Updates in Hepatitis C: What Every Provider Should Know

Transcription

1 Updates in Hepatitis C: What Every Provider Should Know June 14, 2018 Ryan M. Taylor, MD, MS Associate Professor of Medicine Medical Director of Liver Transplantation Medical Director of Hepatology University of Kansas School of Medicine

2 Educational Goals To identify risk factors and screening recommendations for hepatitis C. To review goals and benefits of hepatitis C clearance. To review recent breakthroughs and new therapies for hepatitis C.

3 Hepatitis C: Introduction In the US, HCV is a leading etiology of: Chronic liver disease Cirrhosis Liver Cancer Historically has been the most common indication for liver transplantation

4 Rising Incidence of ESLD and HCC Due to HCV From: Davis GL, et al. Gastroenterology 2010;138(2):

5 Hepatitis C Virus Nucleic Acid: 9.6 kb ssrna Classification: Flaviviridae, Hepacivirus nm Genotypes: 1 to 6 (Genotype 1 ~70% in US) Enveloped In vitro model: primary hepatocyte and T cell cultures; replicon system Image from AGA Teaching Series In vivo replication: in cytoplasm, hepatocyte and lymphocyte; human and other primates

6 Hepatitis B vs. Hepatitis C Hepatitis B Hepatitis C Type of Virus DS DNA SS RNA US Prevalence 0.5% population 1.3% population Mode of Transmission Vaccine available? Antibody protective? Chronicity Sexual transmission Endemic-vertical US-Sexual Yes Yes 90% Childhood 1% Adult High risk US-IV Drug use No No 70-80% Adults Low risk

7 Prevalence of HCV Infection Among Blood Donors *Adapted from CDC Presentation: Epidemiology and Prevention of Viral Hepatitis A to E

8 Hepatitis C Burden of Disease in US NHANES (National Health and Nutrition Survey) IV Nearly 4 million in US infected 85% of cases become chronic Approximately 35,000 new cases yearly 1.3% of Americans with chronic HCV (HCV-PCR positive) Did not include homeless or incarcerated subjects Likely underestimates true prevalence of HCV in the U.S. Armstrong GL et al, Ann Int Med, 2006: 144(10):

9 Hepatitis C: Treatment Cascade: Yehia BR, et al. PLoS ONE. 2014;9(7): 1-7

10 Risk Factors for Hepatitis C Long-Term Hemodialysis Clotting Factor Treatment Prior to 1987 Blood Transfusion or Organ Transplant Prior to 1992 Multiple Sexual Partners Risk Factors for Hepatitis C Injection Drug Use Incarceration, Occupational Exposures Birth from Infected Mother Image from AGA Teaching Series

11 Hepatitis C Risk Factors / Transmissibility From: Murphy EL et al, Hepatology, 2000: 31:

12 HCV Transmission Risks Transfusion ~ 1 in 1,000,000 Maternal-Infant Mother HIV-negative ~ 5% Mother HIV-positive 15-20% Heterosexual partner ~1 in 1,000 per yr Needlestick injury HCV-positive source ~ 5% HCV status unknown ~ 1% From AGA Teaching Series: Terrault NA, Hepatology 2002 ;36(Suppl 1):S99 Roberts EA, Yeung L. Hepatology 2002 ;36(Suppl 1):S106

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14 US Hepatitis C Prevalence 75% of Patients

15 Hepatitis C: Spectrum of Disease Recovery 15%-30% Anti-HCV Ab+ HCV RNA by PCR - Acute HCV Infection Chronic HCV Infection Chronic Hepatitis C Mild Moderate Severe 70%-85% Anti-HCV Ab+ HCV RNA by PCR + Cirrhosis End-Stage Liver Disease Liver Transplantation Hepatocellular Carcinoma Death Adapeted from: Hoofnagle JH. Hepatology. 1997;26(suppl 1):16S.

16 Titer Pattern of Acute HCV Infection with Recovery Symptoms +/- Anti-HCV HCV RNA ALT Normal Months Years Time after Exposure *Adapted from CDC Presentation: Epidemiology and Prevention of Viral Hepatitis A to E

17 Serologic Pattern of Acute HCV Infection With Progression to Chronic Infection Titer Symptoms +/- Anti-HCV HCV RNA ALT Normal Months Years Time after Exposure *Adapted from CDC Presentation: Epidemiology and Prevention of Viral Hepatitis A to E

18 Hepatitis C Initial Evaluation Confirmation of the diagnosis ~25% of subjects HCV Ab+ may be false positive/previously resolved infection Genotyping Evaluate for other associated diseases Hepatitis B, HIV Assessment of fibrosis Imaging with ultrasound Alcohol/Substance abuse counseling Viral transmission counseling Review options for HCV therapy Vaccinate for Hepatitis A/B Assessment for compliance Colon cancer screening

19 HCV Diagnostic Testing HCV IgG Antibody Initial screening test Indirect virus test False positives less with current assays HCV Quantitative PCR Testing Direct virus test, counts viral particles Confirmatory test for viremia Monitors treatment compliance and viral response/clearance HCV Genotyping Direct virus test, similar to HCV Quantitative PCR Most important in determining in treatment response rates and duration

20 HCV RNA Levels and Disease Activity Genotypes HCV RNA does not correlate with hepatic inflammation or stage of fibrosis Ferreira-Gonzalez A et al. Semin Liv Dis 2004;24:9-18.

21 HCV Genotype Worldwide Distribution In US Genotype 1a and 1b comprise ~78% of population Image from Soriano V. 3 rd International Workshop on HIV/HCV

22 Assessment of Liver Fibrosis Liver Biopsy FibroScan FibroTest Images from:

23 Liver Fibrosis Assessment Benefits Liver Biopsy Gold standard for fibrosis assessment FibroSure / FibroTest FibroScan Wide accessibility Real time results Painless Longitudinal monitoring Noninvasive Risks/Limitations Pain Bleeding Invasive Minimal risk Accuracy Minimal risk Obese patients Cost High Low Moderate

24 MELD-Model of End-stage Liver Disease Developed by Mayo for predicting post-tips mortality USED IN CIRRHOSIS ONLY Utilized to rank candidates for liver transplant on the UNOS waiting list Uses objective measurements: Protime (INR) Creatinine Bilirubin +/- Sodium (Na-MELD) Range from 6-40 Equation: 10 x [0.957 x log e (creatinine mg/dl) x log e (bilirubin mg/dl) log e (INR)] Calculator available at

25 MELD Predicts Liver Transplant Waiting List Mortality From: 2003 SRTR Annual Report, adopted from: Wiesner R, et al Gastroenterology 2003; 124:91-96.

26 AFP Alpha-Fetoprotein Glycoprotein screening marker for hepatocellular carcinoma (HCC) Normal range varies by assay, generally >20 elevated Recommend every 6 months in those at risk for HCC: Chronic Hepatitis B patients with active replication Cirrhotic patients No recommendations to screen CHRONIC HEPATITIS C PATIENTS WITHOUT CIRRHOSIS AFP can be elevated in chronic hepatitis C with no association with HCC Can trigger unnecessary evaluation and subsequent imaging leading to unnecessary expenses/risks

27 Hepatitis C and Alcohol Concomitant alcohol use leads to a more rapid and progressive course of HCV Barrier to candidacy for liver transplantation Some state insurances require documented sobriety for HCV therapy Poynard, T, et al. Lancet 1997;349:

28 HIV / HCV Co-Infection Important sub-population ~30% of HIV infected individuals co-infected HIV+ patients should be screened for HCV Faster rate of fibrosis progression 10% vs. 2.5% over 10 year period DAAs have shown safety and efficacy in HIV/HCV+ individuals

29 Hepatitis C Virus Extrahepatic Manifestations Nonspecific auto-antibodies (ANA, ASMA) Essential mixed cryoglobulinemia Glomerulonephritis Porphyria cutanea tarda Leukocytoclastic vasculitis Mooren s corneal ulcer Non-Hodgkin s lymphoma Autoimmune thyroiditis Diabetes mellitus Sjogren s syndrome Fatigue/Depression Cardiovascular disease

30 Numerous Benefits of HCV Cure Reduced liver-related mortality Lower hepatocellular carcinoma rates Reduced decompensation/need for liver transplant Improved Quality of Life Reduction in extrahepatic manifestations Impact on Diabetes 1. Smith BD, et al. MMWR Recomm Rep. 2012;61(RR-4): Ryerson AB et al. Cancer. 2016;122(9): Backus LI et al. Clin Gastroenterol Hepatol. 2011;9(6):

31 Life Expectancy in Chronic HCV Patients 520 patients from 5 large Hepatology Units in Europe and Canada Treated between 1995 and 2003 Median follow-up was 8.4 years Compared to expected survival of age, sex, and calendar time specific matched controls from the general population in Netherlands van der Meer AJ, et al. 31

32 DAA Treated HCV patients Reduction in All-Cause Mortality Observational Cohort from VA HCV Registry 103,346 HCV Genotype 1, 2 and 3 patients Achievement of SVR: 69% Reduction in all-cause mortality vs. untreated patients 59% Reduction in all-cause mortality vs. HCV non- SVR patients Overall SVR of treated cohort: 96.8% Backus LI, et al. Hepatology doi: /hep [Epub ahead of print].

33 Hepatitis C Treatment Image from

34 SVR (%) Evolution of Treatment of Chronic Hepatitis C 100 Direct Acting Antiviral Oral Regimens PI + PegIFN/RBV (2-3 mos) (6-12 mos) [8-10] PegIFN/ribavirin (6-12 mos) [6,7] Standard interferon (6 mos) [1] 8-12 Standard interferon (12-18 mos) [2,3] Interferon/ ribavirin (6-12 mos) [3,4] PegIFN monotherapy (6-12 mos) [5,6] Carithers RL Jr., et al. Hepatology. 1997;26(3 suppl 1):83S-88S. 2. Zeuzem S, et al. N Engl J Med. 2000;343: Poynard T, et al. Lancet. 1998;352: McHutchison JG, et al. N Engl J Med. 1998;339: Lindsay KL, et al. Hepatology. 2001;34: Fried MW, et al. N Engl J Med. 2002;347: Manns MP, et al. Lancet. 2001;358: Poordad F, et al. N Engl J Med. 2011;364: Jacobson IM, et al. N Engl J Med. 2011;364: Sherman KE, et al. N Engl J Med. 2011;365: Slide/Images from Clinical Care Options Hepatitis

35 Patients With SVR (%) SVR: Equivalent to Viral Cure Sustained Virological Response (SVR): Hepatitis C virus PCR is not detected at 12 weeks from last treatment. Nearly 100% of patients who achieve SVR remain undetectable during long-term follow-up [1-4] [1] 99 [2] 100 [3] 100 [4] yrs (mean) 3.4 yrs (median) 3.3 yrs (median) 5.4 yrs (median) Duration of Follow-up 1. Swain MG, et al. Gastroenterology. 2010;139: Giannini EG, et al. Aliment Pharmacol Ther. 2010;31: Maylin S, et al. Gastroenterology. 2008;135: George SL, et al. Hepatology. 2009;49: Slide/Images from Clinical Care Options Hepatitis

36 Initial HCV Therapies Interferons: NO LONGER USED! Standard IFN alpha (INTRON-A, ROFERON-A ) Pegylated Interferon alpha-2a (Pegasys, Roche) 180 mcg SQ weekly Pegylated Interferon alpha-2b (PEG-INTRON, Merck)- Weight based weekly dosing Consensus Interferon Mechanism as general antiviral therapy with enhanced host immune responsiveness Ribavirin (Rebetol /Copegus ): Mechanism not fully elucidated, general antiviral Weight based therapy: >75 kg = 1200 mg daily (600 mg BID) <75 kg = 1000 mg daily (600 mg / 400 mg)

37 HCV Interferon/RBV Treatment Contraindications/ Relative Contraindications Uncontrolled depression Unstable/uncontrolled serious mental illness Ongoing heavy alcohol use/drug use Noncompliance Concurrent autoimmune diseases should be under control/remission Renal disease Presence of severe/chronic anemia Uncontrolled COPD Decompensated cirrhosis Significant retinopathy

38 HCV Interferon/RBV Treatment Side Effects Common Flu like symptoms: Fatigue, headaches, fever, myalgias Gastrointestinal: Nausea, anorexia, diarrhea, weight loss/gain Cytopenias: Hemolytic anemia (Ribavirn), leukopenia, thrombocytopenia Depression/Anxiety/Irritability: Suicide attempts/deaths have been reported Skin Changes: Rashes, alopecia Rare Unmasking of autoimmune disorders: Autoimmune thyroid disease Cardiopulmonary toxicities Teratogenic effects: 2 forms of contraception recommended during and 6 mo following therapy Retinopathy

39 Therapeutic Targets in the HCV Replication Cycle Transport and release Fusion and uncoating HCV RNA Viral assembly Translation RNA replication NS5B polymerase inhibitors NS5A inhibitors Polyprotein processing NS3/4A protease inhibitors NS5B NS3 NS4B CypA NS5A NS2 NS4B NS2 NS3 HCV NS proteins NS5A NS5B NS5A inhibitors Slide Courtesy of Raymond Chung, MD

40 Targets for Direct Acting Antivirals (DAA) C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Core Envelope Glycoproteins Protease Serine Helicase Protease Serine Protease Cofactor Needed for Replication Assembly RNA-dependent RNA polymerase NS3-4A protease inhibitors NS5A inhibitors NS5B polymerase inhibitors nucleoside analogs non-nucleoside analogs McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48: Slide Courtesy of Raymond Chung, MD

41 Hepatitis C FDA Approvals November 2013: Simeprevir December 2013: Sofosbuvir October 2014: Harvoni (Ledipasvir and Sofosbuvir FDC) November 2014: Simeprevir + Sofosbuvir Regimen December 2014: Viekira Pak (Paritaprevir (with Ritonavir)/Ombitasvir/Dasabuvir) July 2015: Daclatasvir January 2016: Zepatier (Elbasvir and Grazoprevir) June 2016: Epclusa (Velpatasvir and Sofosbuvir) July 2016: Viekira XR (Paritaprevir (with Ritonavir)/Ombitasvir/Dasabuvir) July 2017: Vosevi (Voxilaprevir, Velpatasvir and Sofosbuvir) August 2017: Mavyret (Glecaprevir and Pibrentasvir)

42 Direct Acting HCV Therapies NS3/4A Protease Inhibitors: (-previr) Telaprevir (NO LONGER RECOMMENDED) Boceprevir (NO LONGER RECOMMENDED) Simeprevir Paritaprevir (Ritonavir boosting as part of Viekira Pak ) Grazoprevir (Part of Zepatier ) Glecaprevir (Part of Mavyret ) Voxilaprevir (Part of Vosevi ) NS5B Nucleotide Polymerase Inhibitor: (-buvir) Sofosbuvir (Part of Harvoni, Epculsa and Vosevi ) NS5B Non-Nucleotide Polymerase Inhibitor: (-buvir) Dasabuvir (Part of Viekira Pak ) NS5A Inhibitors: (-asvir) Ledipasvir (Part of Harvoni ) Ombitasvir (Part of Viekira Pak ) Daclatasvir Elbasvir (Part of Zepatier ) Velpatasvir (Part of Epclusa and Vosevi ) Pibrentasvir (Part of Mavyret )

43 Current HCV Management

44 Genotype 1 Harvoni (Ledipasvir 90 mg/sofosbuvir 400 mg) Sofosbuvir (NS5B Nucleotide Inhibitor) Ledipasvir (NS5A Inhibitor) Dosage and Administration: 1 tab/day Harvoni Package Insert,

45 Genotype 1 Harvoni Clinical Trial Outcomes 1952 patients in 3 main registry trials ION-1, ION-2, ION-3 Overall SVR rate: 97% Subjects Without Cirrhosis Treatment-naïve 96-99% SVR12 with 12 weeks of treatment 97% SVR12 with 8 weeks of treatment (HCV RNA <6 million IU/mL) Treatment-experienced 95% SVR12 with 12 weeks of treatment Subjects with Compensated Cirrhosis 94% SVR12 with 12 weeks of treatment 100% SVR12 with 24 weeks of treatment Harvoni Package Insert,

46 Genotypes 1-6 Epclusa (Velpatasvir 100 mg/sofosbuvir 400 mg) Sofosbuvir (NS5B Nucleotide Inhibitor) Velpatasvir (NS5A Inhibitor) Dosage and Administration: 1 tab/day (+/- RBV) Discontinuation rate from studies: 0.2% Side effects: HA (22%), Fatigue (15%), Nausea (9%) Genotype SVR Rate 98% 99% 95% 100% 97% 100% Astral-1,2,3 Treatment Course: 12 weeks Epclusa Package Insert, 2016, 46

47 Genotypes 1-6 Mavyret (Glecaprevir 100 mg/pibrentasvir 40 mg) Glecaprevir (NS3/4A Protease Inhibitor) Pibrentasvir (NS5A Inhibitor) Dosage and Administration: 3 tab/day Discontinuation rate from studies: 0.1% Side effects: HA (13%), Fatigue (11%), Nausea (8%) Genotype SVR Rate 99% 98% 95% 93% 100% 100% Treatment Course: Majority eligible for 8 weeks Mavyret Package Insert,

48 HCV Treatment: Safety and Tolerability Harvoni Epclusa Mavyret Fatigue 13-18% (RWD-23%) Headache 11-17% (RWD- 21%) Nausea 6-9% (RWD-8%) 15% 11% 22% 13% 9% 8% Clinical Trial Drop Out Rates <1% 0.2% 0.1% Note: Side effects are presented from registry trials for illustrative purposes, not direct comparison as head to head trials have not been performed. RWD=Real World Data, Terrault NA, et al. Gastroenterology. 2016;151(6): e5. Harvoni Package Insert Epclusa Package Insert Mavyret Package Insert

49 HCV Treatment: Safety and Tolerability All HCV DAAs: Black box warning: Screen/monitor for HBsAg+ and HBcAb+ HBV flares/reactivations have occurred. Harvoni /Epclusa : Use with Amiodarone not recommended GFR <30 safety/efficacy not established Mavyret : Use with atazanavir or rifampin is contraindicated Contraindicated in CTP-C patients Not recommended in CTP-B patients Harvoni Package Insert Epclusa Package Insert Mavyret Package Insert

50 Standard HCV Genotype 1 Treatment: 2010 vs Regimen PEG-IFN + RBV Harvoni Epclusa Mavyret Medication Administration Injection + Tablets 1-3 Tablets only Treatment Course 48 weeks 8-12 weeks % with side effects 99% <20% Efficacy 50% SVR >97% SVR

51 Summary Hepatitis C infection is routinely encountered in the United States Intravenous drug use is the single largest risk factor for developing chronic hepatitis C and this history should prompt HCV screening. One time age based HCV screening in patients born between is now recommended. Current HCV therapies are highly efficacious and well tolerated.

52 Thank You