Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

March 192015talkforresidents final03232015 (1)

1,869 views

Published on

Viral Hepatitis

Published in: Health & Medicine
  • Be the first to comment

March 192015talkforresidents final03232015 (1)

  1. 1. Update on Viral Hepatitis Geri Brown, M.D. Department of Internal Medicine March 19, 2015
  2. 2. Case study  71 yo white male with 2 wk hx of jaundice, dark urine, N/V, ate at new restaurant  Social: Retired  Physical Exam: 6 ft, 180 lbs, jaundice, no evidence of chronic liver disease  Laboratory tests: AST 1584, ALT 1623, AP 321, TB 25, WBC 10.6, Platelets 160K, INR 1.4  U/S Mild increased echogenicity, nl CBD  Serology: HAV IgM - Reactive
  3. 3. HEPATITIS A VIRUS RNA Picornavirus -Single serotype worldwide Acute disease -Asymptomatic or symptomatic Transmission -Food / Water Borne -Nosocomial Serology -HAV IgM-acute -HAV (total)-immune
  4. 4. Diagnosis and Management  Diagnosis and Management of Acute Hepatitis A – History – Aminotransferases – Hepatocellular Injury – HAV IgM – Supportive care (Liver transplantation in FHF)  Mortality – Case fatality rates - 0.004% - 5-14 years – .03-.06 % - 25-35 years – 3-6% >55 years  Prevention of Hepatitis A – Vaccination (HAVRIX, 0 and 6-12 mos) – Proper hygiene  Vaccine recommendations – All children starting at age 1 year – Travelers to certain countries – Others at risk • Persons with chronic liver disease
  5. 5. Case study 2  26 year old African American male with loss of appetite, N/V, yellow eyes, dark urine  Social: No IDU, tattoos, transfusions . ETOH-positive, unprotected sex with prostitutes.  Physical exam: RUQ tenderness, tender liver edge at RCM, scleral icterus  T. Bili – 14.2, AP – 130, AST- 1565, ALT – 2448, GGT – 287, T.P. – 7.1, Alb. – 4.4, LDH – 541  INR – 1.1  Serology: HAV IgM – NR, HBsAg – Reactive, anti-HBc IgM – reactive, anti-HCV - NR
  6. 6. CHRONIC HEPATITIS B
  7. 7. Slide 7 Natural history of HBV
  8. 8. Interpreting HBV Serologic Tests Centers for Disease Control and Prevention. MMWR. 2008;57(RR08):1-28. HBsAg HBsAb Total HBcAb IgM HBcAb Interpretation - - - - Never infected/ not immunized + - + - Chronic ( active, inactive carrier and immune tolerant) + - - + Acute infection - + + - Past infection with immunity(Resolved) - + - - Immune
  9. 9. Slide 8 Immune escape < <> > HBeAg+ve HBeAg–ve ALT HBV-DNA Inactive (carrier) state* HBeAg –ve active chronic hepatitis HBeAg +ve chronic hepatitis Immune tolerance Immune clearance Immune control The phases of chronic hepatitis B *Previously considered to be ‘healthy carriers’
  10. 10. Case study 3  26 year old woman presents to liver clinic after undergoing community screening for viral hepatitis  Family HX: She is of Laotian descent; two older siblings have hepatitis B  Physical exam: BMI 22, normal  T. Bili 2.2 Direct bili 0.2, ALP 90, AST 18, ALT 14, Alb 4.2  INR – 0.9  Serology: HBsAg – Reactive, anti-HBc – reactive, HbeAg positive, Hbeab negative, HBV DNA >200,000 – What is the most appropriate step? • Liver biopsy • Immunize against HBV • Monitoring transaminases, • Tenofovir  Adapted from MKSAP 16
  11. 11. Slide 11 Who should be considered for treatment? Immune escape < <> > HBeAg+ve HBeAg–ve ALT HBV-DNA Inactive (carrier) state HBeAg –ve/+ve active chronic hepatitis HBeAg +ve chronic hepatitis Immune tolerance Immune clearance Immune control treat treat
  12. 12. Slide 12 Overview of Algorithm Used to Determine Need for Treatment of HBV Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008 Lok AS et al Hepatology, 2009 HBeAg Positive Treat Monitor ALT Q3mos for 1y HBeAg Negative HBV DNA >20,000 IU/mL HBV DNA >2,000 IU/mL Normal ALT Consider Liver Biopsy >40 yrs Significant fibrosis or inflammation Elevated ALT ALT Level
  13. 13. Slide 13 Approved HBV treatments 2009 • Interferon alfa-2b – 1991 • Lamivudine – 1998 • Adefovir – 2002 • Entecavir – 2005 • Peginterferon alfa-2a – 2005 • Telbivudine – 2006 • Tenofovir - 2008 For HIV: o Emtricitabine o Tenofovir + emtricitabine (single pill co-formulation)
  14. 14. Vaccination Recommendations • Sexual and household contacts of HBsAg carriers • Newborns of HBV-infected mothers - HBIG and HBV vaccine series (begin at delivery) • Infants of HBsAg-positive mothers, health care workers, HD patients, and sexual partners of carriers • Post-vaccination testing – Infants-age 9 to 15 mos. • 1-2 mos after the last dose in others • Follow-up testing of vaccine response -annually for HD patients • Persons who are positive only for anti-HBc and who are from a low endemic area with no risk factors for HBV should be given the full series of hepatitis B vaccine. • Lok and McMahon, AASLD guidelines
  15. 15. Hepatitis Vaccine- Typical Schedule  Hepatitis Vaccines – Hep A and B (Twinrix) • Three doses (0.5 mL) at 0, 1 and 6 months – Hep B (Engerix-B or Recombivax) • Three doses- (1 mL) at 0, 1, and 6 months – Engerix contains 20 mcg/mL – Recombivax contains 10 mcg/mL
  16. 16. Slide 32 Reactivation of HBV • High rate of reactivation in immunosuppressed patients o Chemotherapy o HIV after immune reconstitution o Post organ transplant o Biologic response modifiers: rituximab (anti- CD20), TNF-inhibitors: GI, hematologists, rheumatologists, dermatologists
  17. 17. Slide 33 Reactivation of HBV • ALL patients undergoing chemotherapy must have tested HBsAg, HBsAb and HBcAb prior to treatment
  18. 18. Slide 36 Require monitoring… • Inactive disease may not remain inactive • Liver damage may occur if HBV reactivates Require treatment 40% 60% HBV is a dynamic disease!!! HBV can be controlled HBV: The importance of monitoring
  19. 19. Hepatitis C http://www.hcvguidelines.org
  20. 20. Question 1  Which of the following statements is TRUE regarding the epidemiology of chronic hepatitis C virus (HCV) infection  A. The prevalence of chronic HCV has risen between 1990- 2000 and 2001-2010  B. Blood transfusions before 1992 represent the most common route of transmission  C. The burden of chronic HCV is higher in North America than the sub-Saharan Africa  D. The prevalence of chronic HCV is highest in US adults born between 1945-1965  E. Approximately 5-10% of individuals with HIV also harbor chronic HCV infection Adapted from DDSEP 7
  21. 21. Question 2  52 year old woman presents to your office for the management of chronic hepatitis C infection. Laboratory testing reveals: HCV genotype 2a, HCV RNA 1.63 million IU/ml, AST 59 U/L, ALT 78 U/L, Albumin 4.3 g/dL, INR 0.9 Hgb 13.1 and platelets 125,000. She is treatment naïve and expresses interest in pursuing antiviral therapy. Which one of the following statements is correct?  A. She will require a liver biopsy prior to consideration for antiviral therapy  B. The standard of care treatment is sofosbuvir 400 mg daily and weight based ribavirin twice daily.  C. The standard of care treatment is protease inhibitor based triple therapy  D. The standard ribavirin dosing is based on patient body weight (600mg/day if body weight<= 75 g, 1200 mg/day if body weight>75kg E. The standard duration of antiviral therapy is 24 weeks Adapted from DDSEP 7
  22. 22. Background  The hepatitis C virus (HCV) with an estimated 180 million people infected worldwide is a leading cause of chronic liver disease.  The prevalence of HCV infection in the U.S has been estimated at 1.6%, equating to about 4.1 million persons positive for the hepatitis C antibody
  23. 23. Screening Recommendations • Annual HCV testing • Persons who inject drugs, HIV seropositive men who have unprotected sex with men and ongoing risk factors • One time Testing • Asymptomatic adults born between 1945 through 1965 • Persons with conditions associated with a high prevalence • Hemodialysis • Abnormal aminotransferases • Recipients of transfusions/organ transplants before 1992 or clotting factor concentrates before 1987 • Children born to HCV-infected mothers • Tatoos or ever incarcerated • AASLD/IDSA Guidelines 02/24/2014 • CDC guidelines 2012
  24. 24. Recommendations Prior to Therapy (AASLD/IDSA 2014)  Quantitative HCV RNA and genotype  Education/interventions – liver disease progression and transmission – Conditions that may accelerate liver fibrosis • Alcohol • HBV and HIV – Advanced fibrosis by liver biopsy, imaging or noninvasive markers – Vaccination against HAV and HBV  Evaluation by an health care provider – Comprehensive management – Antiviral therapy evaluation AASLD/IDSA Guidelines 02/24/2014
  25. 25. Recommendations on Who To Treat (AASLD/IDSA 08/14)  Reduce all-cause mortality and liver-related ESLD and HCC  Treatment is recommended – Highest priority for those patients with • advanced fibrosis (Metavir F3) • compensated cirrhosis (Metavir F4) • TX recipients, and patients with severe extrahepatic HCV Prioritize patients with high risk for liver-related complications and severe extrahepatic hepatitis C complications AASLD/IDSA Guidelines 08/24/2014
  26. 26. Hepatitis C Virus  Hepatitis C Virus – Member of Flaviviridae family of spherical, enveloped, positive- strand RNA viruses – Six genotypes - geographic variance  Hepatitis C Virus Proteins – Envelope glycoproteins E1-E2 – Protease assembly NS3/NS4A complex – NS5A RNA replication assembly – RNA dependent RNA polymerase Moradpour D, Nature Review/Microbiology 2007 5:453
  27. 27. Translation and polyprotein processing NS3/4 protease inhibitors HCV Life Cycle and Targets for Direct-Acting Antivirals (DAAs) Receptor binding and endocytosis Transport and release Virion assembly RNA replication Fusion and uncoating (+) RNA Membranous web NS5B polymerase inhibitors Nucleos(t)ide Non-nucleoside NS5A inhibitors replication and assembly Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
  28. 28. Direct Acting Antivirals (DAA) • Ledipasvir/Sofosbuvir (Harvoni) • Ombitasvir, Paritaprevir/ritonavir + Dasabuvir (Viekira Pak)
  29. 29. Hepatitis C Viral Replication 1 2 3 456 NS3/4A Protease inhibitor
  30. 30. Protease Inhibitors  Simeprevir (Olysio) – HCV serine protease inhibitor- inhibition of a protein essential for viral replication through cleavage of the viral polyprotein – HCV genotype 1 – 1 tablet (150 mg) po qd  Side Effects – Photosensitivity – Hyperbilirubinemia J Med Chem. 2014. 57:1673-93 Nature Reviews Gastro & Hep 2013 10:596-606 .
  31. 31. Hepatitis C Viral Replication 1 2 3 456 Polymerase Inhibitors
  32. 32. NS5B Nucleotide polymerase inhibitor  Sofosbuvir (Sovaldi) (PSI 7977) – HCV-specific nucleotide polymerase inhibitor • Mimics the natural substrates of the RNA dependent RNA polymerase - incorporated into the elongated RNA • Act as chain terminator – 400 mg qd  Side Effects – Insomnia, GI effects Sofia MJ. J Med Chem. 2010. 53:7202-18 Nature Reviews Gastro & Hep 2013 10:596-606
  33. 33. NS5B Non-Nucleoside Polymerase Inhibitors  Dasabuvir (ABT 333) ( 250mg bid) – Non-nucleoside analogue inhibitor • Compound that binds to an allosteric enzyme site, rending a conformational protein change before the elongation complex is formed  Side Effects – Increase bilirubin /transaminases in combo - ABT450- Ritonavir/Ombitasvir and RBV Vermehren J, Clin Microbiol Infect. 2011. 2:122-34 Nature Reviews Gastro & Hep 2013 10:596-606
  34. 34. NS5A Replication Complex inhibitors  Daclatasvir (BMS 790052)(60mg qd) – Genotype 1, 2, 3 – Combo – Sofosbuvir  Ledipasvir (GS-5885) (90 mg qd) – Genotype 1 – Combo - Sofosbuvir  Ombitasvir (ABT 267) – Pan-genotypic HCV inhibitor against GT1-6 – Combo - Paritaprevirwith ritonavir (R) and dasabuvir Taylor JG, J Med Chem. 2014. 57:2033-46. DeGoey DA J Med Chem. 2014. 57):2047-57 Ledipasvir
  35. 35. CLINICAL TRIALS http://www.hcvguidelines.org
  36. 36. Trials with New Direct Acting Antiviral Agents Neutrino Fission-Fusion Positron Electron Quest/Promise Cosmos ION-1 ION-2 ION-3 ALLY Sapphire Turquoise Pearl HCV
  37. 37. Combination Direct Acting Antiviral Therapy Type Clinical Trial Combination Genotypes IDSA/AASLD Recommend NS5B nucleoside polymerase Inhibitor Sofosbuvir FISSION/ FUSION Ribavirin GT2/3 YES COSMOS Simeprevir GT1 YES ION Ledipasvir GT1 YES ALLY Daclatasvir GT1/2/3 NO
  38. 38. 14/38 5/26 Sofosbuvir/Ribavirin – HCV GT2 and GT3 Sofosbuvir/Ribavirin and PegIFN – HCV GT1 and 4-6 No Cirrhosis vs Cirrhosis: SVR12 No cirrhosis Cirrhosis GT 3GT 2GT 1, 4-6 251/273 43/54 58/59 85/92 25/26 23/23 89/145 57/84 25/40 10/11 16/17 6/10 7/9 13/38 3/14 14/23 Mangia A et al. The Liver Meeting 2013 SVR12(%)
  39. 39. COSMOS TRIAL Simeprevir plus sofosbuvir with or without ribavirin in genotype 1 Cohort 1 Treatment naïve and null responders with Metavir F0-2 Response rates 93-96% Cohort 2 Genotype 2, treatment-naïve and null responder patients Cirrhosis- 47% of pts Cohort 2
  40. 40. Trials with New Direct Acting Antiviral Agents Neutrino Fission-Fusion Positron Electron Quest/Promise Cosmos ION-1 ION-2 ION-3 ALLY Sapphire Turquoise Pearl HCV
  41. 41. Sofosbuvir/Ledipasvir – HCV GT 1, Naïve Pts - ION-1  Phase 3 trial – US  Fixed dose combination composed of SOF (400mg) and LDV (90mg) w or w/o RBV for 12 or 24 wks  N=865  15.7% pts w/ cirrhosis 0 10 20 30 40 50 60 70 80 90 100 SOF/LDV + RBVV SVR 12
  42. 42. Sofosbuvir/Ledipasvir GT 1, Treatment-Experienced Pts - ION-2  Phase 3 trial - US  Fixed dose combination composed of SOF and LDV w or w/o RBV for 12 or 24 wks  N=440  20% pts w/ cirrhosis 0 10 20 30 40 50 60 70 80 90 100 Sof/LDV+ RBV SOF/LDV+ RBV SOF/LDV ---12 Wks--- ---24 Wks --- SVR 12
  43. 43. Sofosbuvir/Ledipasvir in GT 1 Treatment-Naïve Patients - ION 3  Phase 3 trial in U.S.  FDC - Sofosbuvir and ledipasvir w or w/o ribavirin - 8 or 12 wks  N=647  No cirrhotic patients 8 weeks 12 weeks SOF/LDV SOF/LDVSOF/LDV /RBV 94% 93 % 95%
  44. 44. Sofosbuvir and Daclatasvir Naïve and Treatment experienced (ALLY)  Patient Cohort – HCV GT1 Naive (n=44) GT 2/3 (n=44) • Regimen – Daclatasvir + sofosbuvir w/wo RBV- 24 wks.  Patient Population – 123 more GT1 • Regimen – Daclatasvir + sofosbuvir, w/wo RBV- 12 wks (82 naïve ) or 24 wks (41 pts exp with PR/T or B  Results – 211 pts •GT1 naive (n=126) - 98% •GT 1 PR/T/B experienced (n=41) - 98% • GT 2 (n=26) – 92% • GT 3 (n=18) - 89% Side effects – Fatigue/ HA/nausea 98% 92% 89% 97% GT1 GT2 GT3 GT1/ PI fail
  45. 45. Trials with New Direct Acting Antiviral Agents Neutrino Fission-Fusion Positron Electron Quest/Promise Cosmos ION-1 ION-2 ION-3 ALLY Sapphire Turquoise Pearl HCV
  46. 46. HCV GT 1a/1b patients Naïve and Treatment Experienced (Turquoise II)  Patient Cohort – HCV cirrhosis (n=380)  Regimen – 12 wks or 24 wks (3D Regimen) (RBV) – Paritaprevir/ritonavir – Ombitasvir – Dasabuvir + RBV Results  191/208 - 12 wks - SVR12 - 91.8%  165 /172 - 24 wks - SVR12 - 96%  Adverse events – Fatigue, headache, nausea – Hgb< 10 g/dL in 7.2% and 11.0% – Discontinue rate 2.1% Poordad et al NEJM, 370: 1973-82.
  47. 47. AASLD/IDSA HCV Treatment Guidelines- Naïve Genotype Recommended Alternative 1a 1b No Cirrhosis: LDV/SOF x12 wks OBV/PTV/r + DSV + RBV x12 wks With Cirrhosis: LDV/SOF x12 wks OBV/PTV/r + DSV + RBV x24 wks No Cirrhosis: LDV/SOF x12 wks OBV/PTV/r + DSV x12 wks With Cirrhosis: LDV/SOF x12 weeks OBV/PTV/r + DSV + RBV x12 weeks No cirrhosis SOF/SMV +/- RBV-12 wks With Cirrhosis SOF/SMV +/- RBV -24 wks Same as 1a 2 SOF + RBV-12 wks SOF + RBV -16 wks - Cirrhosis 3 SOF + RBV-24 wks SOF + Peg/RBV-12 wks 4 Same as 1a ( only 12 wks) Same as 1a (only 12 wks) SOF/RBV -24w
  48. 48. AASLD/IDSA HCV Treatment Guidelines - Treatment Experienced Genotype Recommended Alternative 1a 1b No Cirrhosis: LDV/SOF x12 wks OBV/PTV/r + DSV + RBV x12 wks With Cirrhosis: LDV/SOF x24 wks LDV/SOF + RBV x12 wk OBV/PTV/r + DSV + RBV x24 wks No Cirrhosis: LDV/SOF x12 wks OBV/PTV/r + DSV x12 wks With Cirrhosis: LDV/SOF x24 wks LDV/SOF + RBV x12 wks OBV/PTV/r + DSV + RBV x12 wks No cirrhosis SOF/SMV +/- RBV -12 wks With cirrhosis SOF/SMV +/- RBV - 24 wks 2 SOF + RBV-12 wks SOF + RBV -16 wks - Cirrhosis SOF + Peg/RBV-12 wks 3 SOF + RBV-24 wks SOF + Peg/RBV-12 wks 4 Same as 1a ( only 12 wks) SOF + Peg/RBV-12 wks SOF + RBV -24 wks
  49. 49. Question 1  Which of the following statements is TRUE regarding the epidemiology of chronic hepatitis C virus ( HCV) infection  A. The prevalence of chronic HCV has risen between 1990-2000 and 2001-2010  B. Blood transfusions before 1992 represent the most common route of transmission  C. The burden of chronic HCV is higher in North America than the sub-Saharan Africa  D. The prevalence of chronic HCV is highest in US adults born between 1945-1965  E. Approximately 5-10% of individuals with HIV also harbor chronic HCV infection Adapted from DDSEP 7
  50. 50. Question 2  32 year old woman presents to your office for the management of chronic hepatitis C infection. Laboratory testing reveals: HCV genotype 2a, HCV RNA 1.63 million IU/ml, AST 59 U/L, ALT 78 U/L, Albumin 4.3 g/dL, INR 0.9 Hgb 13.1 and platelets 276,000. She is treatment naïve and expresses interest in pursuing antiviral therapy. Which one of the following statements is correct?  A. She will require a liver biopsy prior to consideration for antiviral therapy  B. The standard of care treatment is sofosbuvir 400 mg daily and weight based ribavirin twice daily.  C. The standard of care treatment is protease inhibitor based triple therapy  D. The standard ribavirin dosing is based on patient body weight (600mg/day if body weight<= 75 g, 1200 mg/day if body weight>75kg E. The standard duration of antiviral therapy is 12 weeks except in patients with cirrhosis of 24 weeks is recommended Adapted from DDSEP 7
  51. 51. Summary  Acute – Hepatitis A • HAV IgM, More severe disease with advancing age. Effective vaccine – Hepatitis B • HBsAg, HBcIgM,  Chronic – Chronic HBV – HBc Ab Total, HBsAg • High HBV VL in HBeAg +/Lower HBV VL in HBeAg - • First line treatment Tenofovir and Entecavir • Goal -Reduce viral levels <10 IU – Chronic HCV • Effective Therapy – SOF/RBV - GT 2 and 3 – LDV/SOF + RBV –GT1 and 4 – OBV/PTV/r + DSV + RBV - GT1a and GT1b

×