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Clinical Advances in Diagnosis, Treatment and Outcome of Hepatitis A, B and C

Clinical Advances in Diagnosis, Treatment and Outcome of Hepatitis A, B and C. Marc Ghany, M.D. LDB, NIDDK, NIH Demystifying Medicine May 19th, 2009. Case Presentation.

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Clinical Advances in Diagnosis, Treatment and Outcome of Hepatitis A, B and C

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  1. Clinical Advances in Diagnosis, Treatment and Outcome of Hepatitis A, B and C Marc Ghany, M.D. LDB, NIDDK, NIH Demystifying Medicine May 19th, 2009

  2. Case Presentation • A 21 year old male college student presents with abdominal pain, nausea, loss of appetite, yellowing of the skin and darkening of his urine x 2 days. • On physical exam he is jaundiced, tender to palpation in the right upper quadrant and his liver is enlarged.

  3. Some More History… On further questioning: • He admits to recent travel to Mexico one month prior to his getting ill • He reports eating street food • Having a one night relationship with someone he met while on vacation • Drinking 6-7 drinks on most nights • He denied using acetaminophen (Tylenol), herbal preparations or using injection drugs

  4. Pertinent Laboratory Results • Serum ALT: 1200 IU/ml • Serum AST: 1121 IU/ml • Serum Alkaline phosphatase 120 IU/ml • Total Bilirubin: 7.3 mg/dL • Direct Bilirubin: 6.0 mg/dL • Abdominal Ultrasound: Enlarged, homogenous appearing liver; No biliary obstruction

  5. Overview of Hepatitis A, B and C

  6. He Asks “What’s Wrong with Me? • How Do We Diagnose Hepatitis A, B or C?

  7. Serologic Course of Hepatitis A HAV RNA Fecal HAV Total anti-HAV Jaundice ALT IgM anti-HAV Normal 4 5 6 12 24 0 1 2 3 Months after exposure

  8. Serologic Course of Hepatitis B HBV DNA anti-HBe HBeAg Jaundice Total anti-HBc anti-HBs IgM anti-HBc HBsAg 0 4 8 12 16 24 28 32 52 100 20 36 Weeks after exposure

  9. Serologic Course of Hepatitis C HCV RNA anti-HCV Jaundice ALT Normal 6 1 2 3 4 0 1 2 3 4 5 Months Years Time after Exposure

  10. He Asks “Could This Have Been Prevented?” Prevention of hepatitis A • Passive immunization with immunoglobulin Pre-exposure prophylaxis • Provides 3-5 months protection • 95% effective Post-exposureprophylaxis • >85% effective • Active Immunization • 2 commercially available vaccines (HAVRIX and VAQTA) • 94-100% effective • Safe

  11. Persons For Whom Hepatitis A Vaccine is Recommended • People traveling to or working in countries that have high or intermediate endemicity of infection • Men who have sex with men • Illicit drug users • People who have occupational risk factors for infection • People who have clotting factor disorders

  12. Prevention of hepatitis B • Passive immunization-HBIG • immunizationPostexposure prophylaxis (perinatal, sexual, household contact of acute case, inadvertent percutenous/permucosal exposure) • Active immunization • Two yeast-derived vaccines available • 80-95% effective

  13. Persons For Whom Hepatitis B Vaccine is Recommended • People with occupational risk • Clients and staff of institutions for the developmentally disabled • Hemodialysis patients • Recipients of clotting factor concentrates • Household contacts and sex partners of HBV carriers • Adoptees from countries where HBV is endemic • International travelers • Injection drug users • Sexually active men and women • Inmates of long-term correctional facilities

  14. Prevention of hepatitis C • Immunoglobulin ineffective • No vaccine available

  15. The Case Continues… • In 4 weeks his jaundice resolves, he feels better and his liver associated enzymes (ALT and AST) improve but have not quite returned to normal • He is lost to follow-up

  16. Scenario 1 • He returns to your office 5 years later. • He feels well but he went for a physical exam prior to getting life insurance and was denied because of elevated liver associated enzymes. • Blood tests reveal the following: • HBsAg positive; HBeAg positive; HBV DNA 5 x108 copies/ml • Serum ALT 150, AST 125 • Total bilirubin 1.0, albumin 4.2 g/dl

  17. HBeAg - positive CHB HBeAg – negative CHB Outcome of CHB by phases Immune tolerance Immune clearance Immune control Immune escape inactive carrier state reactivation minimally active immuno active low replicative state high replicative state 109–1010 107–108 >105 HBV-DNA <105 ALT

  18. Who To Treat?

  19. AASLD Guidelines for Initiation of Treatment in Chronic Hepatitis B HBeAg Negative HBeAg Positive ALT < 1 x ULN ALT > 2 x ULN ALT < 1 x ULN ALT > 2 x ULN Monitor patient HBV DNA > 20,000 IU/mL HBV DNA ≥ 20,000 IU/mL HBV DNA < 2000 IU/mL Treat if persistent Monitor patient Treat if persistent ALT 1-2 x ULN ALT 1-2 x ULN HBV DNA 2000-20,000 IU/mL Consider biopsy; treat if needed HBV DNA > 20,000 IU/mL Consider biopsy if persistent or > 40 yrs; treat if needed Lok AS, et al. Hepatology. 2007;45:507-539.

  20. Definitions of Response Virological • Full: Decrease in HBV DNA to levels that are undetectable by sensitive PCR assay e.g. < 60 IU/mL • Partial: Decrease in HBV DNA by at least 2 logs and to less than 20,000 IU/mL • Primary non-response: Decrease in HBV DNA by <2 logs Serological • HBeAg seroconversion: Loss of HBeAg with gain of anti-HBe • HBsAg seroconversion: Loss of HBsAg with gain of anti-HBs

  21. Definitions of Response Biochemical • Normalization of serum ALT level Histological • Decrease in hepatic necroinflammatory score by at least 2 points with no worsening in fibrosis score Complete response • Combined biochemical, virological,serological (loss of HBsAg) and histological

  22. What to Treat With

  23. Therapy for Chronic Hepatitis B: 2009 LAM “The New Era” Oral therapy 2009 and beyond… 1992 2006 1998 2005 2008 2002 LdT IFN alfa TDF Combination Rx? ETV PegIFN alfa-2a ADV

  24. Factors Influencing Choice of Therapy • Age of patient • HBeAg status of patient • Stage of disease • Co-infection with other hepatotrophic viruses or HIV-1 • Presence of co-morbid conditions • Efficacy and side effects of therapy • Costs associated with therapy • Patient’s preference

  25. The First Decision: Choosing What to Treat With Decision to treat IFN (PegIFN alfa-2a) Nucleos(t)ide analogues

  26. Advantages and Disadvantages of PegIFN

  27. Favorable predictors of response Genotype A or B > C or D Low HBV DNA High ALT Specific patient demographics Generally young persons Young woman wanting future pregnancy Absence of comorbidities Patient preference Concomitant HCV infection Concomitant HIV infection and no indication for HAART When to Consider PegIFN

  28. Virologic Response in HBeAg+ Patients (Undetectable* HBV DNA at Wk 48-52) Not head-to-head trials; different patient populations and trial designs 100 76 80 69 67 60 60 Patients With Undetectable HBV DNA (%) 40-44 40 25 21 0-16 20 0 PLB LAM ADV ETV LdT TDF Peg-IFN Peg-IFN +LAM *By PCR based assay (LLD ~ 50 IU/mL) except for some LAM studies. Lok AS, et al. Hepatology. 2007;45:507-539.

  29. Virologic Response in HBeAg+ Patients (HBeAg Seroconversion at Wk 48-52) Not head-to-head trials; different patient populations and trial designs 100 80 60 Patients Achieving HBeAg Seroconversion (%) 40 32* 27* 22 16-21 21 21 27 20 12 24 4-6 0 PLB LAM ADV ETV LdT TDF Peg-IFN Peg-IFN +LAM *Response 6 months after stopping treatment. Lok AS, et al. Hepatology. 2007;45:507-539. Heathcote EJ, et al. AASLD 2007. Abstract LB6.

  30. HBeAg Seroconversion With Extended Treatment Not head-to-head trials; different patient populations and trial designs 100 100 100 LAM ADV TDF 80 80 80 Patients (%) 60 60 60 Patients (%) Patients (%) 50 48 47 40 40 40 40 29 30 21 22 20 20 20 12 0 0 0 1 2 3 4 5 100 100 ETV LdT 80 80 Patients (%) 60 60 Patients (%) 47 37 40 40 31 29 23 21 20 20 0 0 1 2 3 4 5 1 2 3 4 5 Years of Therapy Years of Therapy Chang TT, et al. J Gastro Hepatol. 2004;19:1276-1282. Lok AS et al. Gastroenterol. 2003;125:1714-1722. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Chang TT, et al. Hepatology. 2006;44(suppl 1):229A. Marcellin P, et al. N Engl J Med. 2003;348:808-816. Marcellin P, et al. Hepatology. 2006;44(suppl 1):548A. Lai CL, et al, Hepatology. 2005;42(suppl 1):748A. Lai CL, et al. Hepatology. 2006;44(suppl 1):222A. Han S, et al. AASLD 2007. A938.

  31. Virological Response in HBeAg+ Patients(HBsAg Loss at Week 48-52) 3% 3% 3% 2% 0-1% 0% PegIFN PegIFN & LAM LAM ADV ETV TDF Lau GKK, NEJM 2005;352:2682; Marcellin P NEJM 2003;348:808; Chang TT NEJM 2006;354:1001; Marcellin NEJM 2008;359:2442

  32. Lamivudine TherapyMaintained Response and Breakthrough Lamivudine HBeAg HBeAg Anti-HBe HBsAg HBV DNA ALT HBV DNA (-) Nl ALT Liver Bx HAI PreRx:14/3 Yr 1:3/1 Yr 4:1/0

  33. Lamivudine Therapy:Sustained Response Lamivudine HBeAg HBsAg Anti-HBs HBV DNA ALT Biopsy scores 13/3 3/3 1/1

  34. Antiviral Resistance

  35. Antiviral Treatment Failure in HBV Antiviral Drug +1.0 Secondary treatment failure 0.0 2 log -1.0 Primary nonresponse* Log HBV DNA -2.0 Genotypic resistance -3.0 1 log -4.0 Time *Defined as < 2 log reduction in serum HBV DNA after 6 months of therapy. Adapted from Lok AS, et al. Hepatology. 2007;45:507-539.

  36. Rates of Genotypic Resistance Nucleos(t)ide Naïve Patients Percent Lai CL N Engl J Med 1998;341:339:61-68; Lok AS. Gastroenterology. 2003;125:1714-1722; Dienstag JL N Engl J Med 1999;341:1256-1263; Westland C. Hepatology 2003; 38:96-103; Hadziyannis S. Gastroenterology. 2006;131(6):1743-51; Colonno RJ Hepatology. 2006;44:1656-1665; Lai CL. N Engl J Med. 2007;20;357:2576-88; Heathcote EJ. Hepatology. 2007;46:LB6; Gilead Sciences

  37. End points of therapy • HBeAg+: -IFN / PegIFN: Loss of HBeAg -Nucleosides: HBeAg loss ?HBeAg seroconversion Loss of HBsAg • HBeAg-: -Undetectable HBV DNA by PCR assay and normal ALT Loss of HBsAg

  38. Scenario 2 • He returns to your office 5 years later • He feels well but he went for a physical exam prior to getting life insurance and was denied because of elevated liver associated enzymes • Blood tests reveal the following: • Anti-HCV positive; HCV RNA level 3.5 x 106 copies/ml; genotype 1b • Serum ALT 150, AST 125 • Total bilirubin 1.0, albumin 4.2 g/dl

  39. Distribution of HCV Genotypes in the U.S. Gt 3 (5.5%) Gt 4 (1%) Gt 6 (2%) Gt 2 (13.5%) Gt 1 (78%) Nainan OV Gastroenterology 2006;131:478-84

  40. Sources of Infection inPersons with Hepatitis C Injection drug use 54% Sexual 24% Transfusion 1% HD* 1% Unknown 12% Nosocomial 8% *Hemodialysis Source: MMWR April 2007

  41. 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

  42. Who To Treat?

  43. Therapy of Hepatitis C: Current Indications • Age above 18 years • HCV RNA in serum • Raised serum aminotransferases • Liver biopsy showing fibrosis or moderate-to-severe necrosis and inflammation • No contraindications Based upon Recommendations from the 2002 NIH Consensus Development Conference: “Management of Hepatitis C”

  44. Outcomes of Therapy of Chronic Hepatitis C Virological Response is defined by absence of HCV RNA from serum using a sensitive method (<50 IU/ml) On treatment: • End-of-Treatment Virological Response • Virological Non-Response (NR) Off Treatment: • Relapse • Sustained Virological Response (SVR)

  45. Non-Response Relapse ETR CHRONIC HEPATITIS CVirological Responses Peginterferon and Ribavirin 7 6 5 4 3 2 SVR Undetectable 1 0 -8 -4 -2 0 4 8 12 16 20 24 32 40 48 52 60 72 Weeks After Start of Therapy

  46. What to Treat With

  47. Optimal Therapy of Hepatitis C: 2009 Combination Therapy • Peginterferon (by injection) • alfa-2a 180 g weekly • alfa-2b 1.5 g/kg weekly • Ribavirin (by mouth) • 800 to 1400 mg in two divided doses daily • For 24 to 48 weeks

  48. Progress in Therapy of Hepatitis C Telapravir Peginterferon Ribavirin 2009 Standard Interferon 2001 2002 2001 69% 1998 54% 1995 1995 1991 42% 39% 34% 16% 6%

  49. Frequency of Virologic Responses to Peginterferon and Ribavirin Shiffman et al NEJM 2007;357:124-134; Ferenci J Hepatol 2005;43:425-433

  50. SVR is Associated with Lower Rates of Liver Related Complications and HCC Liver related complications HCC Bruno et al Hepatology 2007;45:579

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