management of chronic hepatitis c scott k. fung, md, frcpc division of gastroenterology id/ micro...
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Management of Chronic Hepatitis C
Scott K. Fung, MD, FRCPC
Division of Gastroenterology
ID/ Micro Seminar
November 30, 2009
Learning Objectives• To review epidemiology of chronic hepatitis C• To understand the natural history of HCV
– Progression to cirrhosis– Risk of hepatocellular carcinoma
• To discuss pre-treatment evaluation– HCV genotype and viral load– Assessment of hepatic fibrosis
• To evaluate antiviral treatment in 2007– SVR and relapse– HIV/ HCV coinfected cohort
Global Prevalence of HCV
10 to 2010 to 205 to 105 to 102 to 52 to 51 to 21 to 20 to 10 to 1
10 to 2010 to 205 to 105 to 102 to 52 to 51 to 21 to 20 to 10 to 1
HCV Ab+ (%)
Worldwide prevalence is 170 million (3%)
Hepatitis C in Ontario
010002000300040005000600070008000
# N
oti
fica
tio
ns
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
Year
HCV notifications by year
Hepatitis C in Ontario
0
5
10
15
20
25
30
35
% o
f al
l ant
i-HC
V-
posi
tive
0-15 15-20 20-30 30-40 40-50 50-60 >60
Years
Age distribution of positive anti-HCV results
Hepatitis C in Ontario
1.3 1.3
20.1
3.77.6
31.1
82.7
30.1
20.2
05
101520253035
%
No co
ndom
Trave
l/End
emic
IVDU
Mul
tiple
par
tner
s
Blood
/pro
ducts
Sexua
l con
tact
House
hld
cont
act
Tatto
o/Pie
rcing
/acc
...
Oth
er (s
p)
Unkno
wn
Undef
ined
% anti-HCV-positive by risk factor (last 5 years)
HCV in Immigrants
COUNTRY RATE (%) COUNTRY RATE (%)
ITALY 0.5 INDIA 1.8
GREECE 1.5 PAKISTAN 2.4
EGYPT 18.1 PHILLIPINES 3.6
SOMALIA 0.9 RWANDA 17.0
HONG KONG 0.5 VIETNAM 6.1
ROMANIA 4.5 RUSSIA 2.0
KOREA 1.7 POLAND 1.4
Recipients of clotting factors before 1987
75 - 90%
Injection drug users
70 - 85%
Long-term hemodialysis patients
10%
Individuals with > 50 sexual partners
10%
Recipients of blood prior to 1990
5%
Infants born to infected mothers
5%
Long-term sexual partners of HCV positive
1 - 5%
Health workers after random needlesticks
1 - 2%
Recipients of clotting factors before 1987
75 - 90%
Injection drug users
70 - 85%
Long-term hemodialysis patients
10%
Individuals with > 50 sexual partners
10%
Recipients of blood prior to 1990
5%
Infants born to infected mothers
5%
Long-term sexual partners of HCV positive
1 - 5%
Health workers after random needlesticks
1 - 2%
CDC, MMWR 1998;47(No. RR-19):1CDC, MMWR 1998;47(No. RR-19):1
Prevalence In Groups at Risk
CDC, 1995CDC, 1995CDC, 1995CDC, 1995
Surrogate testsSurrogate testson donorson donors
Surrogate testsSurrogate testson donorson donors
00
55
1010
1515
2020
‘82‘82 ‘84‘84 ‘86‘86 ‘88‘88 ‘90‘90 ‘92‘92 ‘94‘94 ‘95‘95
YearYear
Cases per 100,000
Cases per 100,000
Anti-HCV testAnti-HCV testAnti-HCV testAnti-HCV test
Decline amongDecline amonginjection drug usersinjection drug users
Decline amongDecline amonginjection drug usersinjection drug users
Declining Incidence of Acute Hepatitis C in the U.S.
HCV Disease Burden
• At least 3.9 million Americans infected with HCV– 2.7 million chronically infected (HCV RNA+)– Most patients yet to be diagnosed
• Most common blood-borne pathogen• Leading cause of liver disease in USA• #1 reason for liver transplantation• ~13,000 deaths annually from HCV
UNOSUNOS
00
10001000
20002000
30003000
40004000
50005000
9191 9292 9393 9494 9595 9696 9797 9898 9999 '00'00
YearYear
NumberNumber
All CausesAll CausesHepatitis CHepatitis C
Liver Transplantation in the U.S.
Future Prevalence of HCV
0
0.5
1
1.5
2
2.5
Pre
vale
nce
of H
CV
In
fect
ion
(%)
1960 1970 1980 1990 2000 2010 2020 2030
Infected at any time
Infected > 20 years
Armstrong et al, Hepatology 2000
Natural History
Acute hepatitis CAcute hepatitis C
Chronic Chronic infectioninfection
Chronic Chronic hepatitishepatitis
CirrhosisCirrhosis
TimeTime(yr)(yr)
TimeTime(yr)(yr)
55 - 85%55 - 85%55 - 85%55 - 85%
70%70%70%70%
20%20%20%20%
1010 2020 3030
DecompensationDecompensation
HCCHCC1 - 4%/yr1 - 4%/yr1 - 4%/yr1 - 4%/yr
4 - 5%/yr4 - 5%/yr4 - 5%/yr4 - 5%/yr
Outcome of Hepatitis C Infection
Interval (yrs) between Time of Transfusion and Date of Diagnosis of Hepatitis,
Cirrhosis and HCC
Kiyosawa et al., Hepatology 1990;12:673
PortalPortal PeriportalPeriportal
SeptalSeptal CirrhosisCirrhosis
1 2
3 4
Stages of Fibrosis in CHC
Histologic Grade of Hepatic Inflammation and Stage of Fibrosis
Kenny-Walsh et al., N Engl J Med 1999;340:1230
2% 4%
41% 52%
0 1-3 4-8 9-18
49%
10%5%2%
34%
no fibrosisperiportal or portal fibrosisportal-portal bridgingportal-central bridgingprobable or definite cirrhosis
inflammation fibrosis
Factors Influencing Outcome: Chronic Hepatitis C
Viral Host Exogenous
HIV co-infection Race/HLA/HFE Obesity/Steatosis
HBV co-infection Immune status Alcohol
? Viral load Gender/ age
Fibrosis stage
Iron overload
? Smoking
Yano M, et. al., Hepatology 1996; 23:1334Yano M, et. al., Hepatology 1996; 23:1334
00
2020
4040
6060
8080
100100
00 22 44 66 88 1010 1212 1414 1616 1818 2020
Time (yr)Time (yr)
%Progression to Cirrhosis
(stage 4)
%Progression to Cirrhosis
(stage 4)
Initial Stage 3+
Initial Stage 2-2.9
Initial Stage 0-1.9
Progression to Cirrhosis Can Be Estimated From Initial Stage of
Liver Biopsy Fibrosis
Fontaine H et al, Human Pathol 2001;32:904Fontaine H et al, Human Pathol 2001;32:904
Fibrosis Rate (Stage/Yr)
Fibrosis Rate (Stage/Yr)
Mild (0-1)Mild (0-1) Severe (2-3)Severe (2-3)
Initial Biopsy InflammationInitial Biopsy Inflammation
00
0.050.05
0.10.1
0.150.15
0.20.2
Rate of Fibrosis Can Be Estimated From Initial Grade of Liver Biopsy
Inflammation
Progression to Cirrhosis
Cirrhosis
METAVIR score
0 5 10 15 20 25 30
Older male drinker
Young male non-drinker
Young female non-drinker
Time (years)Poynard et al, Lancet 1997
Association between Fibrosis, Duration of Infection and Alcohol in CHC
Poynard et al. Lancet 1997;349:825
Duration of infection (yrs)
10 21-30 31-40 >40
4.0
1.011 - 20
50g EtOH/d
0 - 49g EtOH/d
Fib
rosi
s st
age
n=1039
Normal ALT
• 30% of HCV patients have persistently normal ALT (3 normal ALT values)
• Majority have mild disease on biopsy • SVR rates to PEG-IFN and ribavirin
equivalent to those with abnormal ALT• Patients with persistently normal ALT should
be considered for therapy• Prognostic liver biopsy: determine those with
significant disease who would benefit from treatment vs those who might prefer to wait for newer therapies
Liver Histology: CHC with Normal ALT
N=447 pts
Biopsy %
Normal (non specific) 24Mild hepatitis 54Active hepatitis 21Cirrhosis <1
Marcellin et al. J Hepatol 1999
Mathurin P et al., Hepatology 1998; 27:868Mathurin P et al., Hepatology 1998; 27:868Mathurin P et al., Hepatology 1998; 27:868Mathurin P et al., Hepatology 1998; 27:868
Number 53 101
Fibrosis stage (0-4) 0.91.8
Rate (stage/yr) 0.050.13
Years to cirrhosis (est.) 60 25
Cirrhosis present 2%11%
Number 53 101
Fibrosis stage (0-4) 0.91.8
Rate (stage/yr) 0.050.13
Years to cirrhosis (est.) 60 25
Cirrhosis present 2%11%
Normal ALT ALT Normal ALT ALT
Fibrosis Rate: Normal ALT
ALT and HCV-RNA Behavior in Individual Patients with Constantly Normal ALT
Pontisso et al., Hepatology 1999;29:588
0
50
100
150
200
250
300
1 2 3 4 5 6 7 8 9 10 11 12
months
ALT
(IU
/L)
33.544.555.566.57
HC
V-R
NA
(Log genom
es/ml)
ALT HCV-RNA
Genotype 1b
Probability of ALT Reactivation in HCV Carriers with Normal ALT Levels
Authors Number of cases
Follow-up % ALT reactivation
Puoti et al. 880 3-18 mo 21.5
Martinot-Peignoux et al.
108 1-8.5 yr 21
Persico et al. 37 5 yr 12
Ohmiya et al. 40 2 yr 15
Tassopoulos et al.
39 1 yr 23
Tsuji et al. 120 10 yr 27.4
Alberti et al., Dig Liver Dis 2004:36:646
Mortality + Morbidity
Mortality: 12-15% lifetime estimate
Morbidity: Due to
- chronic hepatitis C
- extrahepatic complications
- co-morbid conditions
A: Fattovich G et al. Gastroenterology 1997;112:463B: Hu K & Tong MJ. Hepatology 1999;29:1311C: Serfaty L et al. Hepatology 1998;27:1435
A: Fattovich G et al. Gastroenterology 1997;112:463B: Hu K & Tong MJ. Hepatology 1999;29:1311C: Serfaty L et al. Hepatology 1998;27:1435
A BCA BCNumber 384 112
103
Follow-up (yr) 5.0 4.53.3
Decompensation (%/yr) 3.9 4.45.0
HCC (%/yr) 1.4 2.33.3
5-Year Survival (%) 91 83 84
Post decompensation (%) 50 51 --
Number 384 112 103
Follow-up (yr) 5.0 4.53.3
Decompensation (%/yr) 3.9 4.45.0
HCC (%/yr) 1.4 2.33.3
5-Year Survival (%) 91 83 84
Post decompensation (%) 50 51 --
Prognosis of Compensated Cirrhosis
Planas et al., J. Hepatol 2004:40;828
Probability of Survival in Relation to the First Hepatic Decompensation
Cumulative Probability of Developing Decompensation in HCV Cirrhosis
Fattovich et al., J Hepatol 1997; 27: 203
years0 1 2 3 4 56
180 174 149 125 82 3715
120 110 95 75 65 5045
0 1 2 3 4 56
5040302010
0
5040302010
0
%
A - IFN
B - no Rx
AB
No.at risk
p<0.0001
adjusted for age, bilirubin and hepatic stigmata
OLT for HCV at UHN
Pre-TreatmentEvaluation
Liver biopsyLiver biopsy
HCV RNA GenotypeHCV RNA Genotype
HCV antibodypositive
HCV antibodypositive
Initial Evaluation
• Indicates past or present infection
• Inexpensive, sensitive and specific
• Poor positive predictive value in low prevalence populations
• Low sensitivity in immunosuppressed patients
• Indicates past or present infection
• Inexpensive, sensitive and specific
• Poor positive predictive value in low prevalence populations
• Low sensitivity in immunosuppressed patients
Antibody Tests for Hepatitis C
• Qualitative– Confirms diagnosis of HCV infection
– Useful in the early diagnosis of acute hepatitis C
– “Gold standard” for documenting response to treatment
• Quantitative
– Generally less sensitive than qualitative
– Predicts response to therapy (EVR)
• Qualitative– Confirms diagnosis of HCV infection
– Useful in the early diagnosis of acute hepatitis C
– “Gold standard” for documenting response to treatment
• Quantitative
– Generally less sensitive than qualitative
– Predicts response to therapy (EVR)
HCV RNA Testing
Hoofnagle JH, Hepatology 1997; 26:15SHoofnagle JH, Hepatology 1997; 26:15S
Time After ExposureTime After Exposure
00
400400
600600
800800
10001000
ALT(IU/L)ALT(IU/L)
0000 2222 4444 6666 8888 10101010 12121212 24242424 1111 2222 3333 4444 5555 6666
Anti-HCVAnti-HCV
SymptomsSymptomsSymptomsSymptoms
WeeksWeeksWeeksWeeks MonthsMonthsMonthsMonths
HCV RNA positiveHCV RNA positive
200200
7777
Normal Normal ALTALTNormal Normal ALTALT
Acute Hepatitis C Infection
40 million copies/mL40 million copies/mL40 million copies/mL40 million copies/mL
10101010 100100100100 1,0001,0001,0001,000 10,00010,00010,00010,000 100,000100,000100,000100,0001,000,0001,000,0001,000,0001,000,00010,000,00010,000,00010,000,00010,000,000
50 copies/mL50 copies/mL50 copies/mL50 copies/mL
2,500 copies/mL2,500 copies/mL2,500 copies/mL2,500 copies/mLBayer bDNA 3.0Bayer bDNA 3.0Bayer bDNA 3.0Bayer bDNA 3.0
HCVHCVcopies/mLcopies/mLHCVHCVcopies/mLcopies/mL
2222 20202020 200200200200 2,0002,0002,0002,000 20,00020,00020,00020,000 200,000200,000200,000200,000 2,000,0002,000,0002,000,0002,000,000 ApproximateApproximateHCV IU/mLHCV IU/mLApproximateApproximateHCV IU/mLHCV IU/mL
Roche QuantitativeRoche QuantitativeRoche QuantitativeRoche Quantitative600 IU/mL600 IU/mL600 IU/mL600 IU/mL 850,000 850,000
IU/mLIU/mL850,000 850,000 IU/mLIU/mL
50 IU/mL50 IU/mL50 IU/mL50 IU/mL
RocheRocheQualitativeQualitativeRocheRocheQualitativeQualitative
BayerBayerTMATMABayerBayerTMATMA
Dynamic Range of HCV RNA Assays
Geographic Distribution of HCV Genotypes
1,2,3
4
5 1,2,3
1,2,3,6
1,2,3
1,2,3
• Six major genotypes found throughout the world
• In Europe and U.S., 60-70% of patients have genotype 1 infection
• Major determinant of response to antiviral therapy
• Not correlated with disease progression
• Six major genotypes found throughout the world
• In Europe and U.S., 60-70% of patients have genotype 1 infection
• Major determinant of response to antiviral therapy
• Not correlated with disease progression
HCV Genotypes
Role of Liver Biopsy
• Degree of hepatic fibrosis most important prognostic indicator
• Reduced response rates in cirrhosis
• Determine the need for Rx
• Exclude other liver diseases– NAFLD– Iron overload
Noninvasive Testing
FibroTest
FibroScan
APRI
FibroScan
• Measurement of hepatic elastography
• More fibrosis less elastic tissue
• Very good correlation with liver biopsy
• Technically difficult in obese or decompensated patients
Antiviral Therapy
Goals of Treatment
Primary Eradicate the virus
Secondary Prevent progression to cirrhosis
Reduce incidence of HCC
Reduce need for transplantation
Enhance survival
Primary Eradicate the virus
Secondary Prevent progression to cirrhosis
Reduce incidence of HCC
Reduce need for transplantation
Enhance survival
Advances in Treatment for HCV
6
15
30
46
55
0
20
40
60
IFN 24wkIFN 24wk IFN 48wkIFN 48wk PEG-IFNPEG-IFN IFN/RIFN/R PEG-IFN/RPEG-IFN/R
SVR %
SVR %
Definitions of Treatment Response
Early virologic response (EVR)Decrease in HCV RNA by >2 log10(or to < 50 IU/ml) after 12 weeks of therapy
End of treatment response (ETR)HCV RNA < 50 IU/ml at end of
treatment Sustained virologic response (SVR)
HCV RNA < 50 IU/ml 6 months after completing treatment
Early virologic response (EVR)Decrease in HCV RNA by >2 log10(or to < 50 IU/ml) after 12 weeks of therapy
End of treatment response (ETR)HCV RNA < 50 IU/ml at end of
treatment Sustained virologic response (SVR)
HCV RNA < 50 IU/ml 6 months after completing treatment
00 2424 4848 727200
5050
100100
150150
00
66
1212
ALTALT
HCV RNAHCV RNA
200200 1818
WeeksWeeks
ALT(IU)
ALT(IU)
HCV RNA (IU/ml)
HCV RNA (IU/ml)
TreatmentTreatment
Sustained Virologic Response
Long Term Outcome Following SVR
Veldt et al., Gut 2004; 53:1506
Survival Relapse
00
5050
100100
150150
66
1212
200200 1818
ALT(IU)
ALT(IU)
HCV RNA (IU/ml)
HCV RNA (IU/ml)
TreatmentTreatment
ALTALT
HCV RNAHCV RNA
00 66 1212 181800
MonthsMonths
Non-Response
Relapse
00 2424 4848 727200
5050
100100
150150
00
66
1212
200200 1818
WeeksWeeks
ALT(IU)
ALT(IU)
HCV RNA (IU/ml)
HCV RNA (IU/ml)
TreatmentTreatment
ALTALTHCV RNAHCV RNA
Factors Influencing Response to Therapy
Therapy Virus Host
Type Genotype Hepatic fibrosisDose Viral load Steatosis/ BMIDuration HIV co-infection AlcoholAdherence Ethnicity
SVR%
SVR%
IFN Alfa-2b3 MIU tiw
IFN Alfa-2b3 MIU tiw
PEG-2b0.5
mcg/kg/wk
PEG-2b0.5
mcg/kg/wk
PEG-2b1.0
mcg/kg/wk
PEG-2b1.0
mcg/kg/wk
PEG-2b1.5
mcg/kg/wk
PEG-2b1.5
mcg/kg/wk
25 23
18
12
00
2020
4040
6060
Lindsay KL, et al., Hepatology 2001;34:395 et al., Hepatology 2001;34:395Lindsay KL, et al., Hepatology 2001;34:395 et al., Hepatology 2001;34:395
PEG vs Standard IFN
IFN alfaalfa-2b
+RBV
IFN alfaalfa-2b
+RBV0.5 mcg/
kg/wk0.5 mcg/
kg/wk1.5 mcg/
kg/wk1.5 mcg/
kg/wk
00
2020
4040
6060
54
4747
PEG IFN alfaPEG IFN alfa-2b+RBV2b+RBV
SVR%
SVR%
PEG-IFN + Ribavirin
Manns MP, et al., Lancet 2001; 358:958 Lancet 2001; 358:958Manns MP, et al., Lancet 2001; 358:958 Lancet 2001; 358:958
*
*p=0.01
00
2020
4040
6060
8080
100100
33
79
34
80
42
82
Genotype 1Genotype 1 Genotype 2/3Genotype 2/3
IFN alfa-2b/RIFN alfa-2b/RPEG IFN alfa -2b 0.5/RPEG IFN alfa -2b 0.5/RPEG IFN alfa -2b 1.5/RPEG IFN alfa -2b 1.5/R
SVR%
SVR%
PEG-IFN + Ribavirin: Impact of HCV Genotype
Manns MP, et al., Lancet 2001; 358:958Manns MP, et al., Lancet 2001; 358:958Manns MP, et al., Lancet 2001; 358:958Manns MP, et al., Lancet 2001; 358:958
PEG-IFN + Ribavirin
Fried MW, et al., N Engl J Med 2002; 347:975 N Engl J Med 2002; 347:975Fried MW, et al., N Engl J Med 2002; 347:975 N Engl J Med 2002; 347:975
00
2020
4040
6060
8080
100100
PEG-IFN-2a+ Placebo
PEG-IFN-2a+ Placebo
29
SVR%
SVR% 56
PEG-IFN-2a+ RibavirinPEG-IFN-2a+ Ribavirin
44
IFN-2a+ Ribavirin
IFN-2a+ Ribavirin
PEG-IFN + Ribavirin
21
4546
76
00
2020
4040
6060
8080
100100
Genotype 1Genotype 1 Genotype 2/3Genotype 2/3
PEGPEGIFN/RIFN/RPEG/RPEG/R
36
61SVR%
SVR%
Fried MW, et al., N Engl J Med 2002; 347:975 N Engl J Med 2002; 347:975Fried MW, et al., N Engl J Med 2002; 347:975 N Engl J Med 2002; 347:975
Canadian Data: POWeR
• Prospective evaluation of SVR in treatment-naïve HCV Canadians
• Weight-based dosing of PEG-IFN2b (1.5 ug/kg) and RBV (800-1200 mg/d)
• Open-label study
• Multi-center (academic and community)
• N=2194 patients
Abadir et al, Hepatology 2005 (abstract)
Sustained Virologic Response
52
8578
68
0
10
20
30
40
50
60
70
80
90
SVR
%
Geno 1 Geno 2 Geno 3 Others
N=483 190 249 22
SVR by Body Weight
67 67 63 65 69
0102030405060708090
100
SVR
%
<50 50-64 64-75 75-85 >85
Weight (kg)
N=30 135 216 228 341
No statistical significance between groups
Optimal Duration and Dose PEG-IFN + RBV SVR Genotype 1: LVL +
HVL
Hadziyannis SJ et al., Ann Intern Med 2004;140:355
41
52 55
65
16
26
36
47
0
10
20
30
40
50
60
70
80
90
100
51 71 60 85 50 47 190 186
Pat
ient
s %
Low Viral Load High Viral Load
24-LD24-SD48-LD48-SD
SVR Genotype 1
Compensated Cirrhosis (Genotype 1)SVR Rates: PEG IFN + RBV
Hadziyannis et al., Ann Intern Med 2004;140:346-355
Early Virologic Response
EVR by Genotype
Genotype 1
EVR*
66%
SVR
63%
Genotype 2 or 3
EVR*
95%
SVR
86%
SVR
63%
* HCV RNA neg or >2 log drop at week 12
Manns et al, Lancet 2001
Treatment Algorithm
HCV Infection
EVR
Continue
Treatment
No
EVR
Mild
Disease
Advanced
Fibrosis
Stop
Treatment
Maintenance
Therapy?
Determinants of Non-Response
Treatment
Dose
Duration
Adherence
Disease
Cirrhosis
Co-infection
Host Factors
Race
Renal failure
Immune status
Viral Factors
Genotype
Viral load
Resistance
Treatment
Failure
Overlapping HCV & HIV Epidemics
40 million170 million
10 million
Co-infected
HIV HCV
HIV and Fibrosis Progression
Benhamou et al. Hepatology 1999;30:1054-8.
4
3
2
1
0
403020100
Duration of HCV Infection (Years)
Fib
rosi
s G
rad
es
(ME
TA
VIR
)
HIV+ (n = 122)
Matched Controls (n = 122)
Simulated Controls (n = 122)
Increase with CD4 <200/mm3 EtOHAge
RIBAVIC: SVR
27%20% 17%
6%
44%43%
0%
20%
40%
60%
80%
100%
% o
f pat
ient
s
All, n=205/207 Genotypes 1,4,n=125/129
Genotypes 2,3,5,n=80/76
PEG-IFN + RBV, n=205
IFN + RBV, n=207
Carrat F. et al, JAMA 2004
† P<0.047 vs. IFN + RBV* P=0.006 vs. IFN + RBV
*
†
Response by Treatment Group, ITT
52%
30%
44%
21%
0%
20%
40%
60%
80%
100%
% o
f pat
ient
s
VR SVR
PEG-IFN + RBV (n=52) IFN + RBV (n=43)
P=0.033P=0.017
Laguno M. et al, AIDS 2004, 18: F27–F36
Response in HCV Genotypes 1,4
41%
11%
38%
7%
0%
20%
40%
60%
80%
100%
% o
f pat
ient
s
VR SVR
PEG-IFN + RBV (n=32) IFN + RBV (n=27)
P=0.011
P=0.007
Laguno M. et al, AIDS 2004, 18: F27–F36
Response in Genotype 2-3, ITT
68% 67%
53%47%
0%
20%
40%
60%
80%
100%
% o
f pat
ient
s
VR SVR
PEG-IFN + RBV (n=19) IFN + RBV (n=15)
P=0.914
P=0.730
Laguno M. et al, AIDS 2004, 18: F27–F36
Response by Degree of Fibrosis
49%
21%
33%
23%
0%
20%
40%
60%
80%
100%
SV
R %
of p
atie
nts
0-2 (n=66) 3-4 (n=34)
PEG-IFN + RBV (n=52) IFN + RBV (n=43)
P=0.019P=0.549
Laguno M. et al, AIDS 2004, 18: F27–F36
African-Americans vs. Caucasians
0
10
20
30
40
50
60
Muir et al Jeffers et al
Caucasians
African-American
52%
19%
39%
26%
SV
R (
%)
Muir et al., N Engl J Med 2004;350:2265-71Jeffers et al., Hepatology 2004;39:1702-8
“Difficult to Treat” Hepatitis C
• Optimize Therapy: – Maintain adherence– Manage side effects– Tailor duration of Rx to virologic pattern of response
• Strategies for Non Responders: – Preventive (BMI, stop alcohol and smoking)– ? Maintenance IFN therapy– Clinical trials
Retreatment of Non-Responders
Favourable Unfavourable
Prior Therapy IFN Mono Combination
Prior Response
Relapse/Partial Null
Genotype 2 or 3 1
HCV RNA Low High
Race Caucasian
Asian
African-
American
Adherence Poor Complete
Effect of IFN Therapy on Inflammation (3010 Paired Biopsies)
0
10
20
30
40
50
60
70
80
90
% P
atie
nts
NR (N=1452) Rel. (N=464) SVR (N=1094)
ImprovedStabilizedWorsened
* P<0.001 vs, Relapsers and NR
*
Poynard et al, Gastro 2002
Follow-Up for SVR
• Noncirrhotic patients may be discharged from clinic
• Cirrhotic patients require annual U/S and possible OGD– Continue to follow
Follow-Up for Non-Responders
• Clinic visit and bloodwork every 6 months
• U/S and OGD for those with cirrhosis• Clinical trials
– Retreatment with different IFN– Protease or polymerase inhibitors– Antifibrotic treatment
• Serial liver biopsy every 3-5 years
Coming Soon
• New oral antiviral agents– Protease inhibitors (NS3/4A)– Polymerase inhibitors (NS5B)– Ribavirin analogues– Caspase inhibitors
• Treatment of nonresponders• Noninvasive testing for hepatic fibrosis
Summary
• Chronic hepatitis C infection is common– Burden of liver disease is staggering– Risk of cirrhosis, HCC and need for OLTx– Often silent until end stage complications
• HCV is treatable and often curable– Treat before onset of cirrhosis– Re-evaluate ‘difficult-to-treat’ patients
• Normal ALT• HIV/HCV coinfected• Nonresponders/ relapsers
Management of Chronic Hepatitis C
Scott K. Fung, MD, FRCPC
Division of Gastroenterology
ID/ Micro Seminar
November 30, 2007
Canadian Data (Transfused 1986-1990)
Krahn et al., Med Dec Making 2004;24:26
95% Mean Standard
ConfidenceValue Deviation
Interval20-yr probability
of cirrhosis 13.9 150-44Lifetime probability
of cirrhosis 26.2 190-6420-yr probability
of liver death 2.5 280-8Lifetime probability
of liver death 12.3 720-27
Obesity and Hepatic Fibrosis
OR
Variable ALT markedly ALT elevated
Age at infection>25 1.37 1.11
BMII 25 3.05 8.04
Ortiz, et al., Am J Gastroenterol 2002:97;2412
Cumulative Probability for Decompensation in Compensated HCV-Cirrhosis
Hu et al., Hepatology 1999;29:1313
No. at risk: 106 97 81 54 32 15
05
101520253035404550
0 6 12 18 24 30 36 42 48 54 60 66 72
follow-up length (months)
pro
bab
ility
(%
)
HCV Genotypes
1
4
65
2
3
Influence of Dose Reduction on12 wk EVR (HCV RNA-ve or >2 logs)
EVRPEG-IFN wk 12 RBV wk 12
n %
> 80% received > 80% received 324 80*
< 80% received 3 60
< 80% received > 80% received 38 70*
< 80% received 15 33
*P < 0.001
Davis et al., Hepatology 2003;38:648
Effect of IFN Therapy on Fibrosis
0
10
20
30
40
50
60
70
% P
atie
nts
NR (N=1452) Rel. (N=464) SVR (N=1094)
ImprovedStabilizedWorsened
*
* P<0.001 vs, Relapsers and NR