Management of Chronic Hepatitis C Scott K. Fung, MD, FRCPC Division of Gastroenterology ID/ Micro Seminar November 30, 2009.

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