1. Case study: Chronic HBV infection Marion Peters University of California San Francisco 2009

2. HBV case 45 year old man admitted with fatigue, malaise and abdominal swelling in June 2003 He was born in Greece, came to US age 14 His brother had a liver transplant for HBV in 1998 On Examination: jaundice, ascites, no muscle wasting, spider nevi

3. HBV Laboratory and Imaging Bilirubin 3.7, AST 129, ALT 106, albumin 2.4, PT 1.7, Ammonia 51, Creatinine 0.9 MELD 19 HBsAg and HBeAg positive HBV DNA 340,000 IU/mL AFP 741 mcg/L Acites: paracentesis WCC 183, albumin <1

4. How would you treat his HBV? Blue Pegylated interferon for 48 week Green Lamivudine 100 mg per day Red Entecavir 0.5 mg per day Yellow Tenofovir 300 mg per day/ Combo

5. How would you treat his HBV? Blue Pegylated interferon for 48 week Green Lamivudine 100 mg per day Red Entecavir 0.5 mg per day Yellow Tenofovir 300 mg per day/ Combo

6. HBV case-3 June 2003 started lamivudine 100 mg daily –Well tolerated, lost ascites –Patient had improved liver function Listed for liver transplantation Ultrasound cirrhotic liver no masses CT quadruple phase no masses

7. DateASTBiliAlbuminAFPHBVDNA 6-03 1603.72.5741 340,000,000 11- 03 590.93.114 400,000 IU/mL LAM 

8. DateASTBiliAlbuminAFPHBVDNA 6-03 1603.72.5741 340,000,000 11- 03 590.93.114 400,000 2-04 741.32.9193 500,000,000 IU/mL LAM 

9. What has occurred? BlueLAM non response RedLAM resistance GreenNon compliance

10. What has occurred? BlueLAM non response RedLAM resistance GreenNon compliance

11. n = HBV DNA at Month 6 of LAM Predicts Later Risk of Resistance N = 159 HBeAg-positive patients Median follow-up: 29.6 months Yuen ME, et al. Hepatology. 2001;34:785-791. Patients With Resistance (%) 8 13 32 64 0 20 40 60 80 100 ≤ 2≤ 3≤ 4> 4 Patients With YMDD Variants (%) HBV DNA at 6 Months (log 10 copies/mL) 122341118

12. HBV status HBV Genotype A, HBeAg positive Polymerase mutations –L180M, +M204V –no precore mutations detected –No ADV mutations detected HIV negative HDV negative

13. HBV: How would you treat his HBV now with LAM resistance? BlueSwitch to Adefovir/TDF Red Switch to Entecavir 0.5 mg per day GreenAdd Entecavir 0.5 mg per day YellowAdd Adefovir/TDF

14. HBV: How would you treat his HBV now? BlueSwitch to Adefovir/TDF Red Switch to Entecavir 0.5 mg per day GreenAdd Entecavir 0.5 mg per day YellowAdd Adefovir/TDF

15. DateASTBiliAlbuminAFPHBVDNA 6-03 1603.72.5741 340,000,000 11- 03 590.93.114 400,000 2-04 741.32.9193 500,000,000 IU/mL LAM add ADV  

16. DateASTBiliAlbuminAFPHBVDNA 6-03 1603.72.5741 340,000,000 11- 03 590.93.114 400,000 2-04 741.32.9193 500,000,000 5-04 691.53.0169 320,000,000 IU/mL LAM add ADV  

17. What has occurred? BlueADV resistance RedADV primary non response GreenADV suboptimal response YellowNon compliance

18. What has occurred? BlueADV resistance RedADV primary non response GreenADV suboptimal response YellowNon compliance

19. Nonresponse, Suboptimal Response, and Virologic Breakthrough Lok AS, et al. Hepatology. 2007;45:507-539. 1 log Change in HBV DNA (log 10 IU/mL) 0 -2.0 -3.0 -4.0 1.0 Nadir Virologic breakthrough Antiviral Drug Months 601218 Primary nonresponse Suboptimal response

20. HBV DNA at Week 48 of ADV Predicts Risk of Resistance at Wk 144 Resistance (%) 1. Locarnini S, et al. EASL 2005. Abstract 36. 2. Hadziyannis SJ, et al. Gastroenterology. 2006;131:1743-1751. HBV DNA at Week 48 (log 10 copies/mL) 6 49 0 20 40 60 80 100 < 3> 3 4 67 26 0 20 40 60 80 100 < 33-6> 6 N = 114 patients, primarily HBeAg negative [1] N = 124 patients, HBeAg negative [2]

21. HBV-case: What would you do? BlueContinue ADV RedAdd Tenofovir 300 mg GreenChange to TDF and ETV YellowChange to TDF and Lam/FTC

22. HBV-case: What would you do? BlueContinue ADV RedAdd Tenofovir 300 mg GreenChange to TDF and ETV YellowChange to TDF and Lam/FTC

23. DateASTBiliAlbuminAFPHBVDNA 6-03 1603.72.5741 340,000,000 11- 03 590.93.114 400,000 2-04 741.32.9193 500,000,000 5-04 691.53.0169 320,000,000 8-04 681.83.442 15,400,000 11-04 671.03.716.2 19,200 5-06 521.14.08 518 5-07 281.04.42.9 undetectable IU/mL LAM add ADV Switch To TDF +LAM   

24. Adefovir monotherapy (Study 438: naive patients) Adefovir + lamivudine (Studies 435 and 460i: lamivudine resistance*; Study 435: pre- and post-OLT; Study 460i: HIV/HBV) Adefovir Resistance Not Observed With Lamivudine Combination Therapy *2 patients enrolled in Study 435 initially received combination therapy with adefovir + lamivudine and subsequently selected adefovir resistance mutation N236T. However, they had switched to adefovir monotherapy at time when adefovir resistance mutation was detected. Incidence of Resistance (%) 00 3 0 11 0 19 30 0 20 40 60 Year 1Year 2Year 3Year 4Year 5 0 Lee YS, et al. Hepatology. 2006;43:1385-1391. Lampertico P, et al. AASLD 2006. Abstract LB5. Schiff E, et al. Liver Transpl. 2007;13:349-360. Hepsera [package insert].

25. Management of HBV Check response at 12 and 24 weeks If no response switch When virologic breakthrough occurs –“Switch to” another drug –“Add on” another drug –“Switch to” and “add on” another drug Choice of second drug generally dictated by lack of cross-resistance

26. Combination therapy Sequential monotherapy with nucleos(t)ide analogues has led to HBV resistance Resistance has been low with combination therapy Peg IFN and LAM showed more HBV DNA suppression while on therapy, but lost after end of therapy, no increased HBeAg serconversion ADV and LAM/FTC less resistance but no increase in efficacy Lampertico Gastro 2007; Yim HJ, et al. Hepatology. 2006:43:S173-181;Shaw T, et al. AASLD 2007. Abstract 986; Schildgen O, et al. N Engl J Med. 2006;354:1807-1812; Reijnders JG, AASLD 2007. Abstract 951; Colonno R, et al. Hepatology. 2006;44:1656-1665.