Hepatitis B: Diagnosis & Therapy Harry L.A. Janssen Dept. of Gastroenterology & Hepatology Erasmus University Medical Center Rotterdam The Netherlands Amersfoort January 2010
Global Burden of HBV Disease 350 million chronic HBV patients 1 million die each year from HCC or liver failure 9th leading cause of death worldwide 8% - High 2-7% - Intermediate <2% - Low
Outcome of Acute HBV infection ACUTE INFECTION 70% 30% 0.1-0.5% Subclinical Hepatitis Acute Hepatitis Fulminant Hepatitis Chronic Infection ~5% * Recovery ~ 95% DEATH * Risk of chronicity is related to age at infection Outcome Neonates Children Adults Chronic infection 90% 20% < 5% Recovery 10% 80% > 95% Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25.
HBV Disease Continuum Resolution Stabilization Compensated Acute infection Chronic Hepatitis Cirrhosis HCC Asymptomatic carrier 30 50 years Decompensation Transplantation Death
Phases Of Infection HBeAg Anti-HBe HBV DNA ALT Immunotolerant Phase Immuno-active Phase Immune control Phase HBeAg-negative Chronic Hepatitis Treatment indicated Treatment indicated
Goals for treatment Clinical milestones HBeAg(+) patients Sustained viral suppression HBeAg seroconversion Reduction or prevention of liver damage Normalization of ALT Event free survival in cirrhosis HBeAg(-) patients Sustained viral suppression Reduction or prevention of liver damage Normalization of ALT Event free survival in cirrhosis Fung S, Lok ASF. Clinical Gastroenterol Hepatol. 2004;2(10):839 848
When to Start Treatment? HBV DNA (IU/mL) AASLD 2007 1 APASL 2008 2 EASL 2009 3 20,000 20,000 >2000 ALT* 2 x ULN 2 x ULN >1 x ULN Histology * > 3-6 months Moderate/severe necroinflammation and/or significant fibrosis 1 Lok, Hepatology 2007; 2 Liaw, Hepatol Int 2008; 3 EASL, J Hepatol 2009
Advances in HBV treatment 1957 Interferon discovered 1990 PMEA anti-hbv activity discovered 1991 3TC anti-hbv and anti-hiv activity discovered 1998 Entecavir anti-hbv activity discovered 2001 Telbivudine anti-hbv activity discovered 2008 Tenofovir approved for HBV 1991 Interferon alfa-2b approved for HBV 1998 Lamivudine (3TC) approved as first nucleoside analogue for HBV 2002 Adefovir dipivoxil (PMEA prodrug) approved for HBV 2005 Entecavir and peginterferon alfa-2a approved for HBV 2006 Telbivudine approved for HBV From 2010 Lamivudine patent expires in Europe
HBV Treatment Options Immuno-modulators IFNα Peg IFN Nx cytokines Vaccine therapy CD8+ HBV Antivirals Lamivudine Adefovir Entecavir Telbivudine Tenofovir Emtricitabine Treatment combinations
HBV Treatment Strategies Sustained remission = Low viremia Maintained remission = Low viremia ALT normalization ALT normalization Immune control, no further need for antiviral drugs No immune control, continued need for antiviral drugs
HBV Treatment Strategies Sustained remission PEG-IFN HBeAg seroconversion HBV DNA <10 4 copies/ml Normal ALT Undetectable HBV DNA HBsAg loss Maintained remission Nucleos(t)ide analogue Undetectable HBV DNA by PCR assay Normal ALT HBeAg seroconversion HBsAg loss?? years
Current treatment end points in CHB Treatment end points Undetectable Serum HBV DNA (<10-15 IU/ml) HBeAg seroconversion HBsAg loss with or without anti-hbs EASL guidelines. J Hepatol 2009;50:227 242.
(Pegylated) Alpha-Interferon
Mode of Action of IFN-alfa Interferon -alfa Immunomodulatory action T helper cell Antigen presenting cell (DC) Antiviral action Cytotoxic T cell Natural killer cell B cell Hepatocyte Immunomodulatory: MHC class I display enhanced; activation of CTL and NK cells Antiviral: 2,5 -oligoadenylate synthetase induction leading to viral cleavage; protein kinase induced
Potential Candidates for PEG-IFN in HBV Strategy according to stage & immunoreactivity PEG-IFN Early cirrhosis Chronic hepatitis Advanced cirrhosis Chronic hepatitis HIV, Dialysis, Transplants Nucleoside analogues
Patients (%) Response to PEG-IFN 6 months post treatment Lau, NEJM 2005; Janssen, Lancet 2005; Marcellin, NEJM 2004. Treatment duration 48 weeks
Percentage of initial responders (%) 3-year follow up of HBeAg responders to PEG-IFNα-2b: HBeAg-positive CHB 100 90 80 81% n=64 78% 70 60 58% 50 45% 40 30 30% 20 10 0 HBeAg negative HBV DNA <10,000 copies/ml HBV DNA <400 copies/ml ALT normal HBsAg negative Buster et al. Gastroenterology 2008
IFN -2b Treatment is Associated with Prolonged Survival Proportion of patients surviving 1.0 Cirrhosis at baseline 1.0 No cirrhosis at baseline 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 0 5 Years 10 15 Responders 0 0 5 Years 10 15 Non-responders v Zonneveld et al. Hepatology 2004
Nucleoside analogues
HBV Replication and Viral Inhibition New cells Golgi Nucleoside analogs ER CCC DNA DNA dependent polymerase RNA dependent polymerase HBV mrna Zoulim, Antiviral research, 2004
Patients (%) Rates of undetectable HBV DNA over time HBeAg negative patients 90% 94% Data from individual studies, not direct comparisons 88% 82% 72% 65% 48% 39% 63% 51% 71% 79% 67% 91% 91% 14% Years ETV LdT LAM PEG IFN ADV TDF Hadziyannis S, et al. Gastroenterology. 2006 ; 31: 1743-51 Marcellin P, et al, study 102, AASLD 2008, Oral presentation #146 Lai CL, et al. N Engl J Med. 2006; 354: 1011 20. Shouval D, et al. J Hepatology. 2006 ; 44(suppl) : S21 Lai CL, et al. N Engl J Med. 2007; 357: 2576-88. Scott LJ et al. Drugs 2009; 69 (8): 1003-1033 Marcellin P, et al. N Engl J Med. 2004; 351: 1206-17
An antiviral drug is a drug that selects for resistance In the absence of selective pressure, one strain dominates the population Antiviral Treatment Pre-existing Variant Selection and Enrichment of Resistant Variants Acquisition of Primary (Resistance) and Compensatory Substitutions (Fitness) Sheldon J, et al. J Viral Hep 2006; Locarnini S. J Hepatol 2003
HBV Replication Incomplete Suppression of Virus Replication Dominate Strain Treatment Initiates Naturally Occurring Variants Drug Resistant Variant Incomplete Suppression - Inadequate Potency/Drug Levels - Inadequate Adherence - Pre-Existing Resistance Variants Time Detection Level Fung SK & Lok ASF. Antivir Ther 2004 ; Locarnini S, et al. Antivir Ther 2004
ALT (U/L) HBV DNA log copies/ml Dynamics of resistance emergence: Genotypic resistance, virological and clinical breakthrough Lamivudine 600 500 Virological breakthrough 8 7 200 150 100 6 5 4 50 0 PCR assay 0 6 12 18 24 30 36 42 3 Months Codon 180 Codon 204 Codon 207 L M V L M V L/M MV M M V M M/V V M M/V V M VV M V V Genotypic resistance Clinical breakthrough Adapted from Si Ahmed et al. Hepatology 2000;32:1078 88
Patients (%) Incidence of Resistance in NUC-naïve Patients *Collation of currently available data not from head-to-head studies 80 1 st generation 67 70 60 2 nd generation 49 40 20 24 38 18 29 17 3 rd generation 0 11 3 4 0.5 1.2? 0 0.2 1.2 1.2 0 0 LAM ADV LDT ETV TDF? adapted from EASL CPG HBV, J Hepatol 2009
EASL recommendations for the management of HBV resistance Lamivudine Adefovir Telbivudine Entecavir Tenofovir ** Add tenofovir (or adefovir, if tenofovir not available) Switch to tenofovir and add a second drug without cross-resistance If N236T present, add lamivudine, entecavir or telbivudine tenofovir plus emtricitabine If A181V/T present add entecavir* or switch to tenofovir plus emtricitabine Add tenofovir (or adefovir if tenofovir not available) Add tenofovir Resistance not described so far Genotyping/phenotyping by expert laboratory to determine the cross-resistance profile Entecavir, telbivudine, lamivudine or emtricitabine could be added EASL guidelines. J Hepatol 2009
New management approaches: tailored regimes for the individual patient Antiviral treatment Treatment failure Viral load assessment Check compliance Viral genome sequence analysis Wild type virus HBV drug resistant mutant Check compliance Primary non response Switch to more potent drug Add-on therapy based on cross-resistance data 1. Zoulim and Perrillo, J Hepatol, 2008 2. EASL. J Hepatol, 2009
Combination Therapy? So far limited additional benefit of combination PEG-IFN and NA For NA not recommended for treatment-naïve patients: Very low rate of drug resistance is possible in nucleoside-naïve patients with mono therapy (ETV en TDF) Host immune response can be effective in suppressing HBV replication (in contrast to HIV) Add a second drug if high residual HBV DNA, particularly if HBV DNA reaches a plateau Addition of rescue therapy is mostly preferred to switching in patients with breakthrough due to drug resistance EASL, J Hepatol 2009
PEG-IFN or Nucleos(t)ide Analogues? Peginterferon Nucleos(t)ide analogues Advantages: Advantages: - Finite duration of therapy - Oral administration - Durable treatment response - Negligible side-effects - No drug resistance - Potent inhibition of replication - HBsAg loss Disadvantages: Disadvantages: - Subcutaneous administration - Indefinite therapy in many patients - Frequent side effects - Risk of antiviral resistance - Low rate of HBsAg loss Perrillo, Hepatology 2006
Buster et al. Gastroenterology 2009 Candidates for PEG-IFN Therapy in HBeAg positive CHB high ALT > 2 ULN; low HBVDNA < 10e9 copies/ml HBV genotype A B or C D PEG-IFN in case of: High ALT OR Low HBV DNA PEG-IFN in case of: High ALT AND Low HBV DNA Generally not good cadidates for PEG-IFN
Conclusions Major improvement in HBV therapy in the last decades Try to aim for sustained off-treatment response Therapy with NA may be indefinite in many patients: Choice of most potent NA with highest resistance barrier PEG-IFN in selected patients Combination therapy only recommended as add-on for HBV resistance
Vincent Rijckborst Hajo Flink Erik Buster Monika v Zonneveld Jurriën Reijnders Wim Leemans Martijn ter Borg Thjon Tang Bettina Hansen HBV Team Jeroen Stoop arjolein o/d Brouw Eric Tjwa Andrea Woltman Dave Sprengers Hanneke van Vuuren Paula Biesta Rekha Binda