Blood Borne VirusesHepatitis C OverviewPhlebotomists Association of Ireland

Dr Ciaran Bannan

Research Fellow

St James’s Hospital / Trinity College Dublin

11th April 2015

Aims of Talk

• Introduction to Hepatitis C

• Diagnosis

• Staging

• Treatment options– Old and New

• Future perspectives

Introduction

• Main causes of chronic liver disease

• Long term impact highly variable– Minimal changes– Chronic hepatitis– Extensive fibrosis– Cirrhosis– Hepatocellular carcinoma (HCC)

• Many people unaware of diagnosis

Hepatic FibrosisHepatic Fibrosis

CirrhosisCirrhosis Liver CancerLiver Cancer

Healthy LiverHealthy Liver

Epidemiology

• 130 – 210 million affected– 3% of world’s population

• Prevalence varies widely– Western Europe 0.3% - 3%– Higher in Eastern Europe and Middle East– Egypt – highest prevalence 9%

• Recent discovery – 1989/1990– Approximately 10 years after HIV

Prevalence - WHO

Risk factors• People who inject drugs (PWID)

• Blood transfusions / products

• Iatrogenic / Occupational

• Tattoos / Acupuncture

• Intranasal drug abuse e.g. cocaine

• Men who have sex with Men (MSM)

• Heterosexual and perinatal risk - v low

• Unknown

Most likely risk factor (%) for cases of hepatitis C notified 2010-2013 (where data available, n=2354,

57%)

Genotypes

• Six genotypes described– Large number of subtypes

• Genotype 1 most prevalent worldwide– Subtype 1a – USA / Ireland– Subtype 1b – Europe

• Genotype 3 – Common in European IVDU

• Genotype 4 – Increasing incidence

• Genotype 5 and 6 rarely found

Natural history of HCV

Natural history

• Acute HCV asymptomatic in 70-80% of cases

• Chronic hepatitis develops in 75% of cases– Associated with variable degrees of hepatic

inflammation and fibrosis progression– Independent of genotype and viral load

Accelerators of liver disease progression

• Alcohol

• Diabetes mellitus / Increased BMI

• Older age of acquisition

• HIV co-infection

• Hepatitis A/B/D co-infection– Vaccinate!

• Depending on presence of co-factors 10-40% of patients will develop cirrhosis

Hepatocellular Carcinoma

• Cirrhotic patients have 4% risk of death per year

• Hepatitis C has become the leading cause of primary liver cancers in Europe

• HCC occurs in cirrhotic patients at a rate of 1-5% per year

• Patients diagnosed with HCC have a 33% probability of death in the first year of diagnosis

Diagnosis

• Diagnosis is based on presence of both– Anti-HCV antibodies

• May not be positive until 6/12 after infection• Detected by enzyme immunoassays• New combined antigen-antibody test

– HCV RNA• Detected by molecular assays• Appears before antibodies

• Genotyping should be requested

Assessment of disease severity

• Important in decision making in chronic Hepatitis C management and prognosis– Liver biopsy – gold standard– Requires at least day ward admission

– Complications• Bleeding• Pain• Pneumothorax• Infection

Assessment of disease severity• Non invasive methods

– Fibroscan measures hepatic elastography (liver stiffness)

• Good for mild fibrosis and cirrhosis• Not good for moderate and severe fibrosis

Assessment of disease severity

• Non invasive methods– Serological and blood markers

– Coagulation – High INR– Low albumin– High Bilirublin– High LFTs– Low platelets– Low sodium

Diagnosis Summary

• HCV Antibody and PCR for RNA

• Genotype– Different treatment options and different

responses to treatment

• Stage disease – invasive / non invasive

Treatment

• Goal of treatment is to eradicate infection

• Endpoint of treatment is a sustained virological response (SVR)– >99% chance of cure

• SVR is defined as no detectable virus 12 weeks after completion of treatment

Rationale for antiviral therapyRationale for antiviral therapy

• Stop viral replication• Normalisation of liver biochemistry• Reduction in histologic activity• Halt progression of disease• Prevent Hepatocellular

Carcinoma

Date of download: 9/23/2014Copyright © 2014 American Medical

Association. All rights reserved.

From: Association Between Sustained Virological Response and All-Cause Mortality Among Patients With Chronic Hepatitis C and Advanced Hepatic Fibrosis

JAMA. 2012;308(24):2584-2593. doi:10.1001/jama.2012.144878

Treatment strategies

• Interferon alpha injections– Previously 3 times a week– Pegylated interferon

• Subcutaneous injection• Weekly dosing

• Daily oral ribavirin tablets– Taken twice a day (usually 5-6 tablets daily)

Side Effects

• Common– Metabolic – loss of appetite– Psychiatric – Depression, poor sleep pattern– CNS – Headache, poor concentration– Respiratory – Cough, SOB– Gastrointestinal– Haematology – Low WCC, Hb, Plts– Skin and joint complaints– Endocrine – Thyroid disease

Contraindications

• Uncontrolled depression, psychosis, epilepsy or substance abuse

• Uncontrolled autoimmune disease

• Pregnant women

• Severe concurrent medical conditions

• Unwilling to comply with contraception

• Decompensated cirrhotic patients– Can consider Childs Pugh B in some

circumstances

The Future … 2013

• Directly Acting Antiviral (DAA) drugs

• Two drugs first to market:– NS3/NS4A Protease Inhibitors– Telaprevir– Boceprevir– Genotype 1 patients only– Given with interferon and ribavirin

• Multitude of new drugs in pipeline

Irish Results

• GUIDE Department in St James’s Hospital

• Included majority of patients with HIV– Pegylated interferon and Ribavirin– SVR rate of 58% for all genotypes– SVR rate of 37% for genotype 1

– Telaprevir / Boceprevir based therapy– SVR rate of 84% for genotype 1

Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD.

SV

R (

%)

IFN6 mos

PegIFN/ RBV

12 mos

IFN12 mos

IFN/RBV12 mos

PegIFN12 mos

2001

1998

2011

StandardIFN

RBV

PegIFN

1991

DAAs

PegIFN/RBV/DAA

IFN/RBV6 mos

6

16

3442 39

55

70+

0

20

40

60

80

100

DAA + RBV

± PegIFN

90+

2013

The Good News

Treatment Limitations

Treatment is more effective but much more difficult

Other Issues With PI-Based TherapyPill burden Food requirement

CYP3A4PI metabolites

Drug-drug interactions

Resistance

BOC = 12/dayRBV = 4-7/day

TVR = 6/dayRBV = 4-7/day

New DAAs: Sites of action

Ref: Feeney E.R, Chung R.T. Antiviral treatment of Hepatitis C. BMJ 2014;349:g3308..

Not All Direct-Acting Antivirals are Created Equal

Characteristic Protease Inhibitor*

Protease Inhibitor**

NS5AInhibitor

Nuc Polymerase

Inhibitor

Non-NucPolymerase

Inhibitor

Resistance profile

Pangenotypic efficacy

Antiviral potency

Adverse events

Good profile Average profile Least favourable profile

*First generation. **Second generation.

Feld J. Keeping up in HCV: Counting down the final days of interferon. Clinical Care Options Hepatitis

Ideal Hepatitis C treatment

• 100% Efficacy• Oral• Interferon free• Short duration• No resistance• Pan-genotypic• Well tolerated• Safe• Low cost

New Drugs – Interferon free

• Gilead– Sofosbuvir (NS5B polymerase inhibitor)– Ledipasvir (NS5A Inhibitor)

• Abbott– Ombitasvir (NS5A inhibitor)– Paritaprevir/ritonavir (Protease inhibitor)– Dasabuvir (NS5B polymerase inhibitor)

• Ribavirin still needed in advanced cases

Who to treat?

• Treatment should be initiated promptly in those with advanced fibrosis and strongly considered in those with moderate fibrosis

• In individuals with less severe disease, indication for therapy is individual– Can wait for new therapies

Conclusion

• Very exciting time for Hepatitis C

• Need to identify cases and prioritise treatments to those who need it most

• Cost is a huge factor– Finding new cases– Financing treatment– Delivering treatment

• Managing drug-drug interactions

Prevention

• Very effective vaccines available for Hepatitis A and B

• Effective safe vaccine would help

• Ongoing Phase 1 and 2 studies with various vaccine candidates that show good promise to date

Questions - ?