Long-Term Anti-HBV Therapy Considerations Adrian M. Di Bisceglie, MD, FACP Badeeh A. & Catherine V. Bander Chair in Internal Medicine Chairman and Professor of Internal Medicine Chief of Hepatology Saint Louis University School of Medicine St. Louis, Missouri Tram T. Tran, MD Associate Professor of Medicine University of California, Los Angeles School of Medicine Medical Director Liver Transplantation Comprehensive Transplant Center Cedars-Sinai Medical Center Los Angeles, California

Recommended Duration of Nucleos(t)ide Analog Therapy 1. Baraclude [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; Viread [package insert]. Foster City, CA: Gilead Sciences, Inc.; Lok AS, et al. Hepatology. 2009;50: Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6: SourceRecommended Duration HBeAg-Positive PatientsHBeAg-Negative Patients Package inserts 1,2 Optimal duration of therapy is unknown AASLD guidelines 3 Continue at least 6 months after anti-HBe seroconversion with HBV DNA undetectable Continue until HBsAg clearance US Algorithm guidelines 4 Continue 12 months after HBeAg seroconversion as long as HBV DNA levels are decreasing and until the HBV DNA levels are undetectable In patients who undergo HBeAg seroconversion but who still have detectable but stable HBV DNA levels, continue treatment for 6 months; then document seroconversion again and consider stopping treatment in patients without cirrhosis. Continue long-term

Responses to Anti-HBV Therapies in Treatment- Naive HBsAg(+) Patients Treated for 1 Year DrugHBV DNA Loss HBeAg Loss HBeAg Sero- conversion HBsAg Loss Dura- bility* PEG IFN25%30%/34% † 27%/32% † 3%NA Lamivudine40%–44%17%–32%16%–21%1%50%–80% Adefovir21%24%12%0%90% Entecavir67%22%21%2%69% Tenofovir76%NA21%3%NA Lok AS, et al. Hepatology. 2009;50:1-36. *Lamivudine and entecavir – no or short consolidation; adefovir and tenofovir – consolidation for most patients. † Results for week 48 end of treatment/week 72 (24 weeks posttreatment). Abbreviation: NA, not available.

Responses to Anti-HBV Therapies in Treatment- Naive HBsAg(-) Patients Treated for 1 Year DrugHBV DNA Loss Durability PEG IFN63%~20% Lamivudine60%–73%<10% Adefovir51%~5% Entecavir90%3% Tenofovir93%NA Abbreviation: NA, not available. Lok AS, et al. Hepatology. 2009;50:1-36.

Tenofovir—Regression of Hepatic Fibrosis After 5 Years Treatment-naive HBeAg(+) or HBeAg(-) patients treated with tenofovir 300 mg/day (N = 641) 348 had paired baseline and 5-year biopsies evaluated by Ishak fibrosis score –98% had undetectable HBV DNA at year 5 98% had improved or no worsening of fibrosis 74% of cirrhotic patients no longer had cirrhosis at year 5 Conclusion: Long-term tenofovir treatment stabilizes or improves fibrosis in most patients Year 5 Response Marcellin P, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst Improvement No Change Worsening Graphic with permission from Marcellin P, et al. Paper presented at: 62nd AASLD; November 4-8, 2011; San Francisco, CA. Hepatology. 2011;54:Abstract 1375.

Entecavir—Histologic Responses at Week 48 and Long-Term *Median time on entecavir at time of long-term biopsy was 6 years (range, 3–7 years). Chang TT, et al. Hepatology. 2010;52: Histologic Improvement Ishak Score ≤1-Point Decrease Ishak Score ≤2-Point Decrease 41/ 56 55/ 57 18/ 56 50/ 57 3/42 25/ 43

Adherence RateNew PatientsExisting Patients >95%39.7%46.1% 91%–95%10.5%9.3% 81%–90%18.1%18.5% 71%–80%8.5%10.5% 61%–70%9%6.1% 51%–60%5%3.9% <50%9.2%5.6% Adherence to Anti-HBV Nucleos(t)ide Analogs  Predictors of adherence –Older than 45 years of age (P =.001) –Receipt of adefovir or entecavir vs lamivudine (P <.001) –Existing vs new patients (P =.002) Chotiyaputta W, et al. J Hepatol. 2011;54:12-18.

Factors Associated with Adherence Rate >90% FactorMultivariate Analysis Odds Ratio (95% CI) P-value Age≤45 years0.82 (0.74–0.91) >45 years1.00P =.001 MedicationLamivudine0.66 (0.58–0.76) Non- lamivudine 1.00P <.001 New/existing patient New0.68 (0.53–0.86) Existing1.00P =.002 Chotiyaputta W, et al. J Hepatol. 2011;54:12-18.

Lamivudine vs Placebo—Clinical Endpoints DrugDisease Progression Child-Pugh Increase HCC Lamivudine (n = 436)7.8%3.4%3.9% Placebo (n = 215)17.7%8.8%7.4% P-value Liaw YF, et al. N Engl J Med. 2004;351: Abbreviation: HCC, hepatocellular carcinoma. Differences between groups for other endpoints were insignificant Renal insufficiency (lamivudine 0.5%; placebo 0%) Bleeding varices (lamivudine 0.5%; placebo 0%) Spontaneous bacterial peritonitis (lamivudine 0%; placebo 0%) Liver-related death (lamivudine 0%; placebo 0%)