Hepatitis C : Complete Overview and Recent Updates 2019

Hepatitis C : Complete Overview and Recent Updates 2019 Introduction, Classification, Clinical features, Staging, Investigation, Management Guidelines, Drugs, Updates 2019 Heaptobiliary disorder Sheila Sherlok Harrison

1. Hepatitis C : Approach and Management Guide : Dr Chandrashekhar KACHAPUR Student : Chetan K Ganteppanavar

2. Epidemiology Population prevalence : 2 – 3% of the world ’ s population 170 million individuals : risk of cirrhosis One of the top 10 causes of death due to infectious diseases

3. Hepatitis c accounted for the vast majority of non - A, non - B post - transfusion hepatitis before screening of hepatitis was started Most common reason for a hepatology consultation Single leading indication for liver transplantation in Europe and north America

4. Epidemiology

5. Transmission Parenterally - m.c intravenous drug use Permucosally Vertically

6. HCV Virus Enveloped RNA virus Family flaviviridae Structural proteins are encoded at the 5 ′ end of the genome Non - structural elements are downstream of this region Two glycoprotein products, E1 or gp35 and E2 or gp70 are seen on the viral envelope

7. E1 and E2 are important antigenic sites Variability may be important in persistence of infection and immunopathogenesis RNA - dependent RNA polymerase Closely related, but different, nucleotide sequences, ‘ quasispecies ’ in infected persons Non – structural region of the HCV genome is divided into regions NS2 to NS5

8. NS2/NS3 encodes a protease with cleavage activity NS3 has helicase activity with replication function NS4a is a cofactor for protease NS5b is a viral RNA - dependent RNA polymerase

9. HCV genome organization and poly-protein processing

10. Genotypes 6 genotypes Genotpes 1 to 6 >100 of subtypes

11. Pathology 15 - 40 % acute illness resolving completely Mechanism of hepatitis is Unknown Lymphocytes are seen in liver parenchyma

12. Immune escpae E2 and NS3 interfere with IFN - induced double - stranded - RNA - activated protein kinase and allow HCV to replicate Retinoic - acid - inducible gene I Ifn regulatory factor 3 pathway

13. Diagnostic tests Anti – HCV : detection of the viral antigen is difficult. Serum HCV RNA : 10 – 15 IU/ mL . No direct correlation with activity or progression of the disease. Change of 1 log value are normal during HCV course Genotyping : Type 6 is prevalent in South East Asia, Asian Americans and Asian Australians. Type 3 : Faster progression. Type 1b : Faster HCC Response to treatment is influenced by the infecting genotype. HCV 1 is least pathogenic.

14. Genotypes in INDIA Genotype 3 : 60% Genotype 1 : 30% Genotype 4 : 6% Genotype 2,6 : 4%

15. Acute hepatitis C Typically unrecognized Incubation period : 2 – 12 weeks (average 7weeks) HCV RNA becomes positive within 2 weeks of exposure Anti - HCV positive within 8 – 10 weeks of exposure Female gender , acute severe hepatitis and jaundice : faster viral clearance

16. MANAGEMENT SPECIFIC ANTIVIRALS SUPPORTIVE TREATMENT IFN – a PEG – IFN –a + RIBAVARIN NO RESPONSE IN 2- 4 MONTHS DONOT WAIT AND WATCH START TREATMENT IMMEDIATELY ASYMPTOMATIC ARE PREFERRED NO ROLE OF PROPHYLACTIC IFN AFTER NEEDLE PRICK STARTING TREATMENT OF 1 YEAR HAS UNSATISFACTORY OUTCOME

17. Chronic Hep C HCV RNA > 6 months in serum Asymptomatic and go unnoticed Usually serum ALT is abnormal after 12 months of infection ( 2x to 8x ) 10-20 % develop cirrhosis in next 20 years Younger the age lesser the cirrhosis 2% infected before the age of 20 developed cirrhosis over a 20 - year period 6% of those infected between 31 and 40 years, 37% infected between the age of 41 and 50 years 63% infected after the age of 50

18. Progressive disease results in worse lab values : AST > ALT Low Serum albumin Prolonged PT Low platelet count Low level of auto antibodies Positive for LKM-1 antibodies

19. Extrahepatic manifestations Autoimmune Hepatitis, Cryoglobulinaemia , Vasculitis , Lichen Planus , Porphyria Cutanea Tarda , Lymphocytic Sialoadenitis And Membranous Glomerulonephritis Non - Hodgkin ’ S Lymphoma Insulin resistance and T2DM

20. Microscopy Mild portal tract inflammation Lymphoid aggregates or follicles Mild periportal piecemeal necrosis Parenchymal steatosis, Apoptosis and mild lobular inflammation Portal fibrosis or portal – central fibrosis Bridging necrosis - rarely Granulomas - rarely

21. Management - Approach HCV RNA in serum Anti HCV antibodies Liver enzymes PT Bilirubin levels HCV Genotyping HBsAg HIV Anti Smooth muscle antibody Anti LKM antibodies

22. Liver biposy Not mandatory for all Unique extra information is available with biopsy like grading of fibrosis and necroinflammation Calculation of fibrosis 1. AST/Platelet ration Index ( APRI ) : 80 -90% accuracy 2. Transient elastography ( Fibroscan ) Normal = 4-6 kilo-pascals Cirrhosis = 12 – 14 kilo pascals

23. The Enhanced Liver Fibrosis Panel Fibrotest Ultrasound Microbubble Hepatic Transit Times (HTT) Two tests show concordance : avoid biopsy Two tests show discordance : do biopsy

24. Indications for treatment All patients Psychiatry patients may worsen with IFN treatment In cirrhotics : Avoid IFN : Plan for transplant

25. Peg IFN – a ( ONCE A WEEK ) & RIBAVARIN ( DAILY ) Peg IFN – a Half life : 3 – 8 hours Peak Sr Conc : 7 – 12 hour after injection Cleared from blood : < 24 hours RIBAVARIN Guanosine analogue Inhibition of guanyltransferase and methytransferase capping enzymes Induce mutation affecting HCV replication <65kg : 800mg 65-85kg : 1000mg >85kg : 1200mg

26. PEG IFN a : 180 microgm /week Genotype 1 48 week therapy < 75 kg : 1000 mg >75kg : 1200 mg Genotype 2 and 3 24 week therapy 800mg / day

27. Response to IFN + Ribavirin > 40% SVR in genotype 1 and 4 > 80% SVR in genotype 2 and 3 In hep B the response of increase in ALT after therapy is good response and it is reverse in case of hep C.

28. SVR of > 24 week is considered as good sign. It is accepted as an equivalent for viral cure Genotype 1 : Total duration of 48 weeks of PegIFN + Ribavirin Genotype 2 and 3 : 24 week of therapy

29. Ribavirin Most common adverse effect is hemolysis . Reduction of Hb % upto 2-3 gm% is seen Reduction of haematocrit upto 10% Risk of usage in patients with stroke / CAD / Hemoglinopathies . Increase in anemia on ribavirin usage, Epo can be supplemented Reduction of dose of ribavirin upto 60% of planned dose is acceptable

30. PegIFN types pegIFN alpha 2a pegIFN alpha 2b 40 kilodalton molecule 12 kilodalton molecule Dose is weight independent Dose is weight dependent 180 microgram / week + 800 mg Ribavirin 1.5 microgram / kg / week + 1000 mg Ribavirin BETTER TOLERABLE GOOD COMPLIANCE

31. Treatment of genotype 1 and 4 Until 2013 the only treatment available was PegIFN and Ribavirin However, with the introduction of protease inhibitors, the treatment of HCV found many new turns and paths PI’s are contraindicated if age < 18 years

32. DROP IN THE LEVEL OF HCV RNA AT 12 WEEKS <2 LOG 10 OF EVR 2 LOG 10 OF EVR UNDETECTABLE HCV RNA NEGLIGIBLE SVR 66% SVR >80% SVR

33. 1 ST GENERATION Protease Inhibitors NS3-4A serine protease inhibitors Boceprevir Telaprevir Introduced in 2011 for both previously failed treatment and untreated patients Never to be used alone

34. Triple therapy with PI’s Protease inhibitor + PegIFN -a + Ribavirin Response to treatment at week 4 and 12 Start Dual therapy with PegIFN + Ribavirin SVR : Telaprevir = 79 % SVR : Boceprevir = 59 – 66 % Telaprevir > Boceprevir in overall SVR rates and tolerability

35. Genotype 1 : naïve = PegIFN + Ribavirin + Boceprevir

36. Terminate the treatment if : HCV RNA detectable in serum of > 100 IU / ml at 24 week with Boceprevir HCV RNA detectable in serum of > 1000 IU / ml at 24 week with Telaprevir

37. Genotype 1 : Prior experienced treatment

38. TELAPREVIR : Adverse effects Rashes : Maculopapular Rectal burning sensation Nausea Anemia Vomiting and diarrhoea

39. BOCEPREVIR : Adverse effects Anemia , leucopenia , thrombocytopenia Fatigue Nausea Vomiting Headache

40. Simeprevir Particularly for Genotype 1 Regimen similar to the 1 st gen Protease inhibitors

41. Sofosbuvir : Polymerase inhibitor

42. Response 40 – 50 % virological response with combination therapy Studies have concluded that optimum dose of ribavarin is 10.6mg/kg/day with response of 48 % for genotype 1 88% for genotype 2 and 3 In genotype 1 : response less than 2 log 10 after 12 weeks of therapy : DISCONTINUE THERAPY Patients who are HCV RNA - positive at 6 months of therapy, should stop therapy

43. There may be benefit in prolonging therapy to 72 weeks in slow responders, Negative PCR after 24 weeks of More than 2 log 10 decline at 12 weeks The response to treatment of genotype 4 is intermediate between genotype 1 and 2 or 3. There are limited published data on treatment outcome in patients with genotype 5.

44. RESPONSES and DEFINITION

45. Side effects – IFN alpha Flu like symptoms Seizure Acute psychosis autoimmune diseases Bacterial infections Hyperthyroidism and thyroiditis Proteinuria Cardiomyopathy IFN antibodies Neuroretinitis ILD Sarcoidosis

46. Haemolytic anaemia, Myalgia, Hyperuricaemia, Dyspepsia, Monitored for haemoglobin , leucocytes and platelets, AST, ALT, albumin, bilirubin every 4 weeks. Uric acid and thyroid function at 1 to 3 - monthly intervals. Risk of teratogenicity, need for contraception up to 6 months after completing treatment. Side effects – Ribavarin

47. Depression 20 – 40 % of cases Moderate severity First 4 – 8 weeks SSRI are DOC Dose modification needed in presence of anemia and cirrhosis Epo and G-CSF are needed in severe cases

48. Non Responders Start with never antivirals Response is poor with success rates of 20% Genotype 2 & 3 > Genotype 1 has better response

49. Retreatment trials EPIC and HALT – C : some response to retreatment of patients with advanced fibrosis or cirrhosis treated with PEG - IFN - α and RBV. EPIC3 and HALT - C have not shown a definite benefit of low - dose IFN in non – responders HALT - C trial did not show a difference in primary clinical outcomes. EPIC3 trial : maintenance IFN therapy : may delay progression of portal hypertension and variceal bleeding in a subset of patients

50. PEG - IFN plus RBV Non - responders or relapses to either standard IFN plus RBV or PEG - IFN monotherapy. PEG - IFN plus RBV retreatment Less value if low SVR inprevious full course of PEG - IFN plus RBV. Treatment should be stopped if no early viral response with re - treatment

51. Drugs Aug 2011 : Boceprevir and Telaprevir Nov 2013 : Simeprevir Dec 2013 : Sofusbuvir Oct 2014 : Ledipasvir/Sofosbuvir Nov 2014 : Simepravir /Sofosbuvir Dec 2014 : Ombitasvir / paritaprevir / ritonavir Dec 2014 : Dasabuvir July 2015 : Daclatasvir Jan 2016 : Sofosbuvir / Velpatasvir

52. Protease inhibitors Boceprevir Telaprevir Simeprevir Aritaprevir

53. NS5A inhibitors Odalasvir Ombitasvir Ravidasvir Samatasvir Velpatasvir Daclatasvir : all genotypes, 60mg OD, Elbasvir Ledipasvir : HCV 1 and 4, 90mg OD,

54. NS5B inhibitors Beclabuvir Dasabuvir Deleobuvir Filibuvir Radalbuvir Setrobuvir Sofosbuvir : Genotypes 1 -6 , 400mg OD, Renal excretion

55. Newer drugs Genotype 1, 4, 5, 6 : Sofosbuvir + Ledipasvir : 12 week orally Genotype 2, 3 : Sofosbuvir monotherapy Genotype 3 : Daclatasvir

56. Genotype 1 (AASLD – 2016) Non cirrhotics SOFOSBUVIR + LEDIPASVIR (12 WEEK) Sofosbuvir + Daclatasvir (12 week) Sofosbuvir + Simeprevir (12 week) Elbasvir + Grazoprevir (12 week) Paritaprevir + Ombitasvir + Dasabuvir + Ribavirin (12 week) Cirrhotics SOFOSBUVIR + LEDIPASVIR (12 WEEK) Sofosbuvir + Daclatasvir +/- Ribavirin (24 week) Sofosbuvir + Simeprevir +/- Ribavirin (24 week) Elbasvir + Grazoprevir (12 week) Paritaprevir + Ombitasvir + Dasabuvir + Ribavirin (24 week)

57. Genotype 2 Non cirrhotics SOFOSBUVIR + DACLATASVIR (12 WEEK) Sofosbuvir + Ribavirin (12 week) Cirrhotics SOFOSBUVIR + DACLATASVIR (24 WEEK) Sofosbuvir + Ribavirin (16 – 24 week)

58. Genotype 3 Non cirrhotics SOFOSBUVIR + DACLATASVIR (12 WEEK) Sofosbuvir + Ribavirin + PegIFN (12 week) Sofosbuvir + Ribavirin (12 week) Cirrhotics SOFOSBUVIR + DACLATASVIR +/- RIBAVIRIN (12 WEEK) Sofosbuvir + Ribavirin + PegIFN (12 week)

59. Genotype 4 Non cirrhotics SOFOSBUVIR + LEDIPASVIR (12 WEEK) Sofosbuvir + Ribavirin + PegIFN (12 week) Elbasvir + Grazoprevir (12 week) Paritaprevir + Ombitasvir + Dasabuvir + Ribavirin (12 week) Cirrhotics SOFOSBUVIR + LEDIPASVIR (12 WEEK) Sofosbuvir + Ribavirin + PegIFN (12 week) Elbasvir + Grazoprevir (12 week) Paritaprevir + Ombitasvir + Dasabuvir + Ribavirin (12 week)

60. Genotype 5 / 6 Non cirrhotics SOFOSBUVIR + LEDIPASVIR (12 WEEK) Sofosbuvir + Ribavirin + PegIFN (12 week) Cirrhotics SOFOSBUVIR + LEDIPASVIR (12 WEEK) Sofosbuvir + Ribavirin + PegIFN (12 week)

61. DRUG INTERACTIONS Sofusbivir Amiodarone : serious bradycardia Daclatasvir CYP450 Inducers : Increase dose from 90mg to higher CYP450 Inhibitors : Reduce dose to 30mg

62. Cost of HCV Treatment ?

63. Cost Boceprevir : Rs 70000 / week Telaprevir : Rs 2,66,000 / week Drug Dollars INR Simeprevir Per 150mg Capsule $790 51,000 28 Days Simeprevir $22120 14,40,000 12-week Supply Of Simeprevir $66360 43,21,064 Simeprevir When Used With A Total Of 24-weeks Of Peginterferon Plus Ribavirin $85,000 55,34,817 Simeprevir Plus Sofosbuvir For 12 Week $150000 97,67,325

64. Wholesale acquisition cost (WAC) for LEDIPASVIR-SOFOSBUVIR  Drug Dollar INR Per Pill $1125 73,254 8-week course of therapy $63000 41,02,276 12-week course of therapy $94000 61,20,857 24-week course of therapy $189000 1,23,06,829

65. VACCINE

66. References Sherlock’s Diseases Of The Liver And Biliary System Harrison's Principles Of Internal Medicine AASLD Guidelines 2016 EASL Guidelines 2017 Preventive And Social Medicine By Park Nelson’s Text Book Of Paediatrics Text Book Of Microbiology By Apurba Shastry Medguideindia.com - Internet