Transcript Hepatitis C Management

Blood Borne Viruses
Hepatitis C Overview
Phlebotomists Association of Ireland
Dr Ciaran Bannan
Research Fellow
St James’s Hospital / Trinity College Dublin
11th April 2015
Aims of Talk
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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
Healthy Liver
Hepatic Fibrosis
Cirrhosis
Liver Cancer
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
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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%)
Other and no
known risk
factor, 5.9%
Vertical
transmission,
2.7%
Possible sexual
transmission,
5.7%
Blood or blood
products, 3.2%
Injecting drug
user, 82.5%
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
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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 1040% 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
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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 therapy
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Stop viral replication
Normalisation of liver biochemistry
Reduction in histologic activity
Halt progression of disease
Prevent Hepatocellular
Carcinoma
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
Date of download: 9/23/2014
Copyright © 2014 American Medical
Association. All rights reserved.
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
The Good News
100
PegIFN
80
2013
2011
90+
2001
RBV
Standard
IFN
DAAs
70+
1998
55
60
1991
42
40
34
39
16
20
6
0
IFN
6 mos
IFN
12 mos
IFN/RBV
6 mos
IFN/RBV
12 mos
PegIFN
12 mos
PegIFN/
RBV
12 mos
PegIFN/
RBV/
DAA
Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting,
April 27-28, 2011, Silver Spring, MD.
DAA
+ RBV
± PegIFN
Treatment Limitations
Treatment is more effective but much more difficult
Other Issues With PI-Based Therapy
Pill burden
Food requirement
Resistance
BOC = 12/day TVR = 6/day
RBV = 4-7/day RBV = 4-7/day
Drug-drug interactions
PI
CYP3A4
metabolites
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**
NS5A
Inhibitor
Nuc
Polymerase
Inhibitor
Non-Nuc
Polymerase
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
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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 - ?