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HEPATITIS C UPDATE LEANNE GRAF, PA-C DIVISION OF GASTROENTEROLOGY AND HEPATOLOGY MEDICAL COLLEGE OF WISCONSIN.

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Presentation on theme: "HEPATITIS C UPDATE LEANNE GRAF, PA-C DIVISION OF GASTROENTEROLOGY AND HEPATOLOGY MEDICAL COLLEGE OF WISCONSIN."— Presentation transcript:

1 HEPATITIS C UPDATE LEANNE GRAF, PA-C DIVISION OF GASTROENTEROLOGY AND HEPATOLOGY MEDICAL COLLEGE OF WISCONSIN

2 5’UTR 3’UTR Structural Non-structural C E1 E2 NS2 NS3 NS4b NS5a NS5b Hepatitis C Virus Identified in 1989, previously Non-A, Non-B hepatitis RNA virus No proofreading abilities (cannot repair itself if mutation develops Half-life: approx. 2.7 hours Daily production: virions Neumann, Science, 1998 Rosenberg, J Mol Biology, 2001 Lauer, NEJM, 2001

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4 HCV Infection: Worldwide Genotype Distribution Simmonds P. Curr Stud Hematol Blood Transfus. 1998;62: a,1b 2a, 2b, 3a 1b 2a, 2b, 2c, 3a 4 5a 4 1b,3a 1b 2a 1b, 6 3b 1b,3a

5 HEPATITIS C: GENOTYPES IN U.S. GENOTYPE 1A 37% GENOTYPE 1B 30% GENOTYPE 2 10% GENOTYPE 3 6% OTHER OR MIXED 9% INDETERMINATE 5%

6 Sources of Infection for Hepatitis C Previously Acquired (<1990s) Transfusion 10% Sexual 18% Other 1%* Unknown 9% Injection Drug Use 68% Unknown 10% Other 1%* Sexual 15% Injection Drug Use 60% * Other includes nosocomial, iatrogenic, perinatal Occupational 4% Occupational 4% Newly Acquired ( ) Sources: Based on Sentinel Counties, NHANES III

7 Sexual Transmission CDC estimates risk between spouses: ~ 3% CDC estimates risk between spouses: ~ 3% Most share other HCV risk factors Most share other HCV risk factors Italian study: Italian study: Both partners (+) in 32/311 (10.3%) of couples Both partners (+) in 32/311 (10.3%) of couples Infected couples shared risk factors Infected couples shared risk factors 8 had same strain 8 had same strain Stroffolini Am J Gastro 2001

8 HCV PREVALENCE BY SELECTED GROUPS IN U.S. Hemophilia Injecting drug users Surgeons Hemodialysis Average Percent Anti-HCV Positive Gen population adults Military personnel STD clients Pregnant women

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10 Future Prevalence of HCV Years Prevalence of HCV Infection Percent Armstrong GL, Alter MJ, McQuillan GM, Margolis HS. The past incidence of hepatitis C virus infection: Implications for the future burden of chronic liver disease in the United States. Hepatology. 2000;31: Individuals infected at any time Individuals infected for > 20 years

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12 MODELING OF LIVER FIBROSIS IN CHRONIC HEPATITIS C n=1157 patients Rapid progressors Intermediate progressors Slow progressors Poynard et al, Hepatology 1999

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14 HCV Testing Routinely Recommended Based on increased risk for infection  Ever injected illegal drugs  Received clotting factors made before 1987  Received blood/organs before July 1992  Ever on chronic hemodialysis  Evidence of liver disease Based on need for exposure management  Healthcare, emergency, public safety workers after needle stick/mucosal exposures to HCV-positive blood  Children born to HCV-positive women Adapted from Hepatitis Slide Kit Accessed 01/18/03.

15 Routine HCV Testing Not Recommended (Unless Risk Factor Identified)  Health-care, emergency medical, and public safety workers  Pregnant women  Household (non-sexual) contacts of HCV- positive persons  General population Adapted from Hepatitis Slide Kit Accessed 01/18/03.

16 HCV RNA Serologic Pattern of Acute HCV Infection with Progression with Recovery Months Years Titer Time after Exposure ALT anti-HCV Normal Symptoms +/- Adapted from MMWR 1998; 47(No. RR19)

17 Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection Normal HCV RNA Symptoms +/ Months Years Titer Time after Exposure ALT anti-HCV Adapted from MMWR 1998; 47(No. RR19)

18 Histological Data: Normal vs. Elevated ALT Normal ALT ML Shiffman et al. J Infect Dis. 2000; 182: Elevated ALT Portal No Fibrosis Mild Cirrhosis Bridging 23% 40% 6% 6% 26% Portal NoFibrosis Mild Cirrhosis Bridging 19% 19% 22% 16% 24%

19 Stage 0 Stage 2 Stage 3 Stage 4 CIRRHOSIS DIAGNOSING CIRRHOSIS LIVER BIOPSY ALL OF THESE PATIENTS MAY HAVE THE SAME ALT

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21 CHILD-TURCOTTE-PUGH CLASSIFICATION 5-YEAR SURVIVAL A = 70-75% B = 40-45% C = 10-15%

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23 HCV Therapy

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25 Viral entry inhibitors Hepatitis C immunoglobulin HCIg) HCV-Ab 68 and Ab 65 (monoclonal Ab) HCV RNA translation inhibitors ISIS (antisense) AVI – 4065 (antisense) Heptazyme (ribozyme) VGX-410C (small molecule IRES inhibitor) TT 033 (siRNA) Posttranslational processing inhibitors NS3-4A serine proteinase inhibitors NS3-4A serine proteinase inhibitors BILN 2061 ITMN 191 VX-950 SCH ACH-806/GS-9132 HCV replication inhibitors NS5B polymerase inhibitors NS5B polymerase inhibitorsMK-0608HCV-796R1626JTK-003NM-283 XTL 2125 Cyclophilin B inhibitors Cyclophilin B inhibitorsDEBIO-025 NIM 811 NS5A inhibitors NS5A inhibitors A-831, A-689 Helicase inhibitors Helicase inhibitorsQU663 Recombinant Ab fragments Virus assembly and release inhibitors UT-231B (iminosugar-glucosidase inhibitor) Celgosivir (glucosidase inhibitor) Phase of Development * * * * PreclinicalIIIIIIIV * * * HCV Drug Development (Pawlotsky JM, Chevaliez S, McHutchison JG, Gastroenterology 2007;132: )

26 RibavirinRibavirinPegylated IFN-  Pegylated + HEPATITIS C TREATMENT (UNTIL RECENTLY) GENOTYPE 1= 12 MONTHS OF TREATMENT GENOTYPE 2/3= 6 MONTHS OF TREATMENT

27 PEG-IFN IFN INTERFERON THERAPY

28 Pegylated Interferon Two brands of Peg-INF Two brands of Peg-INF Weight based Weight based Standard dose Standard dose Administered once a week Administered once a week

29 Pegylated Interferon Side Effects: Side Effects: Fevers, chills, sweat, muscle aches, fatigue, weight loss, hair loss Fevers, chills, sweat, muscle aches, fatigue, weight loss, hair loss Neutropenia, thrombocytopenia Neutropenia, thrombocytopenia Psychiatric Disorders Psychiatric Disorders Thyroid abnormalities Thyroid abnormalities Worsening of: Worsening of: Diabetes Diabetes Autoimmune conditions Autoimmune conditions Decompensation of liver disease Decompensation of liver disease

30 Ribavirin Taken twice a day Taken twice a day Side Effects Side EffectsAnemiaRash Can’t be used in the setting of renal dysfunction Can’t be used in the setting of renal dysfunction Warning: Warning: Severe birth defects Severe birth defects 2 types of birth control 2 types of birth control

31 Contraindications to Treatment Advanced liver disease Advanced liver disease Child’s B-C cirrhosis Child’s B-C cirrhosis Severe psychiatric disease Severe psychiatric disease Severe cardiac/pulmonary disease Severe cardiac/pulmonary disease Pregnancy Pregnancy Severe neutropenia, thrombocytopenia Severe neutropenia, thrombocytopenia Renal failure Renal failure

32 Old HCV Therapy Treatment response: Treatment response: SVR (sustained virologic response) SVR (sustained virologic response) HCV RNA negative 6 months after d/c of therapy HCV RNA negative 6 months after d/c of therapy Relapser Relapser HCV RNA negative at the end of treatment, but + 6 months after end of treatment HCV RNA negative at the end of treatment, but + 6 months after end of treatment Non-responder Non-responder Never achieved negative HCV RNA Never achieved negative HCV RNA

33 Undetectable Non-responsive Relapse SVR Weeks HCV RNA (log IU/mL) Genotype 2/3 Virological Responses to Interferon-Based Therapy Adapted from Lindsay KL. Hepatology. 2002;36:S114-S120. Genotype 1 PEG-IFN and RBV

34 HEPATITIS C: PREDICTORS OF RESPONSE TO THERAPY Genotype (2, 3 > 1) Viral load (< 2 million) Lower body weight Decreased fibrosis Female Age < 40 Absence of co-infection Race

35 Genotype 1, >2M copies 51% Non-1, <2M copies 8% Non-1, >2M copies 19% Genotype 1, <2M copies 22% Genotypes and Viral Titer: US Patients Adapted from McHutchison JG et al. N Engl J Med. 1998;339:

36 Week 4  Week 12  Week 24  Partial  Null                 Week HCV RNA (-) SVR (%  Ferenci P, et al. J Hepatology. 2005;43(3): % of Treated Patients Achieving Undetectable HCV RNA at Various Time Points Rate of SVR

37 SVR Rates with PEG-IFN /RBV According to Genotype Genotype Non-1 Genotype 1 Strader DB et al. Hepatology. 2004;39: SVR (%) 42%-46%42%-46% 76%-82% 76%-82%

38 Treatment of Hepatitis C in African Americans: SVR Virological Response Rates (%) 1. Muir AJ et al. N Engl J Med 2004;350: Jeffers LJ et al. Hepatology 2004;39: n=100 n=78n=28 Peg-IFN  -2b Peg-IFN  -2a

39 European- Americans African- Americans HispanicsCombined T/T T/C C/C SVR (% of Patients) Reprinted by permission from Macmillan Publishers Ltd: Ge D, et al. Nature. 2009;461(7262): Copyright Genotype: P<0.0001P=0.002P=0.004P<0.0001

40 SVR (%) rs C-allele frequency African-Americans (n=61) Hispanics (n=16) European-American (n=271) East Asians (n=107) Ge D, et al. Nature. 2009;461(7262):

41 RESULTS I: IL28B genotype is associated with spontaneous clearance 6.1% 24.4% 64.2% 0% 10% 20% 30% 40% 50% 60% 70% T/T (n=2/33)T/C (n=22/90)C/C (n=43/67) Percent of patients achieving spontaneous clearance

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43 HCV protease inhibitor RibavirinRibavirin Pegylated IFN-  Pegylated + HEPATITIS C TREATMENT (PRESENTLY)

44 Peg-INF/Ribavirin/Protease Inhibitor Only approved for Genotype 1 Only approved for Genotype 1 Very little benefit shown for genotype 2/3 Very little benefit shown for genotype 2/3 Not FDA approved for post-transplant recipients Not FDA approved for post-transplant recipients Not studied in co-infected populations (HBV, HIV) Not studied in co-infected populations (HBV, HIV)

45 Protease Inhibitors MUST NEVER be taken as monotherapy MUST NEVER be taken as monotherapy MUST be taken every 8 hours MUST be taken every 8 hours Imperative that patient’s are compliant Imperative that patient’s are compliant Success of therapy can be predicted by prior response to therapy Success of therapy can be predicted by prior response to therapy Relapsers do better than non-responders Relapsers do better than non-responders

46 Incivek (Telaprevir) Taken for the first 12 weeks of treatment Taken for the first 12 weeks of treatment Taken with fatty foods Taken with fatty foods Side effects Side effects Rash Rash Anemia Anemia Anal pruritus Anal pruritus

47 Victrelis (Boceprevir) Started 4 weeks after starting pegylated interferon/ribavirin Started 4 weeks after starting pegylated interferon/ribavirin Taken during the rest of treatment Taken during the rest of treatment Side effects: Side effects: Anemia Anemia Nausea/vomiting Nausea/vomiting

48 1. McHutchison JG, et al. N Engl J Med. 2009;360(18): Hezode C, et al. N Engl J Med. 2009;360(18): PROVE-1 1 PROVE-2 2 SVR Rate (%) P/R/T (24 wk) P/R/T (24 wk) 61% P/R (48 wk) P/R (48 wk) 69%46% 20% 23% 67% P/R/T (48 wk) 26% 41% P/R/T (12 wk) 60% 14% P: PEG-IFN alfa-2a; R: Ribavirin; T: Telaprevir

49 %75%38% P/R/B (28 wk) P/R/B (48 wk) + lead-in P/R (48 wk) 37% 18% 67%55% P/R/B(28wk) + lead-in P/R/B(48wk) 29% 17% Kwo P, Lancet SVR Rate (%) P: PEG-IFN alfa-2b; R: Ribavirin; B: Boceprevir

50 SUMMARY (1) Hepatitis C is prevalent Hepatitis C is prevalent Multiple genotypes with geographic distribution Multiple genotypes with geographic distribution Recognize risk factors Recognize risk factors The presence of Hepatitis C viral RNA indicates active infection The presence of Hepatitis C viral RNA indicates active infection Can range from spontaneous clearance to cirrhosis necessitating liver transplant Can range from spontaneous clearance to cirrhosis necessitating liver transplant

51 SUMMARY (2) Liver biopsy is the best predictor of prognosis Liver biopsy is the best predictor of prognosis Genotype, viral load and IL28b are best predictors of response to therapy Genotype, viral load and IL28b are best predictors of response to therapy Interferon in combination with ribavirin and protease inhibitors are the standard of care for genotype 1 (protease inhibitors not necessary in genotypes 2/3) Interferon in combination with ribavirin and protease inhibitors are the standard of care for genotype 1 (protease inhibitors not necessary in genotypes 2/3) Next advance will be polymerase inhibitors Next advance will be polymerase inhibitors

52 THANK YOU !!!


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