HCV_The First GI Conference in Palestine

8/2/2019 HCV_The First GI Conference in Palestine

1/58

Rifaat Safadi, M.D.Liver & Gastroenterology Units

Division of MedicineJerusalem

HCV: epidemiology and

Natural History

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


2/58

Source ofvirus

feces blood/blood-derived

body fluids

blood/blood-derived

body fluids

blood/blood-derived

body fluids

feces

Route oftransmission

fecal-oral percutaneouspermucosal

percutaneouspermucosal

percutaneouspermucosal

fecal-oral

Chronicity no yes yes yes no

Prevention pre/post-exposure

immunization

pre/post-exposure

immunization

blood donorscreening;

risk behaviormodification

pre/post-exposure

immunization;risk behavior

modification

ensure safedrinkingwater

Viral HepatitisA DB C E

1. Purcell R, et al. Proc Natl Acad Sci 1994; 91: 2401

2. Ryder S & Beckingham I. BMJ 2001; 322: 1513. WHO. Hepatitis C Fact Sheet no. 164. 2000


3/58

HCV viral structureEnvelope

Nucleocapsid (core) protein

RNA genome


4/58

USA

4 M

SOUTH

AMERICA

10 M

AFRICA

32 M

EASTERNMEDITERRANEAN

20M

SOUTH EAST ASIA30 M

AUSTRALIA0.2 M

WHO, 1999

WESTERNEUROPE

9 M

FAR EAST/ASIA

60 M

170 Million HCV carriers

3-4 MM new cases / year


5/58

Prevalence of infection

>10% 2.510% 12.5%

WHO. Wkly Epidemiol Rec 2002; 77: 41


6/58

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

02000 2010 2020 2030 2040

Num

berofdeaths

Year

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

5 00010 000

15 000

20 000

25 00030 000

35 000

40 000

45 000

13 000

27 732

36 48339 875 39 064


7/58

HCV the major cause of livertransplantation today

Kim W. Hepatology 2002; 36: S30

Year

37% of US liver transplant recipients in 2000 were HCV+ve

1991 1992 1993 1994 1995 1996 1997 1998 1999 20000

500

1000

1500

2000

2500

3000

3500HCV-related Other


8/58

Genotype prevalence variesaccording to geographic region

75%1a, 1b

1a, 1b, 2, 3

4

5

4

1a, 1b,

2, 3

3

1a, 1b,3, 6

1a, 1b, 3

2, 1b

1. Hoofnagle J. Hepatology 2002; 36: S21

2. Zein N. Clin Microbiol Rev 2000; 13: 2233. Alter M, et al. N Engl J Med 1999; 341: 556


9/58

1% Nosocomial;

iatrogenic; perinatal

Unknown 10%

Transfusion 10%(before screening)

Source: Centers for Disease Control & Prevention

Occupational 4%

Sexual 15%

Sources of Infection With HCV


10/58

Posttransfusion Hepatitis C

0

5

10

15

20

25

30

1965 1970 1975 1980 1985 1990 1995 2000

Year

%o

fRecipien

tsInfected

All volunteer donors

HBsAg

Donor Screening for HIV Risk FactorsAnti-HIV

ALT/Anti-HBc

Anti-HCV

Improved HCV Tests

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


11/58

Occupational Transmission of HCV

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

Case reports of transmission from bloodsplash to eye; one from exposure to non-intactskin

Prevalence 1-2% among health care workers Lower than adults in the general population 10 times lower than for HBV infection


12/58


13/58

HCV Testing Routinely Recommended

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

Healthcare, emergency, public safety workers afterneedle stick/mucosal exposures to HCV+ve blood

Children born to HCV-positive women

Based on increased risk for infection

Based on need for exposure management


14/58

Natural History of HCV

20% Acute

Variceal bleeding

Liver Failure

HCC

F4F3F2F1F0

80% Chronic

HCV Infection

Modified from Poynard

~ 25 - 30 yrs

~ 1 - 5 yrs

Incubation period: Range 2-26 wks


15/58

Serologic Pattern of Acute HCV Infection withRecovery

Symptoms +/-

Time after

Titer

anti-HCV

ALT

Normal

0 1 2 3 4 5 6 1 2 3 4YearsMonths

HCV RNA


16/58

Serologic Pattern of Acute HCV Infection withProgression to Chronic Infection

Symptoms +/-

Time after

Titer

anti-HCV

ALT

Normal

0 1 2 3 4 5 6 1 2 3 4YearsMonths

HCV RNA


17/58

Extra Hepatic Manifestations of

Chronic HCV Infection

Fatigue, Depression

Sjogren Syndrome

Cryoglobulinemia (frequent):

Glumerolunephretis & Nephrotic syndrome

Vasculitis

NeuropathyArthralgia & arthritis

Porphyria Tarda

High association with lymphoma


18/58

Hepatic Fibrosis is the LiversWound Healing Response

HepatitisViruses Alcohol

InheritedMetabolicDisorders

ExcessVitamin A

CholestaticDisorders

ImmuneDisorders

DrugsFIBROSIS & HCC


19/58

What is Fibrosis & Cirrhosis?

Fibrosis- reversible accumulation of scar fibrillar collagens

sulfated proteoglycans

glycoproteins

Cirrhosis- scar & distortion of liver architecture

& nodule formation


20/58

Hepatic Stellate cells -Perisinusoidal cells of Normal Liver

Friedman and Arthur, Science & Medicine, in press


21/58

Hepatic Stellate cell Activation -A Central Event in Liver Fibrosis

Normal LiverActivated Myofibroblast

with Fibrosis

Friedman SL and Arthur, Science and Medicine, 2002


22/58

Multiple Sources of Myofibroblasts

Friedman SL and Arthur, Science and Medicine, 2002

P th f St ll t ll A ti ti


23/58

RESOLUTION

APOPTOSIS?

REVERSION?

INJURY

PDGF ET-1

TGF-b1

PDGF,MCP-1

PDGF,Serum

MCP-1

Proliferation

Fibrogenesis

HSCChemotaxis

Retinoid LossWBC

Chemoattraction

MatrixDegradation

OxidativeStress,cFn

MMP-2

Initiation Perpetuation

Contractility

Pathways of Stellate cell Activation

Friedman SL, J Biol Chem, 2000


24/58

Immune Modulation of HSC

B

ataller&Brenner.JCI

2005;115:

209

218

CirrhosisProgre

ssion


25/58


26/58

NK cells exert an anti fibrotic effect bydirect killing of activated HSC

Safadi, et al, J Hep, 2006

Hepatic

Fibrosis

In vitro LX2 & PBL


27/58

In vitroLX2 & PBL

Adhesion

(immunesynapse)

Phagocytosi

s

Safadi, et alHepatology2008; 48:

963-977


28/58

Normal Liver Liver Injury

Quiescent

HSC

HepaticSinusoid

Hepatocytes

ActivatedHSC

Depositionof ScarMatrix

Space of Disse

KupfferCell

EndothelialCell

Loss of Hepatocyte Microvilli

Loss ofFenestrate

Kupffer Cell

Activation

Sinusoidal Changes during Liver Injury


29/58

Staging ofFibrosis


30/58

Metavir Scoring System for Fibrosis

F1

F3

F2

F4

Modified from Poynard

Sampling Error of Li er Biops


31/58

Sampling Error of Liver Biopsy

Fibrosis Score: 65%

Fibrosis Score: 15%Courtesy of M Pinzani and A Burt

Fibrosis Content Is Not Linear with


32/58

METAVIRSTAGE 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

Fibrosis Content Is Not Linear withMetavir Stage

0

5

10

15

20

25

30

F4

F3

F2

F1

F0

F0F1

F2

F3

F4

from Bedossa et al,Hepatology 6:1149, 2003

Area of fibrosis (%) (27 patients)

F4

F3

F2

F1

F0


33/58

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


34/58

FIBROTEST


35/58

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


36/58

Sandrin et al, Ultrasound in Biol Med,2003

Transient Elastography for Assessment ofHepatic Fibrosis

Measures U/S and elastic wavesCorrelates with stiffness

R= 0.71

ROC= 0.88 for sign fibrosis > F2

ROC= 0.99 for cirrhosis (F4)

1

10

100

F0 F1 F2 F3 F4

Fibrosis Grade

Elas

ticity

(kPa)

Logarithmicscale

Patients distribution

5 22 17 14 9

0

5

10

15

20

25

30

F4

F3

F2

F1

F0

F0F1

F2

F3

F4

Area of fibrosis (%) (27 patients)

Cirrhosis is not a Single Stage


37/58

HVPG:

Clinical:

Stage:

Biology:

METAVIR stage:

F1-F3F4

None

Non-cirrhotic

Fibrogenesis

& Neovasc.

None

Compensated(Stage 1)

ScarX-linking

Nodule size

> 5 10

Varices

formation

Compensated

(Stage 2)

Thickscar & small

nodules

Worse

prognosis

in VH

20 12

Development of

ascites,VH, HE

Decompensated

(Stages 3/4)

Insoluble scar

With contributions from Pinzani M, Garcia-TsaoG.

Cirrhosis is not a Single Stage


38/58

Portal Hypertension:

Varices

Splenomegally

Ascites

f


39/58

Factors forprogressivefibrogenesis


40/58

F METAVIR

Duration (years)

Rapid

Intermediate

Slow fibroser

Poynard et al. Lancet 1997; 349: 825

N=1157

Progression of Liver Fibrosis in HCV

Genetic andGenetic and nongeneticnongenetic factors associated with fibrosis progression in different typesfactors associated with fibrosis progression in different types of chronic liver diseasesof chronic liver diseases


41/58

Type of liver disease Candidate genes Candidate genes (full name) Nongenetic factors

Chronic HCV infection HFE Hereditary hemochromatosis gene Alcohol intakeAngiotensinogen Angiotensinogen Coinfection HIV and/or HBVTGF-1 Transforming growth factor 1 Age at time of acute infectionTNF- Tumor necrosis factor Liver transplantationApoE Apolipoprotein E Diabetes mellitusMEH Microsomal epoxide hydroxylase No response to therapyMCP-1 Monocyte chemotactic protein type 1MCP-2 Monocyte chemotactic protein type 2Factor V Factor V (Leiden)

Alcohol-induced IL-10 Interleukin 10 Alcohol intakeIL-1 Interleukin 1 Episodes of alcoholic hepatitis

ADH Alcohol dehydrogenase

ALDH Aldehyde dehydrogenase

CYP2E1 cytochrome P450,(family 2, subfamily e, polypeptide 1)

TNF- Tumor necrosis factor CTLA-4 Cytotoxic T lymphocyte antigen type 4

TAP2 Transporter-associatedantigen-processing type 2

MnSOD Manganese superoxide dismutase

NASH HFE Hereditary hemochromatosis gene AgeAngiotensinogen Angiotensinogen Severity of obesityTGF-1 Transforming growth factor 1 Diabetes mellitus

PBC IL-1 Interleukin 1TNF- Tumor necrosis factor A oE A oli o rotein E

Autoimmune hepatitis HLA-II HLA type II haplotypes Type II autoimmune hepatitis

No response to therapy

Factors accelerating


42/58

Factors acceleratingprogression 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: 8252. Di Martino V, et al. Hepatology 2001; 34: 1193

3. Lana R, et al. Med Clin. (Barc). 2001; 117: 607

Fibrosis progression occurs


43/58

Fibrosis progression occursin patients with normal ALT

2 4 6 8 10 12 Years0

20

40

60

80

100

Normal ALT

ElevatedALT

p=0.06

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

77% of patients with normal ALT


44/58

77% of patients with normal ALT

have some degree of liver damage

Normal ALT

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

Elevated ALT

NoFibrosis

23%

Mild

39%

Portal26%

Bridging6%

Cirrhosis6%

NoFibrosis

19%

Mild19%

Cirrhosis22%

Bridging16%

Portal24%

Old ti t h hi h b bilit


45/58

Older patients have a higher probabilityof progression to cirrhosis

0 10 20 30 400.00

0.25

0.50

0.75

1.00>50 years

4150

3140

2130


46/58

25-hydroxyvitamin-D in ethnic groups

From the National Health & Nutrition Examination Survey (NHANES) 20002004 by racial orethnic group.

Am J Clin Nutr 2008;88(suppl):558S

64S

SVR 49%

SVR 34%

SVR 19%nmol/L

Age (years)

Non Hispanic white

Mexican American

Non Hispanic Black

Low vitamin D serum level is related to severe


47/58

Low vitamin D serum level is related to severefibrosis & low responsiveness to IFN-based

therapy in genotype 1 chronic HCV

Antonio Crax et al., Hepatology. 2010

In Vitro: Vitamin D decreased Hepatic


48/58

In Vitro:Vitamin D decreased HepaticStellate Cell activation

Safadi R. et al., Unpublished data

Alpha Smooth Muscle Actin INT.

0

10000

20000

30000

40000

50000

60000

0 1/1000 1/500 1/100

25 OH- VIT D

Vitamin D serum levels before & 12 weeks


49/58

10

20

30

40

50

VitaminDLevels(ng/ml)

*

Vitamin D levels afterVitamin D levels Before

Vitamin D serum levels before & 12 weeksafter initiation of antiviral treatment

0

20

40

60

80

100 P


50/58

M b li S d & Ch i HCV


51/58

Steatosis in HCV

1. Younossi ZM, et al. J Clin Gastroenterol. 2004;38:705-709.2. Asselah T, et al. Gut. 2006;55:123-130.

3. Browning JD, et al. Hepatology. 2004;40:1387-95.4. Nomura H, et al. Jpn J Med. 1988;27:142-149.

No steatosis (41%)

Steatosis (41%)

NASH (18%)

Metabolic Syndrome & Chronic HCV

HCV & Diabetes Mellitus


52/58

Harrison SA. J Clin Gastroenterol 2006;40:6876

Reference

(location)Year

CohortSize

Prevalence ofDM in HCV (%)

Preventionof DM incontrols

(%)

Prevalence of DM inHBV (%)

Mason et al, USA 1999 1117 21 NA 12Caronia et al, Italy 1999 1332 23.6 NA 9.4

Knobler et al, Israel 2000 133 33 5.6 12

Zein et al, USA 2005 179 14.5 7.8 NALabropoulou-Karatza et al,Greece

1999 108 45.3 11.3 NA

Allison et al, USA 1994 100 50 9 NAGrimbert et al, France 1996 304 24 9 NA

El-Zayedi et al, Egypt 1998 591 25.4 11.2 NA

Mehta et al, USA 2000 9841 3x more likely 8 8%

Mangia et al, Italy 1998 385 30.1 9.7 25

Fraser et al, Israel 1996 168 39.1 NA 2.5

Wang et al, Taiwan 2003 2327 31 NA 12.7Arao et al, Japan 2003 866 20.9 NA 11.9

Lecube et al, Spain 2004 642 32 12 NA

Thuluvath et al, USA 2003 291 19.6 11.5 NA

Ozyilken et al, Turkey 1996 427 26.2 1.5 9.2

Zein et al, USA 2000 204 22 8.4 NA

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

HCV & Diabetes Mellitus


53/58

HCV Vi l L d i t d IR i d d tl


54/58

HCV Viral Load associatedwith IR 55.3% versus

42.3% for LVL, p=0.009

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

7.0

6.5

6.0

5.5

5.0

4.5

4.0

4HCVRNA(log

IU/mL)

HOMA-IR

15

12

9

6

3

0

F0-1

HOMA-IR

Fibrosis (METAVIR)

F2 F3 F4

IR independentlyassociated with

significant fibrosis


55/58

Is CirrhosisReversible?


56/58

WEIGHT-based dosing

PEG-Intron1 PEGASYS2

FIXED dose

Lyophilized powder thatneeds to be reconstituted

before each injection

Dispensed as a stablesolution ready for

injection

Pegylated IFNs

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

Reversibility of Cirrhosis Following


57/58

Reversibility of Cirrhosis FollowingTreatment of HCV

Poynard et al, Gastroenterology 2002; 122:1303-1313

N

o.

Patien

ts


58/58

Thank YouRifaat Safadi M.D

HCV_The First GI Conference in Palestine

Documents

Transcript of HCV_The First GI Conference in Palestine