therapy in chronic hepatitis B Dr Grace Lai-Hung Wong MBChB (Hons, - PowerPoint PPT Presentation

International Symposium on Hepatology 2012 & 25th Annual Scientific Meeting New perspective of anti-viral therapy in chronic hepatitis B Dr Grace Lai-Hung Wong MBChB (Hons, CUHK), MD (CUHK), MRCP, FHKCP, FHKAM (Medicine) Associate Professor Institute of Digestive Disease Department of Medicine and Therapeutics The Chinese University of Hong Kong

What’s New? Evolving treatment guidelines in Hepatitis B APASL 2012 US Treatment Algorithm EASL 2012 AASLD APASL US Treatment Algorithm US Treatment AASLD Algorithm EASL KASL APASL APASL AASLD APASL AASLD EASL 2000 2001 2003 2004 2005 2006 2007 2008 2009 2011 2012

APASL guideline 2012 Recommendation 5 - Which drug or strategy • Nucleos(t)ide analogs (NA)-naïve patients can be treated with IFNa (IB), Peg IFN (IA), ETV (IA), TDF (IA), ADV (IB), LdT (IB) or LAM (IB). Thymosin-a can also be used (IB). • ETV or TDF is the preferred NA APASL 2012 Liaw et al. Hepatol Internat 2012

ETV or TDF is the preferred NA Because of the high antiviral potency, low resistance profile

Drug resistance of different NAs Low genetic barrier High genetic barrier No data 0 0 up to 6 years data from AASLD 2012 Ayoub and Keeffe. Aliment Pharmacol Ther 2011

Long-term efficacy of entecavir in trial setting HBeAg(+) ETV long-term cohort (ETV-022  ETV-901) ETV-022 Proportion of patients with HBV DNA Year 1 Year 2 Year 3 Year 4 Year 5 Year 1 100 94% 91% 89% 83% <300 copies/mL, % 80 67% 60 55% 40 20 0 236/354 80/146 116/140 116/131 98/108 88/94* * Five patients who remained on treatment at the Year 5 visit had missing PCR values (Non-completer = missing). Chang TT, et al. Hepatology 2010

Long-term efficacy of entecavir in real-life setting Week 48 viral load and 3-year outcomes HBeAg-positive (N = 160) HBeAg-negative (N = 280) Maintained viral suppression at 3 years, % 98 99 100 100 HBV DNA at week 48 < 20 IU/ml 80 72 80 achieved in 324/440 (74%) patients 60 60 46 40 40 20 20 226/228 37/52 94/96 30/64 0 0 <20 IU/ml ≥ 20 IU/ml HBV DNA <20 IU/ml ≥ 20IU/ml at week 48 Entecavir resistance at 3 years, % 100 100 80 80 Only 1/116 (0.9%) developed drug resistance even HBV DNA 60 60 at week 48 ≥ 20 IU/ml 40 40 0/96 1/64 0/228 0/52 20 20 2 0 0 0 0 0 <20 IU/ml ≥ 20 IU/ml <20 IU/ml ≥ 20 IU/ml Wong GL, et al. Aliment Pharmacol Ther2012

Low resistance with entecavir in real-life cohorts ORIENTE VIRGIL study 1 (naïve) 2 No resistance has No resistance has been observed up to been documented up 1 year to 3 years (n = 190) (n = 333) Italian Hong cohort 3 Kong study 4 One patient (0.2%) One patient (0.2%) developed ETV developed ETV resistance over resistance in 42 months 3 years (n = 418) (n = 440) 1. Buti M, et al. Eur J Gastroenterol Hepatol 2012. 2. Zoutendijk et al. Hepatology 2011. 3. Lampertico P, et al. Curr Hepatitis Rep 2012. 4. Wong GL, et al. Aliment Pharmacol Ther 2012.

Liver fibrosis improved with long-term ETV 60 Ishak fibrosis score n=57 Missing 50 6 5 40 Patients, n 4 3 30 2 1 20 0 10 * Up to 7 years Range: 3 – 7 years Median time: 280 weeks 1† 0 Long term* Baseline Week 48 † In the randomized controlled studies, patients received 0.5 mg ETV. In the 901 rollover study, patients received 1 mg ETV. Chang TT, et al. Hepatology 2010

Virologic response during ETV is not influenced by severity of liver disease 100 P =0.62 Patients with virologic 75 response (%) No cirrhosis n=274 50 Cirrhosis n=89 Decompensated cirrhosis n=9 25 0 Virologic response: 0 48 96 144 HBV DNA <80 IU/mL Time (weeks) Zoutendijk R, et al. Gut 2012

Virologic response is associated with a lower probability of disease progression 30 Hazard rate (HR): 0.29, 95% CI 0.08 – 1.00 Probability of event (%) No virologic response 20 Virologic response (<80 IU/mL) 10 P =0.05 0 0 48 96 144 Time at risk (weeks) Remained significant when correcting for age or MELD score Zoutendijk R, et al. Gut 2012

Efficacy of 48 weeks ETV in LAM/LdT-experienced HBeAg( – ) patients 100 100 86 82 80 75 80 Proportion of patients (%) 60 60 40 40 20 20 78/95 74/99 54/63 0 0 ALT <1xULN † HBV DNA HBV DNA <50 IU/mL* <12 IU/mL* * Among patients with quantifiable HBV DNA or ALT test results at baseline and Week 48, con-completer = missing. † The majority of patients who achieved HBV <50 IU/ml also achieved HBV DNA <12 IU/mL. Hou JL, et al. APASL 2011

Efficacy of 48 weeks ETV in ADV-experienced patients 100 95 100 Proportion of patients, % 80 80 74 62 57 60 60 40 40 20 20 20/21 85/138 54/63 65/115 0 0 HBeAg(+) HBeAg( – ) All ALT <1xULN HBV DNA <50 IU/mL 16% of HBeAg(+) patients experienced HBeAg loss; 12% seroconverted Hou JL, et al. APASL 2011

Long-term efficacy of ETV in ADV-experienced patients  ETV was analysed for 43 of 51 ADV-experienced (+LAM experienced in 29 [67%]) patients who were directly switched to ETV  One (2.3%) patient experienced virological breakthrough and developed genotypic ETV resistance Median ADV treatment duration was 18 (3 – 55) months. Adjusted estimated survival curve for the cumulative probability of achieving virological response. For ADV-naïve, ADV- experienced patients and ADV- resistant patients. Based on a Cox’s model for mean values of baseline HBV DNA, ALT, HBeAg status and previous LAM exposure and resistance. Zoutendijk, et al. EASL 2011

Long-term efficacy of tenofovir in trial setting Study 102 (HBeAg- Patients) and 103 (HBeAg+ Patients) Year 1 Year 8 Tenofovir DF RANDOMIZATION Tenofovir DF N=235 300 mg 300 mg N=154 N=250 & N=176 2:1 Adefovir Dipivoxil Tenofovir DF N=112 10 mg 300 mg N=84 N=125 & N=90 Pre-treatment Year 1 Year 5/ Week 240 Liver Biopsy 1 Liver Biopsy Week 72 Year 3 Year 8 Liver Biopsy • At Week 72, patients with HBV DNA ≥ 400 copies/mL had the option at the discretion of the investigator to add emtricitabine (FTC) • Retention rate at Week 240: 81% for HBeAg-, 70% for HBeAg+ Marcellin, P, et al. AASLD 2011; Oral #238

Long-term efficacy of tenofovir in trial setting HBeAg-positive patients: On-Treatment 100 Proportion of Subjects 90 TDF-TDF 99% 80 ADV-TDF 99% 70 (%) 60 50 40 30 20 10 0 288 0 8 16 24 32 40 48 56 64 72 80 88 96 108 120 132 144 156 168 180 192 204 216 228 240 Weeks on Study HBeAg-negative patients: On-Treatment 100 Proportion of Subjects 90 TDF-TDF 100% 80 ADV-TDF 96% 70 (%) 60 50 40 30 20 10 0 288 0 8 16 24 32 40 48 56 64 72 80 88 96 108 120 132 144 156 168 180 192 204 216 228 240 Weeks on Study No Resistance to TDF up to 6 years Marcellin et al. AASLD 2012

Liver fibrosis regression with long-term TDF • Patients with Ishak score ≤2: 39% at Baseline, 63% at Year 5 • Patients with Ishak score ≥4: 38% at Baseline, 12% at Year 5 • Patients with cirrhosis (Ishak score ≥ 5): 28% at Baseline, 8% at Year 5 P < 0.001 P < 0.001 *Sign test P < 0.001 P < 0.001 100 100 12% 12% Ishak Fibrosis 90 90 Scores 38% 38% 80 80 6 6 Percentage of Patients 70 70 5 5 60 60 4 4 50 50 40 40 3 3 63% 63% 30 30 2 2 39% 39% 20 20 1 1 10 10 0 0 0 0 Baseline Baseline Y Y ear 1 ear 1 Y Y ear 5 ear 5 Gane et al. APASL 2012

Regression of cirrhosis with long-term TDF • 28% (96/348) of patients with paired biopsies had cirrhosis at Baseline • 74% (71/96) were no longer cirrhotic (Ishak score <5) at Year 5 Change in Ishak Scores at Year 5 for Patients with Cirrhosis at Baseline 3 2 n=1 73% of patients had ≥2 unit reduction 1 0 n=24 -1 n=1 -2 n=14 -3 n=41 -4 n=15 -5 Gane et al. APASL 2012

Long-term efficacy of TDF in real-life setting European Retrospective/prospective multicenter cohort study 100 91 91 90 100 84 undetectable ‡ HBV DNA HBeAg seroconversion 80 80 % patients with 65 % patients with HBeAg seroconversion: 60 60 15 patients** 40 40 33% 20 20 0 0 Month 18 30 6 12 24 0 6 12 18 24 30 Patients Patients on at risk 61 55 45 32 20 6 271 272 245 193 109 follow-up Lampertico P, et al. AASLD 2011