Hepatitis C virusA new era

Kate Nash

Consultant Hepatologist

Southampton

Hepatitis C

– What is it?– Case histories– Who is at risk?– Natural history of infection– Clinical presentation– Clinical evaluation– Treatment

Hepatitis C virus

• 1975 - Non A-non B hepatitis

Hepatitis C virus

• 1975 - Non A-non B hepatitis• 1989 – HCV identified

Hepatitis C virus

• 1975 - Non A-non B hepatitis• 1989 – HCV identified

– Flavivirus– Parenteral infection

(Blood)– Infects hepatocytes

• Hepatitis• Cirrhosis• Hepatocellular carcinoma

Hepatitis C virus

RNA genome

• High genetic variability– Genotypes (1-6)– Subtypes (>50)

• Mutates rapidly– Evades immune response– Poor vaccine prospects– Resistance to drugs

Cases

Case 1

• Male, 58 year old plasterer• 2001 - Fatigue, raised ALT• HCV positive

– IVDU (1985-88)

• Liver biopsy 2001– Mild fibrosis

• Not eligible for treatment

Case 1

• Clinical trial– Interferon-alpha + ribavirin– No virological response

• Repeat biopsy 2006– Moderate fibrosis

• Re-treatment– Pegylated interferon + ribavirin– No virological response

Case 1

• 2007 - US suggests cirrhosis– 6 month HCC surveillance programme

Case 1

• 2008 – Focal liver lesion– Liver resection – Well differentiated HCC

Case 1

• 2011 – New focal lesion– Liver transplantation– Vascular issues – venous outflow obstruction– Recurrent HCV

• 2012 – Moderate fibrosis– Optimise immunosuppression– Repeat antiviral treatment

Case 2

• 40 year old haemophiliac• HIV diagnosed 1986

– Long-term non-progressor– 2008 – HIV 25iu/ml, CD4 count 300

• HCV diagnosed 1991• Moderate alcohol consumption

Case 2

• 2008 – Pneumonia– Pleural effusion– Ascites– Bilirubin 300– US – cirrhosis with portal hypertension

• Improved– Diuretics– Varices banded– Listed for liver transplantation

Case 2

• 15 months on transplant waiting list– Variceal haemorrhage

• Multiple endoscopies with banding

– Pleural effusion– Haemarthrosis

• Septic arthritis• Multi-organ failure• Died

Case 3

• 60 year old housewife• Hypertension check – ALT =60• HCV positive• Risk factors

– No transfusion– No IVDU– Travel

• Hong Kong (dental treatment)• Gibraltar (Ear piercing)

Case 3

• Clinical assessment– Mild liver disease– HCV genotype 4

• 1 year treatment pegylated interferon + ribavirin– HCV RNA negative 6 months after– CURED!

Case 4

• 64 year old lady• 2008 - USA

– Variceal haemorrhage– Pleural effusion– Sepsis– Jaundice

• HCV related cirrhosis• Risk factor

– Appendicectomy 1960 Morocco

Case 4

• Recurrent hydrothorax– TIPS

• Recovered• Stable cirrhotic• 2010 – Bilateral peripheral oedema

– Swollen to mid thigh– Dopplers normal– Urgent follow up in hepatology clinic

Case 4

• Gross peripheral oedema• Vasculitic marks over her shins• ++++ Proteinuria

Case 4

• Gross peripheral oedema• Vasculitic marks over her shins• ++++ Proteinuria

Cryoglobulinaemia

Cases

1 Cancer

2 HIV co-infection

3 Treatable CURE

4 Extra-hepatic manifestations

Prevalence of HCV

Prevalence of HCV

• 180 million worldwide– 3% of the population

• 200,000 United Kingdom– Many unaware

Prevalence of HCV

Prevalence of HCV

20-25%

HCV transmission

HCV transmission

• Intravenous drug use– Shared needles– Shared equipment

HCV transmission

• Intravenous drug use– Shared needles– Shared equipment

• Transfused blood and blood products– Pre-1986 factor VIII– Pre-1992 blood

HCV transmission

• Intravenous drug use– Shared needles– Shared equipment

• Transfused blood and blood products– Pre-1986 factor VIII– Pre-1992 blood

• Unsterilized objects– Tattoo– Piercing– Health care

HCV transmission

• Vertical– Uncommon– 5%

• Sexual– Very rare– STDs– HIV positive MSM

Natural history of HCV infection

Exposure

Acute infection

Incubation period 6-8 weeks

Natural history of HCV infection

Exposure

Acute infection

Chronic infection (60-85%)

Incubation period 6-8 weeks

15-40% spontaneous clearance

Natural history of HCV infection

Exposure

Acute infection

Chronic infection (60-85%)

Cirrhosis (~ 20% after 20 years)

Incubation period 6-8 weeks

15-40% spontaneous clearance

Natural history of HCV infection

Exposure

Acute infection

Chronic infection (60-85%)

Cirrhosis (~ 20% after 20 years)

Incubation period 6-8 weeks

15-40% spontaneous clearance

Alcohol Older ageObesity MaleDiabetes HIV/HBV

Co-factors:

Natural history of HCV infection

Exposure

Acute infection

Chronic infection (60-85%)

Cirrhosis (~ 20% after 20 years)

Hepatocellular carcinoma1-4% of cirrhotics / yr

Liver failure2-5% of cirrhotics / yr

Incubation period 6-8 weeks

15-40% spontaneous clearance

Alcohol Older ageObesity MaleDiabetes HIV/HBV

Co-factors:

Largely asymptomatic until...

Natural history of HCV infection

HCV symptoms

• Usually none• Acute infection

– Usually unrecognised– Vague symptoms

• Fatigue• Arthralgia• Abdominal pain

– Clinical hepatitis is rare– Jaundice is very rare

HCV symptoms

• Chronic infection– Fatigue– Poor concentration– Abdominal discomfort– Arthralgia

Extra-hepatic manifestations

• Autoimmune– Thyroid– ITP

• Haematological– Cryoglobulinaemia– Lymphoma

• Renal– Glomerulonephritis

• Skin– Porphyria cutanea

tarda– Lichen planus– Vasculitis

• Other– Pulmonary fibrosis– Dry eye– Dry mouth

Clinical evaulation

• Viral status• Liver assessment• Other considerations

Clinical evaulation

• Virological status– Screening – HCV antibody

• Positive indicates exposure• Ab remains positive for life

– Active infection– Spontaneous resolution– Post successful treatment

• May be negative in immunocompromised

– Dry blood testing

Clinical evaluation

• Virological status– Active infection

• HCV RNA PCR– Qualitative – Quantitative

• HCV genotype– Guides treatment decision– Doesn’t change

Clinical evaluation

• Liver disease– ALT

• Useless!

– Liver ultrasound• Features of cirrhosis

– Liver texture– Splenomegaly– Varices

• Normal does not exclude serious liver disease

Clinical evaluation

• Fibrosis severity– Mild– Moderate– Severe

• Bridging fibrosis• Cirrhosis

Clinical evaluation

• Fibrosis severity– Liver biopsy

• Assess fibrosis• Reveal other pathology• Morbidity• Mortality• Sampling error

Clinical evaluation

• Fibrosis severity– Serum markers

• Fibrotest• Enhanced liver fibrosis test (ELF)• “Traffic light test”

– Hyaluronic acid– Procollagen -3 N-terminal peptide (P3NP)

Clinical evaluation

Fibroscan

• Transient elastography• Mechanical pulse generates

an elastic wave• Wave is propagated through

the liver• Velocity is measured by

ultrasound• Numerical value according

to liver stiffness• 14.5KPa (sensitivity 84%,

specificity 94%)

Clinical evaluation

• Other considerations– Co-factors

• HIV/HBV• Obesity• Diabetes• Alcohol• Medical / psychiatric health

– Motivation for treatment– Vaccinate against HAV, HBV

Treatment

• 1991 - Interferon-α– Natural antiviral agent– 5 MU given 3 x week subcutaneously

~15 % sustained virological response (SVR)

Genotype 1 – 9%

Genotype 2/3 – 30%

Treatment

• 1998 - Ribavirin– Antiviral agent– No activity alone against HCV– Augments interferon response– Reduces relapse

• Interferon + ribavirinGenotype 1 (48 weeks) – 27%

Genotype 2/3(24 weeks) – 60%

Treatment• 2001 - Pegylated interferon

– Polyethylene glycol addition– Increased half life– Once a week delivery

Con

cen

trat

ion

Con

cen

trat

ion

PEG-IFN-αIFN-α

Treatment

• Pegylated interferon– Genotype 1 - 14% – Genotype 2/3 – 47%

• Pegylated interferon + ribavirin– Overall ~50% SVR– Genotype 1

• 35-40% SVR

– Genotype 2/3• 75-85% SVR

All genotypesGenotype 1Genotype 2/3

Rate of sustained virological response according to treatment

0

20

40

60

80

Interferon α-2b + ribavirin

Peg-interferon Peg-interferon + ribavirin

Interferon α-2b 48 weeks

Interferon α-2b 24 weeks

% S

VR

All genotypesGenotype 1Genotype 2/3

Rate of sustained virological response according to treatment

0

20

40

60

80

Interferon α-2b + ribavirin

Peg-interferon Peg-interferon + ribavirin

Interferon α-2b 48 weeks

Interferon α-2b 24 weeks

% S

VR

20%

60%

Treatment side effects

Pegylated interferon Ribavirin

Influenza-like symptoms

Bone marrow depression

Depression/mood disturbance

Sleep disturbances

Alopecia

Haemolytic anaemia

Cough, dyspnoea

Rash

Teratogenicity

GI disturbance

Autoimmune phenomenon

Injection site pain/erythema

Retinopathy

Thyroid dysfunction

Weight loss

New treatments

• Difficulties culturing HCV• 2005 HCV replicon systems• 2006 Mouse model• Allowed testing of directly acting antiviral

agents

BoceprevirTelaprevir

Boceprevir

DaclatasavirSofosbuvir

Directly acting antiviral agents

• 2011 first DAAs licensed for genotype 1 HCV– NS3/4A protease inhibitors

• Boceprevir (Victrelis)• Telaprevir (Incivo)

• 2012 NICE approval

0

20

40

60

80

100

Peg-interferon

+ ribavirin

Peg-interferon

+ ribavirin +

boceprevir

Peg-interferon

+ ribavirin +

telaprevir

%

Rate of sustained virological response according to treatmentGenotype 1 virus – treatment naive

0

20

40

60

80

100

Peg-interferon

+ ribavirin

Peg-interferon

+ ribavirin +

boceprevir

Peg-interferon

+ ribavirin +

telaprevir

%

Rate of sustained virological response according to treatmentGenotype 1 virus – treatment experienced

Protease inhibitors (PIs)

• Triple therapy– Still use PEG-IFN + Ribavirin

• Directly acting antiviral agents• Potential for resistance

– Strict dosing regime– Avoid missing doses– Must not restart

Protease inhibitors

• Toxicity– IFN/Ribavirin side effects– Telaprevir – rash

• 50% mild• 4% severe• <1% DRESS• <1% Steven-Johnson

Protease inhibitors

• Telaprevir– Worse cytopaenias– Ano-rectal discomfort

• Boceprevir– Worse cytopaenias– Dysguesia

Protease inhibitors

• Drug interactions– CYP3A inhibitors– > 300 drugs known to interact

HCV – the future

• Other protease inhibitors• Polymerase inhibitors• Interferon-free regimes• Combination therapy• Clinical trials

HCV take home messages

• Common infection• Many unaware• Risk factor not always acknowledged• High index of suspicion• Screen those at risk

HCV take home messages

• 20-30% of patients develop liver disease• Early treatment best• Potentially curable illness• New drugs

– Better treatment success – 70-80% and more– Difficult treatment– Side effects– Drug interaction