Clinical Focus: Impact of HBV Therapy on Liver Fibrosis and Cirrhosis Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC Clinical Focus: Impact of HBV Therapy on Liver Fibrosis and Cirrhosis Maria Buti, MD Professor of Medicine Hospital Universitario Vall d'Hebron Barcelona, Spain This program is supported by an educational grant from Gilead Sciences Image: Sanit Fuangnakhon/Copyright©2014 Shutterstock Images LLC. All Rights Reserved

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Faculty Maria Buti, MD Professor of Medicine Hospital Universitario Vall d'Hebron Barcelona, Spain

Disclosures Maria Buti, MD, has disclosed that she has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Tibotec/Janssen. 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.

Natural History of Chronic Hepatitis B Not all patients have progressive disease No further progression HCC Normal liver Chronic hepatitis B ESLD, end-stage liver disease; HBV, hepatitis B virus; HCC, hepatocellular carcinoma. Cirrhosis HBV-related ESLD or HCC are responsible for > 0.5-1 million deaths per yr and currently represent 5% to 10% of cases of liver transplantation ESLD 1. EASL. J Hepatol. 2012;57:167-185.

REVEAL: Higher HBV DNA Associated With Higher Risk of Cirrhosis Over Time Serum HBV DNA ~ 2000 IU/mL (≥ 104 copies/mL) is an independent predictor of cirrhosis development All Participants (N = 3582 Taiwanese Patients) 9.8 10 8 5.9 6 Adjusted Relative Risk of Cirrhosis* (95% CI) 4 2.5 2 1.4 1.0 < 300 300-9999 10,000-99,999 100,000-999,999 ≥ 1 million HBV DNA (copies/mL) *Adjusted for age, sex, cigarette smoking, and alcohol consumption. 5. Iloeje UH, et al. Gastroenterol. 2006;130:678-686.

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] 25 20 15 10 5 n = 43 Placebo P = .001 Pts With Disease Progression (%) n = 173 HBV, hepatitis B virus; HCC, hepatocellular carcinoma; CHB, chronic hepatitis B. Lamivudine n = 122 n = 198 n = 385 n = 417 6 12 18 24 30 36 Kaplan-Meier Estimate of Time to Disease Progression in Asians With CHB (Mos) 6. Liaw YF, et al. N Engl J Med. 2004;351:1521-1531. 7

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 Drug Therapy Duration, Yrs Subjects Evaluated, n/N* (%) Subjects With Baseline Cirrhosis,† n Lamivudine[1] 3 63/152 (41) 11‡ Adefovir[2] 4-5 24/185 (13) 4 Entecavir[3] 3-7 57/679 (8) Telbivudine[4] 5 57/1699 (3) 2 Tenofovir[5] 348/641 (54) 96 HBV, hepatitis B virus; HAI, histology activity index. *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;124:105-117. 8. Hadziyannis SJ, et al. Gastroenterol. 2006;131:1743-1751. 9. Chang TT, et al. Hepatol. 2010;52:886-893. 10. Hou J, et al. APASL 2012. Abstract PP09-054. 11. Marcellin P, et al. Lancet. 2013;381:468-475.

Tenofovir and Liver Histology

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) TDF 300 mg QD (n = 250, 176) 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) ADV, adefovir; FTC, emtricitabine; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; QD, once daily; TDF, tenofovir. ADV 10 mg QD (n = 125, 90) Study Yr Biopsies 1 2 3 4 5 8 *FTC could be added for confirmed viremia on/after Wk 72. 13. Marcellin P, et al. Lancet. 2013;381:468-475.

Nonhistologic Efficacy Results at Yr 5 On Treatment Response, % (n/N)[14] HBeAg- Patients HBeAg+ Patients HBV DNA < 400 copies/mL 99 (292/295) 97 (170/175) ALT ≤ 1 x ULN 85 (236/277) 73 (124/169) HBeAg loss -- 49 (81/165) HBsAg loss 10* (6.8-14.7) *Kaplan-Meier estimated % (95% CI) of patients. No HBV variants associated with tenofovir resistance have been detected in patients during 7 yrs of treatment[15] ALT, alanine aminotransferase; HBV, hepatitis B virus; ULN, upper limit of normal. 14. Marcellin P, et al. Lancet. 2013;381:468-475. 15. Marcellin P. et al. AASLD 2013. Abstract 926.

96% of Pts Treated With Tenofovir Had Stable or Improved Fibrosis at Yr 5 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) P < .001 P < .001 Ishak Fibrosis Scores 100 12% 6 5 4 3 2 1 80 38% 60 Patients (%) 40 63% 20 39% Baseline Yr 1 Yr 5 N = 348 matched biopsies 17. Marcellin P, et al. Lancet. 2013;381:468-475.

Fibrosis Improvement at Yr 5 by Baseline Ishak Fibrosis Score 100 No histologic improvement Histologic improvement 80 60 Patients (%) 40 20 n = 10 126 79 37 19 77 1 2 3 4 5 6 Ishak Fibrosis Score at Baseline 18. Marcellin P, et al. Lancet. 2013;381:468-475.

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 Subjects With Baseline Cirrhosis (N = 96) +1 n = 24 n = 1 -1 n = 1 -2 n = 14 -3 n = 41 -4 n = 15 -5 Adapted from 19. Marcellin P, et al. Lancet. 2013;381:468-475.

Entecavir and Liver Histology

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 HBeAg+ ETV 0.5 mg/day (n = 354) Chronic HBV patients Open-Label ETV 1.0 mg/day Long-term histology cohort (n = 57) ETV, entecavir; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus. HBeAg- ETV 0.5 mg/day (n = 354) Study Yr Biopsies 1 2 3 4 5 8 * *Median time on ETV treatment at the time of long-term biopsy was 280 weeks (~ 6 yrs; range: 3-7 yrs) 22. Chang TT, et al. Hepatology. 2010;52:886-893.

Nonhistologic Efficacy Results On Treatment Response, % (n/N) Week 48 (n = 57) Long Term* HBV DNA < 300 copies/mL on treatment 70 (40/57) 100 (57/57) ALT ≤ 1 x ULN 67 (38/57) 86 (49/57) HBeAg loss on treatment 2 (1/41) 55 (22/40) HBsAg loss 0 (0/57) *Median duration of ETV therapy at time of long-term biopsy: 6 yrs (range: 3-7 yrs) ALT, alanine aminotransferase; ETV, entecavir; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; ULN, upper limit of normal. Genotypic testing for resistance was not performed because all the patients achieved a serum HBV DNA level < 300 copies/mL 24. Chang TT, et al. Hepatology. 2010;52:886-893.

Histologic Responses With Long-term Entecavir 100 Wk 48 96 Long-term biopsy* 88 80 73 60 Patients (%) 40 ETV , entecavir. 32 20 n = 41 55 18 50 Histologic Improvement Fibrosis Improvement *Median duration on ETV at time of long-term biopsy: 280 wks (~ 6 yrs; range: 3-7 yrs) 26. Chang TT, et al. Hepatology. 2010;52:886-893.

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 = 10 Ishak Fibrosis Score 60 6 5 4 3 2 1 0 Missing 50 40 . Patients (n) 30 20 10 Baseline Wk 48 Long Term N = 57 matched biopsies 27. Chang TT, et al. Hepatology. 2010;52:886-893.

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 Subjects With Baseline Advanced Fibrosis/Cirrhosis (N = 10) Change From Baseline in Fibrosis Score +1 -1 ETV, entecavir. n = 5 -2 -3 n = 1 -4 n = 1 n = 3 -5 *Median duration of ETV at time of long-term biopsy: 277 wks (range: 267-297); long-term biopsies taken Wk 288 ± 24 wks. 31. Schiff ER, et al. Clin Gastroenterol Hepatol. 2011;9:274-276.

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 HBV, hepatitis B virus; HCC, hepatocellular carcinoma.

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

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

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 HBV, hepatitis B virus; HCC, hepatocellular carcinoma. 45. Chang TT, et al. Hepatology. 2010;52:886-893. 46. Marcellin P, et al. Lancet. 2013;381:468-475

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