SCREENING AND TREATMENT OF

HEPATITIS CJack R. Wands, MD

Jeffrey and Kimberly Greenberg - Artemis and Martha Joukowsky, Professor in Gastroenterology

and Professor of Medical Sciences, Director, Division of Gastroenterology and Liver Research

Center, Brown University

Risk of HCC DevelopmentFo

ld In

crea

se R

isk

of H

CC

Alcoholic Cirrhosis

PBC Auto-immune CAH

Wilson's Disease

HBV HCV HBV + HCV0

20

40

100

120

140

160

Liver Cancer

ObjectivesA. HCV

1. Virology, clinical and pathologic features of acute and chronic HCV infection.

2. Current concepts on treatment and clinical expected outcome.

3. Viral/cellular protein interactions as a feature of malignant transformation.

HCV Genome

HCV Genotypes Are Important in Response to Treatment with INF and Ribavirin

HCV Genotype

USA Population

Response Rate

1A and 1B 80% 50%2 5% 80%3 5% 80%4 5% 50%

5, 6 2% ?

World Map Illustrating the Prevalence of HCV Antibodies in Blood Donors

Natural Course of Chronic HCV Infection

Screening for HCV Infection

1. Anti-HCV antibodies – Does not exclude past infection and immunity.

1. HCV RNA by qRT-PCR – Gold standard and gives viral load (copies HCV RNA/ml)

0.2

1.6

2.9

0.70.4

2

3.4

2.4

0.7

1.8

6.1

2.9

0

1

2

3

4

5

6

7

<19 20-29 30-49 >50Age group

Prev

alen

ce (%

)

CaucasianMexicanAfrican

Prevalence of antibody to HCV in the US

Alter MJ, NEJM 1999;341:556-562Anti HCV+ =1.8% = 3.9 millionsHCV RNA + = 1.5% = 2.7 millions

0

100

200

300

400

500

600

700

800

900

2 4 6 8 10 12 24 1 2 3 4 5 6

ALT

(U/L

)

Anti HCV

Symptoms

HCV RNA

ALT

102

104

106

108

HC

V RN

A (IU/m

l)

Weeks Years

HCV RNA - + + + + + + + + + - - - - - - - - - - - - - - - - - - -

Acute Resolving Hepatitis C

Time After Exposure

Acute Hepatitis C Evolves into Chronic Infection

0

100

200

300

400

500

600

700

800

900

2 4 6 8 10 12 24 1 2 3 4 5 6

ALT

(U/L

)

Anti HCV

Symptoms

HCV RNA

ALT

102

104

106

108

HC

V RN

A (IU/m

l)

Weeks Years

HCV RNA - + + + + + + + + + - + + + + + + + + + + + + + +

Time After Exposure

0

1000

2000

3000

4000

5000

6000

7000

8000

1995 1996 1997 1998 1999 2000

Num

ber o

f pat

ient

s

HCV Other

Liver Transplant Waiting List in the U.S.

Kim W Hepatology 2002;36:S30-S34

1.4 1.61.9

2.4

3

0

1

2

3

4

1976-1980

1981-1985

1986-1990

1991-1995

1996-1998

case

s pe

r 100

,000

Incidence of Hepatocellular Carcinoma in the U.S.

Modified from El-Serag & Mason, NEJM 1999

Progression of Fibrosis in Chronic hepatitis C

- 123 patients withchronic hepatitis C- 2 liver biopsies without therapy- Mean 44 months- To better define natural progressionof fibrosis in HCV

Ghany MG, Gastroenterology 2003;124:97-104

Age at Initial Biopsy and Progression of Fibrosis

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

Patient Age at Initial Biopsy (Years)

31-45(n = 14) (n = 76) (n = 23) (n = 11)

< 30 46-59 > 60

-0.050.14

0.33 0.52

Mea

n ch

ange

in fi

bros

is s

core

/ yr

Ghany MG, Gastroenterology 2003;124:97-104

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

1.2

ALT at Initial Biopsy (Fold elevation)

1-2 x(n = 16) (n = 33) (n = 47) (n = 22)

Normal 2-5 x >5 x

0.05 -0.07 -0.12

0.96

Mea

n ch

ange

in fi

bros

is s

core

/ yr

ALT and Progression of Fibrosis

Ghany MG, Gastroenterology 2003;124:97-104

0

0.2

0.4

0.6

0.8

1

0-1 3-4 5-6, 10

Mea

n ch

ange

in fi

bros

is s

core

/ ye

ar

n=30 n=66 n=27Composite periportal inflammation and necrosis score (0-10)

.05

.19

.37

Periportal Inflammation and Progression of Fibrosis

Ghany MG, Gastroenterology 2003;124:97-104

Factors Associated With Fibrosis Progression

Age (at onset of infection).Gender: M>F.Alcohol: ?Low level consumption.Immune status: HIV, post OLT.Viral factors (-).Others: racial, genetic, heterozygous HFE, overweight/steatosis.

HCV infection

SpontaneousRecovery Chronic Hepatitis

Cirrhosis

Decompensation HCC

Death

15% 85%

15%

6% 4%

3.6%

Summary: Outcomes of HCV Infection

Di Bisceglie Hepatology 2000;31:1014

Progress in Therapy of Hepatitis C

16%

54%

6%

34%42% 39%

0

0.2

0.4

0.6

0.8

1

1.2

IFN 6 m IFN 12 m IFN/R 6 m IFN/R 12 m PegIFN 12m Peg/R 12m PI/Peg/R PI/Pol

80%

100%

I

Nucleotide Polymerase Inhibitor Sofosbuvir plus Ribavirin for Hepatitis C (N Engl J Med 2013)

Treatment Group Response Rate*Genotype 1 and 1B 84%Genotype 2 and 3 100%

*No side effects with SVR at 24 weeks.

Outcome of Sustained Virological Responders(SVR) with Histologically Avanced Hepatitis C

7.5 year follow-upDeath/liver transplantation - was 2.2% / 2.7% / for SVR vs. 21.3% / 27.2% for non-responders (NR)HCC was higher in NR vs. SVR (p<0.001)LFTs markedly improved in SVR

Conclusion…Patients with advanced HCV and cirrhosiswho achieved SVR had a marked reductionin death/liver transplantation and in liver-related morbidity/mortality, although theyremain at-risk for HCC and need to be in ascreening program.

SummaryA. HCV

1. RNA virus, high mutation rate, persistent viral infection common on exposure.

2. INFα + ribavirin induce SVR dependent on viral genotype and ± cirrhosis.

3. Major risk factor for HCC.