Hepatitis C

Core slides

This material was prepared by the Viral Hepatitis

Prevention Board

The slides (or subsets) can be reproduced for educational

use only, with reference to the original source and to the

VHPB

Update January 2014

Update January 2014

1. Introduction

2. Virology

3. Transmission

4. Clinical Features

5. Serologic markers

6. Epidemiology

7. Public health impact

8. Prevention

9. Screening

10.Treatment

Overview

Introduction

The disease

Infectious inflammatory illness of the liver caused by the hepatitis

C virus (HCV)

Mild resolving illness or progression to chronic disease with

permanent liver damage

Together with hepatitis B, most common cause of liver cirrhosis

and cancer (hepatocellular carcinoma)

HCC (+cirrhosis) Cirrhosis Chronic hepatitis

Update January 2014

Virology

The hepatitis C virus (HCV)

HCV belongs to the genus

Hepacivirus, within the family

Flaviviridae

First identification in 1989

Extensive genetic heterogeneity

Update January 2014

Virology

Morphology

Enveloped RNA virus with an inner nucleoprotein core

Envelope contains two glycoproteins (E1 and E2), which

form heterodimers at the surface of the virion

Update January 2014

Virology

Replication

Replication in the cytoplasm of hepatocytes

Rapid viral replication, resulting in frequent HCV RNA

genome mutations

Update January 2014

Virology

Genotypes

Substantial genetic diversity: 7 genotypes (1 to 7) and at

least 67 subtypes (represented by lower-cased letters)1

Genotype is clinically important in determining potential

response to interferon-based therapy and the required

duration of therapy

Genotype 1 (1a,1b) and 3 (3a) are responsible of vast

majority of infections in Western countries2

1. Smith DB et al. Hepatology. 2014 Jan;59(1):318-27

2. Simmonds P. J Gen Virol 2004;85(Pt11):3173-88 Update January 2014

Virology

Global distribution of HCV genotypes

Source: Hepatitis C education and prevention

society (hepcbc). http://hepcbc.ca/genotypes/ Update January 2014

Virology

Evolutionary tree of genotypes

Source: Simmonds P. J Gen Virol

2004;85(Pt11):3173-88

Evolutionary tree of the principal genotypes of HCV in industrialized countries

and their association with specific risk groups

Update January 2014

Transmission

Transmission

HCV enters a susceptible host

directly, through needle inoculation or transfusion of

contaminated blood products,

inadvertently, through breakage of a percutaneous barrier

(sexual or perinatal transmission), but risk of transmission

is low

Most common route of transmission reported in Europe in

2011 was injecting drug use (78% of reported cases)1

In resource-poor countries, unsafe medical practices account

for a considerable proportion of new HCV infections 2

Update January 2014 1. ECDC. Hepatitis B and C surveillance

report, 2006-2011. 2. EASL. J Hepatol. 2014. vol 60;392-420

Transmission

Causes of hepatitis C

Blood transfusions (prior to 1990)

Intravenous drug use (sharing needles or other equipment)

Unsafe medical or surgical procedures (iatrogenic exposure)

Body piercing, tattooing

Mother to child transmission

Unprotected sex with multiple partners (high risk behavior)

Decreasing risk of transmission

Update January 2014

Clinical features

Pathogenesis

Incubation period 7 weeks (range 4-20 weeks)1

HCV is not directly cytopathic. Persistent infection relies on

rapid production of virus along with a lack of vigorous T-cell

immune response to HCV antigens2

Progression of liver diseases over several decades

Risk factors for the progression of chronic hepatitis C to

cirrhosis and HCC: age of infection, alcohol consumption,

degree of inflammation and fibrosis on liver biopsy, HIV and

HBV coinfection, comordid conditions (diabetes…)

1. Hoofnagle JH. Hepatol. 1997;26(3Suppl1):15S-20S

2. Chen SL & Morgan TR. Int J Med Sci. 2006;3(2):47–52 Update January 2014

Clinical features

Symptoms

Acute HCV infection symptomatic (fatigue, abdominal pain,

jaundice…) in 20-30%

Chronic infection is associated with variable degrees of

hepatic inflammation and fibrosis progression

Update January 2014

Natural course and clinical outcomes

Exposure (acute infection)

Cirrhosis

Chronic infection

Stable

Death HCC

Adapted from EASL Clinical Practice

Guidelines. J Hepatol. 2014. vol 60;392-420

20% 80%

Clinical features

4% per year 1-5% per year

Resolved (HCV clearance)

Update January 2014

10-20% 80-90%

33% first year

Serologic markers

Laboratory diagnosis

Based on

hepatitis C serologic testing (anti-HCV antibodies)

HCV RNA testing (by real-time PCR)

Most characteristic indicator of active liver disease =

increase in serum ALT levels

Update January 2014

HCV markers in acute resolving infection

Source: CDC. In MMWR September 28, 2008 Serologic markers Update January 2014

HCV markers in chronic infection

Serologic markers Source: Hoofnagle JH. Hepatol.

1997;26(3Suppl1):15S-20S Update January 2014

Interpretation of tests results for HCV

Serologic markers

Marker Result Interpretation

HCV antibody HCV RNA

- -

No HCV infection

HCV antibody HCV RNA

+ -

(Probable) Resolved HCV infection. HCV RNA follow-up recommended if suspected HCV-exposure ≤ 6 months

HCV antibody HCV RNA

+ +

Current HCV infection

Update January 2014

Recommended testing for HCV infection

Serologic markers Source: CDC. In MMWR 2013;62(18) Update January 2014

Epidemiology

Hepatitis C in the world

Source: WHO Framework for global action 2012

1. El-Zanaty F & Way A. Egypt Demographic and

Health Survey 2008

Every year, 3–4 million people are infected with

HCV

130-180 million persons are chronically infected (2-

3% world population)

350,000 people are estimated to die each year from

HCV-related liver diseases

Highest prevalence in Egypt (14.7% nationwide)1

Update January 2014

Epidemiology

Worldwide prevalence of HCV infection

Source: WHO, 2008 Update January 2014

Epidemiology

Prevalence of HCV infection in Europe

Sources: Esteban JI et al. J Hepatol 2008

Jan;48(1):148-62

WHO Europe, Health topics, Hepatitis

Within the WHO European region, approximately 15 million

people are chronically infected with HCV

Update January 2014

Epidemiology

Surveillance of hepatitis C in Europe

Quality and standardised viral hepatitis surveillance data are

scarce

Key issues:

Heterogeneity of reporting systems

Use of different case definitions

Reporting of acute and/or chronic cases

Changes in reporting practices and case definitions over time

(for trends over time analysis)

Incompleteness of data

High rate of asymptomatic HCV infections, data reported reflect

testing strategies rather than underlying epidemiology

Update January 2014

Case definitions HCV infection

CDC (2012) ECDC (2012)

Cinical description acute HCV An acute illness with a discrete onset of any sign consistent with acute viral hepatitis and either (a) jaundice or (b) elevated serum ALT (> 400 IU/L)

NA (clinical criteria not included in case defintion)

Laboratory criteria (past or present infection) One or more of the following three criteria: (a) antibodies to hepatitis C virus (anti-HCV) positive or (b) hepatitis C virus Recombinant Immunoblot Assay (HCV RIBA) positive or (c) Nucleic Acid Test (NAT) for HCV RNA positive and (if done) IgM anti-HAV & anti-HBC negative

At least one of the following three: (a) detection of hepatitis C virus nucleic acid (HCV RNA) (b) detection of hepatitis C virus core antigen (HCV-core) (c) hepatitis C virus specific antibody (anti-HCV) positive (confirmed by confirmatory test) in persons >18 months without evidence of resolved infection

Epidemiology Update January 2014

Epidemiology

Incidence in Europe (EU/EEA)

Sources: ECDC. Annual epidemiological report

2013 (2011 data)

Reported incidence of acute infection in 2011 (among

11 countries able to report acute cases): range from

<0.1 in Portugal to 2.5 per 100,000 in Austria

Reported incidence of chronic infection in 2011 (among

8 countries able to report chronic cases): range from 0.1

in Greece to 14.0 per 100,000 in Estonia

BUT lack of reliable and comparable epidemiological data

Update January 2014

Epidemiology

Incidence in Europe (2)

Based on the total number of reported hepatitis

C cases in 2011, ECDC, Annual

epidemiological report 2013

Incidence rate (per 100,000) of hepatitis C in Europe (EU/EEA), 2011

Caution ! No standardized case definition; including acute AND/OR chronic cases * 2009 data

** 2008 data

Update January 2014

0,2 0,3 0,3 0,3 0,4 0,4 0,4 0,4 0,8 1,3 4,3 4,6 5,2 5,4 5,7 6,0 6,4

7,7

14,5 15,1 15,2

19,5 21,1

22,4 22,6

27,9

34,1

54,6

0,0

10,0

20,0

30,0

40,0

50,0

60,0

Incid

en

ce / 1

00 0

00

Public health impact

Public health impact

Burden of HCV infection still unknown or underestimated

(asymptomatic infection in early stages, no access to testing

in many countries)

Globally, 27% of cirrhosis and 25% of hepatocellular

carcinoma is attributable to HCV1

Morbidity and mortality of HCV-related diseases expected to

continue to rise in the coming decades

1. Perz JF et al. J Hepatol. 2006

Oct;45(4):529-38 Update January 2014

Public health impact

Cirrhosis

15% of HCV infected will develop cirrhosis after 30 years1

An estimated 27% of cirrhosis is attributable to HCV2

Liver cirrhosis (all causes) accounts for 1-2% of all deaths in

Europe (WHO)

1. El–Serag HB & Rudolph KL. Gastroenterology.

2007 Jun;132(7):2557-76

2. Perz JF et al. J Hepatol. 2006 Oct;45(4):529-38

Proportion of patients with HCC related to viral hepatitis1

Update January 2014

Public health impact

Estimated cirrhosis mortality rate by country (EU27)

Source: ECDC. Hepatitis B and C in the EU

neighbourhood: prevalence, burden of disease and

screening policies. 2010

Update January 2014

Public health impact

Liver cancer

1. GLOBOCAN 2012, International Agency for Research on Cancer. http://globocan.iarc.fr

2. Perz JF et al. J Hepatol. 2006 Oct;45(4):529-38

3. Global burden of disease (GBD) for hepatitis C. J Clin Pharma 2004;44:20-9

6th most common cancer and 3rd most common cause of

death from cancer worldwide1

Europe (WHO region): estimated incidence of 4.3 per

100,000 and 69,000 deaths in 20121

HCC accounts for 70-90% of liver cancers1

An estimated 25% of HCC is attributable to HCV2

1-2.5% of HCV infected will develop HCC after 30 years3

Update January 2014

Public health impact

Burden of liver cancer in Europe

Estimated liver cancer incidence* in Europe (WHO region), 2012

Source: GLOBOCAN 2012, International Agency for

Research on Cancer. http://globocan.iarc.fr Update January 2014

* Age-standardised rate per 100,000

Public health impact

Liver transplants

More than 5000 liver transplantations in Europe (EU27) per

year

Number stopped growing over the last 10 years because of

limited availability of organs

Cirrhosis is leading disease in 57% of transplants in Europe

Among liver transplants for cirrhosis, 39% are caused by

viral hepatitis

Source: European Liver Transplant Registry

http://www.eltr.org Update January 2014

Public health impact

Liver transplants

Source: European Liver Transplant Registry

http://www.eltr.org Update January 2014

Prevention

Strategies to control the disease

Infection source

Susceptible host

Transmission

preventive measures

to avoid transmission

Screening and treatment

(suppression of HCV) Primary prevention

Secundary and tertiary prevention

in chronic carriers

Update January 2014

Prevention

Primary prevention

Vaccination: studies ongoing but so far unsuccessful

because of frequent HCV mutations and numerous existing

subtypes

Blood safety procedures, including screening of donors of

blood and blood products

Safe injection practices

Needle exchange programs for IDU

(Safer sex practices)

Update January 2014

Screening

Screening programs

Target populations:

IDU

Blood and organ donors

Persons with HIV-infection

Persons with possible exposure to HCV (HCWs,

haemodialysis patients…)

Pregnant women and children born to HCV-positive

mothers

Wide variety between countries

Update January 2014

Screening

Screening in Europe

Target population Nb of countries

(N=29)

Blood and organ donors 27 (90%)

Haemodialysis patients 20 (69%)

Injecting drug users 16 (52%)

Prison population 10 (38%)

Health care workers 7 (24%)

STI clinic patients 6 (31%)

Pregnant women 3 (10%)

* EU27 (except Czech Republic) + Norway, Iceland and Liechtenstein

Screening programs for hepatitis C in 29 European countries*, 2009

Source: ECDC. Surveillance and prevention

of hepatitis B and C in Europe. 2010 Update January 2014

Screening

Screening in the US

Source: CDC. In MMWR 2012;61(RR04):1-18

HCV testing recommended for previously identified risk

groups for HCV infection

Since 2012: one-time blood test recommended for all baby

boomers (born from 1945-1965), who account for 75% of all

HCV infections in the US

Update January 2014

Treatment

Treatment

Goal

Eradication of HCV infection (in the infected patient), in order to prevent

complications of HCV related diseases and to prevent transmission of

the disease

Indications

Treatment-naïve patients with compensated HCV related disease

Patients with significant fibrosis (METAVIR score F3 to F4)

Less severe disease on an individual basis

End point

Sustained virological response (SVR), defined as undetectable HCV

RNA level in a sensitive assay (<15 IU/ml), 24 weeks after the end of

therapy

Source: EASL Clinical Practice Guidelines.

J Hepatol 2014. vol 60;392-420 Update January 2014

Treatment

Pre-therapeutic assessment

Establish causal relationship between HCV infection and

liver disease

Assessment of liver disease severity by non-invasive

methods. Liver biopsy if uncertainty or additional etiologies

HCV RNA detection and quantification

HCV genotyping (and subtyping); influence on choice of

therapy, dose and duration of treatment

Update January 2014 Source: EASL Clinical Practice Guidelines.

J Hepatol 2014. vol 60;392-420

Treatment

Available drugs

Standard-of-care for chronic hepatitis genotype 2 to 6:

combination of pegylated interferon (PegIFN)-α and ribavirin

(RBV)

Standard-of-care for chronic hepatitis genotype 1:

combination of PegIFN/RBV and boceprevir or telaprevir

(triple therapy)

Large number of new drugs are in development and studies

on combinations and IFN-free regimens are ongoing

Goal new treatments: higher efficacy, shorter treatment,

easier administration, improved tolerability and patient

adherence

Source: EASL Clinical Practice Guidelines.

J Hepatol 2014. vol 60;392-420

Update January 2014

Treatment

Not all patients are eligible for treatment, remaining difficult-

to-treat groups (patients with cirrhosis, liver failure, renal

failure, HIV co-infection…)

High cost, with limited acces to treatment in many countries

Logistic challenge to treat all eligible patients (physicians,

expertise, funding…)

Despite improved tolerance of new therapies, still side effects,

resulting in low adherence to treatment

Rates of uptake of treatment are very low, estimated

at 5% of HVC infected people in the US1

Source: EASL. J Hepatol 2014. vol 60;392-420

1. Holmberg SD et al. NEJM 2013.368(20):1859-1861 Update January 2014

Remaining issues

Treatment

Conclusion

Global efforts are needed to prevent new

infections, detect infected people and ensure

they have access to care

Update January 2014