Recent achievements in the treatment of hepatitis B by nucleosides and nucleotides. K. Zhdanov

Transcription

1 EASL endorsed conference White Nights of Hepatology 2012 Adverse events during antiviral therapy: how to predict, manage and monitor June 7-8 Saint-Petersburg Recent achievements in the treatment of hepatitis B by nucleosides and nucleotides K. Zhdanov

2 EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection «The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to decompensated cirrhosis HCC and death. This goal can be achieved if HBV replication can be suppressed in a sustained manner. However, chronic HBV infection cannot be completely eradicated due to the persistence of cccdna in the nucleus of infected hepatocytes, which may explain HBV reactivation (В1)» End points of therapy: 1. HBsAg loss (+/- HBsAg seroconversion) (А1) 2. Sustained off-therapy BR and VR with maintained HBeAgnegative status (А1) 3. Maintained virological remission (undetectable HBV DNA) under long-term antiviral therapy (А1) Indications for treatment: 1. HBV DNA > 2000 IU/ml (А1) 2. АLТ > ULN (А1) 3. А 2-3 and/or F 2-4 (А1) J Hepatol, 2012, July

3 Mechanisms of IFN and NA action Immune-mediated cytolisis: - Cytotoxic CD8 - NK-cells IFN-γ, TNF-α, IL-12 Impact on viral replication HBsAg production NA Viral replication HBеAg production В-cell production of neutralizing antibodies

4 Mechanisms of IFN and NA action IFN Immune-mediated antiviral action Direct antiviral action NA decrease of viral replication immune system Immune-mediated cytolisis

5 What can be achieved during the treatment? Sustained response (immune control) Peg-IFN HBeAg seroconversion HBV DNA <2,000 IU/mL ALT normalization HBV DNA suppression HBsAg loss Maintained response Nucleos(t)ides years Possible relapse after discontinuation Undetectable HBV DNA by PCR ALT normalization HBeAg seroconversion HBsAg loss

6 HBeAg seroconversion, % HBeAg seroconversion during 5 years Entecavir treatment e+ In a cohort of long-term therapy included all patients with preservation of HBeAg during treatment or when it appears after the end of treatment (representative group) 60 54% % 31% +23% 0 Week 48 Week 96* 5 years * cumulative confirmed analysis Gish RG. et al., Gastroenterology Nov;133(5): ; Chang TT et al., Hepatology 2010; 51:

7 % cumulative response HBeAg seroconversion is not a good marker for immune control in patients treated with NAs e N=42 HBeAg negative and HBV DNA <10,000 copies/ml after HBeAg seroconversion 35% Treatment month Sustained remission of disease is not achieved in the majority of patients with HBeAg seroconversion during NA therapy Continuation of therapy until HBsAg seroconversion appears necessary 20% of patients had HBV DNA >10,000 cp/ml at time of HBeAg seroconversion Reijnders et al. Gastroenterology 2010

8 cumulative probability HBsAg loss increases with long-term treatment in HBeAg-positive CHB e+ HBsAg loss during 4 years Tenofovir therapy HBsAg seroconversion 7,7% 10.8% Genotype A was associated with higher HBeAg seroconversion rate Week *Kaplan-Meier J. Heathcote, AASLD 2010, EASL 2011

9 HBV DNA <300 copies/ml (%) Sustained HBV DNA suppression after the end of NA therapy e- Patients who completed therapy within 48 weeks after the protocol provided for an answer Lamivudine 82% 93% Entecavir N=201 EOT 5% N=10 6 months Follow-up N=257 EOT 3% N=7 6 months Follow-up Shouval et al. J Hepatol 2009

10 HBsAg loss in patients with undetectable HBV DNA after 4-5 years Adefovir therapy e- 33 HBeAg(-) patients received Adefovir therapy during 4-5 years. Next therapy was stopped and patients were observed during 5 years. HBV DNA (-) 12 pat. HBV DNA < 2000 IU/ml 3 pat. HBV DNA fluctuation 3 pat. HBsAg seroconversion 18% 22/33 11/33 3/33 19/33 14/33 9/33 18/33 15/33 10/33 2 years 4 years 5 years BR Relapse Adapted from Hadziyannis, S et al. 44th EASL, April 22-26, 2009, Copenhagen, Denmark. Oral 18. J Hepatol. 2009;50 (suppl. 1):S9-10.

11 Capabilities of long-term NA therapy e- 74 HBeAg (-) patients received Lamivudine therapy for a mean of 90 months (60 144) 59/74 9/53 Undetectable HBV DNA HBsAg Loss Hoofnagle JH, EASL 2009

12 Long-term monitoring of HBsAg kinetics and prediction of HBsAg clearance in patients with CHB treated with NA 30 patients received different NA regimens for a mean of 93 months (49 123) Prediction of HBsAg clearance during treatment after undetectable HBV DNA achievement 3/26 5/26 5/26 13/26 years years years years «HBsAg clearance is a rare and late event, in most cases unlikely to occur during the patients lifetime. As a result, the goal of NUC therapy should remain the maintenance of HBV DNA at undetectable levels, and stopping NUC therapy is unlikely in the vast majority of patients» S. Chevaliez, C. Hezode, M. Grare, J-M. Pawlotsky, AASLD 2010

13 Summary data on the effectiveness of NA in patients with chronic hepatitis B HBeAg + HBeAg - 60% 50% 40% 30% 20% 10% 0% HBeAg seroconversion entecavir telbivudine tenofovir 120% 100% 80% 60% 40% 20% 0% Undetectable HBV DNA entecavir telbivudine tenofovir Resistance Resistance 30% 12% 25% 10% 20% 8% 15% 6% 10% 4% 5% 2% 0% 0% entecavir telbivudine tenofovir entecavir telbivudine tenofovir Gish RG. et al., Gastroenterology Nov;133(5): ; Lai CL et al. N.Engl.J.Med. 2007; 357; ; Han S, et al. 59th AASLD; 31 Oct 04 Nov 2008; USA. Poster 893; Liaw YF et al. Gastroenterology. 2009; 136; 2; ; Wang Y et al. Hepatology. 2009;50(Suppl):Abstract 482; Zeuzem S et al. J.Hepatol. 2009; 51; 1; 11-20; Chang TT et al., Hepatology 2010; 51: ; Marcellin P. AASLD 2008, 2010; Heathcote E. AASLD 2010, EASL 2011

14 Telbivudine therapy in HBeAg (-) patients with baseline HBV DNA < 7 log 10 copies/ml and in HBeAg (+) patients with baseline HBV DNA < 9 log 10 copies/ml 82% HBeAg ( ) patients and 69% HBeAg (+) patients had such criteria 95% and 71% of patients achieved undetectable HBV DNA level at week 24 of LdT therapy 91% and 89% of patients had undetectable HBV DNA level after 2 years LdT therapy, 52% - HBeAg seroconversion Only 2.3% and 1.8% of patients developed resistance after 2 years LdT therapy Zoulim F. et al., EASL 2012

15 3 years of Telbivudine treatment for undetectable HBV DNA level at week 24 92,5% 94% HBV DNA < 300 copies/ml Genotypic resistance 1% 2,1% HBeAg+ HBeAg- Risk of resistance is minimal in monitoring of HBV DNA level every 6 months and maintaining undetectable HBV DNA level at each visit Gane EJ. Efficacy and safety of prolonged 3-year telbivudine treatment in patients with chronic hepatitis B. Liver Int May;31(5): doi: /j x. Epub 2011 Mar 16.

16 Comparison of efficacy is difficult because of differences in the design of the registration studies Study drug Design of the study Analysis Telbivudine ITT vs. Lamivudine 2 years therapy ITT analysis during 2 years therapy. Cases of missing data is equal to the failure Entecavir ITT vs. Lamivudine 1 year Only part of the patients treated more than 1 year Week 48 Week 72 ITT during 1 year. Cumulative rates more than 1 year. 44, 8, 6 and 5 patients entered, respectively, at 2, 3, 4 and 5 year. Tenofovir ITT vs. Adefovir 1 year ITT 1 year ITT, according to the performed treatment All patients received tenofovir Emtricitabine was added in PCR-positive patients Lai CL et al. N Engl J Med. 2007;357: ; Chang TT et al. N Engl J Med. 2006;354: ; Lai CL et al. N Engl J Med. 2006;354: ; Heathcote EJ et al. Hepatology. 2007;46(4 suppl 1):861A (Abstract LB6); Marcellin P et al. Hepatology. 2007;46(4 suppl 1):290A 291A (Abstract LB2); 7. Marcellin P, et al. N Engl J Med. 2008;359:

17 Proportion of patients, % Zheng MH. Et al. Clin. therapeutics. April 2010, Comparative study of entecavir and telbivudine in HBeAg-positive patients during 24 weeks of therapy Open-label study in parallel groups Included 131 patients (91 men, 40 women), mean age 32.5 years Previously untreated HBeAg-positive HBV DNA 6 log 10 copies / ml, ALT 2 N 43% 35% 68% 55% 58% 58% 79% 74% P< % 3% 37% 29% P< % 3% 25% 14% e+ 12 week HBV DNA - 24 week HBV DNA - 12 week ALT - N 24 week ALT - N Телбивудин Telbivudine 12 week HBeAg loss Энтекавир Entecavir 24 week HBeAg loss 12 week HBeAg seroconversion 24 week HBeAg seroconversion

18 Algorithm of monitoring in patients with CHB during NUC therapy (roadmap) Virological response at week 12 (Decrease of HBV DNA level < 1 log 10 IU/ml change of therapy) Virological response at week 24 Complete virological response (HBV DNA -) Partial virological response (60<HBV DNA<2000 IU/ml) Insufficient virologic response (HBV DNA > 2000 IU/ml) To continue therapy with assessment of HBV DNA level every 6 months Drug with low barrier to resistance: To add second drug without cross resistance or switch to it Drug with high barrier to resistance : To continue therapy to week 48 and more Drug with suboptimal antiviral action: To continue therapy to week 48 and more To change drug or add second drug without cross resistance Keeffe EB. et al. Clin Gastroenterol Hepatol 2008;6: Complete virologic response: To continue therapy No complete virologic response : To add more potent drug without cross resistance

19 Roadmap strategy in LDT600A2410 study e+ Baseline Decision point Primary endpoint EOT Follow-up Week copies/ml add-on tenofovir Telbivudine + Тenofovir Telbivudine (N=105) Week 24 <300 copies/ml continue monotherapy Telbivudine Follow-up during weeks 16 0 week 24 week 52 week 104 week 120 Characteristics of patients: Mean HBV DNA level: 9log 10 copies/ml, АLТ 133 IU/L 68% - asian race, 56% - genotype С T.Piravitsuth et al. Hepatol Int (2011) 5:3-558.

20 Undetectable HBV DNA (%) 2-year results of NA therapy roadmap study in HBeAg positive chronic hepatitis B e+ 100% 100% 84% 93% 95% 93% 94% 55% 55/55 55/100 55/55 38/45 93/100 52/55 42/45 94/100 0% 24 week 52 week 104 week Telbivudine Telbivudine + Tenofovir Overall T.Piratvisuth et al. EASL 2012

21 Effectiveness and safety of telbivudine in field practice: a multicentre German real-life observational study 273 patients with CHB, 76% - HBeAg-, 62% - male, 73% - pretreated patients. 101 patients completed 12 month survey up to end of Sept Virological response during 1 year of telbivudine therapy 97% 73% 73% 74% All В patients целом Pretreated Ранее леченые patients Naive "Наивные" patients Ответившие Undetectable на HBV 24 DNA неделе at week 24 Petersen J. et al. Journal of hepatology 2011, vol.54, S209-S361, abstract 746

22 Regression of liver fibrosis by using of different NUC therapy * NUC HbeAg+ HbeAg- Regression criteria Lamivudine 35-61% 36-46% Different Adefovir 41% 48% Improvement on 1 point (Ishak) and more Telbivudine 68% 56% Decrease (Ishak) from 4-6 tо 0-3 points Entecavir 39% 36% Improvement on 1 point (Ishak) and more Tenofovir 74% 71% Decrease in necroinflammatory activity (> 2 points in HAI) without worsening in fibrosis stage by Knodell * data for 1 year of therapy Bourlier M et al. Gastroenterologique Clinique et Biologique, 2009 Oct-Nov;33(10-11):923-9.

23 Number of patients and fibrosis stages Distribution of patients by fibrosis stages (Ishak): baseline, 1 year and 3-7 years Baseline 1 year 3-7 years ~ 6 years Fibrosis stages by Ishak n=57 no data 58% of patients decrease of fibrosis ( 2 points) Liaw Y-F, et al. AASLD, October 3 November 4, 2008, San Francisco, USA. Poster 894. Hepatology 2008;48:706A.

24 Long term telbivudine therapy with effective viral control results in resolution of liver inflammation and fibrosis in patients with chronic hepatitis B Necroinflammation score by Knodell 100% 2% 90% 28% 80% 100% 90% 80% 23% Pat No Fibrosis score by Ishak 2% 2% 2% 7% 8% 14 5% 70% 60% 50% 40% 30% 50% 98% % 60% 50% 40% 30% 37% % % 10% 3% 18% 20% 10% 30% 0% 0% Baseline (57 patients) Year 5 (57 patients) Baseline (57 patients) Year 5 (57 patients) J.Hou et al. APASL 2012, poster.

25 Serum HBV DNA and HBsAg levels HBV DNA Virions HBsAg Virions + defective particles (exceeding virions by a factor of ) replication Brunetto et al. J Hepatol 2010 replication cccdna transcription/ mrnas translation Serum HBsAg: a marker of transcriptionally active cccdna

26 HBsAg (log IU/mL) On-treatment HBsAg levels during NA therapy (162 HBeAg+ patients and 143 HBeAg- patients) Patients who clear HBsAg may be able to stop therapy? HBsAg decline patterns during treatment with telbivudine Rapid decline in HBsAg levels is associated with HBsAg clearance 5 4 Steady Decline during year 1 Patients N=162 HBsAg clearance at year 3 3 Slow Rapid >1 log 20% (32) 25% (8) Slow <1 log 46% (74) 1.4% (1) 2 Rapid BL Week 24 Year 1 Year 2 Year 3 Steady 35% (56) 0% (0) Reduction of HBsAg level at week 24 was associated with significantly more frequent of HBsAg loss in HBeAg + (p = 0.002) and HBeAg - (p = 0.036) patients Wursthorn et al. Hepatology 2010

27 Algorithm for prevention of perinatal transmission of HBV infection Yogeswaran K., Fung S. The Korean Journal of Hepatology 2011;17:1-8

28 Prophylaxis of perinatal transmission of HBV infection Lamivudine* + vaccine + HBIG (n=56) Characteristics of mothers Placebo + vaccine + HBIG (n=59) Age (year) HBeAg-positive 99% 100% Mean HBV DNA level (Мeq/mL) Outcomes of infants HBsAg-positive (week 52) 6% 12% Detectable HBV DNA (week 52) 20% 46% Р * Lamivudine treatment initiated at week 32 of gestation and is completed within week 4 after delivery Xu WM. et al. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicenter, randmomized, double-blind, placebo-controlled study. J. Viral Hepat 2009;16:

29 Prophylaxis of perinatal transmission of HBV infection A prospective, nonrandomized, open-label study of the "case-control Survey terms Children of mothers received telbivudine 600 mg/day (n = 95) Children of mothers of control group (n = 92) P At birth 6 (6.3) 28 (30.4) <.001 At week 28 (sensitive analysis) At week 28 (ITT [I = M] analysis) 0 8 (8.7) (2.1) 12 (13.0).004 Pan C. et al. AASLD Abstract 212.

30 Telbivudine in pregnancy for the prevention of perinatal transmission of HBV infection 9,0 8,0 7,0 6,0 5,0 4,0 3,0 2,0 1,0 0,0 HBV kinetics in patients treated and not treated with LdT baseline week 2 week 4 week 8 delivery week 4 week 8 Drug withdrawal LdT Control Detection of HBV DNA and HBsAg in infants at 7 month 8% p<0,001 83% p=0,013 p=0,001 57% 0% 33% LdT Control 0% Undetectable HBV DNA ALT normalization Han G. et al. J Hepatol, 2011

31 Renal dysfunction in chronic hepatitis B patients Renal dysfunction is common in decompensated CHB cirrhosis and associated with high mortality In Europe, 20% of the CHB patients had baseline GFR of 60 to 89 ml/min Nucleotide analogues have been reported to cause renal toxicity in the clinic There is incidence of HBV related membranoproliferative glomerulonephritis De Jongh FE. et al., Gastroenterology 1992; 103 (5): , Ha NB. et al., Hepatology 2009; 50: , Fernandez B. et al., AIDS Res Treat 2011, Mauss S. et al., J Hepatol 2011; 55 (6):

32 38 LAM or LAM+ADV pre-treated patients with virological breakthrough randomized to LdT+TDF or LAM+TDF treatment during 2 years Mean GFR at Baseline and Weeks 24,52 and 104 Gane E. et al., EASL 2012

33 Antiviral treatment effect on glomerular filtration rate (GFR) based on an analysis of 7 various studies on the efficacy and safety during telbivudine therapy in patients with CHB Gane E. et al., EASL 2012

34 CONCLUSIONS In patients with CHB replication sustained suppression and histological improvement are observed during long-term therapy (more than 3 years) with potent antiviral activity and a high barrier to resistance NUC. Undetectable HBV DNA level after 6 months of treatment in patients with low baseline viremia allows the use of the telbivudine as well as entecavir and tenofovir for long-term therapy of HBeAg-positive and HBeAg-negative CHB. Further study of HBsAg kinetics during NUC therapy is a promising predictor of the possible end points of treatment. Antiviral therapy using telbivudine, lamivudine or tenofovir can be used during pregnancy for those who have active liver disease and for HBsAg-positive pregnant with HBV DNA level > 6-7 log IU/mL in the third trimester for the prevention of perinatal transmission of HBV infection. Long-term telbivudine treatment is associated with steady improvement of renal function in patients with potential risk of renal dysfunction.