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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
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
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 (
%)
Alter MJ, et al. N Eng J Med. 1999;341:556-562.
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 (
%)
Alter MJ, et al. N Eng J Med. 1999;341:556-562.
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
Illustration by Mitchell L. Shiffman, MD.
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
Illustration by Mitchell L. Shiffman, MD.
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
Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.
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
Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.
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
Illustration by Mitchell L. Shiffman, MD.
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
Illustration by Mitchell L. Shiffman, MD.
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
Duration of Infection (Years)
Fib
rosi
s S
core
4.0
3.0
2.0
1.0
0
Poynard T, et al. Lancet. 1997;349:825-832.
HCV Fibrosis ProgressionEffect of Age
Age at time of infection
> 40 years< 40 years
Poynard T, et al. Lancet. 1997;349:825-832.
HCV Fibrosis ProgressionEffect of Histology
< 10 11-20 21-30 31-40 > 40
Duration of Infection (Years)
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
Go Online to View More CCO Programs!
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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