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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