Maria Buti, MD Professor of Medicine Hospital Universitario Vall d'Hebron Barcelona, Spain Clinical Focus: Impact of HBV Therapy on Liver Fibrosis and Cirrhosis This program is supported by an educational grant from Gilead Sciences

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clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis  Maria Buti, MD Professor of Medicine Hospital Universitario Vall d'Hebron Barcelona, Spain Faculty

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis Disclosures Maria Buti, MD, has disclosed that she has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, and Merck Sharp & Dohme. The following planners and managers, Edward King, MA; Michael Westhafer, MD; and William Hatch, PhD, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis Natural History of Chronic Hepatitis B Normal liver Chronic hepatitis B ESLD No further progression HBV-related ESLD or HCC are responsible for > million deaths per yr and currently represent 5% to 10% of cases of liver transplantation Not all patients have progressive disease Cirrhosis 1. EASL. J Hepatol. 2012;57: HCC

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis  Serum HBV DNA ~ 2000 IU/mL (≥ 10 4 copies/mL) is an independent predictor of cirrhosis development *Adjusted for age, sex, cigarette smoking, and alcohol consumption. Adjusted Relative Risk of Cirrhosis* (95% CI) All Participants (N = 3582 Taiwanese Patients) < ,000-99,999100, ,999≥ 1 million HBV DNA (copies/mL) REVEAL: Higher HBV DNA Associated With Higher Risk of Cirrhosis Over Time 5. Iloeje UH, et al. Gastroenterol. 2006;130:

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis Successful Hepatitis B Treatment Reduces Clinical Endpoints  HBV suppression with nucleos(t)ide analogue therapy reduces risk of hepatic decompensation and HCC in pts with advanced fibrosis or cirrhosis [6] Pts With Disease Progression (%) P = n = 198 n = 173 n = 417 n = 385 n = 43 n = Lamivudine Placebo Kaplan-Meier Estimate of Time to Disease Progression in Asians With CHB (Mos) 6. Liaw YF, et al. N Engl J Med. 2004;351:

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis Drug Therapy Duration, Yrs Subjects Evaluated, n/N* (%) Subjects With Baseline Cirrhosis, † n Lamivudine [1] 363/152 (41)11 ‡ Adefovir [2] 4-524/185 (13)4 Entecavir [3] 3-757/679 (8)4 Telbivudine [4] 557/1699 (3)2 Tenofovir [5] 5348/641 (54)9696 *Total number of subjects at baseline in respective pivotal clinical trials. † Defined as Ishak fibrosis score ≥ 5 at baseline. ‡ Defined as HAI fibrosis score. 7. Dienstag JL, et al. Gastroenterol. 2003;124: Hadziyannis SJ, et al. Gastroenterol. 2006;131: Chang TT, et al. Hepatol. 2010;52: Hou J, et al. APASL Abstract PP Marcellin P, et al. Lancet. 2013;381: Reversal of Fibrosis in Biopsy Series With Different Anti-HBV Agents  Several small studies suggest liver fibrosis may also be reversible with successful nucleos(t)ide analogue therapy [7-11] –Limited by lack of control for antiviral use or duration of therapy

Tenofovir and Liver Histology

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis Studies 102/103: Long-term Histology Study During Open-Label Follow-up  2 randomized, double-blind, placebo-controlled phase III trials  All pts received open-label TDF after Yr 1 for a total study duration of 8 yrs*  Liver biopsies obtained at baseline, Yr 1, and Yr 5 (nonmandatory) *FTC could be added for confirmed viremia on/after Wk Marcellin P, et al. Lancet. 2013;381: Chronic HBV pts (HBeAg- or HBeAg+) Open-Label TDF HBV, hepatitis B virus; (n = 585 entered, n = 489 completed 5 yrs, n = 348 with biopsy samples at Yr 5) Study Yr Biopsies TDF 300 mg QD (n = 250, 176) ADV 10 mg QD (n = 125, 90)

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis  No HBV variants associated with tenofovir resistance have been detected in patients during 7 yrs of treatment [15] Nonhistologic Efficacy Results at Yr Marcellin P, et al. Lancet. 2013;381: Marcellin P. et al. AASLD Abstract 926. *Kaplan-Meier estimated % (95% CI) of patients. On Treatment Response, % (n/N) [14] HBeAg- PatientsHBeAg+ Patients HBV DNA < 400 copies/mL99 (292/295)97 (170/175) ALT ≤ 1 x ULN85 (236/277)73 (124/169) HBeAg loss--49 (81/165) HBsAg loss010* ( )

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis  Pts with Ishak score ≥ 4: 38% at baseline, 12% at Yr 5  Pts with cirrhosis (Ishak score ≥ 5): 28% at baseline, 8% at Yr 5 (n=96) Ishak Fibrosis Scores Patients (%) 96% of Pts Treated With Tenofovir Had Stable or Improved Fibrosis at Yr 5 N = 348 matched biopsies 17. Marcellin P, et al. Lancet. 2013;381: BaselineYr 1Yr 5 38% 39% 12% 63% P <.001

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis 18. Marcellin P, et al. Lancet. 2013;381: Fibrosis Improvement at Yr 5 by Baseline Ishak Fibrosis Score Patients (%) Ishak Fibrosis Score at Baseline No histologic improvement Histologic improvement n =

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis Impact of Tenofovir on Liver Fibrosis at Yr 5 in Subjects With Baseline Cirrhosis  74% (n/N = 71/96) of subjects had Ishak fibrosis score ≤ 5 at Yr 5 –73% (n = 70) had decreases of ≥ 2 points –25% (n = 24) did not change –1% (n = 1) had 1-point increase in fibrosis score Change From Baseline in Fibrosis Score n = 24 n = 14 n = 41 n = 15 n = Subjects With Baseline Cirrhosis (N = 96) Adapted from 19. Marcellin P, et al. Lancet. 2013;381:

Entecavir and Liver Histology

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis Study ETV-901: Long-term Histology Study During Open-Label Follow-up  Pts from 2 phase III studies (HBeAg+ in ETV-022, HBeAg- in ETV-027)  Pts entered open-label rollover study (ETV-901) and received ETV for total of at least 3 yrs  Liver biopsies obtained at baseline, Wk 48, Wk 96, and after at least 3 yrs of cumulative ETV therapy Chronic HBV patients Open-Label ETV 1.0 mg/day Long-term histology cohort (n = 57) Study Yr Biopsies HBeAg+ ETV 0.5 mg/day (n = 354)  HBeAg- ETV 0.5 mg/day (n = 354) 22. Chang TT, et al. Hepatology. 2010;52: *Median time on ETV treatment at the time of long-term biopsy was 280 weeks (~ 6 yrs; range: 3-7 yrs) *

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis  Genotypic testing for resistance was not performed because all the patients achieved a serum HBV DNA level < 300 copies/mL Nonhistologic Efficacy Results *Median duration of ETV therapy at time of long-term biopsy: 6 yrs (range: 3-7 yrs) 24. Chang TT, et al. Hepatology. 2010;52: On Treatment Response, % (n/N)Week 48 (n = 57) Long Term* (n = 57) HBV DNA < 300 copies/mL on treatment 70 (40/57)100 (57/57) ALT ≤ 1 x ULN67 (38/57)86 (49/57) HBeAg loss on treatment2 (1/41)55 (22/40) HBsAg loss0 (0/57)

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis Histologic Responses With Long-term Entecavir *Median duration on ETV at time of long-term biopsy: 280 wks (~ 6 yrs; range: 3-7 yrs) Histologic ImprovementFibrosis Improvement Patients (%) n = Wk 48 Long-term biopsy* 26. Chang TT, et al. Hepatology. 2010;52:

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis All Patients Treated With Long-term Entecavir Had Stable or Improved Fibrosis  All patients with advanced fibrosis/cirrhosis (Ishak fibrosis score ≥ 4) at baseline demonstrated at least a 1-point reduction (median change: -1.5)  Subjects with baseline advanced fibrosis/cirrhosis n = Chang TT, et al. Hepatology. 2010;52: N = 57 matched biopsies Missing Baseline Wk 48 Long Term 60 Patients (n) Ishak Fibrosis Score

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis Impact of Entecavir on Fibrosis in Pts With Advanced Fibrosis/Cirrhosis at Baseline  100% (N = 10) of subjects had Ishak fibrosis score < 5 and decreases of ≥ 1 points after long-term ETV –Mean change from baseline: 2.2 Change From Baseline in Fibrosis Score n = 1 n = 3 n = Subjects With Baseline Advanced Fibrosis/Cirrhosis (N = 10) 31. Schiff ER, et al. Clin Gastroenterol Hepatol. 2011;9: *Median duration of ETV at time of long-term biopsy: 277 wks (range: ); long-term biopsies taken Wk 288 ± 24 wks.

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis Implications for Patient Management: Which HBV Patients Should Be Treated?  Treatment can be recommended in cirrhotic patients  Treatment may also benefit patients with early to advanced fibrosis –Prevention of cirrhosis, HCC; improved histology  Patients with additional risk factors for disease progression are best candidates –Older than 40 yrs of age, family history of chronic hepatitis B and cirrhosis or HCC  Balance recommendation with cost of long-term treatment

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis Implications for Patient Management: Identifying Patients With Fibrosis  Noninvasive tests –Transient elastography –Biochemical panel –Work well when used together  Biopsy patients with equivocal results from noninvasive measures

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis Treatment Regimen Consideration for Fibrosis Reversal  Long-term viral suppression is important to prevent fibrosis progression  Both entecavir and tenofovir are recommended treatment options for treatment-naive patients  Important to assess treatment history and resistance profile when selecting therapy in treatment-experienced patients

clinicaloptions.com/hepatitis Clinical Focus: Impact of HBV Therapy on Liver Fibrosis/Cirrhosis Summary of Key Conclusions  Long-term tenofovir and entecavir therapy improved liver histology and fibrosis in nucleoside-naive HBV patients –Including patients with advanced fibrosis/cirrhosis  Reversal of liver fibrosis and cirrhosis possible if underlying cause of liver damage continuously suppressed  These patients still at risk of HCC and continued surveillance is recommended 45. Chang TT, et al. Hepatology. 2010;52: Marcellin P, et al. Lancet. 2013;381:

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