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Hepatitis C in 2014

Hepatitis C in 2014. Lisa M. Chirch , M.D. Assistant Professor of Medicine University of Connecticut Health Center A Local Performance Site of the New England AETC. Disclosures. None. Objectives. Describe epidemiology, transmission, and clinical presentation of Hepatitis C infection

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Hepatitis C in 2014

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  1. Hepatitis C in 2014 Lisa M. Chirch, M.D. Assistant Professor of Medicine University of Connecticut Health Center A Local Performance Site of the New England AETC

  2. Disclosures • None

  3. Objectives • Describe epidemiology, transmission, and clinical presentation of Hepatitis C infection • Understand and implement new testing and screening recommendations • Apply relevant data from recent publications regarding treatment of chronic hepatitis C infection

  4. Hepatitis C - Chapter 3 - 2012 Yellow Book | Travelers' Health | CDC wwwnc.cdc.gov

  5. Magnitude of the Problem • Nearly 4 million persons in United States infected • Approximately 35,000 new cases yearly • Acute infections on the rise since 2010 • <10% chronically infected patients are treated • Leading cause of • Chronic liver disease • Cirrhosis • Liver cancer • Liver transplantation http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm.

  6. “Silent Epidemic” • NHANES survey: estimated unidentified HCV infections – 43% • May 2011: U.S. Viral Hepatitis Action Plan • Federal platform • Educate providers and communities • Increase awareness, testing and linkage to care • USPSTF has aligned with CDC on testing recommendations – Grade B Ronald Valdiserri – DHHS Deputy Assistant Secretary; The Liver Meeting 2013

  7. Hepatitis C, a Silent Killer, Meets Its Match November 4, 2013

  8. Sources of Infection with HCV

  9. Indications for HCV screening? • HIV • IDU • History of chronic HD, transfusion, blood product or organ transplant prior to 1992 • Unexplained persistent elevation in ALT (?RNA) • and….

  10. Hepatitis C: Screening guidelines • CDC 2012: • Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965 • Recommendations and Reports, August 17, 2012 …one-time testing without prior ascertainment of HCV risk for persons born during 1945 -1965, a population with a disproportionately high prevalence of HCV infection and related disease.

  11. 2013: Update of Guidance for Clinicians and Laboratories • MMWR May 2013 • Availability of rapid test for HCV antibody (OraQuick) • Fingerstick or venipuncture • CLIA waiver by FDA in 2011 • Discontinuation of the RIBA HCV • Recommended testing sequence:

  12. MMWR May10, 2013

  13. Question • A 50 year old female with a history of HTN and DM is referred to you after her primary care physician performed hepatitis C antibody testing as part of routine evaluation, which was positive. She would like you to explain the chances that she does NOT have chronic hepatitis C infection. What do you tell her? • A) 0% • B) 15% • C) 50% • D) 75% • E) 99%

  14. Answer • A 50 year old female with a history of HTN and DM is referred to you after her primary care physician performed hepatitis C antibody testing as part of routine evaluation, which was positive. She would like you to explain the chances that she does NOT have chronic hepatitis C infection. What do you tell her? • A) 0% • B) 15% • C) 50% • D) 75% • E) 99%

  15. Hepatitis C Virus InfectionNatural History Acute HCV Resolved 15% (15%) Chronic HCV 85% (85%) Stable 80% (68%) Cirrhosis 20% (17%) Slowly progressive 75% (13%) HCC Liver failure 25% (4%) HCC, hepatocellular carcinoma

  16. Hepatitis C VirusGenotypes in the USA Type 2 17% Type 3 10% Type 1 72% All others 1% McHutchinson JG, et al. N Engl J Med. 1998;339:1485-1492.

  17. Management of Chronic HCV

  18. IL28B IL28B:gene coding for IFN-λ3, associated with IFN sensitivity –C/C genotype (vsC/T or T/T) associated with favorable response to HCV treatment in pts treated with PEG/ribavirin Clark PJ, Am J Gastroenterol Oct 2010

  19. HCV RNA and Liver HistologyFibrosis • Serum HCV RNA does not correlate with level of fibrosis 8 Genotype 6 1 Log HCV RNA (copies/mL) 2 4 3 4 2 0 No Fibrosis Portal Fibrosis Bridging Fibrosis Cirrhosis Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

  20. How to Stage

  21. Hepatitis C Virus InfectionLiver Biopsy • Only test that can accurately assess • Severity of inflammation • Degree of fibrosis • Determines • Risk for developing cirrhosis in future • Need for therapy • Need for ongoing therapy when initial treatment has failed

  22. Sampling error of liver biopsy

  23. Serum Markers of Liver Fibrosis

  24. Fibroscan

  25. Validity of Fibroscan Versus Biopsy

  26. HCV Fibrosis Progression Effect of Alcohol 4.0 3.0 Alcohol intake 2.0 Fibrosis Score > 50 g/day* < 50 g/day 1.0 0 11-20 21-30 31-40 > 40 < 10 Duration of Infection (Years) *50 g is equal to approximately 3.5 drinks Poynard T, et al. Lancet. 1997;349:825-832.

  27. Fibrosis Progression in HCVEffect of Steatosis Cumulative Probability of Fibrosis According to Level of Steatosis 100 80 60 Year 4 Cumulative Probability of Fibrosis Progression (%) Year 6 40 33% 30% 18% 18% 20 7% 6% 4% 2% 0 < 5% 5%-10% 11%-30% > 30% Percentage of Steatosis at Initial Biopsy Fartoux L, et al. Hepatology. 2005;41:82-87.

  28. Chronic Hepatitis C VirusExtrahepatic Manifestations • Nonspecific antibodies • Essential mixed cryoglobulinemia • Glomerulonephritis • Porphyria cutanea tarda • Leukocytoclastic vasculitis • Mooren’s corneal ulcer • Non-Hodgkin’s lymphoma • Autoimmune thyroiditis • Diabetes mellitus • Sjögren’s syndrome

  29. HCV Treatment Goals • Goals of treatment for chronic HCV • Viral eradication (undetectable viral load) • Delay progression of fibrosis • Prevent decompensation, HCC, and death • Best indicator of successful treatment is sustained virologic response (SVR)

  30. Sustained virologic response • SVR: serum HCV RNA is undetectable based on a quantitative HCV RNA assay with lower limit of detection of 50 IU/mL or less at 24 weeks after treatment ends • SVR 12: …12 weeks after treatment ends • RVR • EVR

  31. Treatment of Chronic HCVPeginterferon and Ribavirin 100 80 60 Sustained Virologic Response (%) PegIFN-2a/RBV 40 PegIFN-2b/RBV 20 0 1 2-3 Genotype Fried MW, et al. N Eng J Med. 2002;347:975-982. Manns MP, et al. Lancet 2001;358:958-965.

  32. Interferon • Flu-like symptoms: fatigue, headache, myalgias • Dose-related myelosuppression • Reversible with dose reduction (cost?) • Use of G-CSF and erythropoietin • Depression: risk assessment prior to therapy initiation • 35-40% • Management with SSRIs and TCAs

  33. Time Course of Treatment-Associated Psychiatric Adverse Effects 100 80 Depression 60 Incidence/Severity Fatigue 40 20 Influenza-like symptoms 0 0 1 2 3 4 Months Dan A, et al. J Hepatol. 2006;44:491-498. Constant A, et al. J Clin Psychiatry. 2005;66:1050-1057.

  34. Ribavirin • Nucleoside analog • Inhibits inosine monophosphate dehydrogenase • Potentiates purine analogs, ie didanosine • Immune modulator, shift from Th2 to Th1 response • Teratogenic • both men and women must use contraception during and for 6 months aftertreatment • Dose-dependent hemolytic anemia • Increased risk for lactic acidosis

  35. HCV Life Cycle and DAA Targets Receptor bindingand endocytosis Transportand release Fusion and uncoating Translation andpolyprotein processing ER lumen Virionassembly (+) RNA LD LD LD Membranousweb RNA replication NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside ER lumen NS5A* inhibitors *Block replication complex formation, assembly Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

  36. What Are the Key Elements of an Ideal HCV Regimen? Easy Dosing Once daily, low pill burden Highly Effective High efficacy in traditionally challenging populations (ie, poor IFN sensitivity, cirrhosis) All Oral PegIFN/RBV replaced with alternate backbone with low chance of resistance Simple Regimen Short duration, simple, straightforward stopping rules Pan-Genotypic Regimen can be used across all genotypes Safe and Tolerable Few or easily manageable adverse effects

  37. HCV Therapy: Past, Present and Future Frequent curability of diverse populations without IFN IFN-free DAA combinations (GT1) Ribavirin Suppression of HCV with DAA combination (PI + NI) Potential approval of other DAAs with IFN Proof of concept for DAA (PI) Telaprevir and boceprevir Interferon 1990 2000 2005 2010 2011 2012 2013 2014 2015- Curability of HCV without interferon • Approval of simeprevir and sofosbuvir with IFN • First approved IFN-free therapy: SOF + RBV for GT2/3 Pegylated interferons

  38. Telaprevir- PROVE 12-wk TVR + pegIFN/RBV (n = 17) 100 12-wk TVR + 24-wk pegIFN/RBV (n = 79) 81* 81* 12-wk TVR + 48-wk pegIFN/RBV (n = 79) 80 80 Control (n = 75) 67‡ 71 71 68 65 61† 59* 60 57 57 Patients (%) 47 45 41 40 35 33 23 20 11 6 2 N/A N/A N/A 0 Wk 4 Wk 12 Wk 24 Wk 48 SVR Relapse Undetectable HCV RNA N/A, not applicable. *P < .001 vs control. †P = .02 vs control. ‡P = .002 vs control. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

  39. Summary of Key Conclusions • 12-week course of TVR with 24 or 48 weeks of pegIFN/RBV increased SVR rates in treatment-naive patients infected with genotype 1 HCV vs 48 weeks of pegIFN/RBV alone • TVR also resulted in higher rate of RVR and lower relapse rate compared with pegIFN/RBV • TVR increased rate of treatment discontinuation due to adverse effects, predominantly anemia, rash, rectal symptoms (FIARRHEA) • Small subset experienced virologic breakthrough with protease resistance mutations McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

  40. No Free Lunch Treatment is more effective but much more difficult Jordan Feld, MD, MPH. Toronto Western Hospital Liver Centre

  41. Other Issues With PI-Based Therapy Pill burden Food requirement Resistance BOC = 12/day RBV = 4-7/day TVR = 6/day RBV = 4-7/day Drug-drug interactions PI metabolites CYP3A4

  42. 20 grams of fat… • Breakfast Ideas • 2-egg omelet with 1 ounce shredded cheese; oatmeal with 1 ounce nuts and ½ tablespoon butter; toast with 2 tablespoons unsalted peanut butter and glass of 2% milk; bagel with 2 tablespoons cream cheese and glass of whole milk 1 egg and 1-3 sausage links (check sausage label, need 15 g fat) • Lunch / Dinner • 6 ounces salmon; ½ box prepared macaroni and cheese; 3 tablespoons of 2 cups of canned chili with meat; sandwich with 3 slices bologna; 1½ beef hot dogs; 1 chicken leg and thigh with skin; burrito with beans, cheese, and guacamole; 2 pork chops; french fries, medium order; quarter-pound hamburger or double cheeseburger

  43. Drug–Drug Interactions a Clinical Challenge With Current Therapy • Several drugs contraindicated; many more require dose adjustment or caution 1Boceprevir [package insert]. November 2012. 2. Telaprevir [package insert]. October 2012.

  44. Limited Efficacy With Telaprevir and Boceprevir in Some Patient Groups 100 75-83[1,2] 80 68-75[3,4] 53-62[3,4] 42-62[3,4] 60 40-59[1,2] SVR (%) 29-40[1,5] 40 20 14[6]* 0 NaiveCirrhotic Relapser Naive White/ Nonblack Naive Black Partial Responder Null Responder Cirrhotic Null Responder *Pooled TVR arms of REALIZE trial. 1. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 5. Bronowicki J, et al. EASL 2012. Abstract 11. 6. Zeuzem S, et al. EASL 2011. Abstract 5.

  45. Question • A 44 year old male with a history of prior heroin abuse (clean for 1 year +) is referred for hepatitis C therapy. His HCV RNA level is 5.2 million IU/mL, genotype 1b, ALT 65, and there are no stigmata or lab values to suggest ESLD. He does have a history of depression and anxiety, requiring mirtazapine and citalopram therapy. How should you proceed? • A) get a liver biopsy – this will help me decide • B) He cannot receive therapy due to comorbidities • C) Treat with just IFN/ribavirin, he will not likely tolerate a PI • D) Treat with just telaprevir, he will not likely tolerate IFN • E) wait for something better

  46. Answer • A 44 year old male with a history of prior heroin abuse (clean for 1 year +) is referred for hepatitis C therapy. His HCV RNA level is 5.2 million IU/mL, genotype 1b, ALT 65, and there are no stigmata or lab values to suggest ESLD. He does have a history of depression and anxiety, requiring mirtazapine and citalopram therapy. How should you proceed? • A) get a liver biopsy – this will help me decide • B) He cannot receive therapy due to comorbidities • C) Treat with just IFN/ribavirin, he will not likely tolerate a PI • D) Treat with just telaprevir, he will not likely tolerate IFN • E) wait for something better

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