Advances in Management of Hepatitis C

Patients with acute hepatitis C virus (HCV) infection appear to have an excellent chance of responding to 6 months of standard therapy with interferon (IFN). Because spontaneous resolution is common, no definitive timing of therapy initiation can be recommended; however, waiting 2-4 months after the onset of illness seems reasonable.
Treatment for chronic HCV is based on guidelines from the Infectious Diseases Society of America (IDSA) and the American Associations for the Study of Liver Diseases (AASLD), in collaboration with the International Antiviral Society-USA (IAS-USA). These guidelines are constantly being updated. For more information, see HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C.


The guidelines propose that because all patients cannot receive treatment immediately upon the approval of new agents, priority should be given to those with the most urgent need.

The recommendations include the following :
Patients with advanced fibrosis, those with compensated cirrhosis, liver transplant recipients, and those with severe extraheptic hepatitis are to be given the highest priority for treatment
Based on available resources, patients at high risk for liver-related complications and severe extrahepatic hepatitis C complications should be given high priority for treatment
Treatment decisions should balance the anticipated reduction in transmission versus the likelihood of reinfection in patients whose risk of HCV transmission is high and in whom HCV treatment may result in a reduction in transmission (eg, men who have high-risk sex with men, active injection drug users, incarcerated persons, and those on hemodialysis)

1. A dvances in management of Hepatitis C (September 2016) Dr. Arun Vasireddy Dept of Medicine

2. Background High worldwide prevalence of HCV with regional differences Transmission by blood and associated risk factors High genomic variability of HCV Extrahepatic manifestations ( especially B-cell proliferative disorders) Multiple infections possible (lack of sterilizing immunity) Traditionally IFN containing regimens Newer DAAs IFN free regimens are soon going to be reality No prophylactic vaccine yet available

3. Epidemiology 185 million people are HCV infected worldwide 3-4 million is the incidence/year HCV : Leading cause of liver transplantation 27% of cirrhosis and 25 % of liver cancer can be attributed to hepatitis C worldwide 1. Abstract 23; Benjamin C. Cowie et al. Presented at the 64th AASLD meeting, Nov 1-5, 2013; Washington, DC. 2. J Hepatol 2006;45:529-538. 3. Hepatology 2013;57:1333-1342 4. J. Biosci . 2008;33 465–473. 5. Indian J Gastroenterol 1998;17:100 –3.

4. Global HCV prevalence among adults

5. Relative genotype prevalence of HCV genotypes Hepatology. 2014 Jul 28. doi: 10.1002/hep.27259. HCV genotype 1 is the most prevalent worldwide, comprising 83.4 million cases (46.2% of all HCV cases), approximately one third of which are in East Asia Genotype 3 is the next most prevalent globally (54.3 million, 30.1%)

6. Indian Epidemiology The prevalence of HCV infection in India is estimated at between 0.5% and 1.5% (15-18 million) It is higher in the north-eastern part, tribal populations and Punjab, areas that may represent HCV hotspots, and is lower in the western and eastern parts of the country Genotype 3 is the most common HCV genotype in India (accounting for 54–80% of cases), followed by genotype 1 Genotype 1 has been reported more commonly from southern India and there are increasing reports of genotype 4 from India. Journal of Clinical and Experimental Hepatology 2014; 4(2):106–116.

7. Structure of HCV HCV genome has one 9.6 kb single-stranded RNA The viral RNA codes a precursor polyprotein of approximately 3,000 amino acid residues During viral replication, the polyprotein is broken down by viral as well as host enzymes into three structural proteins (core, E1, E2) and seven non-structural proteins (p7/NS1, NS2, NS3, NS4A, NS4B, NS5A, and NS5B)

8. Natural history of HCV mono-infection over 10-15 years Clin Liver Dis. 2005;9:383-398 Eur J Gastroenterol Hepatol. 1996;8:324-328. Hepatology. 2002;36( suppl ):S1-S2. Hepatology. 2002;36( suppl ):S35-S46. Ann Intern Med. 2000;132:296-305. Gastroenterology. 1997;112:463-472.

9. HCV: Major epidemic that is untreated

10. Why every patient cant be on Peg IFN-RBV therapy In some patients IFN or RBV contraindicated HCV may spontaneously resolve Fibrosis may be absent or nonprogressive Injections may be intolerable Autoimmune conditions or mental illness may be exacerbated Cost/benefit evaluation Peg-IFN toxicity Flu-like and GI symptoms Cytopenias (thrombocytopenia, neutropenia) Depression (including suicidal ideation), somnolence Autoimmune disease Hair loss RBV toxicity Cardiovascular disease Hemolytic anemia Risk of fetal malformations Renal failure Semin Liver Dis. 1999;19( suppl 1):67-75.

11. Challenges with existing Peg IFN-RBV therapy Genotype 1 HCV infections are more severe and are less responsive to Peg/Ribavirin therapy than either type 2 or 3 infections Approximately 25-35% of G1 treatment naïve patients and 50-60% of G1 HCV patients who failed to respond to a first course of treatment with PEG-IFN and RBV do not achieve SVR and are not cured of HCV infection with even triple combination with telaprevir/boceprevir Cure—sustained virologic response (SVR) achieved in only ~40-50% of genotype1 patients and 70-80% of genotype 2 or 3 patients

12. Targets for directly acting antivirals in the HCV Liver International 2012; 32, Supplement s1:88–102.

13. Overview of DAAs NS3/4A NS5A NS5B Function Serine Protease Component of HCV Replication Complex RNA-dependent RNA polymerase Drugs Covalent Boceprevir Telaprevir   Non-covalent Faldaprevir Simeprevir ABT-450 Asunaprevir MK-5172( Grazoprevir ) Ledipasvir Daclatasvir Ombitasvir MK-8742 ( Elbasvir ) PPI-668 Nucleos(t)ide analogs Sofosbuvir ACH-3422   Non-nucleoside BMS-791325 /Beclabuvir Dasabuvir Deleobuvir C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Core Envelope Glycoproteins Protease Serine Protease Helicase Serine Protease Cofactor RNA-dependent RNA polymerase Component of HCV Replicase

14. Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD. SVR (%) IFN 6 mos PegIFN/ RBV 12 mos IFN 12 mos IFN/RBV 12 mos PegIFN 12 mos 2001 1998 2011 Standard IFN RBV PegIFN 1991 DAAs PegIFN/ RBV/ DAA IFN/RBV 6 mos 6 16 34 42 39 55 70+ 20 40 60 80 100 DAA + RBV ± PegIFN 90+ 2013 The Good News

15. Treatment indications-2015

16. Treatment Guidelines

17. Treatment Naïve Patients Genotype 1 Treatment History Cirrhosis Status IFN Eligibility Preferred Regimen Naive Non – Cirrhotic or Cirrhotic Eligible Sofosbuvir + PEG-IFN/RBV x 12 weeks Non – Cirrhotic Ineligible Sofosbuvir + RBV x 24 weeks or Sofosbuvir + Simeprevir +/- RBV x 12 weeks (NOT FDA Approved) Cirrhotic Ineligible Sofosbuvir + Simeprevir +/- RBV x 12 weeks (NOT FDA Approved) Abbreviations: PEG-IFN = Peginterferon ; RBV = Ribavirin Dosages: PEG-IFN alfa-2a 180mcg subcutaneously weekly or Peg-IFN alfa-2b 1.5 mcg/kg subcutaneously weekly; RBV weight based 1,000 mg (<75kg) or 1,200 mg (>75kg) orally daily in two divided doses with food; S imeprevir 150 mg orally with food; Sofosbuvir 400mg orally daily

18. Treatment Naïve Patients Genotype 2 Treatment History Cirrhosis Status IFN Eligibility Preferred Regimen Naive Non -Cirrhotic Either Sofosbuvir + RBV x 12 weeks Cirrhotic Either Sofosbuvir + RBV x 16 weeks Abbreviations: PEG-IFN = Peginterferon ; RBV = Ribavirin Dosages: PEG-IFN alfa-2a 180mcg subcutaneously weekly or Peg-IFN alfa-2b 1.5 mcg/kg subcutaneously weekly; RBV weight based 1,000 mg (<75kg) or 1,200 mg (>75kg) orally daily in two divided doses with food; S imeprevir 150 mg orally with food; Sofosbuvir 400mg orally daily

19. Treatment Naïve Patients Genotype 3 Treatment History Cirrhosis Status IFN Eligibility Preferred Regimen Naive Non -Cirrhotic or Cirrhotic Eligible Sofosbuvir + RBV x 24 weeks or Sofosbuvir + PEG-IFN/RBV x 12 weeks Non -Cirrhotic or Cirrhotic Ineligible Sofosbuvir + RBV x 24 weeks Abbreviations: PEG-IFN = Peginterferon ; RBV = Ribavirin Dosages: PEG-IFN alfa-2a 180mcg subcutaneously weekly or Peg-IFN alfa-2b 1.5 mcg/kg subcutaneously weekly; RBV weight based 1,000 mg (<75kg) or 1,200 mg (>75kg) orally daily in two divided doses with food; S imeprevir 150 mg orally with food; Sofosbuvir 400mg orally daily

20. Treatment Naïve Patients Genotype 4,5 or 6 Treatment History Cirrhosis Status IFN Eligibility Preferred Regimen Naive Non -Cirrhotic or Cirrhotic Eligible Sofosbuvir + PEG-IFN/RBV x 12 weeks Non -Cirrhotic or Cirrhotic Ineligible Sofosbuvir + RBV x 24 weeks Abbreviations: PEG-IFN = Peginterferon ; RBV = Ribavirin Dosages: PEG-IFN alfa-2a 180mcg subcutaneously weekly or Peg-IFN alfa-2b 1.5 mcg/kg subcutaneously weekly; RBV weight based 1,000 mg (<75kg) or 1,200 mg (>75kg) orally daily in two divided doses with food; S imeprevir 150 mg orally with food; Sofosbuvir 400mg orally daily

21. Treatment guidelines - Treatment failure cases

22. Treatment Failure Cases Genotype 1 Recommended regimens for patients with HCV genotype 1a or 1b infection who have compensated cirrhosis, in whom prior PEG-IFN and RBV treatment has failed. Daily fixed-dose combination of ledipasvir (90 mg)/ sofosbuvir (400 mg) for 24 weeks is recommended for patients with HCV genotype 1a or 1b infection who have compensated cirrhosis, in whom prior PEG-IFN and RBV treatment has failed OR Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks is recommended for patients with HCV genotype 1 infection , regardless of subtype, in whom prior PEGIFN and RBV treatment has failed.

23. Treatment Failure Cases Genotype 2 Recommended regimen for patients with HCV genotype 2 infection, in whom prior PEG-IFN and RBV treatment has failed. Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [> 75 kg]) for 12 weeks to 16 weeks is recommended for patients with HCV genotype 2 infection, in whom prior PEG-IFN and RBV treatment has failed. Alternative regimen for patients in whom previous PEG-IFN and RBV treatment failed who have HCV genotype 2 infection and are eligible to receive IFN. Retreatment with daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [< 75kg ] to 1200 mg [>75 kg]) plus weekly PEG-IFN for 12 weeks is an alternative for patients in whom previous PEG-IFN and RBV treatment failed who have HCV genotype 2 infection and are eligible to receive IFN.

24. Treatment Failure Cases Genotype 3 Recommended regimen for patients with HCV genotype 3 infection in whom prior PEG-IFN and RBV treatment has failed. Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [> 75 kg]) for 24 weeks is recommended for treatment of HCV genotype 3 infection in patients in whom prior PEG-IFN and RBV treatment has failed . Alternate regimen for patients with HCV genotype 3 who are eligible to receive IFN, in whom prior PEG-IFN and RBV treatment has failed. Retreatment with daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [< 75kg ] to 1200 mg [>75 kg]) plus weekly PEG-IFN for 12 weeks is an alternative for patients with HCV genotype 3 infection who are eligible to receive IFN, in whom prior PEG-IFN and RBV treatment has failed.

25. Treatment Failure Cases Genotype 4 Recommended regimen for patients with HCV genotype 4 infection in whom prior PEG-IFN and RBV treatment has failed Daily sofosbuvir (400 mg) for 12 weeks and daily weight-based RBV (1000 mg [< 75kg ] to 1200 mg [>75 kg]) plus weekly PEG-IFN for 12 weeks is recommended for retreatment of IFN-eligible patients with HCV genotype 4 infection, in whom prior PEG-IFN and RBV treatment has failed . OR Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [> 75 kg]) for 24 weeks is recommended for retreatment of patients with HCV genotype 4 infection, in whom prior PEG-IFN and RBV treatment has failed . Genotype 5 and 6 Recommended regimen for patients with HCV genotype 5 infection in whom prior treatment has failed. Daily s ofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [> 75 kg]) plus weekly PEG-IFN for 12 weeks is recommended for patients with HCV genotype 5 and 6 infection in whom prior treatment has failed.

26. Treatment guidelines - Patients with Decompendated Cirrhosis

27. Patients with Decompensated Cirrhosis Genotype 1 and 4 For patients with decompensated cirrhosis in whom prior sofosbuvir -based treatment has failed, daily fixed-dose combination ledipasvir (90 mg)/ sofosbuvir ( 400 mg) and RBV (initial dose of 600 mg, increased as tolerated) for 24 weeks . Genotype 2 and 3 Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [> 75 kg]) (with consideration of the patient’s creatinine clearance rate and hemoglobin level) for up to 48 weeks is recommended for patients with HCV genotype 2 or 3 who have decompensated cirrhosis. This regimen should be used only by highly experienced HCV practitioners .

28. Treatment guidelines - Patients with recurrent hcv infection post liver transplant

29. Recurrent Post Liver Transplantation Genotype 1 or 4 Daily fixed-dose combination of ledipasvir (90 mg)/ sofosbuvir (400 mg) with weight based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks is recommended for patients with HCV genotype 1 or 4 infection in the allograft, including compensated cirrhosis . Genotype 2 Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [> 75 kg]) for 24 weeks is recommended for patients with HCV genotype 2 in the allograft , including compensated cirrhosis Genotype 3 Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [> 75 kg]) for 24 weeks is recommended for treatment-naive patients with HCV genotype 3 infection in the allograft, including compensated cirrhosis.

30. Treatment guidelines - Patients with Hepatocellular Carcinoma

31. Patients with Hepatocellular Carcinoma Genotype Treatment History Cirrhosis Status IFN Eligible Preferred Regimen 1,2,3 or 4 Naïve or Experienced Hepatocellular carcinoma Either Sofosbuvir + RBV x 24-48 weeks or until liver transplant, whichever occurs first Dosages: Sofosbuvir – 400mg once daily with or without food RBV( Ribavirin ) – Weight based 1000mg (<75 kg) or 1200mg (>75kg) orally daily in two divided doses with food

32. Summary Dosages: PEG-IFN alfa-2a 180mcg subcutaneously weekly or Peg-IFN alfa-2b 1.5 mcg/kg subcutaneously weekly; RBV weight based 1,000 mg (<75kg) or 1,200 mg (>75kg) orally daily in two divided doses with food; Sofosbuvir 400mg orally daily with or without food

33. Rationale for IFN-Free Direct-Acting Antiviral Therapy for HCV Drawbacks of IFN-based Therapy Challenging tolerability High percentage of patients are ineligible for IFN Long duration of therapy Low SVR rates compared to modern all-oral regimens PR: ~40-50% in treatment-naïve patients Triple therapy PR + boceprevir or telaprevir: ~70% Many patient-specific and virus-specific factors affecting eligibility or treatment response (Race, IL28B, cirrhosis, prior treatment, etc) Development of resistance Requires injection

34. Not All Direct-Acting Antivirals are Created Equal Characteristic Protease Inhibitor * Protease Inhibitor ** NS5A Inhibitor Nuc Polymerase Inhibitor Non- N uc Polymerase Inhibitor Resistance profile Pangenotypic efficacy Antiviral p otency Adverse events Good profile Average profile Least favorable profile *First generation. **Second generation.

35. Future HCV treatment Clinical and Translational Medicine 2013, 2:9 IFN - sparing regimens IFN /RBV - free regimens

36. Newer DAA’s globally for HCV treatment IFN free DAA combinations Sofosbuvir +ledipasvir FDC ± RBV (Genotype 1 ) Sofosbuvir + Simeprevir ± RBV (Genotype 1 ) AbbVie's 3D regimen : paritaprevir (ABT-450) boosted with ritonavir , ombitasvir as FDC and dasabuvir ± RBV (Genotype 1 ) Grazoprevir + Elbasvir ± RBV (Genotype 1 ) (pending approval ) Sofosbuvir + Daclatasvir ± RBV (Pangenotypic) (pending approval in USA) Sofosbuvir + GS 5816 ± RBV (Pangenotypic) (pending approval in USA)

37. Studies with newer daa drugs

38. FISSION Trial: Sofosbuvir + RBV (12 weeks) : GT2 &3 Gane E, et al. J Hepatol. 2013;58( suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. SVR12, % Patients Genotype 2 98% 91% 82% 62% No Cirrhosis Cirrhosis SVR12, % Patients Genotype 3 61% 71% 34% 30% No Cirrhosis Cirrhosis Sofosbuvir + RBV PR n=59 n=54 n=11 n=13 n=145 n=139 n=38 n=37 Sofosbuvir + RBV PR

39. POSITRON: Sofosbuvir + RBV for 12 Weeks interferon-ineligible, -intolerant, or -unwilling patients Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. SVR12 (%) Genotype 2 92% 94% No Cirrhosis (n=92) Cirrhosis (n=17) Patients (%) Genotype 3 68% 21% No Cirrhosis (n=84) Cirrhosis (n=14) SVR12 rate was 0% in the placebo arm.

40. FUSION Trial: SVR12 Rates by Genotype and Cirrhosis Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. Patients (%) Genotype 2 96% 60% 100% 78% No Cirrhosis Cirrhosis Patients (%) Genotype 3 37% 63% 19% 61% No Cirrhosis Cirrhosis Sofosbuvir + RBV 12 weeks 16 weeks Sofosbuvir + RBV 12 weeks 16 weeks n=26 n=23 n=10 n=9 n=38 n=40 n=26 n=23 Failed prior IFN-based therapy 30 % with cirrhosis

41. VALENCE Trial: Sofosbuvir + RBV Zeuzem S, et al. Hepatology. 2013;58(suppl 1):733A-734A. Abstract 1085. SVR12 (%) 93 100 85 91 97 Overall 94 92 87 Genotype 2 (12 weeks) Genotype 3 (24 weeks) Noncirrhotic 60 88 Treatment-Naive Cirrhotic Noncirrhotic Cirrhotic Treatment-Experienced No resistance detected in patients with relapse. n=73 n=250 n=30 n=92 n=2 n=13 n=33 n=100 n=8 n=45 Treatment-naïve or experienced Approximately 20% with cirrhosis

42. Conclusions Most GT3 patients will be able to be treated with 24 wks of SOF/RBV GT3, treatment-experienced, cirrhotic patients most challenging group to treat with all-oral regimens Experts recommend 12 wks of SOF + pegIFN/RBV in short term

43. Sofosbuvir +Ledipasvir FDC LDV/SOF ±RBV for 8, 12 or 24 weeks in GT 1 patients

44. All-Oral 12-Week Combination Treatment With Daclatasvir and sofosbuvir in Patients Infected With HCV Genotype 3: ALLY-3 Phase 3 a Cirrhosis status determined in 141 patients by liver biopsy (METAVIR F4), FibroScan (> 14.6 kPa), or FibroTest score ≥ 0.75 and APRI (aspartate aminotransferase to platelet ratio index) > 2. b Cirrhosis status for 11 patients was inconclusive (FibroTest score > 0.48 to < 0.75 or APRI > 1 to ≤ 2). Hepatology. 2015;61(4):1127-35.

45. SVR ±RBV with paritaprevir, ombitasvir+ dasabuvir for 12 weeks in GT 1 patients

46. Paritaprevir +ombitasvir + dasabuvir SVR12 in GT 1a cirrhosis TN and TE

47. IFN-free therapy combinations high efficacy Genotype 1

48. Recommendations from the AASLD-IAS –IDSA and EASL guidelines based on new DAAs

49. Summary Multiple all-oral DAA regimens will be available over the next 12-18 mos : Dual and triple DAA regimens yield the highest SVR rates (90%+) ever described Treatment duration of 12 wks (maybe shorter) Well tolerated across all populations Importance of RBV varies with regimen and virologic characteristics Preliminary data indicate that traditionally difficult to cure populations (cirrhosis, previous PI failures) will benefit greatly from IFN/RBV-free DAA regimens