HCV: epidemiology and Natural History

Rifaat Safadi, M.D.

Liver & Gastroenterology Units Division of Medicine Jerusalem

The First GI conference in Palestine (20-22) May 2010

Viral Hepatitis
A
Source of virus
feces

E
feces

blood/ blood/ blood/ blood-derived blood-derived blood-derived body fluids body fluids body fluids percutaneous percutaneous percutaneous permucosal permucosal permucosal

Route of transmission

fecal-oral

fecal-oral

Chronicity
Prevention

no

yes

yes

yes

no

pre/postpre/postblood donor pre/postensure safe exposure exposure screening; exposure drinking immunization immunization risk behavior immunization; water modification risk behavior 1. Purcell R, et al. Proc Natl Acad Sci 1994; 91: 2401 2. Ryder S & Beckingham I. BMJ 2001; 322: 151 modification
3. WHO. Hepatitis C Fact Sheet no. 164. 2000

HCV viral structure

Envelope Nucleocapsid (core) protein

RNA genome

170 Million HCV carriers 3-4 MM new cases / year

WESTERN FAR EAST/ASIA EUROPE 60 M 9 M EASTERN MEDITERRANEAN 20M SOUTH EAST ASIA 30 M AFRICA 32 M

USA

4M

SOUTH AMERICA 10 M
WHO, 1999

AUSTRALIA 0.2 M

Prevalence of infection

>10%

2.510%

12.5%

WHO. Wkly Epidemiol Rec 2002; 77: 41

Number of HCV liver-related deaths expected to increase further in the US

Number of deaths
45 000 39 875 39 064 40 000 36 483 35 000 27 732 30 000 25 000 20 000 15 000 13 000 10 000 5 000 0 2000 2010 2020 2030 2040

Year

Davis G, et al. Liver Transpl 2003; 9: 331

HCV the major cause of liver transplantation today

37% of US liver transplant recipients in 2000 were HCV+ve
3500 3000 2500 2000 1500 HCV-related Other

1000 500
0 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 Year
Kim W. Hepatology 2002; 36: S30

Genotype prevalence varies according to geographic region

75% 1a, 1b
1a, 1b, 2, 3 4 3 4 1a, 1b, 2, 3 5 1a, 1b, 3 2, 1b 1a, 1b, 3, 6

1. Hoofnagle J. Hepatology 2002; 36: S21 2. Zein N. Clin Microbiol Rev 2000; 13: 223 3. Alter M, et al. N Engl J Med 1999; 341: 556

Sources of Infection With HCV

Sexual 15% Transfusion 10% (before screening) Occupational 4% 1% Nosocomial;

iatrogenic; perinatal

Unknown 10%

Source: Centers for Disease Control & Prevention

Posttransfusion Hepatitis C
30
% of Recipients Infected
All volunteer donors HBsAg

25 20 15 10 5 0 1965 1970 1975 1980 Year 1985

Donor Screening for HIV Risk Factors Anti-HIV ALT/Anti-HBc Anti-HCV Improved HCV Tests

1990

1995

2000

Adapted from HJ Alter and Tobler and Busch, Clin Chem 1997

Occupational Transmission of HCV

Average incidence 1.8% following needle stick from HCV-positive source
Associated with hollow-bore needles

Case reports of transmission from blood splash to eye; one from exposure to non-intact skin Prevalence 1-2% among health care workers
Lower than adults in the general population 10 times lower than for HBV infection

Mother-to-Infant HCV Transmission

Postexposure prophylaxis not available No need to avoid pregnancy or breastfeeding
Consider bottle feeding if nipples cracked/bleeding

No need to determine mode of delivery based on HCV infection status

Test infants born to HCV-positive women

>15-18 months old Consider testing any children born since woman became infected Evaluate infected children for CLD

HCV Testing Routinely Recommended

Based on increased risk for infection

Ever injected illegal drugs Received clotting factors made before 1987 Received blood/organs before July 1992 Ever on chronic hemodialysis Evidence of liver disease Population at risk

Based on need for exposure management

Healthcare, emergency, public safety workers after needle stick/mucosal exposures to HCV+ve blood Children born to HCV-positive women

Natural History of HCV

HCV Infection

Incubation period: Range 2-26 wks

20% Acute 80% Chronic

F0 ~ 25 - 30 yrs F1

F2
F3 ~ 1 - 5 yrs
Variceal bleeding Modified from Poynard

F4
Liver Failure HCC

Serologic Pattern of Acute HCV Infection with Recovery

Symptom s +/HCV RNA Titer
antiHCV

ALT

Normal 0 1 2 3 4 Months 5 6 1 2 3 Years 4

Time after

Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection

antiHCV

Symptom s +/HCV RNA Titer

ALT

Normal 0 1 2 3 4 Months 5

2 3 Years

Time after

Extra Hepatic Manifestations of

Chronic HCV Infection
Fatigue, Depression Sjogren Syndrome Cryoglobulinemia (frequent): Glumerolunephretis & Nephrotic syndrome Vasculitis Neuropathy Arthralgia & arthritis

Porphyria Tarda
High association with lymphoma

Hepatic Fibrosis is the Livers Wound Healing Response

Hepatitis Viruses Inherited Metabolic Disorders

Alcohol

FIBROSIS & HCC

Drugs

Excess Vitamin A

Cholestatic Disorders

Immune Disorders

What is Fibrosis & Cirrhosis?

Fibrosis - reversible accumulation of scar fibrillar collagens sulfated proteoglycans glycoproteins

Cirrhosis - scar & distortion of liver architecture & nodule formation

Hepatic Stellate cells Perisinusoidal cells of Normal Liver

Friedman and Arthur, Science & Medicine, in press

Hepatic Stellate cell Activation A Central Event in Liver Fibrosis

Normal Liver

Activated Myofibroblast with Fibrosis

Friedman SL and Arthur, Science and Medicine, 2002

Multiple Sources of Myofibroblasts

Friedman SL and Arthur, Science and Medicine, 2002

Pathways of Stellate cell Activation

Initiation
INJURY
Oxidative Stress, cFn

Perpetuation
Proliferation Contractility

PDGF

ET-1

Fibrogenesis
TGF-b1

MMP-2

PDGF, MCP-1

Matrix Degradation

REVERSION?
MCP-1 PDGF, Serum

RESOLUTION
APOPTOSIS?

HSC Chemotaxis

WBC Chemoattraction Friedman SL, J Biol Chem, 2000

Retinoid Loss

Bataller & Brenner. JCI 2005; 115: 209218

Immune Modulation of HSC Cirrhosis Progression

Lymphocyte Subsets
1) Mice CD8 cells stimulate fibrogenic activity. 2) CD4 significantly decreased post fibrosis
3) In IL-10 TG mice, the anti proliferative effect of IL-10 on CD8 subset mediate its anti fibrogenic response. Hepatic Fibrosis
CD8

HSC

Safadi R. et al, Gastroenterology, 2004; Safadi-R, et al, J Immunol. 2005; Safadi R. et al, Am J Physiol Gastrointest Liver Physiol. 2006 Safadi R. et al, Am J Gastroenterology. 2007 Safadi R. et al, Clin Immunol. 2006 Safadi R. et al, Hepatology. 2008

NK cells exert an anti fibrotic effect by direct killing of activated HSC

Safadi, et al, J Hep, 2006
Hepatic Fibrosis

In vitro LX2 & PBL Adhesion (immune synapse)

Safadi, et al Hepatology 2008; 48: 963-977

Phagocytosis

Sinusoidal Changes during Liver Injury

Normal Liver
Hepatocytes

Liver Injury
Loss of Hepatocyte Microvilli

Space of Disse

Hepatic Sinusoid
Kupffer Cell Endothelial Cell Deposition of Scar Kupffer Cell Matrix Activation Loss of Fenestrate

Quiescent HSC

Activated HSC

Staging of Fibrosis

Metavir Scoring System for Fibrosis

F1
F3

F2
F4
Modified from Poynard

Sampling Error of Liver Biopsy

Fibrosis Score: 65%

Fibrosis Score: 15%

Courtesy of M Pinzani and A Burt

Fibrosis Content Is Not Linear with tes Metavir Stage lonne 1

Area ofpar : Colonne 1 (%) (27 patients) METAVIR Eclat fibrosis
30 25 20
Units

Graphe en botes

STAGE F4

Area of fibrosis by image analysis (mean + SEM) 2 + 0.14 3.4 + 0.25 5.8 + 1.7 14.7 + 3.77 25.1 + 4.44

F0
F0 F1 F1

15 10 5 0

F3 F2

F2
F3

F2

F3 F4 F4

F0

F1

Colonne 2

Colonne 2

from Bedossa et al, Hepatology 6:1149, 2003

Surrogate markers of hepatic fibrosis

FIBROTEST: apoA1, haptoglobin, 2MG, GGT, bilirubin Fibroscan:

Effective at identifying patients with mild fibrosis Large percentage within indeterminate range ? Enhanced by incorporating ECM markers

FIBROTEST

Fibrosis Assessment with Fibroscan

Measurements are performed on the right lobe of the liver in intercostal position The patient is lying supine with the right arm placed behind his head Examination time is about 5 minutes Inter observer reproducibility CVS < 10 %,

L = 4 cm = 1 cm

Courtesy of M. Ziol

Transient Elastography for Assessment of Hepatic Fibrosis

Area ofpar : Colonne 1 (%) (27 patients) Eclat fibrosis
100

Graphe en botes

Patients distribution 22 17 14

30
9

25
Elasticity (kPa) Logarithmic scale

F4
F0 F1

20
Units
10

15 10 5

F3 F2

F2 F3 F4

1 F0 F1 F2 F3 F4

F0

F1

Fibrosis Grade

0 Colonne 2

Measures U/S and elastic waves

Correlates with stiffness R= 0.71 ROC= 0.88 for sign fibrosis > F2 ROC= 0.99 for cirrhosis (F4)

Sandrin et al, Ultrasound in Biol Med,2003

Cirrhosis is not a Single Stage

METAVIR stage:

F1-F3
HVPG: Clinical: Stage:

F4
>5 10
None

12
Varices formation

20

None

Biology:

Compensated Compensated Non-cirrhotic (Stage 1) (Stage 2) Scar Thick Fibrogenesis X-linking scar & small & Neovasc. Nodule size nodules

Development of Worse ascites,VH, HE prognosis in VH Decompensated (Stages 3/4) Insoluble scar

With contributions from Pinzani M, Garcia-Tsao G.

Portal Hypertension:
Varices Splenomegally Ascites

Factors for progressive fibrogenesis

Progression of Liver Fibrosis in HCV

F METAVIR

N=1157 Rapid Intermediate

Slow fibroser

Duration (years)
Poynard et al. Lancet 1997; 349: 825

Genetic and nongenetic factors associated with fibrosis progression in different types of chronic liver diseases Genetic liver nongenetic Candidate genes with Candidate genes (full name) factors associated fibrosis progression in different types ofNongenetic factors chronic liver diseases Type of and disease Type of liver disease Candidate genes Candidate genes (full name) Nongenetic factors Type ofHCV infection Candidate genes Candidatehemochromatosis gene Nongenetic factors Chronic liver disease HFE Hereditary genes (full name) Alcohol intake Chronic HCV infection HFE Hereditary hemochromatosis gene Alcohol intake and/or HBV Angiotensinogen Angiotensinogen Coinfection HIV Chronic HCV infection HFE 1 Hereditary hemochromatosis1 Alcoholtime HIV and/or HBV Angiotensinogen Angiotensinogen Coinfection of TGFTransforming growth factor gene Age at intake acute infection Angiotensinogen Angiotensinogen Coinfection HIV and/or HBV TGF-1 Transforming growth factor 1 Age at time of acute infection TNF- Tumor necrosis factor Liver transplantation TGF-1 Transforming growth factor 1 Age at time of acute infection TNFTumor necrosis Liver transplantation ApoE Apolipoprotein Efactor Diabetes mellitus TNF- Tumor necrosisEfactor Liver transplantation ApoE Apolipoprotein Diabetes mellitus MEH Microsomal epoxide hydroxylase No response to therapy ApoE Apolipoprotein E Diabetes mellitus MEH Microsomal epoxide hydroxylase No response to therapy MCP-1 Monocyte chemotactic protein type 1 MEH Microsomal epoxide hydroxylase 1 No response to therapy MCP-1 Monocyte chemotactic protein type 2 MCP-2 MCP-1 V Monocyte chemotactic protein type 1 MCP-2 2 Factor Factor V (Leiden) MCP-2 V Monocyte chemotactic protein type 2 Factor Factor V (Leiden) Factor V Factor V (Leiden) Alcohol-induced IL-10 Interleukin 10 Alcohol intake Alcohol-induced IL-10 10 Alcohol intake IL-1 Interleukin 1 Episodes of alcoholic hepatitis Alcohol-induced IL-10 Interleukin 10 Alcohol intake IL-1 1 Episodes of alcoholic hepatitis ADH Alcohol dehydrogenase IL-1 Interleukin 1 Episodes of alcoholic hepatitis ADH Alcohol dehydrogenase ALDH Aldehyde dehydrogenase ADH Alcohol dehydrogenase ALDH Aldehyde dehydrogenase CYP2E1 cytochrome P450, ALDH Aldehyde dehydrogenase CYP2E1 cytochrome P450, (family 2, subfamily e, polypeptide 1) CYP2E1 cytochrome P450, e, (family necrosis factor polypeptide 1) TNF- Tumor 2, subfamily (family necrosis factor antigen type 4 TNF- Tumor 2, subfamily e, CTLA-4 Cytotoxic T lymphocytepolypeptide 1) TNF- Tumor necrosis factor antigen type 4 CTLA-4 Cytotoxic T lymphocyte TAP2 Transporter-associated CTLA-4 Cytotoxic T lymphocyte antigen type 4 TAP2 Transporter-associated antigen-processing type 2 TAP2 Transporter-associated dismutase antigen-processing type MnSOD Manganese superoxide 2 antigen-processing typedismutase MnSOD Manganese superoxide 2 MnSOD Manganese superoxide dismutase NASH HFE Hereditary hemochromatosis gene Age NASH HFE Hereditary hemochromatosis gene Age Angiotensinogen Angiotensinogen Severity of obesity NASH HFE 1 Hereditary hemochromatosis1 gene Age Angiotensinogen Angiotensinogen Severity of obesity TGFTransforming growth factor Diabetes mellitus Angiotensinogen Angiotensinogen Severity of obesity TGF-1 Transforming growth factor 1 Diabetes mellitus TGF-1 Transforming growth factor 1 Diabetes mellitus Hypertriglyceridemia Hypertriglyceridemia Hypertriglyceridemia PBC IL-1 Interleukin 1 PBC IL-1 Interleukin 1 TNF- Tumor necrosis factor PBC IL-1 Interleukin 1 Efactor TNFTumor necrosis ApoE Apolipoprotein TNF- Tumor necrosisEfactor ApoE Apolipoprotein Autoimmune hepatitis HLA-II HLA type II haplotypes Type II autoimmune hepatitis ApoE Apolipoprotein E Autoimmune hepatitis HLA-II HLA type II haplotypes Type II autoimmune hepatitis No response to therapy Autoimmune hepatitis HLA-II HLA type II haplotypes Type II autoimmune hepatitis No response to therapy No response to therapy

Factors accelerating progression of chronic HCV

Previous & concurrent alcohol consumption1 Older age at time of infection (>40 years)1 Male gender1 Other comorbidities:
HIVHCV co-infection2 HBVHCV co-infection3 Obesity
1. Poynard T, et al. Lancet 1997; 349: 825 2. Di Martino V, et al. Hepatology 2001; 34: 1193 3. Lana R, et al. Med Clin. (Barc). 2001; 117: 607

Fibrosis progression occurs in patients with normal ALT

100
80 Elevated ALT

60
40 20 0 2 4 6 8

p=0.06 Normal ALT

10

12

Years

Hui C-K, et al. J Hepatol 2003; 38: 511

77% of patients with normal ALT have some degree of liver damage
Portal 26% Bridging 6%

Cirrhosis 6%

Portal 24%

Bridging 16%

Cirrhosis 22%

No Fibrosis 23%

Mild 39%

No Fibrosis 19%

Mild 19%

Normal ALT

Elevated ALT
Shiffman M, et al. J Infect Dis 2000; 182: 1595

Older patients have a higher probability of progression to cirrhosis

Probability of progression to cirrhosis 1.00 0.75 >50 years 3140

4150
0.50 0.25 0.00

2130
<21

10 20 30 Duration of infection (years)

40

Adapted from Poynard T, et al. J Hepatol 2001; 34: 730

25-hydroxyvitamin-D in ethnic groups

SVR 49%

nmol/L

SVR 34% SVR 19%

Non Hispanic white

Mexican American
Non Hispanic Black

Age (years)
From the National Health & Nutrition Examination Survey (NHANES) 20002004 by racial or ethnic group. Am J Clin Nutr 2008;88(suppl):558S 64S

Low vitamin D serum level is related to severe fibrosis & low responsiveness to IFN-based therapy in genotype 1 chronic HCV

Antonio Crax et al., Hepatology. 2010

In Vitro: Vitamin D decreased Hepatic Stellate Cell activation

60000 50000 40000 30000 20000 10000 0 0 1/1000 1/500 25 OH- VIT D 1/100 Alpha Smooth Muscle Actin INT.

Safadi R. et al., Unpublished data

Vitamin D serum levels before & 12 weeks after initiation of antiviral treatment
60
* P<0.001

50

Vitamin D Levels ( ng/ml)

40

SVR % 100

* P<0.001
15/17 Pts. 88%

30

20

80
60 40

10

Vitamin D levels Before

Vitamin D levels after

5/12
Vitamin D + SOC SOC

Pts.

20
0

42%
Abu Much et al., EASL 2010, Vienna

Metabolic Syndrome & Chronic HCV

Steatosis in HCV
NASH (18%) No steatosis (41%)

Steatosis (41%)
1. 2. 3. 4. Younossi ZM, et al. J Clin Gastroenterol. 2004;38:705-709. Asselah T, et al. Gut. 2006;55:123-130. Browning JD, et al. Hepatology. 2004;40:1387-95. Nomura H, et al. Jpn J Med. 1988;27:142-149.

HCV & Diabetes Mellitus

Reference (location) Mason et al, USA Caronia et al, Italy Knobler et al, Israel Zein et al, USA Labropoulou-Karatza et al, Greece Allison et al, USA Grimbert et al, France El-Zayedi et al, Egypt Mehta et al, USA Mangia et al, Italy Fraser et al, Israel Wang et al, Taiwan Arao et al, Japan Lecube et al, Spain Thuluvath et al, USA Ozyilken et al, Turkey Zein et al, USA Year 1999 1999 2000 2005 1999 1994 1996 1998 2000 1998 1996 2003 2003 2004 2003 1996 2000 Cohort Size 1117 1332 133 179 108 100 304 591 9841 385 168 2327 866 642 291 427 204 Prevention Prevalenc Prevalence of of DM in e of DM in DM in HCV (%) controls HBV (%) (%) 21 NA 12 23.6 33 14.5 45.3 50 24 25.4 3x more likely 30.1 39.1 31 20.9 32 19.6 26.2 22 NA 5.6 7.8 11.3 9 9 11.2 8 9.7 NA NA NA 12 11.5 1.5 8.4 9.4 12 NA NA NA NA NA 8% 25 2.5 12.7 11.9 NA NA 9.2 NA

DM = diabetes mellitus; HBV = hepatitis B virus; NA = not applicable

Harrison SA. J Clin Gastroenterol 2006;40:6876

Metabolic Syndrome, Steatosis & HCV

Insulin Resistance in HCV[1] 3 P = .002 Mean HOMA-IR Score Patients With Steatosis (%) 100 80 60 40 20 16 P = .02 40 Steatosis in HCV Patients[2]

0
HCV-Infected Patients (n = 121) Healthy Controls (n = 137)

0
Nonobese (n = 91)
*BMI 30.

Obese* (n = 42)

1. Hui JM et al. Gastroenterology 2003;125:1695-1704. 2. Cesario K, et al. J Hepatol. 2005;42(suppl 2):201-202.

HCV Viral Load associated with IR 55.3% versus 42.3% for LVL, p=0.009
HCV RNA (log IU/mL)
7.0

IR independently associated with significant fibrosis

15

6.5

12

6.0

HOMA-IR
<2 2-4 HOMA-IR >4

5.5

5.0

4.5

4.0

F0-1 F2 F3 F4 Fibrosis (METAVIR)

Moucari et al, Gastroenterology 2008;134:416-423.L

Is Cirrhosis Reversible?

Pegylated IFNs
PEG-Intron1

PEGASYS2

WEIGHT-based dosing Lyophilized powder that needs to be reconstituted before each injection

FIXED dose Dispensed as a stable solution ready for injection

1. PEG-Intron. PDR . 56th ed. 2002. 2. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288.

Reversibility of Cirrhosis Following Treatment of HCV

No. Patients
Poynard et al, Gastroenterology 2002; 122:1303-1313

Thank You
Rifaat Safadi M.D