1. Hepatitis B- what GI nurses Need to Know Mary Pat Pauly MD Gastroenterology and Hepatology Kaiser Permanente Clinical Professor of Internal Medicine and GI at UC Davis

2. Hepatitis B Epidemiology Modes of transmission Hepatitis B vaccine Natural History Interpretation of serology Indications for treatment Newer drugs available for treatment Importance of ongoing follow up

3. Hepatitis B Epidemiology –Modes of transmission Role of Hepatitis B vaccine Natural History Interpretation of serology Indications for treatment Newer drugs available for treatment Importance of ongoing follow up

4. Global Impact of Hepatitis B World Population 6 billion 2 billion with past / present HBV infection 350–400 million with chronic hepatitis B 15–40% develop cirrhosis, liver failure or hepatocellular carcinoma Worldwide: ~1 million / year die from HBV-associated liver disease United States: Chronically infected ~1.25 million; ~5000 / year die

6. Korean Mummy Found With HBV Virus discovered in the liver of the South Korean Handong mummy –500-year-old child –First time HBV ever been found in a mummified body Study of the genome of the 500-year-old virus under way –To see if there have been any significant changes to HBV over time Source: Seoul National University http://www.sciencedaily.com/releases/2007/07/070725093556.htm

8. Prevalence of HBV in immigrant populations Prevalence reflects pattern of infection in country of origin –Africa 10 – 15% –Asia 10.4% –Eastern Europe 2-7% Survey of Asian Am populations – 23% in NYC* – 11.1% in Chicago** *Sherman A et al. Hepatology 2005;42: 214A **Cotler S et al. Clin Gastro & Hep 2009;7:776-80

9. Chronic HBV Prevalence: Asian Americans in San Francisco (2001- 2006) Lin SY, et al Hepatology. 2007;46:1034-1040. Chronic HBV Positive At Risk: Lack of Protective Antibodies 8.9% Chronic HBV Positive, Unaware of Serostatus 65.4% 44.8% Prevalence (%) 0 30 50 80 40 20 10 60 70

10. Transmission of HBV HBVHCV IVDAcommoncommon Transfusion Before 1980 Before 1992 sexualcommonuncommon MSMcommonrare Vertical – mother to baby Common > 90% ->chronic disease < 5% Child  child Africa 20 – 30%  chronic disease Tattoos, piercing possiblepossible health care worker possiblepossible

11. 28 year old nursing school colleague –From Taiwan –In USA since age 10 Applying for job at your hospital –She was told to get HBV vaccine –Requirement Hepatitis B vaccine in employees who are not already immune to HBV she was vaccinated when she went to nursing school –But HBsAB is neg. What is your recommendation?

12. Hepatitis B vaccine Recommended 3 doses at 0,1 and 6 months Protection – – 30 – 50% first dose – – 75% second dose – – 96% with three dose series Vaccine is not perfect – –Economic barriers – –Cultural barriers Some is better than none…. Protection lower in Older HIV chronic liver diseases diabetes obese smokers Two vaccines available –Energix B – 20 mcg –Recombivax HB – 10 mcg

13. Acute HBV Infection Incidence* in the US (1982-2006) Universal vaccination of infants recommended in 1991 80% decline in incidence 0 2 4 6 8 10 12 14 198219841986 Incidence 19881990199219941996 199820002002 20042006 *Per 100,000 population. MMWR: Surveillance Summary March 21, 2008 / Vol. 57 / No. SS—2. Year

14. Risk factors for HBV in US 42% 42% 18% 18% 19% 19% 16% 16% 5% 5% CDC Sentinel Counties Study 1991-2006

16. Case continued Check further into history –No FH of HBV 21 year old sister in LA who is healthy and without problems –Family history of mother who died at age 45 from “cancer in the liver.” Additional laboratory data –HBsAG positive –HBcAB positive –HBsAB negative –ALT 20 What can you tell her about her condition?

17. Hepatitis B Epidemiology Modes of transmission Hepatitis B vaccine Natural History Interpretation of serology Indications for treatment Newer drugs available for treatment Importance of ongoing follow up

18. Spectrum of Disease Acute HBV infection 90% neonates 25–30% children <10% adults Progressive chronic hepatitis Cirrhosis HCCDeath Decompensated cirrhosis Inactive carrier state EASL Consensus Guidelines. J Hepatol 2003; Lok, McMahon. Hepatology 2004 (AASLD Guidelines) Chronic infection 15–40% Fulminant hepatic failure ~2%

19. Hepatitis B Epidemiology Modes of transmission Hepatitis B vaccine Natural History Interpretation of serology Indications for treatment Newer drugs available for treatment Importance of ongoing follow up

20. Hepatitis B terminology There are three proteins expressed by the Hepatitis B virus Surface antigen –HBsAg Core antigen –HBcAg Envelope antigen –HBeAg

21. NameAbbreviationDefinition Hepatitis B Surface Antigen HBsAg Protein found on the surface of virus, indicates active infection. Hepatitis B Surface Antibody HBsAb Antibody to the surface protein – confers immunity. Can be result of vaccination or past infection. Hepatitis B Core Antigen HBcAg The core protein is inner structure of the virus and encloses the DNA. Found only in the liver. Hepatitis B Core Antibody HBcAb Antibody to the core antigen is found in chronic hepatitis, resolved acute or chronic infection. NOT seen in those immune because of vaccine. Hepatitis B e Antigen HBeAg This is a soluble protein detected when viral titers are high. Correlates with infectivity with the “wild type” HBV. Hepatitis B e Antibody HBeAb Antibody to the “e” Antigen. Can be seen in inactive HBV, or chronic active hepatitis secondary to a mutant: precore or core promoter mutant.

22. A few other terms ALT alanine amino transferase AST aspartate aminotransferase –Enzymes liberated by the liver when cells injured and destroyed –Tests of liver injury HBV viral load –Amount of virus measured in serum Measured in IU/ml

23. Courtesy of W. Ray Kim, MD. Chen DS, et al. J Gastroenterol Hep. 1993;8:470-475. Seeff L, et al. N Engl J Med. 1987;316:965-970. Cirrhosis Inactive Carrier < 5% Immune Tolerance Early Childhood > 95% HBeAg- Chronic Hepatitis B Natural History of HBV Infection HBeAg+ Chronic Hepatitis B Adulthood

24. Natural History of Hepatitis B Dynamic –Can go from Active  inactive  active Liver disease on biopsy – can progress during periods of activity and regress during periods of inactivity. HCC can occur –in patients with and without cirrhosis Close clinical follow up is important

26. Serology of HBV InfectionALTHBeAG Anti- HBeAb HBV DNA IU.ml histology Immune tolerant nlPos+Neg-Highnormal Chronic hepatitis HBeAg + upPos+Neg->20,000active Inactive carrier nlNeg-Pos+<2,000normal Chronic hepatitis HBeAg- upNeg-Pos+>2,000active

27. Our colleague saw a gastroenterologist and had additional tests ordered. She presents the following to you for interpretation: She presents the following to you for interpretation: –HBeAg positive –HBeAb negative –ALT 15, AST 16 –Bilirubin, INR and platelet count – normal –HBV DNA –1,000,000 IU/ml 10 (6) –Alpha feto protein –normal –Ultrasound of the liver – normal. See AASLD guidelines – www.AASLD.org www.AASLD.org –This is exactly what is suggested in the AASLD guidelines for the evaluation of patients with HBV. One would also like to do complete history. Rule out other causes of liver disease such as AIH, HCV and HIV. And hemochromatosis. Adapted from Lok AS, et al. Hepatology. 2007;45:507-539

28. The next question she asks Is she a candidate for treatment?

29. Hepatitis B Epidemiology Modes of transmission Role of Hepatitis B vaccine Natural History Interpretation of serology Indications for treatment Newer drugs available for treatment Importance of ongoing follow up follow up

34. Treatment of HBV Current Recommendations Monitor patients in –Immune tolerant phase –Inactive –carrier state Consider treatment –Chronic Active hepatitis Wild type – HBeAg positive Mutant type – HBeAg negative and HBeAb positive Treat –Cirrhosis with active viral replication Consider: –Age, severity of liver disease, likelihood of response, potential adverse events

35. ccc DNA…. nasty little viral form Does not replicate Impervious to nucleoside/tide analogue-based therapy Sits in cell for life of cell –up to 10 years in immune tolerant or inactive state Clearance based on immune driven hepatocyte clearance or cell death

36. Goals of treatment Suppression of HBV DNA –Goal is undetectable Normal ALT –No inflammation or ongoing liver injury Convert from active phase to inactive –HBeAG positive  negative and HBeAb pos. Holy Grail –HBsAg negative, HBsAb positive.

37. Hepatitis B – what every GI nurse should know Epidemiology Modes of transmission Role of Hepatitis B vaccine Natural History Interpretation of serology Indications for treatment Newer drugs available for treatment Importance of ongoing follow up

38. Treatment of HBV Interferon alfa-2b LamivudineAdefovirEntecavir Pegylated interferon alfa 2a TelbivudineTenofovir1990199820022005200520062008

39. Treatment available Interferon alpha –Useful in select patients with HBV Genotype A and B –Side effects significant –No resistant mutants –MOA Anti-viral Destroys infected hepatocytes –Defined treatment duration Nucleoside and nucleotide analogs –Currently the Rx of choice –Minimal SE –Possibility of resistant mutants –MOA Supresses but does not eliminate the virus –Treatment indefinite

40. Arauz-Ruiz P, et al. J Gen Virol. 2002;83:2059-2073. Bell SJ, et al. J Clin Virol. 2005;32:122-127. Chu CJ, et al. Gastroenterology. 2003;125:444-451. Kidd-Ljunggren K, et al. J Gen Virol. 2002;83:1267-1280. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106. A, B, C, D, G F A, D, E B, C A G D H, F Global Distribution of the 8 HBV Genotypes D A, B, C, D

41. Impact of HBV Genotype on Disease Progression Genotype C –severe liver disease –HCC Genotype B –Seroconversion from HBeAg -> anti-HBe at younger age Genotypes A and B –Increased response to Peginterferon alfa-2a Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962. HBV Genotyping Line Probe Assay marker line conj. control amp. control Genotype A Genotype B Genotype C Genotype D Genotype E Genotype F Genotype G 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

42. Treatment DrugPotencyResistance FDA approved Lamivudine++ 20% at 1 yr; 70% at yr 5 Yes Adefovir+ 3% at 2 yr 28% at 5 yr 28% at 5 yrYes Entecavir++++ <2% at 4 yr* Yes Tenofovir++++ None yet yes Telbivudine+++ 4% at one yr 11-25% at year 2 yes Emtricitabine++ Similar to lamivudine Not yet

43. Hepatitis B Epidemiology Modes of transmission Role of Hepatitis B vaccine Natural History Interpretation of serology Indications for treatment Newer drugs Importance of ongoing follow up

44. Importance of follow up To monitor for progression of disease –To monitor those in inactive phases and –To recommend treatment in active phases Treament –Monitor for efficacy –Monitor for resistance –monitor for toxicity To screen patients at high risk for HCC regularly.

45. Chronic HBV: recommended followup Immune – tolerant: 1. Check ALT every 3-6 months. 2. If ALT increases – check HBV DNA Work up further Consider treatment or biopsy 3. Screen for HCC in high risk patients - Inactive HBsAg carrier : 1. Check ALT every 6 – 12 months 2. If ALT increases Check HBV DNA work up further consider biopsy and treatment 3. Screen for HCC in high risk patients.

47. Screening for HCC Ultrasound and AFP –AFP every 6 months and –Ultrasound every 6 – 12 months Screen high risk patients: –Family history of HCC –men over 40, women over 50 –patients with chronic hepatitis with high viral load –patients with cirrhosis.

48. “You can stab it with your steely anti-virals but you just can’t kill the beast.” The Eagles 1977 – Hotel California

49. Hepatitis B with your help, we can do better… with your help, we can do better…