Management of chronic hepatitis B : recent advance in the treatment of antiviral resistance

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1 anagement of chronic hepatitis B : recent advance in the treatment of antiviral resistance / 김강모 연수강좌 anagement of chronic hepatitis B : recent advance in the treatment of antiviral resistance 김강모 울산대학교의과대학서울아산병원소화기내과 REEAL Study: HB DNA Levels and Long-Term Outcomes iral Load at Baseline < 3 (Undetectable) 1,-99, ,999 1,-999,999 Cumulative Incidence of HCC (%) (n = 363) 3.7% 1.3% 1.37% Chen CJ, et al. JAA. 26;29:6-73. Iloeje UH, et al. Gastroenterology. 26;13: % 12.17% illion ultivariate-adjusted relative risk of cirrhosis (n = 382) CHB treatment goal: sustained suppression of HB replication Primary goal of treatment Outcomes Sustained suppression of HB replication to the lowest possible level 1,2,3 Delay in progression to cirrhosis and HCC Improved survival Reduction in the development of resistance 6 Increased rate of seroconversion 7,8 Improvement in liver histology 7 Normalization of ALT levels 7 CHB = chronic hepatitis B; HB = hepatitis B virus; HCC = hepatocellular carcinoma; ALT = alanine aminotransferase; 1. Lok A & cahon B. Hepatology 27;: Liaw YF, et al. Liver Int 2;2: Keeffe EB, et al. Clin Gastroenterol Hepatol 26;: Liaw YF, et al. N Engl J ed 2;31: Niederau C, et al. N Engl J ed 1996;33: Yuen F, et al. Hepatology 21;3: arcellin P, et al. N Engl J ed 23;38: Gauthier J, et al. J Infect Dis 1999;18: Phases of Chronic HB Infection Candidates for Therapy Immune tolerance HBeAg (+); HB DNA high ( ); ALT normal Immune clearance/hbeag-positive CHB HB DNA (1 6-1 ) and ALT levels high or fluctuating; active inflammation on liver biopsy Inactive HBsAg carrier HBeAg (-); HB DNA low (<1 ); ALT normal HBsAg may later become undetectable Reactivation/HBeAg-negative CHB HB DNA (1 3-8 ) and ALT levels high or fluctuating; active inflammation on liver biopsy Follow up plan and treatment decision in CH B patients: APASL 28 11

2 연수강좌 Follow up plan and treatment decision in CH B patients: APASL 28 Follow up plan and treatment decision in CH B patients: APASL 28 When to Start Therapy: 1) Elevated HB DNA Level HBeAg(+) CHB > 2, IU/ml (>1 ) HBeAg(-) CHB >2, IU/ml (>1 ) 2) ALT Level above ULN AASLD, KASL ; > 2X ULN EASL, Keefe et al ; > 1X ULN Currently Available Antiviral drugs Conventional Interferon-α2b Pegylated Interferon-α2a (Pegasys ) Lamivudine Adefovir Entecavir Telbivudine Clevudine Tenofovir, Emtricitabine Prevalence of resistance (%) Cumulative probability Resistance profiles of antiviral agents in naive patients of resistance (%) Genotypic resistance to LD 2 HBeAg(+) patients Genotypic resistance to AD 3 HBeAg(-) patients Cumulative probability of resistance (%) Cumulative incidence of resistance (%) Genotypic resistance to ET 1 HBeAg(+) and (-) patients Collation of available data and not from head-to-head comparison studies. 1. Tenney DJ, et al. 18th APASL. Seoul, Korea, arch 28;Abstract O Lok AS, et al. Gastroenterology 23;12: Borroto-Esoda K. J Hepatol 26;(Suppl.2):S179 S18(Poster 83).. Standrigg DN, et al. J Hepatol 26;(Suppl.2):S191(Poster 1).. Lai CL, et al. Hepatology 26;(Suppl.1):222A(Oral 91) HBeAg(+) iral rebound with genotypic resistance to LdT, HBeAg(-) 12

3 anagement of chronic hepatitis B : recent advance in the treatment of antiviral resistance / 김강모 L-nucleosides LA LdT FTC CL utant HB With Nucleos(t)ides Nucleosides Cyclopentane ET L18 2/I T18G/X S22G/I 2 Not approved for HB treatment in the US Acyclic Nucleotides AD TDF? A181/T N236T A19I Allen I, et al. Hepatology. 1998;27: Qi X, et al. EASL 2. Abstract 7. Tenney D, et al. Antimicrob Agents Chemother. 2;8: Telbivudine [package insert]. Locarnini S. IDRW 26. Abstract P2. Qi X, et al. Antivir Ther. 27;12: van Bommel F, et al. AASLD 27. Abstract 96. iral breakthrough while receiving NA therapy: AASLD 29 Compliance should be ascertained A confirmatory test for antiviral-resistant mutation should be performed All patients with virologic breakthrough(>1log 1 ) should be considered for rescue therapy (genotypic resistance? iral rebound(>1 )? Biochemical breakthrough(>uln)?) For patients in whom there was no clear indication for hepatitis B treatment and who continue to have compensated liver disease, withdrawal of therapy may be considered but these patients need to be closely monitored and treatment reinitiated if they experience severe hepatitis flares anagement of resistance to oral antiviral therapies Possible resistance cases in clinical field L-r AD-r AD-r after L-r ET. mg-r, ET-r after L-r AD+L combination-r Clevudine-r, Telbivudine-r AD+ET combination-r after L-r or ET-r anagement of L-r When should rescue therapy be considered? Genotypic resistance? irological breakthrough(>1log)? iral rebound(>log)? Biochemical breakthrough(>uln)? Lamivudine ALT (U/L) Codon 18 Codon 2 Codon 27 PCR assay L L L/ Genotypic resistance irological breakthrough / / onths HB DNA log Biochemical breakthrough 2 year AD+LA in 7 HBeAg-neg, LA-R patients: irological response genotypic resistance(<6 log HB-DNA): NL ALT 2 year AD+LA in 7 HBeAg-neg, LA-R patients: Biochemical response phenotypic resistance(6 8 log HB-DNA): ALT elevation Genotypic resistance Phenotypic resistance Patients still at risk phenotypic resistance(>8 log HB DNA): ALT elevation p<.1 onths Lampertico P et al. Hepatology 2;2: Baseline p<.1, p<.1 onths of treatment Lampertico P et al. Hepatology 2;2:

4 연수강좌 anagement of L-r When should rescue therapy be considered? Rescue AD+L therapy before biochemical breakthrough could be better than after biochemical breakthrough in terms of virological response Time lag between genotypic and phenotypic resistance: ranges from 3 to 2 months 3-month interval surveilance would enable timely identification of genotypic resistance Unresolved issues irological breakthrough(>1log)? vs some other point? eaning of biochemical response? Timing of rescue therapy of LA-r Roadmap concept Gane EJ et al. Hepatol Int 28;2:3 7. Applicable to antivirals with low genetic barrier Response at 2 week was the most accurate predictor of long term efficacy ALT normalization, HB DNA non-detectability, HBeAg seroconversion, lack of resistance GLOBE trial Telbivudine vs L in 1,37 patients Timing of rescue therapy of LA-r year LA in 7 HBeAg-positive Ideal response definition: HB DNA <2, ( IU/mL), HBeAg seroconversion, normal ALT, YDD mutations(-) Treatment failure: HB DNA >1, (2, IU/mL), HBeAg(+), abnormal ALT Cut-off HB DNA: 2, or 8 IU/mL at or 16 week 83.8% or 87.7% chance of -year treatment failure addition of or switch to an alternative antiviral should be considered Yuen F et al. Hepatology 27; 6: Lai CL, et al. N Engl J ed 27;37: anagement of L-r Which agents should be used? Previous rescue therapy of L-r L resistance Switch to AD mono or ET 1mg mono Cross resistance: L, telbivudine, clevudine High genetic barrier in ET 1

5 anagement of chronic hepatitis B : recent advance in the treatment of antiviral resistance / 김강모 Development of AD-r mutants at baseline and 8 weeks with AD monotherapy % patients with AD-r 2% 1% 1% % % All were A181T/ p <.1 Baseline Week 8 LA-resistant Treatment-naïve n = 7 n = 38 AD-r = A181T/ ± N236T Lee YS. Hepatology 26; 3: Lamivudine-Refractory Cohort (HBeAg+): Cumulative Probability of ET-r Through Years Cumulative Probability (%) 1% 7% ETr = LDr (2 ± L18) + T18, S22 and/or 2 substitutions ETr + irologic Breakthrough ( 1 log increase from nadir) 1 % % % Years 1 N=187 2 N=16 3 N=8 N=3 N=33 72/187 (39%) achieved HB DNA < 3 c/ml; 3/72 (%) had subsequent genotypic ET resistance Tenney DJ, et al. Plenary presentation at APASL 28 Tenney DJ, et al. Hepatology International 28;2(1):A88. PL2 AD+L vs AD mono in L-r: meta-analysis, 29 Biochemical response ET 1mg vs AD mono vs AD+L in L-r: retrospective cohort study irological response Emergence of AD resistance Kim HJ, et al. J Gastroenterol Hepatol 21;2(8): anagement of L-r AD+L combination is better than AD mono or ET mono in terms of subsequent antiviral resistance Timing of rescue therapy After genotypic and virological breakthrough and Before biochemical breakthrough could be better in terms of virological response Cut-off HB DNA 6-2, IU/mL at 2 week 2, or 8 IU/mL at or 16 week 83.8% or 87.7% chance of -year treatment failure Unresolved issues irological breakthrough(>1log)? vs some other point? eaning of biochemical response? Role of tenofovir? Tenofovir + L combination? anagement of AD-r Quality of Evidence Grade II-2 or III Cohort or case-control study, opinions of respected authorities Nucleoside analog is effective, but combination therapy is recommended Tenofovir mono is effective, but in vitro evidence of cross resistance In AD-r with no previous history of NA AD + L or telbivudine or ET., Tenofovir + L. In AD-r with history of nucleoside analog resistance AD + ET 1 ( 보험문제가있는경우 AD + L or ET.) Tenofovir + ET 1 or L or ET.? 1

6 연수강좌 anagement of ET-r Quality of Evidence Grade II-3 ultiple time series, dramatic uncontrolled experiments In ET.-r No sufficient experience ET. + AD or tenofovir, AD mono? Tenofovir mono? In ET 1-r ET 1 + AD or tenofovir, AD mono? Tenofovir mono? ET 1 mg + AD combination Could it be the promising combination regimen before the launch of tenofovir? 89 patients with previous NA resistance, retrospective - Number of previous failed NA - One: L only - Two: L + AD or ET - Three: L + AD + ET Lim YS, et al. Antivir Ther 212;17(1):3-6. anagement of Antiviral-Resistant HB: AASLD 29 update Lamivudine-resistant Add adefovir or tenofovir Stop lamivudine, switch to Truvada (tenofovir + emtricitabine) Stop lamivudine, switch to entecavir 삭제됨 Adefovir -resistant Add lamivudine Stop adefovir, switch to Truvada Switch to or add entecavir Entecavir -resistant Switch to or add adefovir or tenofovir switch to tenofovir or Truvada Telbivudine-resistant Add adefovir or tenofovir Stop telbivudine, switch to entecavir Stop telbivudine, switch to Truvada In HI co-infected patients; scanty in vivo data in non-hi Lok AS, cahon BJ. Hepatology. 27;:7-39. infected persons. Durability of viral suppression unknown, especially in patients with LD resistance. Clinical data not available. When to Stop Therapy Two Distinct Patient Populations HBeAg-positive (wild-type) HBeAg loss seroconversion Durable suppression of HB DNA to low or undetectable Therapy discontinued 6-12 months after HBeAg seroconversion and undetectable HB DNA HBeAg-negative (precore and core promoter mutants) HBeAg seroconversion not an endpoint Durable suppression of HB DNA to low or undetectable Relapse common after stopping oral therapy; therapy usually administered long-term; several years of undetectable HB DNA may decrease the relapse rate Summary Treatment of Hepatitis B When to start therapy Elevated HB DNA [>2, IU/mL for HBeAg(+) and >2, IU/mL for HBeAg(-)] plus elevated ALT, and/or significant disease on liver biopsy When to stop or alter therapy HBeAg(+): HBeAg seroconversion and HB DNA (-) HBeAg(-): HBsAg seroconversion, long-term therapy? Primary non-response at week 2(<2 log 1 reduction) Development of antiviral drug resistance Inadequate R ( 2, IU/mL) at week 2? Conclusion anagement of L-r AD+L combination is better than AD mono or ET mono in terms of subsequent antiviral resistance Timing of rescue therapy After genotypic and virological breakthrough and Before biochemical breakthrough could be better in terms of virological response Cut-off HB DNA 6-2, IU/mL at 2 week 2, or 8 IU/mL at or 16 week 83.8% or 87.7% chance of -year treatment failure 16

7 anagement of chronic hepatitis B : recent advance in the treatment of antiviral resistance / 김강모 Future perspectives Tenofovir is now available in Korea Effective in both naïve and LAr as a monotherapy Low efficacy as a TDF mono in ADr and high viral load Other combination regimen ET + tenofovir? LA + tenofovir? Reappraisal of Peg-interferon using HBsAg titer Intermittent antiviral therapy? Clinical course after L off treatment in 12 HBeAg(+) patients Group A HB DNA < with HBeAg loss Group B HB DNA -1 with HBeAg loss Group C HB DNA -1 without HBeAg loss Group D HB DNA 1 irrespective HBeAg loss Clinical course after L off treatment in 36 HBeAg(-) patients Group A1 HB DNA < Group B1 HB DNA -1 Group C1 HB DNA 1 17