Treatment of hepatitis B

Transcription

1 Treatment of hepatitis B Prof. Dr. Cihan Yurdaydin University of Ankara Medical School Department of Gastroenterology 2 nd CEE Meeting on Viral Hepatitis and Co-infection with HIV Bucharest, Romania, 6-7 October 2016 Ankara Uni.

2 HBV The problem Ankara Uni.

3 Good old days of Hepatology Unfortunately only 20% respond Still more than 50% do not respond to treatment Baseline factors predisposing response etc The Hepatologist: The caring physician

4 HBV Vaccine and HCC Chang MH et al, Gastroenterology 2016

5 Morris Sherman

6 HBV epidemiology as of 2005 based on published 396 articles Ott JJ et al, Vaccine 2012 Ankara Uni.

7 HBsAg seroprevalence comparison : 1990 vs Ott JJ et al, Vaccine 2012 Ankara Uni.

8 HBsAg seroprevalence comparison : 1990 vs Ott JJ et al, Vaccine 2012 Ankara Uni.

9 Slow decline of HBsAg prevalence in Taiwan CL Chen et al, J Hepatol 2015

10 Ankara Uni.

11 Problem overall in HBV Tx HBsAg Prevalence in Turkey: 4,29 % West Turkey: 3,54 % Central Turkey: 4,55 % East Turkey: 6,88 % Number of HBsAg Positives: x 4,29 % = If 10 % were to have active chronic hepatitis = patients Patients under Therapy: * *SGK According to net sold pill tablets in Turkey 02/ / 2009 Toy et al, Eur J Health Econ 2012

12 Mean duration of complications development after appearance of ascites Duration (mean ± SD) Variceal bleeding Hepatic encephalopathy SPB HRS HCC 8 ± 9 months 9 ± 19 months 13 ± 19 months 8 ± 8 months 21 ± 25 months Ankara Uni.

13 Survival in HBV End Stage Liver Disease 100 Historical Comparisons 80 Patients surviving (%) Decompensated cirrhosis 14% De Jongh et al., Years Ankara Uni.

14 Goals of treatment in chronic viral hepatitis PREVENTION OF: Progression of disease Development of cirrhosis Development of HCC Death from liver disease Ankara Uni.

15 (Surrogate) Treatment Endpoints in CHB HBeAg loss HBeAg seroconversion ALT normalization Histological improvement Undetectable serum HBV DNA HBsAg clearance ccc DNA clearance HBeAg (+) wishfull thinking? for both HBeAg (+) and HBeAg(-) treatment end points. HBeAg (-) Ankara Uni.

16 How to assess treatment response? Pegylated interferon therapy: 12 months off tx HBV DNA < 2000 IU/mL NA therapy Undetectable HBV DNA by a sensitive PCR assay Off tx sustained virologic response: HBV DNA < 2000 IU/mL EASL HBV Guidelines, J Hepatol 2012 Ankara Uni.

17 Guidelines & HBV Treatment AASLD 2009 EASL 2012 APASL 2012 Lamivudine Not preferred Not preferred Not preferred Adefovir Not preferred Not preferred Not preferred Entecavir First line First line First line Telbivudine Not preferred Not preferred Not preferred Tenofovir First line First line First line PEG-IFN First line First line First line Lok and McMahon 2009, Liaw et al., 2012, J Hep 2012

18 Reversal of disease progression with lamivudine Placebo (n=215) YMDDm (n=209) (49%) Wild Type (n=221) Placebo 21% % with Disease Progression YMDDm 13% 5 WT 5% Liaw et al, NEJM 2004 Time after Randomisation (months) Ankara Uni.

19 Benefits of long-term NA therapy: Fibrosis regression over 5 years Marcellin P et al, Lancet 2013

20 Cirrhosis regresssion after 5 years of treatment with TDF Change from Baseline in Fibrosis Score n = 15 n = 41 Cirrhosis regression in 71 out of 96 pts n = 14 n = 1 n = 24 n = 1 Sirozlu 96 hastada (Ishak fibroz skoru 5) eşlenmiş BL ve 5. yıl biyopsileri vardı 5 yılda hastaların %74 ünde siroz (n=71) tersine dönmüş (Ishak fibroz skoru <5) ve %73 ünde (n=70) 5. yılda 2 puan azalmalar olmuştur; hastaların %25 inde (n=24) değişiklik olmamıştır - FTC ilavesi yapılmayan 94 hastadan %73 ünde siroz tersine dönerken, %26 sı değişiklik göstermemiştir. Marcellin, P, et al. Lancet 2013 *Ne Truvada (TVD = TDF + FTC) ne de emtrisitabin (FTC) HBV de kullanım onayı almamıştır.

21 Nucleos(t)ide analog therapy in patients Villeneuve et al, 2000 with decompensated cirrhosis Reference Drug Patients Duration CTP at Decrease HBV DNA LT Survived Viral N (LVD R) of therapy entry CTP 2 pts below LQ breakthrough Perillo et al, 2001 Fontana et al Hann et al, 2003 Schiff et al, 2007 Shim et al, 2010 Liaw et al, 2011 Liaw et al, 2011 LVD % 100% 20% 77% 9% LVD NA NA 77% NA 80% 17% LVD NA 80% 56% 89% 11% LVD % 73% 1% 85% 11% ADV 226 (100%) 48 5 NA 59% 19% 86% 2% ETV % 93% 4% 90% 0 ADV ETV ETV TDF TRU 91 (33%) 100 (36%) 22 (13%) 45 (18%) 45 (22%) Roche & Samuel, Clin Liver Dis % 35% 42% 26% 48% 20% 57% 73% 71% 88% 3% 11% 0 4% 9% 80% 82% 91% 96% 96%

22 LVD vs no tx in decompensated cirrhosis: Effect on transplantation free survival One year transplantation free survival (%) N= % Lamivudine N= % No treatment From: Singal & Fontana, APT 2012, based on Yao et al J Hepatol 2000; Perillo et al, Hepatology 2001; Fontana et al, Liver Transpl 2002 ; Andreone et al, Transplantation 2002

23 ETV vs. LVD in Acute on Chronic Liver Failure Chen CH et al, J Hepatol 2014

24 Kaplan Meier plot survival Survival (%) Total cohort = 154 NS n=25 SURV n= AII n= NS = surviving < 6 months Surv = surviving 6 months and those with < 6 months of follow-up Fontana R, et al. Gastroenterology 2002;123(3):719.. Months Ankara U

25 Predicted 6 month survival in patients with HBV cirrhosis receiving lamivudine (modelled) Index = 0.5 x bili x creatinine x HBV DNA (0 or 1) (LLD: 7e5 copy/ml) 1.0 Index: % Survival Months 8 Fontana R, et al. Gastroenterology 2002;123(3):719. Ankara U

26 Predictors of survival Serum creatinine and bilirubin levels and detectable DNA associated with six month mortality Index calculation 0.5 x bilirubin x creatinine x HBV DNA (0 or 1) Example 1: serum bilirubin 2 mg/dl (34 µmol/l) creatinine 1.2 mg/dl (106 µmol/l) undetectable DNA index score 3 5% probability 6 months mortality whilst on LAM Example 2: serum bilirubin 6.0 mg/dl (102 µmol/l), creatinine 2 mg/dl (176 µmol/l), detectable DNA: index score % probability death within 6 months whilst on LAM Fontana R, et al. Gastroenterology 2002;123(3):719. Ankara U

27 Regression of es. varices under NA therapy 107 HBeAg-negative patients with compensated cirrhosis Lampertico P, et al. J Hepatol 2015

28 NA therapy leads to decrease in Child Pigh and MELD scores Hugo-Cheinqer, 21 st APASL 2011

29 HCC incidence under NA therapy HCC incidence Cumulative probability of HCC <100,000 >=100, Years since NUC initiation HCC incidence Cumulative probability of HCC Papatheodoridis et al, Gut 2011, J Hepatol 2015 CHB Compensated cirrhosis Decompensated cirrhosis Years since NUC initiation

30 Risk of HCC decreases after 5 years of ETV or TDF therapy Papatheodoridis, Yurdaydin et al, AASLD 2016

31 HBsAg clearance in CHB after 1 yr of tx HBsAg clearance rate HBeAg-positive 3% <1% <1% <1% <1% 3% <1% Peg-IFN AD ENT Plac LAM LdT TDF HBsAg clearance rate HBeAg-negative 4% <1% <1% <1% <1% <1% <1% Peg-IFN AD ENT Plac LAM LdT Plac

32 Life without IFN Zoutendijk et al, JID 2011

33 Ganem & Prince, NEJM 2004

34 CHRONIC HEPATITIS B INFECTION Treatment Do not Treat! Treatment Do not Treat! HBeAg (+), HBV DNA (+), high ALT HBeAg (+), HBV DNA (+),normal ALT (immune tolerance) HBeAg (-), HBV DNA (+), high ALT (Precore mutant chronic hepatitis B) HBeAg (-), HBV DNA (-), normal ALT (Inactive HBsAg carrier) Ankara Uni.

35 % of patients N ALT HBV DNA HBV DNA HBsAg < c/ml <400 c/ml clearance Marcellin P et al, J Hepatol 2013

36 High rate of HBsAg clearance among sustained responders to PEGASYS ± LAM 25 PEGASYS ± LAM (N=230) 5 years post-treatment Patients (%) % 64% 12% 5 0 Marcellin P et al, Hepatol Int 2013 <400 cp/ml* Cleared HBsAg Ankara Uni.

37 HBsAg algorithm for poor response in HBeAg + patients treated with PEG-IFN (Based on 3 global studies with HBsAg levels) HBeAg-positive patient n= 803 Genotype A Genotype B Genotype C Genotype D WEEK 12 No decline >20,000 IU/mL >20,000 IU/mL No decline NPV: 100% NPV: 92% NPV: 98% NPV: 97% or or or or WEEK 24 >20,000 IU/mL >20,000 IU/mL >20,000 IU/mL >20,000 IU/mL NPV: 96% NPV: 100% NPV: 100% NPV: 100% Sonneveld et al. Hepatology 2013

38 On-treatment HBsAg + HBV DNA may predict response in HBeAg-negative CHB treated with peg-ifn Ricjkborst et al, Hepatology 2010 Week patients HBsAg decline: No 54 patients Yes 48 patients HBV DNA decline < 2log > 2log < 2log > 2log (copies/ml) n:20 n:34 n:20 n:28 Chance of SR 0% 24% 25% 39%

39 Peg-IFN after LT NA therapy Patient flow through the study Li G et al, EASL 2014, Oral #117

40 Results HBeAg loss + HBV DNA < 2000 IU/mL % NUC + Peg 14% NUC HBsAg loss % NUC + Peg 0% NUC Li G et al, EASL 2014, Oral #117

41 Tx dc under NA tx HBeAg (+) CHB: After 1 year consolidation tx after HBeAg seroconversion (EASL, AASLD, APASL) HBeAg (-) CHB: After HBsAg seroconversion (EASL, AASLD) After 3 sequential HBV DNA negativity, 6 months apart (APASL)

42 Outcome after discontinuation of 4-5 years of adefovir therapy (n:33) Hadziyannis et al, Gastroenterology Proportion of patients with (-) DNA or (-) HBsAg N=18 (55%) N=13 (39%) Proportion of patients with SVR % Predictors of HBsAg loss by MVA: High ALT, low EOT HBsAg, no retx Ankara Uni.

43 Cumulative relapse rates after tx dc in ETV vs LVD or LdT-treated patients (n=95) Median tx duration: 2 years (50% > 2 years) Relapse defined as ALT >2xULN and HBV DNA > 2000 IU/mL Relapse rate: 45% Median duration until relapse: 230 days (74% after > 6 months) HBsAg levels did not predict remission Jeng WJ et al, Hepatology 2013; 58:

44 Cumulative relapse rates after 3 years of ETV treatment (n=184) Patients had undetectable HBV DNA on 3 occasions 6 months apart Mean tx duration: 3 ± 0.6 yrs. Relapse defined as HBV DNA > 2000 IU/mL Quantitative HBsAg did not predict relapse or remission Use ETV indefinitely Seto WK et al, Gut 2014

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46 NA dc in HBeAg-negative CHB Discordant results between studies: Heterogenous definitions of relapse Use of different NAs Different duration of NA treatment Studies where mean NA treatment before treatment discontinuation was 3 years or less, relapse rates at post-treatment high Vast majority in HBV genotypes B & C (Far East)

47 Chen Ch et al, J Hepatol 2014

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49 FU of 21 pts who stoppped TDF

50 Follow-up of pts who stopped LT TDF treatment Berg T et al, EASL 2015

51 Tx dc in CHB- Ankara experience Prospective study At least 5 years of NA tx Liver bx: No cirrhosis- 23 pts NA tx re-instituted when confirmed viral relapse defined as > IU/mL- 8 pts had relapse Mean FU in non-relapsers: 71 months (12-96 months) Karakaya F et al, submitted

52 HBsAg levels)(iu/l) 3,5 3 2,5 2 1,5 1 0,5 P= Relapser (n=8) Non-relapser (n=13) Figure 3A: Quantitative HBsAg levels after 6 years of follow-up of patients who did or did not develop viral relapse after treatment discontinuation

53 HBsAg < 100 IU/L, % P= Relapser (n=8) Non-relapser (n=13) Figure 3B: Proportion of patients wirh quantitative HBsAg levels less than 100 IU/mLafter at 6 years of follow-up of patients who did or did not develop viral relapse after treatment discontinuation

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55 Successful treatment of HBV Normal ALT Negative HBV DNA Compare platelets to baseline platelets Compare albumin to baseline albumin

56 THE ALCOHOL PROBLEM OF TURKEY BEFORE ERDOGAN, THE MAGNIFICENT AFTER ERDOGAN, THE MAGNIFICENT