sources of hepatitis c infection (u.s.) previously acquired (
TRANSCRIPT
Sources of Hepatitis C Infection(U.S.)
Previously Acquired (<1990s)
Transfusion10%
Sexual18%Other
1%*
Unknown9%
Injection Drug UseInjection Drug Use68%68%
Unknown10%
Other1%*
Sexual15%
Injection Drug UseInjection Drug Use 60%60%
* Other includes nosocomial, iatrogenic, perinatal
Occupational4%
Occupational4%
Newly Acquired (1995-2000)
Sources: Based on Sentinel Counties, NHANES III
Differences in Risk Behaviors for HCV Acquisition in IDUers
8
26
37
65
43
72
16
32
0
20
40
60
80
Initiated bySex Partners
Injected byOther
Injected withSex Partner
BorrowedNeedle fromSex Partner
Evans J, J Urban Health, 2003
%
N=584 malesN=260 females
Young IDUers(< 30 yrs) in San Francisco
Predictors of Unsafe Syringe Sharing in Women IDUers
Predictor OR(95% CI)* P Value
Shared needles/syringes with partner previously
18.36 (2.2, 154)
0.007
Injection partner was primary male partner
5.05 (1.2, 21.0)
0.03
Felt they were not in control of injecting safely
2.56 (0.94, 8.33)
0.06
Felt “very close” to their injection partners
3.53 (0.89, 14.1)
0.08
Tortu S, AIDS and Behavior, 2003* Adjusted odds ratios
Risk of HCV Transmission Risk of HCV Transmission Between Sex PartnersBetween Sex Partners
STD Patients
Partner Status
Total N
N (%) Anti-HCV Positive
OR P Value
Female
Male partner HCV+
Male partner HCV-
49
243
5 (10)
7 (3)
3.7 0.04
Male
Female partner HCV+
Female partner HCV-
14
232
1 (7)
18 (8)
0.9 NS
Thomas D, JID, 1995
Natural History of HCV InfectionNatural History of HCV InfectionLiver Disease ProgressionLiver Disease Progression
Exposure(Acute Phase)
Resolved Chronic
CirrhosisStable
HCC
5%-25% over 20 years
15-45% 55-85%
3% per year
75-95%
Alter MJ. Semin Liver Dis. 1995Freeman, Hepatology 2001
5% per year
DecompensationLiver Failure
Rate of Spontaneous Clearance of HCV Following Exposure
704 Irish women infected with HCV by contaminated anti-D immune globulin were tested for HCV 17 years after exposure --> 55% HCV RNA+
Liver biopsies performed in 363 patients
49
34
15
2
0
10
20
30
40
50
60
70
No Fibrosis Periportal/portalfibrosis
Bridging fibrosis Cirrhosis
Kenny-Walsh et al, N Engl J Med 1999
%
Chronic HCV Infection with Chronic HCV Infection with Persistently Normal ALT LevelsPersistently Normal ALT Levels
Accounts for ~30% of persons with chronic HCV infection
Histological disease tends to be mild Cirrhosis present in 2.5% (X-sectional studies)
Rate of disease progression is slower than patients with abnormal ALT levels
Same genotype distribution and viral load as abnormal ALT
Female gender predominates -> 61-90% of the normal ALT population
Persistently elevated ALT levels
Longer duration of infection
Alcohol excess (>50 gm/day)
Age >40 years at time of infection
HIV or HBV coinfection
High BMI
Male gender
Risk Factors for Progressive Fibrosis and Cirrhosis
Poynard T, Lancet 1997 349:825-32Mathurin P, Hepatology 1998 27:868-72Benhamou J, Hepatology 1999 30:1054-8
Rate of Fibrosis ProgressionRate of Fibrosis ProgressionBy GenderBy Gender
543210
1
2
3
4
Duration of Infection (yrs)
Males
Females
Poynard, Lancet, 1997
Cirrhosis
Bridging Fibrosis
Portal Fibrosis + Septae
Portal Fibrosis
NoFibrosis
Fibrosis and Alcohol ConsumptionFibrosis and Alcohol Consumption
50403020101
4
Duration of Infection (Years)
Fib
ros
is S
tag
e
60504030201
4
Age of Biopsy (Years)
Fib
ros
is S
tag
e
0-49 g alcohol/day
≥50 g alcohol/day
0-49 g alcohol/day
≥50 g alcohol/day
Poynard T et al, Lancet 1997
0 25-50 75-100 125-150 > 175 gms0
20
40
60
80
100
120
140
160
Lifetime Daily Alcohol Intake
Corrao and Arico, Hepatology 1998;27:917.
Risk of Cirrhosis in Alcohol and HCVRisk of Cirrhosis in Alcohol and HCV
12 gms = 1 drink
HCV negativeHCV positive
With ingestion of equivalent amounts of alcohol, females
are at higher risk of alcohol-related liver injury
than males
Women with HCVwho drink alcohol may be at
higher risk ofprogressive liver disease
than male who drink
Alcohol is an importantAlcohol is an importantcofactor in HCV diseasecofactor in HCV disease
progressionprogression
Becker U, et al. Hepatology 19961 beverage = 12 g/alcohol
Alcoholic CirrhosisAlcoholic CirrhosisE
stim
ated
rel
ativ
e ri
sk
20
18
16
14
12
10
8
6
4
2
0 <1 1-6 7-13 14-27 28-41 42-69 >70
Beverages per week
Alcoholic Liver Alcoholic Liver DiseaseDisease20
18
16
14
12
10
8
6
4
2
0
Women
Men
Women
Men
Est
imat
ed r
elat
ive
risk
Beverages per week
<1 1-6 7-13 14-27 28-41 42-69 >70
Alcohol Consumption and Alcohol Consumption and Risk of Chronic Liver DiseaseRisk of Chronic Liver Disease
• Odds of developing CLD and cirrhosis are increased in women consuming 1 or more drinks per day (≥13 g/day)– Dose-response is present --> More alcohol means
higher risk of developing cirrhosis
• In setting of chronic HCV infection, the “safe” level of alcohol is unknown but predicted to be less than that for alcoholic liver disease
– Risk of cirrhosis increased significantly by ingestion of >50/gm day alcohol (but gender specific data lacking)
Chronic HCV Infection and Hepatocellular Carcinoma (HCC) Age-adjusted incidence of HCC increasing in the
U.S. Doubling in past 2 decades (1975 -1998) 3.0/100,000 persons in 1996-1998
Incidence is expected to risk further as number of prevalent HCV cases with cirrhosis and other complications of long-standing disease increases
Ethnic, geographic and gender differences are evident In all ethnic groups, men have twice the rate of
HCC as females
Reproductive Status and HCC Risk in Women with CVH
Reproductive Factor HCC OR (95%CI)
P Value
# full-term pregnancies (≥4 vs ≤1)
0.45 (0.24,0.84) 0.0216
Older age of natural menopause (≥50, 45-49, <45 yrs respectively)
1.46 (0.52,4.08)
2.14 (0.80,5.73)
4.27 (1.01,18.07)
0.0251
Bilateral Oophorectomy < age 50 yrs
2.57 (1.42,4.63) 0.0003
218 women HCC (majority infected with HBV or HCV), 719 controls
Yu MW, Hepatology, 2003
Gender Differences in the Gender Differences in the Natural History of HCV DiseaseNatural History of HCV Disease Rate of spontaneous clearance of virus following
exposure is high in (young) women
Among persons with chronic HCV infection and persistently normal liver enzymes, the majority are women
Severity of disease is less and rate of disease progression slower in women than men
Alcohol use by women with HCV is likely to have more pronounced effects on the liver than men
Rates of HCC are lower in women than men and reproductive factors may influence HCC risk.
Summary
Summary of Advances in Summary of Advances in Antiviral TherapyAntiviral Therapy
13-19%
55-56%
38-45%
0%
20%
40%
60%
% P
ati
en
ts
IFN -2b + RBV
IFN 48 wks
PEG-IFN+ RBV
McHutchison JG. Semin Liver Dis. 1999; Manns M, Lancet 2001; Fried M, N Engl J Med 2002
Host FactorsHost FactorsViral FactorsViral Factors
GenotypeGenotype Viral LoadViral Load
Predictors of Virologic ResponsePredictors of Virologic Response
Treatment FactorsTreatment Factors
Target RBV dose Treatment Duration Adherence to full dose therapy
AgeAge CirrhosisCirrhosis RaceRace GenderGender WeightWeight
Factors Influencing Response to Factors Influencing Response to Interferon Plus RibavirinInterferon Plus Ribavirin
Weight > 75 kgWeight 75 kg
Advanced fibrosisMinimal fibrosis
MaleFemale
Age > 40Age 40
High HCV RNALow HCV RNA
Genotype 1
Increasing usefulnessin predicting
viral clearance with Rx
20 40 60 80
Sustained Virologic Response (%)
Genotype 2 or 3
Adapted from McHutchison JG et al. Semin Liver Dis. 1999;19(suppl 1):63.
Baseline Factors Independently Baseline Factors Independently Associated with SVRAssociated with SVR
FDA Antiviral Drugs Advisory Committee Proceedings Peginterferon alfa-2a. November 14, 2002.
00
2020
4040
6060
8080
100100
120120
140140
160160
180180
Genoty
pe (1
vs
non-1)
Genoty
pe (1
vs
non-1)
Pretre
atm
ent V
iral L
oad
Pretre
atm
ent V
iral L
oadAgeAge
ALT Quotie
nt
ALT Quotie
nt
Histo
logy
Histo
logy
Race
Race
Wei
ght
Wei
ght
800
vs 1
000/
1200
mg R
BV
800
vs 1
000/
1200
mg R
BV
24 v
s 48
Wks
Tx
24 v
s 48
Wks
Tx
US vs
Non US
US vs
Non US
Gender
Gender
Wal
d C
hi-
Sq
uar
eW
ald
Ch
i-S
qu
are
N= 1737N= 1737
PEG IFN Alfa-2a + RBVPEG IFN Alfa-2a + RBV