Hepatitis C - Etiology Pathogenesis Clinical Features Diagnosis Management

Etiology Pathogenesis Clinical Features Diagnosis Management

1. Hepatitis C GUIDE:DR SACHIN HOSKATTI STUDENT : DR ABHAY KIRAN

2. Epidemiol o gy  Population prevalence : 2 – 3% of the world ’ s population  70 and 130 million individuals may be chronically infected  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  Single leading indication for liver transplantation in Europe and north America

4. Epidemiology

5. Transmission  Parenterally  Permucosally  Vertically

6. HCV Virus  Discovered in 1989 small single stranded Enveloped RNA virus  Family flaviviridae  A single polyprotein that is processed into 10 functional proteins

7.  E1 and E2 are important antigenic sites  Variability may be important in persistence of infection and immunopathogenesis  RNA - dependent RNA polymerase  Non – structural region of the HCV genome is divided into regions NS2 to NS5 NS5A is essential for assembly of hcv into mature virions 

8. Because of low fidelity of HCV RNA polymerase ,viral genome is very unstable 6 genotypes Genotypes 1 to 6

9. HCV genome organization

10. Pathology in 15 - 40 % acute illness resolving completely In others it progress to chronic infection HCV uses variety of strategies to escape innate and adaptive immune responce

11. HCV induces hepatocellular injury by cell mediated immune mecha nism is supported by the following: i ) It is possible that the host lymphoid cells are infected by HCV. ii) HCV-activated CD4+ helper T lymphocytes stimulate CD8+ T lymphocytes via cytokines elaborated by CD4+ helper T cells.

12. iii) The stimulated CD8+T lymphocytes, in turn, elaborate antiviral cytokines against various HCV antigens. iv) Further support to this T- cell mediated mechanism comes from the observation that immune response is stronger in those HCV-infected persons who recover than those who harbour chronic HCV infection.

13. v) There is some role of certain HLA alleles and innate immunity in rendering variable response by different hosts to HCV infection. vi) Natural killer (NK) cells also seem to contribute to containment of HCV infection.

14. vii) In as subset of patients, there is cross reactivity between viral antigens of HCV and host autoantibodies to liver-kidney microsomal antigen (anti-LKM) which explains the association of autoimmune hepatitis and HCV hepatitis .

15. Diagn o sti c tests  Anti – HCV : doesnot identify active infection .  Serum HCV RNA : 5 – 15 IU/mL .  Genotyping

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

17. Acute hepatitis C  generally asymptomatic  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

18. MANAGEMENT SUPPORTIVE TREATMENT SPECIFIC ANTIVIRAL THERAPY IFN MONOTHERAPY[>90% SVR] ASYMPTOMATIC PATIENT- DIRECT ANTIVIRAL AGENTS SOFOSBUVIR +LEDIPASVIR[6-8WKS]

19. Chronic Hep atitis C Presence of HCV RNA > 6 months in serum Asymptomatic and go unnoticed 10-20 % develop cirrhosis in next 20 year s

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

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

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

23. Management - Approach HCV RNA in serum Anti HCV antibodies Liver enzymes PT Bilirubin levels HCV Genotyping HBsAg HIV Anti LKM antibodies

24. Liver biposy  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

25. Indications for treatment  All patients  Psychiatry patients may worsen with IFN treatment  In cirrhotics : Avoid IFN

26. Peg IFN – a ( ONCE A WEEK ) & RIBAVAR ( DAILY ) Peg IFN – a 1. Half life : 3 – 8 hours 2. Peak Sr Conc : 7 – 12 hour after in j ec tion 3. Cleared from blood : < 24 hours RIBAVARIN 1. Guanosine analogue 2. Inhibition of guanyltransferase and methytransferase capping enzymes 3. Induce mutation affecting HCV replication 4. <65kg : 800mg 5. 65-85kg : 1000mg 6. >85kg : 1200mg

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

28. 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

29. PegIFN types pegIFN alpha 2a pegIFN alpha 2b 40 kilodalton mol e cu l e 12 kilodalton mol e cu l e Dose is weight independent Dose is weight d e p e nd e nt 180 microgram / w e e k + 800 mg Ribavirin 1.5 microgram / kg / week + 1000 mg Ribavirin BETTER TOLERABLE GOOD COMPLIANCE

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

31.  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

32. 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

33. NS5A inhibitors  Odalasvir  Ombitasvir  Ravidasvir  Samatasvir  Velpatasvir  Daclatasvir  Elbasvir  Ledipasvir

34. NS5B inhibitors  Beclabuvir  Dasabuvir  Deleobuvir  Filibuvir  Radalbuvir  Setrobuvir  Sofosbuvir

35. Sofosbuvir nucleotide NS5B polymerase inhibitor Can be given in cirrhotic patient excreted by the kidneys and not recommended for patients with an estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m2

36. Sofosbuvir and ledipasvir fixed drug combination of an NS5B polymerase inhibitor and an NS5A inhibitor Daily once tablet containing 400 mg of sofosbuvir and 90 mg of ledipasvir Biliary excretion of unchanged ledipasvir is the major route of elimination.

37. Sofosbuvir and velpatasvir fixed drug combination of the NS5B and a second‐generation NS5A inhibitor Once dialy tablet containing 400 mg of sofosbuvir and 100 mg of velpatasvir

38. Ritonavir-boosted paritaprevir , ombitasvir , and dasabuvir ( PrOD ) combination comprises a tablet containing 75 mg of paritaprevir 12.5 mg of ombitasvir , 50 mg of ritonavir 250 mg of dasabuvir

39. Two tablets of paritaprevir – ombitasvir –ritonavir are taken once daily. One tablet containing 250 mg of dasabuvir is taken twice daily Paritaprevir is an NS3–4A protease inhibitor Ombitasvir is an NS5A inhibitor Dasabuvir is a non‐nucleoside NS5B polymerase inhibitor .

40. Grazoprevir and elbasvir Grazoprevir -protease inhibitor elbasvir - NS5A inhibitor One tablet containing 100 mg of grazoprevir and 50 mgof elbasvir is taken once daily

41. Daclatasvir NS5A inhibitor The combination of sofosbuvir and daclatasvir has activity against genotypes 1–6 Dosage-60mg No dose adjustment of daclatasvir is required in advanced liver disease or for patients with renal failure. Almost 90% of daclatasvir is eliminated in faeces

42. Simeprevir is a protease inhibitor one capsule containing 150 mg No dose adjustment of simeprevir is necessary in moderate renal impairment

43. Pibrentasvir and glecaprevir Glecaprevir (formerly ABT‐493) is a pangenotypic NS3–4A protease inhibitor Pibrentasvir (formerly ABT‐530) is a Pangenotypic NS5A inhibitor Pibrentasvir shows potent activity against genotypes 1–6 once daily as three 100 mg/40 mg pills for a total dose of 300 mg/120 mg. The drugs are excreted primarily by biliary excretion

44. Prevention Safe blood transfusion Safe injections Education Preventing injecting drug use Clean needle programmes Treatment forms part of attempts to control the disease and to prevent transmission

45. Other co‐morbid conditions or modifiable factors, particularly alcohol, obesity, and coinfection with hepatitis B and HIV should be addressed Screening of undiagnosed individuals Improving the cascade of linkage to care Future vaccination

46. References Sherlock’s Diseases Of The Liver And Biliary System Harrison's Principles Of Internal Medicine Robbins basic of Pathology

47. THANK YOU