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John Scott, MD, MSc

John Scott, MD, MSc. Infectious Diseases Fellows Course July 7, 2011. Outline. Hepatitis B biology epidemiology natural history treatment HIV coinfection Hepatitis C biology epidemiology natural history treatment HIV coinfection. Alphabet soup of viral hepatitis.

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John Scott, MD, MSc

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  1. John Scott, MD, MSc Infectious Diseases Fellows Course July 7, 2011

  2. Outline • Hepatitis B • biology • epidemiology • natural history • treatment • HIV coinfection • Hepatitis C • biology • epidemiology • natural history • treatment • HIV coinfection

  3. Alphabet soup of viral hepatitis • Hepatitis A: contaminated food and water, ~1% fatality with acute form, no chronic infection, vaccine available • Hepatitis B: Blood borne and sexual transmission, most common world wide, can become chronic, vaccine and treatment available • Hepatitis C: primarily blood borne, chronic in 60-85%, treatment available • Hepatitis D: rare, only seen w/ Hep B, severe disease w/ cirrhosis in 70% cases • Hepatitis E: contaminated food and water, acute only, rare in US, severe in pregnant women (~10% fatality)

  4. Hep B Biology • partially ds DNA virus, 3200 bp • Hepadnavirus • 42 nm • 8 genotypes (A-H) • Covalently closed circular (ccc) DNA

  5. Geographic Distributionof Chronic HBV Infection HBsAg Prevalence High (>8%) Intermediate (2%-8%) Low (<2%) Mast EE, et al. MMWR Recomm Rep. 2006;55(16):1-33. Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S158-S168.

  6. Natural history of chronic hep B in Asia • 25-40% of male carriers will die from sequelae (either cirrhosis or HCC) • ~15% of female carriers • Additional risk factors for adverse outcome include: • Male sex • Older age • Smoking • Alcohol • Cirrhosis (as a risk factor for HCC) • Liver cancer is the most common cause of cancer death among men in Asia

  7. 1.0 Survival 0.95 0.9 Baseline HBV DNA (copies/mL) <300 0.85 300-9,999 10,000-99,999 100,000-999,999 0.8 >1 million P<0.001 0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 14 Year of follow-up REVEAL: Relationship BetweenHBV DNA Level and All-Cause Mortality Viral load presented as copies/mL. Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

  8. 4 Phases of Chronic HBV Infection Immune tolerant phase* HBeAg positive HBV DNA 105-10 ALT normal Non-replicative phase (inactive HBsAg carrier) HBeAg negative HBV DNA <104 ALT normal HBsAg may later become undetectable Immune active HBeAg positive chronic HBV HBV DNA 105-10 ALT levels high or fluctuating Active inflammation on liver biopsy HBeAg negative HBeAg negative chronic HBV HBV DNA 104-8 ALT levels high or fluctuating Active inflammation on liver biopsy Not Candidates for Therapy Candidates for Therapy *Not seen in adult-onset infection. Yim HJ, et al. Hepatology. 2006;43:S173-S181.

  9. Treatment of chronic hepatitis B 2008 2005 <1999 1999 2001 2002 interferon lamivudine tenofovir (HIV) adefovir • Peginterferon • entecavir • tenofovir • telbivudine

  10. Treatment endpoints • Loss of HBeAg • Development of HBeAb (seroconversion) • Loss of sAg • HBV DNA suppression • Improve liver histology • Reduce rates of progression to cirrhosis or hepatocellular carcinoma

  11. Chronic HBV Treatment:Simplified Flow Chart HBeAg Positive HBeAg Negative HBV DNA >20,000 IU/mL HBV DNA >2,000 IU/mL ALT Evaluation Normal ALT Elevated ALT Monitor Liver Biopsy Abnormal Histology Treat Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

  12. Chronic HBV Treatment: Simplified Flow Chart for Patients With Cirrhosis Compensated Decompensated Detectable HBV DNA Undetectable HBV DNA HBV DNA <2,000 IU/mL HBV DNA >2,000 IU/mL Treat Observe or Treat Treat Observe Wait List for Transplant Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

  13. Q: All of the following are candidates for HBV therapy except: • 35 yo Asian eAg+, HBV DNA 10 million IU/ml and ALT over 60 (x 6 mos) • 45 yo Somali man eAg-, HBV DNA 17k, ALT 35, cirrhosis on ultrasound • 29 yo Asian woman eAg+, HBV DNA 20 million, ALT 22 • 65 yo Asian woman eAg-, HBV DNA 700k, ALT 100

  14. HBV Combination Therapy • Consider de novo combination therapy in: • Decompensated HBV cirrhosis • Patients with prior resistance to HBV medications • Patients with prior exposure to HBV medications (i.e HIV+ pts) • Post-transplant patients • Patients requiring long-term therapy Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

  15. HBV Treatment Options inHIV/HBV-Coinfected Patients Lok AS, et al. Hepatology. 2007;45:507-539. European AIDS Clinical Society Guidelines. Available at: http://www.eacs.eu.

  16. HIV/HBV Coinfection • Liver-related disease is a major cause of death among HIV-infected individuals1 • Up to 10% of HIV+ patients may be HBV carriers 1Smith, et al. J Urban Health. 2003 Dec;80(4):676-88.

  17. Hep B case 2: • 43 year old Somali man sent to you because he is sAg+ • What labs do you order next?

  18. Hep B case 2: • eAg-, eAb+ • ALT 63 (slightly above normal)

  19. Hep B: Case 2 • HBV DNA = 240 copies/ml • Your diagnosis? Inactive hepatitis B carrier

  20. Hep B: Case 2 • HBV DNA = 1.6 million copies/ml • Your diagnosis? Chronic hepatitis B, precore mutant

  21. What would be the best choice for treatment? Tenofovir 300 mg daily or Entecavir 0.5 mg daily Because of need for prolonged treatment (no endpoint) and low rate of resistance

  22. Outline • Hepatitis B • biology • epidemiology • natural history • treatment • HIV coinfection • Hepatitis C • biology • epidemiology • natural history • treatment • HIV coinfection

  23. Biology • ss RNA virus • RNA-dependent RNA polymerase, lacks proofreading function • Flaviviridae • 6 genotypes, type 1 accounts for 70% of infections in US, types 2,3 account for rest • No easy culture system! www.hepcprimer.com/3dmodel.html

  24. HCV problem persists because… Source: 2010 Institute of Medicine Report on Viral Hepatitis

  25. Occupational Exposures • Blood borne exposures (i.e needlestick) • Greatest risk comes from hollow bore needle w/ deep puncture from patient w/ high viral load • Rule of 3’s • HIV 1/300 • HCV 1/30 • HBV 1/3

  26. Summary of HCV Tests

  27. Who to test? • Persons who ever have injected illicit drugs • Persons with high prevalence of HCV • HIV+ • Hemophiliacs who received clotting factor concentrates before 1987 • Persons who were ever on hemodialysis • Persons with unexplained abnormal aminotransferase levels • Children born to HCV-infected mothers CDC guidelines. MMWR 1998;47(RR-19):1-39

  28. Liver Biopsy • Currently the best way to determine how much scarring is present • Needle, local anesthetic • Risks: bleeding • Scar Stages: 0-1-2-3-4 (Batts-Ludwig)

  29. Progression of Fibrosis on Biopsy Stage 4: Fibrous expansion of portal areas with marked bridging (portal to portal and portal to central) No Fibrosis Stage 1: Fibrous expansion of some portal areas Stage 4: Cirrhosis Stage 3: Fibrous expansion of most portal areas with occasional portal to portal bridging Cirrhotic liver: Gross anatomy of cadaver Courtesy of Gregory Everson, MD.

  30. Likelihood of progression to cirrhosis based on stage of fibrosis 100 90 80 70 Stage 3 60 50 Stage 2 % progression to cirrhosis 40 Stage 1 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 Years

  31. Death from end-stage liver disease (ESLD) as a% of all deaths among HIV patients 60 Pre-HAART era 50% 50 45% HAART era 40 35% Mortality (%) 30 20 13% 12% 10 5% 0 Italy (Brescia) Spain (Madrid) USA (Boston) Liver Disease has Emerged as a Major Cause of Death in the HAART Era Bica Clin Infect Dis 2001; Puoti JAIDS 2000; Soriano Eur J Epidemiol 1999; Soriano PRN Notebook 2002; Martin-Carbonero AIDS Res Human Retrovirus 2001

  32. Evolution of treatment for hepatitis C

  33. Side Effects of PegIFN/Ribavirin • Depression ranging from mild to suicidality • Irritability, aggressive behavior • Worsening of mania • Fatigue • Insomnia • Myalgias, fever, flu-like symptoms • Hair loss • Cytopenias “Interferon Man”

  34. Protease Inhibitors • Approved May 2011 • Boceprevir (Victrellis) and Telaprevir (Incivek) • Potent • Rapid antiviral resistance if used by itself • Will still need peginterferon and ribavirin • More side effects • Anemia, GI, rash • Drug interactions! Cyp 3a/4

  35. Key Phase III Clinical Trial Data for Protease Inhibitors Treatment-Naïve HCV G1 Patients -Boceprevir: SPRINT-2 -Telaprevir: ADVANCE

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