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Case study: Chronic HBV infection

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

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Case study: Chronic HBV infection

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  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. LAM

  8. LAM

  9. What has occurred? Blue LAM non response Red LAM resistance Green Non compliance

  10. What has occurred? Blue LAM non response Red LAM resistance Green Non compliance

  11. HBV DNA at Month 6 of LAM Predicts Later Risk of Resistance N = 159 HBeAg-positive patients Median follow-up: 29.6 months 100 80 64 60 Patients With Resistance (%) Patients With YMDD Variants (%) 40 32 20 13 8 12 23 41 118 n = 0 ≤ 2 ≤ 3 ≤ 4 > 4 HBV DNA at 6 Months (log10 copies/mL) Yuen ME, et al. Hepatology. 2001;34:785-791.

  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? Blue Switch to Adefovir/TDF Red Switch to Entecavir 0.5 mg per day Green Add Entecavir 0.5 mg per day Yellow Add Adefovir/TDF

  14. HBV: How would you treat his HBV now? Blue Switch to Adefovir/TDF Red Switch to Entecavir 0.5 mg per day Green Add Entecavir 0.5 mg per day Yellow Add Adefovir/TDF

  15. LAM  add ADV 

  16. LAM  add ADV 

  17. What has occurred? Blue ADV resistance Red ADV primary non response Green ADV suboptimal response Yellow Non compliance

  18. What has occurred? Blue ADV resistance Red ADV primary non response Green ADV suboptimal response Yellow Non compliance

  19. Nonresponse, Suboptimal Response, and Virologic Breakthrough 1.0 Antiviral Drug 0 Primary nonresponse Virologic breakthrough -1.0 Change in HBV DNA (log10 IU/mL) Suboptimal response -2.0 -3.0 1 log Nadir -4.0 0 6 12 18 Months Lok AS, et al. Hepatology. 2007;45:507-539.

  20. HBV DNA at Week 48 of ADV Predicts Risk of Resistance at Wk 144 N = 124 patients, HBeAg negative[2] N = 114 patients, primarily HBeAg negative[1] 100 100 80 80 67 60 60 49 Resistance (%) 40 40 26 20 20 6 4 0 0 < 3 3-6 > 6 < 3 > 3 HBV DNA at Week 48 (log10copies/mL) 1. Locarnini S, et al. EASL 2005. Abstract 36. 2. Hadziyannis SJ, et al. Gastroenterology. 2006;131:1743-1751.

  21. HBV-case: What would you do? Blue Continue ADV Red Add Tenofovir 300 mg Green Change to TDF and ETV Yellow Change to TDF and Lam/FTC

  22. HBV-case: What would you do? Blue Continue ADV Red Add Tenofovir 300 mg Green Change to TDF and ETV Yellow Change to TDF and Lam/FTC

  23. LAM  add ADV   Switch To TDF +LAM

  24. Adefovir Resistance Not Observed With Lamivudine Combination Therapy Adefovir monotherapy (Study 438: naive patients) 60 Adefovir + lamivudine (Studies 435 and 460i: lamivudine resistance*; Study 435: pre- and post-OLT; Study 460i: HIV/HBV) 40 Incidence of Resistance (%) 30 20 19 11 3 0 0 0 0 0 0 Year 1 Year 2 Year 3 Year 4 Year 5 *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. 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.

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