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 Distribution of 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. REVEAL: Relationship Between HBV DNA Level and All-Cause Mortality Iloeje UH, et al. Gastroenterology. 2006;130:678-686. Viral load presented as copies/mL. 0.8 0.85 Baseline HBV DNA (copies/mL) <300 300-9,999 10,000-99,999 100,000-999,999 >1 million 01234567 Year of follow-up P<0.001 891011121314 0.9 0.95 1.0 Survival

8. 4 Phases of Chronic HBV Infection  Immune tolerant phase* –HBeAg positive –HBV DNA 10 5-10 –ALT normal  Non-replicative phase (inactive HBsAg carrier) –HBeAg negative –HBV DNA <10 4 –ALT normal –HBsAg may later become undetectable  Immune active HBeAg positive chronic HBV –HBV DNA 10 5-10 –ALT levels high or fluctuating –Active inflammation on liver biopsy  HBeAg negative –HBeAg negative chronic HBV –HBV DNA 10 4-8 –ALT levels high or fluctuating –Active inflammation on liver biopsy Candidates for TherapyNot Candidates for Therapy Yim HJ, et al. Hepatology. 2006;43:S173-S181. *Not seen in adult-onset infection.

9. Treatment of chronic hepatitis B <1999199920012002 2005 2008 interferonlamivudinetenofovir (HIV) adefovirPeginterferon 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. HBeAg Positive Treat Monitor Chronic HBV Treatment: Simplified Flow Chart Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962. HBeAg Negative HBV DNA >20,000 IU/mL HBV DNA >2,000 IU/mL Normal ALT Liver Biopsy Abnormal Histology Elevated ALT ALT Evaluation

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

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 in HIV/HBV-Coinfected Patients Preferred Other Options Comments HIV and HBV need treatment HBV treatment- naïve Tenofovir/emtricitabine Tenofovir + lamivudine Entecavir + HAART Avoid single-agent HBV therapy with lamivudine, emtricitabine, or tenofovir due to the increased risk of HBV resistance risk of HBV resistance LamivudineresistantTenofovir/emtricitabine Tenofovir + entecavir Emtricitabine not active against lamivudine-resistant HBV lamivudine-resistant HBV HBV only needs treatment Peginterferon 2a Adefovir Adefovir + telbivudine (monitor HBV DNA at week 24) Initiate HAART Monitor HBV DNA Monitor liver function 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 individuals 1  Up to 10% of HIV+ patients may be HBV carriers 1 Smith, 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

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

28. 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

30. Summary of HCV Tests DiagnosisTreatment TestScreenConfirmationResponse Predicting response EIAX RIBA X (?) RNA qual ?XX RNA quant X (if real time PCR) XX GenotypeX

31. 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

32. 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)

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

34. 0 10 20 30 40 50 60 70 80 90 100 02468 10 1214 16 1820 Years % progression to cirrhosis Stage 3 Stage 2 Stage 1 Likelihood of progression to cirrhosis based on stage of fibrosis

40. 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 0 10 20 30 40 50 60 Mortality (%) Death from end-stage liver disease (ESLD) as a % of all deaths among HIV patients Italy (Brescia)Spain (Madrid)USA (Boston) 13% 35% 5% 12% 45% 50% Pre-HAART era HAART era

41. Evolution of treatment for hepatitis C

43. 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”

44. 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

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

55. All of the following are TRUE about protease inhibitors EXCEPT:  Telaprevir may be administered in combination with boceprevir in order to prevent antiviral resistance  Protease inhibitors must be used together with PegIFN/RBV  The addition of a protease inhibitor to PegIFN/RBV increases the chance of SVR for GT 1 patients  Telaprevir and boceprevir increase the rate of rapid virologic response when used with PegIFN/RBV

56. IFN sparing regimens?  Roche: protease + polymerase inhibitor (phase II)  Merck/Schering: protease + polymerase inhibitors (phase II)  BMS: NS5a + protease + polymerase inhibitor (phase II)

57. Kinder, gentler IFN?  Peginterferon lambda  Zymogenetics  More restricted host range of receptors  Phase 1: equivalent antiviral potency but minimal neuropsychiatric side effects

58. 2002-11 Peginterferon + Ribavirin ~50% cure rate Peginterferon + Ribavirin + Protease Inhibitor ~70% cure rate Now PI + Poly Inh + IFN? >80% cure rate? 2014?

59. Web Resources  www.aasld.org www.aasld.org  www.hivandhepatitis.org www.hivandhepatitis.org  www.hepwebstudy.org www.hepwebstudy.org  www.cdc.gov/ncidod/disea ses/hepatitis/c/index.htm www.cdc.gov/ncidod/disea ses/hepatitis/c/ www.cdc.gov/ncidod/disea ses/hepatitis/c/ jdscott@u.washington.edu