genotype

• Correlation between rheumatoid factor titer and

– Cryoglobulinemia

– But not symptomatic cryoglobulinemia

• Circulating autoantibodies from autoimmune disorders may result in

– False positive anti-HCV

Cacoub P, et al. Curr Opin Rheumatol. 2002;14:29-35.

CryoglobulinemiaClassification

Immunoglobulin Classification

IMonoclonal

No rheumatoid factorPrimary

II

Polyclonal IgG

Monoclonal IgM

Rheumatoid factor

Secondary mixed

HCV infection

IIIPolyclonal IgG

Polyclonal IgM

Secondary mixed

Infections

Autoimmune disorders

Lymphoproliferative diseases

Immune Manifestations of HCVPathogenesis

Monoclonal IgM rheumatoid factor

Cryoglobulin traps HCV

HCV evades theimmune response

Chronic immune stimulation by

single HCV antigen

Polyclonal IgG YGenetic and

environmentalfactors

Illustration by Mitchell L. Shiffman, MD

HCV and CryoglobulinemiaDermatitis

• Occurs in dependent areas

• Deposition of cryoglobulins in small capillaries

• Ulcerations may develop• Pruritic

Extrahepatic Effects of HCVCryoglobulinemia

0

20

40

60

80

100

Cryoglobulinemia Controls

Per

cen

tag

e o

f P

atie

nts

Elevated ALTAnti-HCVHCV RNA

Misiani R, et al. Ann Int Med. 1992;117:573-577.

HCV and CryoglobulinemiaManifestations• Dermatitis (dependent areas)

• Vasculitis

• Myalgias (fibromyalgia?)

• Arthralgias (RA and/or ANA positive)

• Membranoproliferative glomerulonephritis

• Neuropathy

• Chronic fatigue syndrome (?)

CharacteristicHCV

SialadenitisPrimary

Sjögren’s Syndrome

SS-A, SS-B Negative Positive

Lymphocytic capillaritis

Mild

Pericapillary

Mostly CD8 cells

Severe

Periductal

Mostly CD4 cells

Sicca syndrome:

Xerophthalmia

Xerostomia

Absent

8%-36%

Present

Present

Extrahepatic Effects of HCVLymphocytic Sialadenitis

Extrahepatic Effects of HCVExtrahepatic Effects of HCVB-Cell LymphomaB-Cell Lymphoma

8 case series

1754 pts evaluated

Ferri (1994)

Mazzaro (1996)

Silvestri (1996)

Izumi (1996)

McColl (1996)

Zignego (1997)

DeRosa (1997)

Zuckerman (1997)

0102030

B Cell Lymphoma

0 10 20 30

Controls

Zein CO, et al. Am J Gastroenterol. 2005;100:48-55.

Chronic HCV and Diabetes MellitusCase Prevalence

• N = 179 with chronic HCV• Prevalence of diabetes

mellitus and insulin resistance noted

• Compared with expected rate based on NHANES III study after adjusting for– Age– Sex– Race

• Prevalence of DM or insulin resistance higher in those with chronic HCV

0

4

8

12

16

20

Females Males

Nu

mb

er o

f C

ases

ObservedExpected

Zein CO, et al. Am J Gastroenterol. 2005;100:48-55.

Chronic HCV and Diabetes MellitusRelationship to Fibrosis Stage

0

10

20

30

40

0 1 2 3 4

Histologic Stage

Per

cen

tag

e o

f P

atie

nts

Extrahepatic Effects of HCVPorphyria Cutanea Tarda

2 case series

3 uncontrolled series

280 patients

Alcohol: 36%-77%

Fargion (1992)

De Castro (1993)

Criber (1995)

Stolzel (1995)

Kondo (1997)

020406080100

PCT

0 5 10 15 20

Control

Nagao Y, et al. J Gastroenterol Hepatol. 2004;19:1101-1113.

Extrahepatic Effects of HCVLichen Planus• Occurs in < 1% of the general population

• 10%-30% of patients with chronic HCV

• Appearance– Flat topped, violaceous, pruritic papules– Throughout body – Oral mucosa

• Histology– Dense infiltration of dermis with T lymphocytes

Treatment of Chronic HCVPeginterferon and Ribavirin

0

20

40

60

80

100

1 2-3

Genotype

Su

stai

ned

Vir

olo

gic

Res

po

nse

(%

)

PegIFN-2a/RBVPegIFN-2b/RBV

Fried MW, et al. N Eng J Med. 2002;347:975-982. Manns MP, et al. Lancet 2001;358:958-965.

The Many Faces of HCV InfectionSummary• Chronic HCV infection leads to cirrhosis and liver failure

in a large number of persons• Primary care physicians must recognize that chronic

HCV is common in specific nonliver disorders• Effective treatment of chronic HCV can prevent fibrosis

progression and reduce complications of HCV

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Conference Coverage of all the key data presented at major hepatitis meetings

News and Capsule Summaries covering the latest findings in the field of hepatitis

Downloadable Slides, and much more!

clinicaloptions.com/hep

Screening for Liver Cancer:Lack of ConsensusAt what age should HCC screening be initiated?

1) Among HBV-infected individuals, HCC can occur at any age, including childhood

2) Optimal age for initiation of screening unknown1

3) Patients ≥ 35 yrs are at much higher risk for HCC than those < 35 years2

1. Lok AS, and McMahon BJ. Hepatology. 2001; 34:1225-1241.2. Liaw YF, et al. Gastroenterology. 1986;90:263-267.

Screening for Liver Cancer: Alpha-fetoprotein (AFP)

• Up to 1/3 of patients with HCC have normal AFP

• AFP may be elevated in 1/3 of patients with cirrhosis without HCC

• Very high level of AFP (> 1000 ng/mL) diagnostic of HCC, with few exceptions

• Persistently rising AFP levels highly suggestive of HCC but not often seen

Screening for Liver Cancer:Screening for Liver Cancer:Patients With Chronic HBVPatients With Chronic HBV

• Cancer screening strategies:Cancer screening strategies:

High Risk- High Risk- AFP + U/S every 6 AFP + U/S every 6 monthsmonths

– CirrhosisCirrhosis

– Family history HCCFamily history HCC

Medium Risk- AFP + U/S every Medium Risk- AFP + U/S every yearyear

– Age ≥ 30-40Age ≥ 30-40

– Active disease (ALT)Active disease (ALT)

• If rising AFP or high AFP > 20 If rising AFP or high AFP > 20 ng/mL, spiral CT or MRI at least ng/mL, spiral CT or MRI at least onceonce

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Global burden of hbv

Education

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