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Hepatitis C virus A new era Kate Nash Consultant Hepatologist Southampton.

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Presentation on theme: "Hepatitis C virus A new era Kate Nash Consultant Hepatologist Southampton."— Presentation transcript:

1 Hepatitis C virus A new era Kate Nash Consultant Hepatologist Southampton

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

3 Hepatitis C virus Non A-non B hepatitis

4 Hepatitis C virus Non A-non B hepatitis 1989 – HCV identified

5 Hepatitis C virus Non A-non B hepatitis 1989 – HCV identified –Flavivirus –Parenteral infection (Blood) –Infects hepatocytes Hepatitis Cirrhosis Hepatocellular carcinoma

6 Hepatitis C virus RNA genome High genetic variability –Genotypes (1-6) –Subtypes (>50) Mutates rapidly –Evades immune response –Poor vaccine prospects –Resistance to drugs

7 Cases

8 Case 1 Male, 58 year old plasterer Fatigue, raised ALT HCV positive –IVDU ( ) Liver biopsy 2001 –Mild fibrosis Not eligible for treatment

9 Case 1 Clinical trial –Interferon-alpha + ribavirin –No virological response Repeat biopsy 2006 –Moderate fibrosis Re-treatment –Pegylated interferon + ribavirin –No virological response

10 Case US suggests cirrhosis –6 month HCC surveillance programme

11 Case – Focal liver lesion –Liver resection –Well differentiated HCC

12 Case – New focal lesion –Liver transplantation –Vascular issues – venous outflow obstruction –Recurrent HCV 2012 – Moderate fibrosis –Optimise immunosuppression –Repeat antiviral treatment

13 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

14 Case – Pneumonia –Pleural effusion –Ascites –Bilirubin 300 –US – cirrhosis with portal hypertension Improved –Diuretics –Varices banded –Listed for liver transplantation

15 Case 2 15 months on transplant waiting list –Variceal haemorrhage Multiple endoscopies with banding –Pleural effusion –Haemarthrosis Septic arthritis Multi-organ failure Died

16 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)

17 Case 3 Clinical assessment –Mild liver disease –HCV genotype 4 1 year treatment pegylated interferon + ribavirin –HCV RNA negative 6 months after –CURED!

18 Case 4 64 year old lady USA –Variceal haemorrhage –Pleural effusion –Sepsis –Jaundice HCV related cirrhosis Risk factor –Appendicectomy 1960 Morocco

19 Case 4 Recurrent hydrothorax –TIPS Recovered Stable cirrhotic 2010 – Bilateral peripheral oedema –Swollen to mid thigh –Dopplers normal –Urgent follow up in hepatology clinic

20 Case 4 Gross peripheral oedema Vasculitic marks over her shins ++++ Proteinuria

21 Case 4 Gross peripheral oedema Vasculitic marks over her shins ++++ Proteinuria Cryoglobulinaemia

22 Cases 1Cancer 2HIV co-infection 3Treatable CURE 4Extra-hepatic manifestations

23 Prevalence of HCV

24 180 million worldwide –3% of the population 200,000 United Kingdom –Many unaware

25 Prevalence of HCV

26 20-25%

27 HCV transmission

28 Intravenous drug use –Shared needles –Shared equipment

29 HCV transmission Intravenous drug use –Shared needles –Shared equipment Transfused blood and blood products –Pre-1986 factor VIII –Pre-1992 blood

30 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

31 HCV transmission Vertical –Uncommon –5% Sexual –Very rare –STDs –HIV positive MSM

32 Natural history of HCV infection

33 Exposure Acute infection Incubation period 6-8 weeks Natural history of HCV infection

34 Exposure Acute infection Chronic infection (60-85%) Incubation period 6-8 weeks 15-40% spontaneous clearance Natural history of HCV infection

35 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

36 Exposure Acute infection Chronic infection (60-85%) Cirrhosis (~ 20% after 20 years) Incubation period 6-8 weeks 15-40% spontaneous clearance AlcoholOlder age ObesityMale DiabetesHIV/HBV Co-factors: Natural history of HCV infection

37 Exposure Acute infection Chronic infection (60-85%) Cirrhosis (~ 20% after 20 years) Hepatocellular carcinoma 1-4% of cirrhotics / yr Liver failure 2-5% of cirrhotics / yr Incubation period 6-8 weeks 15-40% spontaneous clearance AlcoholOlder age ObesityMale DiabetesHIV/HBV Co-factors: Largely asymptomatic until... Natural history of HCV infection

38 HCV symptoms Usually none Acute infection –Usually unrecognised –Vague symptoms Fatigue Arthralgia Abdominal pain –Clinical hepatitis is rare –Jaundice is very rare

39 HCV symptoms Chronic infection –Fatigue –Poor concentration –Abdominal discomfort –Arthralgia

40 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

41 Clinical evaulation Viral status Liver assessment Other considerations

42 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

43 Clinical evaluation Virological status –Active infection HCV RNA PCR –Qualitative –Quantitative HCV genotype –Guides treatment decision –Doesn’t change

44 Clinical evaluation Liver disease –ALT Useless! –Liver ultrasound Features of cirrhosis –Liver texture –Splenomegaly –Varices Normal does not exclude serious liver disease

45 Clinical evaluation Fibrosis severity –Mild –Moderate –Severe Bridging fibrosis Cirrhosis

46 Clinical evaluation Fibrosis severity –Liver biopsy Assess fibrosis Reveal other pathology Morbidity Mortality Sampling error

47 Clinical evaluation Fibrosis severity –Serum markers Fibrotest Enhanced liver fibrosis test (ELF) “Traffic light test” –Hyaluronic acid –Procollagen -3 N-terminal peptide (P3NP)

48 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%)

49 Clinical evaluation Other considerations –Co-factors HIV/HBV Obesity Diabetes Alcohol Medical / psychiatric health –Motivation for treatment –Vaccinate against HAV, HBV

50 Treatment Interferon-α –Natural antiviral agent –5 MU given 3 x week subcutaneously ~15 % sustained virological response (SVR) Genotype 1 – 9% Genotype 2/3 – 30%

51 Treatment Ribavirin –Antiviral agent –No activity alone against HCV –Augments interferon response –Reduces relapse Interferon + ribavirin Genotype 1 (48 weeks) – 27% Genotype 2/3(24 weeks) – 60%

52 Treatment Pegylated interferon –Polyethylene glycol addition –Increased half life –Once a week delivery Concentration PEG-IFN-α IFN-α

53 Treatment Pegylated interferon –Genotype % –Genotype 2/3 – 47% Pegylated interferon + ribavirin –Overall ~50% SVR –Genotype % SVR –Genotype 2/ % SVR

54 All genotypes Genotype 1 Genotype 2/3 Rate of sustained virological response according to treatment Interferon α-2b + ribavirin Peg-interferon + ribavirin Interferon α-2b 48 weeks Interferon α-2b 24 weeks % SVR

55 All genotypes Genotype 1 Genotype 2/3 Rate of sustained virological response according to treatment Interferon α-2b + ribavirin Peg-interferon + ribavirin Interferon α-2b 48 weeks Interferon α-2b 24 weeks % SVR 20% 60%

56 Treatment side effects Pegylated interferonRibavirin 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

57 New treatments Difficulties culturing HCV 2005 HCV replicon systems 2006 Mouse model Allowed testing of directly acting antiviral agents

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60 Boceprevir Telaprevir

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64 Boceprevi r Daclatasavir Sofosbuvir

65 Directly acting antiviral agents 2011 first DAAs licensed for genotype 1 HCV –NS3/4A protease inhibitors Boceprevir (Victrelis) Telaprevir (Incivo) 2012 NICE approval

66 Peg-interferon + ribavirin Peg-interferon + ribavirin + boceprevir Peg-interferon + ribavirin + telaprevir % Rate of sustained virological response according to treatment Genotype 1 virus – treatment naive

67 Peg-interferon + ribavirin Peg-interferon + ribavirin + boceprevir Peg-interferon + ribavirin + telaprevir % Rate of sustained virological response according to treatment Genotype 1 virus – treatment experienced

68 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

69 Protease inhibitors Toxicity –IFN/Ribavirin side effects –Telaprevir – rash 50% mild 4% severe <1% DRESS <1% Steven-Johnson

70 Protease inhibitors Telaprevir –Worse cytopaenias –Ano-rectal discomfort Boceprevir –Worse cytopaenias –Dysguesia

71 Protease inhibitors Drug interactions –CYP3A inhibitors –> 300 drugs known to interact

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73 HCV – the future Other protease inhibitors Polymerase inhibitors Interferon-free regimes Combination therapy Clinical trials

74 HCV take home messages Common infection Many unaware Risk factor not always acknowledged High index of suspicion Screen those at risk

75 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

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