Hepatitis C. Core slides

Transcription

1 Hepatitis C Core slides

2 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

3 Overview 1. Introduction 2. Virology 3. Transmission 4. Clinical Features 5. Serologic markers 6. Epidemiology 7. Public health impact 8. Prevention 9. Screening 10.Treatment

4 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) Chronic hepatitis Cirrhosis HCC (+cirrhosis) Introduction

5 The hepatitis C virus (HCV) HCV belongs to the genus Hepacivirus, within the family Flaviviridae First identification in 1989 Extensive genetic heterogeneity Virology

6 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 Virology

7 Replication Replication in the cytoplasm of hepatocytes Rapid viral replication, resulting in frequent HCV RNA genome mutations Virology

8 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 countries 2 Virology 1. Smith DB et al. Hepatology Jan;59(1): Simmonds P. J Gen Virol 2004;85(Pt11):

9 Global distribution of HCV genotypes Virology Source: Hepatitis C education and prevention society (hepcbc).

10 Evolutionary tree of genotypes Evolutionary tree of the principal genotypes of HCV in industrialized countries and their association with specific risk groups Virology Source: Simmonds P. J Gen Virol 2004;85(Pt11):

11 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 Transmission 1. ECDC. Hepatitis B and C surveillance report, EASL. J Hepatol vol 60;

12 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 Transmission

13 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 antigens 2 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 ) Clinical features 1. Hoofnagle JH. Hepatol. 1997;26(3Suppl1):15S-20S 2. Chen SL & Morgan TR. Int J Med Sci. 2006;3(2):47 52

14 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 Clinical features

15 Natural course and clinical outcomes Exposure (acute infection) 20% 80% Resolved (HCV clearance) Chronic infection 80-90% Stable 10-20% Cirrhosis 4% per year 1-5% per year Death 33% first year HCC Clinical features Adapted from EASL Clinical Practice Guidelines. J Hepatol vol 60;

16 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 Serologic markers

17 HCV markers in acute resolving infection Serologic markers Source: CDC. In MMWR September 28, 2008

18 HCV markers in chronic infection Serologic markers Source: Hoofnagle JH. Hepatol. 1997;26(3Suppl1):15S-20S

19 Interpretation of tests results for HCV Marker Result Interpretation HCV antibody HCV RNA HCV antibody HCV RNA HCV antibody HCV RNA No HCV infection (Probable) Resolved HCV infection. HCV RNA follow-up recommended if suspected HCV-exposure 6 months Current HCV infection Serologic markers

20 Recommended testing for HCV infection Source: CDC. In MMWR 2013;62(18) Serologic markers

21 Hepatitis C in the world Every year, 3 4 million people are infected with HCV 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 Epidemiology Source: WHO Framework for global action El-Zanaty F & Way A. Egypt Demographic and Health Survey 2008

22 Worldwide prevalence of HCV infection Epidemiology Source: WHO, 2008

23 Prevalence of HCV infection in Europe Within the WHO European region, approximately 15 million people are chronically infected with HCV Epidemiology Sources: Esteban JI et al. J Hepatol 2008 Jan;48(1): WHO Europe, Health topics, Hepatitis

24 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 Epidemiology

25 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) 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 NA (clinical criteria not included in case defintion) 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

26 Incidence in Europe (EU/EEA) 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 Epidemiology Sources: ECDC. Annual epidemiological report 2013 (2011 data)

27 Incidence / Incidence in Europe (2) Incidence rate (per 100,000) of hepatitis C in Europe (EU/EEA), ,0 54,6 50,0 40,0 34,1 30,0 20,0 14,5 15,1 15,2 22,422,6 21,1 19,5 27,9 10,0 0,0 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 * 2009 data ** 2008 data Caution! No standardized case definition; including acute AND/OR chronic cases Epidemiology Based on the total number of reported hepatitis C cases in 2011, ECDC, Annual epidemiological report 2013

28 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 HCV 1 Morbidity and mortality of HCV-related diseases expected to continue to rise in the coming decades Public health impact 1. Perz JF et al. J Hepatol Oct;45(4):529-38

29 Cirrhosis 15% of HCV infected will develop cirrhosis after 30 years 1 An estimated 27% of cirrhosis is attributable to HCV 2 Liver cirrhosis (all causes) accounts for 1-2% of all deaths in Europe (WHO) Proportion of patients with HCC related to viral hepatitis 1 Public health impact 1. El Serag HB & Rudolph KL. Gastroenterology Jun;132(7): Perz JF et al. J Hepatol Oct;45(4):529-38

30 Estimated cirrhosis mortality rate by country (EU27) Public health impact Source: ECDC. Hepatitis B and C in the EU neighbourhood: prevalence, burden of disease and screening policies. 2010

31 Liver cancer 6 th most common cancer and 3 rd most common cause of death from cancer worldwide 1 Europe (WHO region): estimated incidence of 4.3 per 100,000 and 69,000 deaths in HCC accounts for 70-90% of liver cancers 1 An estimated 25% of HCC is attributable to HCV % of HCV infected will develop HCC after 30 years 3 1. GLOBOCAN 2012, International Agency for Research on Cancer Perz JF et al. J Hepatol Oct;45(4): Global burden of disease (GBD) for hepatitis C. J Clin Pharma 2004;44:20-9 Public health impact

32 Burden of liver cancer in Europe Estimated liver cancer incidence* in Europe (WHO region), 2012 * Age-standardised rate per 100,000 Public health impact Source: GLOBOCAN 2012, International Agency for Research on Cancer.

33 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 Public health impact Source: European Liver Transplant Registry

34 Liver transplants Public health impact Source: European Liver Transplant Registry

35 Strategies to control the disease Infection source Transmission Susceptible host preventive measures to avoid transmission Screening and treatment (suppression of HCV) Primary prevention Secundary and tertiary prevention in chronic carriers Prevention

36 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) Prevention

37 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 Screening

38 Screening in Europe Screening programs for hepatitis C in 29 European countries*, 2009 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 Source: ECDC. Surveillance and prevention of hepatitis B and C in Europe. 2010

39 Screening in the US HCV testing recommended for previously identified risk groups for HCV infection Since 2012: one-time blood test recommended for all baby boomers (born from ), who account for 75% of all HCV infections in the US Screening Source: CDC. In MMWR 2012;61(RR04):1-18

40 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) End point Less severe disease on an individual basis Sustained virological response (SVR), defined as undetectable HCV RNA level in a sensitive assay (<15 IU/ml), 24 weeks after the end of therapy Treatment Source: EASL Clinical Practice Guidelines. J Hepatol vol 60;

41 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 Treatment Source: EASL Clinical Practice Guidelines. J Hepatol vol 60;

42 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 Treatment Source: EASL Clinical Practice Guidelines. J Hepatol vol 60;

43 Remaining issues Not all patients are eligible for treatment, remaining difficultto-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 US 1 Treatment Source: EASL. J Hepatol vol 60; Holmberg SD et al. NEJM (20):

44 Conclusion Global efforts are needed to prevent new infections, detect infected people and ensure they have access to care Treatment