Peking University Hepatology Institute Is resistance still a problem in Asia? Lai Wei Peking University People’s Hospital Peking University Hepatology Institute June 7, 2014 Singapore Peking University Hepatology Institute Presentation Overview • Molecular Biology of HBV and Mutation • Resistance to Antiviral Agents and Clinical Relevance • Asian Resistance and Future Directions Peking University Hepatology Institute HBV replication characteristics • High replication rate, as many as 1012 virions/day. • High mutational rate of 105 to 104 substitutions/base/cycle. • HBV RT does not have a proofreading function to repair incorrectly incorporated nucleotides. Mirandola, D. Campagnolo,G. Bortoletto,et al.Large-scale survey of naturally occurring HBV polymerase mutations associated with anti-HBV drug resistance in untreated patients with chronic hepatitis BJournal of Viral Hepatitis, 2011, 18, e212–e216. (Ganem & Prince, N Engl J Med 2004;350:2719-20) Peking University Hepatology Institute HBV Characteristics that Protect Against Resistance • Conservatory constraints on overlapping open reading frames • Control of HBV replication by the immune system • Barrier to resistance and viral variant fitness Peking University Hepatology Institute Presentation Overview • Molecular Biology of HBV and Mutation • Resistance to Antiviral Agents and Clinical Relevance • Asian Resistance and Future Directions Peking University Hepatology Institute Incidence of Resistance in Lamivudine Refractory Patients 40 30 20 Year 4 Year 3 Year 2 10 0 Year 1 baseline Adefovir switch Adefovir add-on Entecavir Tenofovir + switch FTC/3TC Lampertico et al Hepatology 2005 & Gastroenterology 2007; Colonno et al AASLD 2007; Lacombe et al AIDS 2006 Peking University Hepatology Institute Incidence of Resistance in Nucleoside Naive Patients 80 70 60 50 40 year 5 year 4 year 3 year 2 year 1 30 20 10 0 Lamivudine Adefovir Entecavir Telbivudine Tenofovir Lai et al CID 2003; Hadzyiannis et al Gastroenterology 2006; Colonno et al AASLD 2006; Di Bisceglie et al AASLD 2006; Lai et al NEJM 2007; Marcellin et al NEJM 2008 Peking University Hepatology Institute Cross-resistance data for the most frequent resistant mutants Lamivudine Telbivudine Entecavir Adefovir Tenofovir Wild-type S S S S S M204l R R I S S L180M + M204V R R I S S A181 T/V I S S R S N236T S S S R I I169T + V173L + M250V* R R R S S T184G + S202lI/G * + M204I/V).R *: (+ L180M R R S S Durantel et al Hepatology 2004; Brunelle et al Hepatology 2005; Yang et al Antiviral Therapy 2005; Villet et al Gastroenterology 2006 & 2008; Delaney et al AAC 2006; Villet et al J Hepatol 2007 & 2008; Brunelle et al AAC 2007; Qi et al Antiviral therapy 2007; Tenney et al AAC 2004 & 2007 Peking University Hepatology Institute Lamivudine Resistance Accelerates Progression of Liver Disease )N=215(Placebo )49%(YMDDm (N=209) % With disease progression 25 20 Placebo 21% )N=221(Wild Type 15 YMDDm 13% 10 WT 5 5% 0 0 6 12 18 24 30 36 Time after randomization (Months) Liaw YF et al. N Engl J Med. 2004;351:1521-1531 Peking University Hepatology Institute Presentation Overview • Molecular Biology of HBV and Mutation • Resistance to Antiviral Agents and Clinical Relevance • Asian Resistance and Future Directions Peking University Hepatology Institute Characteristics That Predispose to Antiviral Drug Resistance • Viral features • Rapid replication dynamics • Genotypes • Quasispecies distribution • Host factors • Chronic infection • Drug targets • Specifically targeted antiviral therapy • Reimbursement policy • Physician Practice following guideline Peking University Hepatology Institute Distribution of 8 HBV Genotypes (A-H) Worldwide * Defined by divergence in the entire genome sequence > 8% Peking University Hepatology Institute Asian vs European Resistance Profiles (Mono-infections) Resistance Pathways Antiviral Agents Total Sequences = 469 L-nucleoside analogues D-Cyclopentane LMV Or LdT ETV ADV Asian HBV Genotypes p-values A% (N=37) D% (N=106) B% (N=108) C% (N=218) 84 (n = 31) 72 (n = 76) 81 (n = 87) 77 (n = 167) rtM204V (± rtL1180M) 70.6 (24) 34.1 (30) 34.4 (32) 37.1 (62) rtM204I (± rtL1180M) 17.6 (6) 50.0 (44) 57.0 (53) 54.5 (91) rtM204I/V (± rtL1180M) 2.9 (1) 2.3 (2) 2.2 (2) 0.6 (1) 8 (n=3) 11 (n=12) 5 (n=6) 6 (n=13) rtT184 (and LMVr) - 5.7 (5) 4.3 (4) 3.6 (6) - rtS202 (and LMVr) 5.9 (2) 3.4 (3) 2.2 (2) 1.8 (3) - rtM250 (and LMVr) 2.9 (1) 2.3 (2) - 1.2 (2) - - 2.3 (2) - 1.2 (2) - 8 (n = 3) 17 (n = 18) 14 (n = 15) 17 (n = 38) rtA181T/V 33.3 (1) 33.3 (6) 46.7 (7) 78.9 (30) rtN236T 33.3 (1) 16.7 (3) 33.3 (5) 10.5 (4) rtA181T/V + rtN236T 33.3 (1) 50.0 (9) 20.0 (3) 10.5 (4) rtT184 + rtS202 (and LMVr) Acyclic phosphonates European HBV Genotypes 0.0002 (1) - < 0.0001 (2) Lilly Yuen, Stephen Locarnini. Different Drug Resistance Pathways Observed Between European and Asian HBV Genotypes. 2011 Peking University Hepatology Institute The paradigm of antiviral therapy is the suppression and maintenance of viraemia below the limit of detection No Replication = No Resistance NR = NR EASL Clinical Practice Guidelines Panel. J Hepatol. 2009;50:227-42. Peking University Hepatology Institute NAs: Potency versus resistance Potency of HBV DNA suppression Nucleoside analogue Nucleotide analogue TDF ETV LdT LAM ADV Likelihood of resistance Peking University Hepatology Institute Incidence of Resistance in Lamivudine Refractory Patients 40 30 20 Year 4 Year 3 Year 2 10 0 Year 1 baseline Adefovir switch Adefovir add-on Entecavir Tenofovir + switch FTC/3TC Lampertico et al Hepatology 2005 & Gastroenterology 2007; Colonno et al AASLD 2007; Lacombe et al AIDS 2006 Peking University Hepatology Institute Hepatitis B Genome and Primary Antiviral Resistance Substitutions POL/RT rt1 rt 344 YMDD MDD F__V__LLAQ__Y I(G) II(F) A L-Nucleoside Resistance LMV L-dT Acyclic Phosphonate Resistance ADV/TFV D-Cyclopentane Resistance ETV rtI169 B C rtA181T/V rtA181T/V rtM204V/I rtM204I rtA181T/V rtL180M plus rtM204V/I rtT184 rtS202 D E rtN236T rtM250 Peking University Hepatology Institute CR-HepB: China Registry for Hepatitis B Peking University Hepatology Institute Patients using IFN or NUCs, n=37694 Up to May 28th, 2014 Peking University Hepatology Institute Patients using Nucleotide Analogues, n=26144 Up to May 28th, 2014 Peking University Hepatology Institute Recommend antiviral prophylaxis for HBV patients who receive immunosuppressive therapy Differences in recommending antiviral prophylaxis and regular follow-up between gastroenterologists, hepatologists, and general medicine physicians. gastroenterologists and hepatologists; , general medicine physicians. Ning LH, et al. European Journal of Gastroenterology & Hepatology 2012, 24:884–889 Peking University Hepatology Institute CHB treatment and Reimbursement In urban area, China Heilongjiang 宁夏 Jining Xinjiang Liaoning Gansu Beijing Inner Mongolia Hebei Shanxi Ningxia Qinghai Tibet Shandong Shaanxi Henan Sichuan Jiang su Anhui Hubei Shanghai Zhejiang Jiangxi Hunan Guizhou Fujian Yunnan Guangxi Guangdong Lamivudine(II) Lamivudine//Peginterferon α-2a(II) Hainan Lamivudine/Adefovir Dipivoxil/Entecavir/Telbivudin/Interferon –α/Peginterferon α-2a[α-2b](II) Lamivudine/Adefovir Dipivoxil/Entecavir/Telbivudin/Peginterferon α-2a[α-2b](II) Peking University Hepatology Institute National HBV Drug Resistance Monitoring Network in China 9998 CHB patients 29 provinces and cities 267 hospitals Eleventh Five-Year Major Projects in China ZENG Yi-jun, ZHANG Xin-xin,ZHUANG Hui,Chinese Journal of Viral Diseases.2013.03 Peking University Hepatology Institute CHB resistance monitoring statistics— Medication history n=2135 Medication history LAM ADV ETV LdT LAM-ADV LAM-LdT LAM-ETV LAM+ADV LAM+ETV LAM+ADV-ADV LAM+ADV-ETV LAM+ADV-LdT LAM-ADV+LAM LAM-ADV+ETV LAM-ADV+LAM-ADV LAM-ADV+LAM-ADV+ETV LAM-ADV+LAM-ETV LAM-ADV+LAM-ETV+ADV LAM-ADV+LdT LAM-ADV-ADV+ETV LAM-ADV-ADV+ETV-LdTADV+ETV LAM-ADV-ADV+LAM LAM-ADV-ADV+LdT LAM-ADV-ETV LAM-ADV-ETV+ADV LAM-ADV-ETV-ADV+LdT n 560 447 108 90 82 9 36 73 1 1 1 1 94 5 1 1 3 1 1 2 Medication history n Medication history n Medication history n LAM-ADV-LAM LAM-ADV-LAM+ADV LAM-ADV-LdT LAM-ADV-LdT-ETV LAM-ETV+ADV LAM-ETV+LAM LAM-ETV-ADV LAM-ETV-ETV+ADV LAM-ETV-LAM LAM-LAM+ADV-ADV LAM-LAM+ADV-ADV+ETV LAM-LAM+ADV-ADV-LAM+ADV LAM-LAM+ADV-ETV LAM-LAM+ADV-ETV+ADV LAM-LAM+ADV-LdT LAM-LAM+ADV-LdT+ADV LAM-LAM+ETV LAM-LdT+ADV LAM-LdT-ADV LAM-LdT-ADV+LAM 1 5 6 2 3 1 3 1 1 2 3 1 1 6 1 1 1 1 2 1 ADV+ETV ADV+LdT ADV+ETV+LAM ADV+LAM-ADV+ETV ADV+LAM-ETV ADV-ADV+LAM ADV-ADV+ETV ADV-ADV+LAM-ADV+ETV ADV-ADV+LAM-ETV ADV-ADV+LdT ADV-ADV+LdT-ADV+ETV ADV-ETV-ADV+LAM ADV-ETV-LdT ADV-ETV-LdT+ADV ADV-LAM+ADV ADV-LAM+ADV-ETV ADV-LAM-ADV ADV-LAM-ADV+LAM-LdT ADV-LAM-ADV-ETV ADV-LAM-ETV 4 8 4 1 3 23 3 1 3 5 1 1 1 1 4 1 1 1 1 1 ADV-LdT-ETV ETV-ADV ETV-LAM ETV-LdT ETV+LAM ETV-ADV+ETV ETV-ETV+ADV ETV-LAM+ADV ETV-LAM-ADV LdT+ADV LdT+ETV LdT-ADV LdT-ADV+LAM LdT-ADV+LAM-ADV+LdT LdT-ADV+LdT LdT-ADV-ETV LdT-ADV-LAM-ADV LdT-ADV-LdT LdT-ETV LdT-LAM+ADV 2 2 1 3 2 3 3 1 1 2 2 7 1 1 4 3 1 1 3 4 1 LAM-LdT-LAM+ADV 1 ADV-LAM-LAM+ADV 1 LdT-LAM-ADV 1 2 2 12 1 1 LAM-LdT-LdT+ADV LAM-ADV-LdT-ETV+ADV ADV-LdT ADV-ETV ADV-LAM 2 1 16 11 7 ADV-LAM-LdT ADV-LAM-LdT-ETV ADV-LdT+ADV ADV-LdT-ADV 3 1 1 2 LdT-LAM-ADV+ETV LdT-LAM-ADV+LAM LdT-LdT+ADV LdT-LdT+ETV 1 1 7 1 ZENG Yi-jun, ZHANG Xin-xin,ZHUANG Hui,Chinese Journal of Viral Diseases.2013.03 Peking University Hepatology Institute Distribution of resistance on HBV Genotypes Genotype B Genotype C GT B: 2421cases, 32.06% GT C: 5088 cases, 67.38% GT D: 42 cases, 0.56% ZENG Yi-jun, ZHANG Xin-xin,ZHUANG Hui,Chinese Journal of Viral Diseases.2013.03 Peking University Hepatology Institute Preventing Resistance from the Start to Ensure Long-Term Treatment Success Prevention Judicious timing of treatment Education regarding adherence First-line therapy High potency drug with a high genetic barrier to resistance, eg, ETV or TDF Consider PEG IFN in suitable patients (eg, high ALT, low HBV DNA) Monitoring Regular 3-6 monthly monitoring of viral load with sensitive HBV DNA assay Genotypic resistance testing in patients with virological breakthrough Salvage therapy Early initiation of “add on” salvage therapy Avoid “switch” sequential monotherapy Avoid combination therapy using drugs with similar cross resistance profiles EASL Clinical Practice Guidelines Panel. J Hepatol 2009;50:227–242. Peking University Hepatology Institute Possible Rescue Therapy Options for Antiviral Drug-Resistant HBV Type of resistance Preferred rescue therapy* Other options Lamivudine or Telbivudine • Switch to or add tenofovir • Add adefovir • Switch to tenofovir + emtricitabine • Switch to entecavir (not preferred) Adefovir • Switch to or add entecavir • Switch to tenofovir + emtricitabine • Add lamivudine or telbivudine Entecavir • Switch to or add tenofovir *Depending on availability and/or approval • Add adefovir EASL Guidelines J Hepatol;50:227 Zoulim & Locarnini 2009. Gastro;137:1593 Zoulim & Locarnini 2011. J Hepatol (in press) Peking University Hepatology Institute Summary • The major HBV DNA mutations of antiviral resistance are associated with HBV genotypes • Preventing Resistance from the Start to Ensure Long-Term Treatment Success • HBV resistance is decline, but challenge remain Peking University Hepatology Institute Challenges in the treatment of CHB in Asia • • • • • • High disease burden and resistance management Accessibility & affordability to treatment Insufficient reimbursement for rural residents Inadequate therapy-First line therapy not first New target to eradicate HBV …… Peking University Hepatology Institute Thanks
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