6/9/2015. Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF, FAASLD Director, Schiff Center for Liver Diseases University of Miami

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1 Grant/Research Support: AbbVie, BMS, Gilead, Merck, Orasure Technologies, Roche Molecular, Janssen, Discovery Life Sciences, Beckman Coulter, Inc., Siemens Corporation, MedMira Inc., Conatus Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF, FAASLD Director, Schiff Center for Liver Diseases University of Miami Consultant: Gilead, Merck Scientific Advisory Board: BMS, Gilead, Janssen, Acorda Therapeutics, Salix Other: Data Monitoring Board: Arrowhead, BMS, Pfizer and Salix Hepatitis B Hepatitis A Hepatitis D Hepatitis C Hepatitis E Curing Hepatitis B Special Issues Treating immunotolerant patients Preventing reactivation Preventing HCC Recognizing malignant transformation at a molecular level 1

2 The prevention of chronic HBV infection has become a high priority in the global community Epidemiology of chronic hepatitis B in children before and after universal infant immunization program. Seven countries in the developed nation have not yet introduced universal immunization against Hepatitis B: Denmark, Finland, Iceland, Norway, Sweden, United Kingdom, and Japan. Universal infant immunization could effectively reduce the prevalence of HBV infection to approximately 10% of the prevalence before the vaccination program Hepatitis B vaccine is the first vaccine against cancer Available since the early 80 s Prevents >0.5 million deaths/year from acute and chronic hepatitis B virus (HBV) infection Recommendation by WHO (1992) Hep B vaccine should be introduced into Natl. Imm. Programs: Countries with HBsAg prevalence 8% by 1995 Global introduction by 1997 World Health Organization 2

3 Immunotolerance HBV DNA Immune Clearance Immune Control (Non-Replicative) HBeAg Negative Inactive Carrier HBeAg+ HBeAg- HBeAb+ HBsAg+ HBsAg- HBsAb+ ALT Infection 5-30 years months-years months-years HBeAg+ HBeAg- HBeAb+ E Negative Immunotolerance Immune Clearance Chronic HBV (precore mutant) Treatment? HBV DNA 5-30 years months-years Infection ALT Treatment Treatment months-years Immunosuppression (Chemo/HIV/BMT) Treatment Cure the infection Reduce morbidity & mortality Need years to see this Surrogates: HBV DNA suppression? Improve liver histology Promote HBeAg loss Promote HBsAg loss 3

4 Approved Hepatitis B drugs Drug Structure Approved Side Effects Use Lamivudine (Epivir-HBV, Zeffix, or Heptodin) Cytidine analog, L-nuc 1998 Few side effects Children and adults Adefovir(Hepsera) Adenosine phosphonate 2002 Few side effects Adults Entecavir (Baraclude) Guanosine analog 2005 Few side effects Adults Tenofovir disoproxil fumarate(viread) Adenosine phosphonate 2008 Few side effects Adults 13 Fibrosis improves even cirrhosis! Marcellin Lancet 2012 APASL 2012 EASL 2012 AASLD 2009 HBeAg-positive chronic hepatitis B HBeAg seroconversion with undetectablehbv DNA for at least 12 mo HBsAgserclearanceor HBeAg seroconversion with undetectable HBV DNA and 12 mo of consolidation therapy HBeAg seroconversion with undetectable HBV DNA and >6mo of consolidation therapy HBeAg-negative chronic hepatitis B HBsAgseroclearanceor NA therapy >2 yr and undetectable HBV DNA on three separate occasions, 6 mo apart HBsAg seroclearance HBsAg seroclearance Kang W and Park JY, World J. Gastro. June 21, Kang W and Park JY, World J. Gastro. June 21,

5 Predictive markers are needed for stoppage of Nucleos(t)ide Therapy HBsAg levels correlate with amount of cccdna Serial monitoring of HBsAglevels may provide information about off-treatment response. Low serum levels of HBsAgand HBV DNA is predictive of serum clearance in treatment naïve patients. Additional studies are needed to validate its utility with mathematical models demonstrating limited utility. Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: Finite treatment duration unlikely Long-term follow-up of patients with chronic hepatitis B treated with potent nucleoside/nucleotide analogues (8.5 years: interquartile range: mos, N=30). Showed that HBsAgclearance is unlikely to occur during the patient s lifetime if it does not happen within a few months after HBV replication is well controlled. Concluded that lifetime therapy is required in the vast majority of HBV-infected patients; however, HBsAglevel monitoring may help identify the few patients who may clear HBsAgon long-term therapy. How long treatment should be continued in these patients after HBsAg loss in order to prevent a recurrence of infection is unknown. J. Hepatology, Hepatic decompensation HCC Survival Levels of cccdna As close to cure functional cure, as we can expect to achieve in chronic hepatitis B Fattovich G, et al. Am J Gastro 1998; 93: Werle-Lapostolle B, et al. Gastroenterology 2004; 126(7): Perrillo R. Hepatology 2009; 49:

6 O- Translocation new (-) strand DNA synthesis dadadg 5 Cap (A)n 3 pgrna 6/9/2015 Curing Hepatitis B HBV Persistence cccdnapersistence is thought to be the cause of chronic HBV disease cccdna exists as a minichromosome in the nucleus cccdna persists in the absence of active viral replication cccdnalevels reduced, but not eliminated with treatment/ liver regeneration HBV Cure: Elimination, suppression, cleavage, or control of cccdna S Ag Attachment and Penetration Golgi complex Release HBV Virion e Ag transport to cell nucleus CCC DNA uncoating DNA repair Envelope Proteins S, M, L Pregenomic RNA Core Protein DNA Synthesis HBV RNA Transcripts Encapsidation of pg RNA e Ag Polymerase Protein Block DNA replication Do not affect cccdna 1. Reservoir of cccdna 2. Dysfunctional T-cell Response 1. Tcell exhaustion 3. Insufficient B-cell Response Strategies to overcome these barriers 1. Deplete or Silence cccdna 2. Activate Antiviral Immunity 6

7 In the blood: HBV DNA/HBsAg negative anti-hbs positive Potent NA agent to prevent viral spread and cccdna re-amplification In the liver: no HBV cccdna no HBV RC/DSL DNA HBcAg staining negative ±HBsAg [reflecting integrated HBV DNA] cccdna Inhibitor Immune Activator HBV Antigen Inhibitor safe and selective agent to reduce or silence cccdna agent(s) to activate specific antiviral immune responses or relieve repression/exhaustion of the system agent(s) to block/inhibit the HBV life-cycle [entry, cell-spread, capsid assembly, HBx, HBeAg, HBsAg] Curing Hepatitis B Special Issues Treating immunotolerant patients Preventing reactivation % yrs of TDF or TDF/FTC, normal ALT, mean DNA 9.2 logs 55 * 76 TDF n=64 TDF/FTC n=62 Well tolerated No renal problems HBV DNA <69 IU/mL HBeAg Loss HBeAg Seroconversion HBsAg Loss HBV DNA can be suppressed but what does it mean? Chan et al EASL 2013 Abst 101 7

8 Current understanding of chronic HBV infection of chronic HBV infection HBeAg Phase Immuno-tolerance Immunoclearance Liver histology Minimal inflammation and fibrosis Chronic active inflammation HBeAb Inactive carrier state Mild hepatitis and minimal fibrosis Optimal treatment times Reactivation Active inflammation International Guidelines and Clinical Recommendations Regarding Immune Tolerant Patients Organization/Guidelines Recommendation regarding Immuno-tolerant patients European Association for Most patients under 30 years of age with persistently normal ALT levels, a high HBV DNA the Study of the Liver level, no suspicion of liver disease, and no family history of HCC or cirrhosis do not (EASL) require immediate therapy. American Association for HBeAg-positive patients with persistently normal ALT levels should have their ALT levels the Study of Liver Disease tested at 3-6 month intervals. ALT and HBV-DNA levels should be tested more often when (AASLD) ALT levels become elevated. Hbe status should be checked every 6-12 months Asian Pacific Association Patients with viral replication but persistently normal or minimally elevated ALT levels for the Study of the Liver should not be treated, except patients with advanced fibrosis or cirrhosis. Immune tolerant (APASL) patients need adequate follow-up and HCC surveillance every 3-6 months. National Institutes of Health Consensus (NIH) US Algorithm Therapy is not recommended for patients who are in the immune tolerant phase, which includes the presence of HBsAg, high HBV-DNA levels, normal ALT levels, and liver histology showing mild or minimal inflammation and fibrosis Younger patients are often immune tolerant. A biopsy should be considered, particularly if a patients is older than years of age. Patients should be treated if there is evidence of histologic disease on liver biopsy. In the absence of biopsy, patients should be observed for elevation in ALT levels. If we had the perfect drug probably yes Potent Once daily No side effects with long-term therapy No resistance Cheap We re not there yet even with tenofovir/entecavir so no More than a virus it s a liver disease They don t need it!! Resistance/toxicity/cost What about older immunotolerant, esp with FHx of HCC? Seems reasonable no data yet Optimistic, conservative and relies upon the long-term course of benignity of the disease Two Opposing Views Evidence of the benign long-term course of the imunotolerant phase Antiviral therapy in the immune-tolerant phase hardly reaches 19% Cost burden of treatment Pessimistic, and relies upon the great risk of HCC, even without cirrhosis and may depend patient having high levels of HBV DNA. Earlier treatment intervention may be beneficial in preventing HCC cirrhosis 8

9 Viral Factors HBV- DNA level HBsAg HBeAg Anti-HBc Anti-HBs cccdna Occult HBC infection Genotype non-a (especially, genotype B) Gene mutation of precore and/ or core promotor Host Factors Combination therapy with steroid Rituximab-plus steroid Malignant lymphoma Male gender Absence of anti-hbs before chemotherapy Decrease of anti-hbs titers during chemotherapy (in patients for anti-hbs before chemotherapy Yeo W. et al 2000 Lau GKK. et al 2002 Cheng AL. et al 2003 ZohongS. et al 2004 Yeo W. et al patients who underwent cytotoxic chemotherapy as an outpatient for the first time at the Mayo Clinic (Rochester, MN) between January 1, 2006, and September 30, Only a small percentage of patients receiving chemotherapy are screened for HBV infection. However, a larger proportion of patients was screened during 2009 to 2011 than during 2006 to 2008, especially patients with hematologic malignancies. Strategies are needed to ensure that patients receiving chemotherapy are protected from the consequences of undiagnosed HBV infection. Wi CI et al. Clinical Gastroenterology and Hepatology 2015 Curing Hepatitis B Special Issues Treating immunotolerant patients Preventing reactivation Preventing HCC Recognizing malignant transformation at a molecular level BASELINE Baseline AFP: 21,000 IU/mL Week 6 AFP:283 IU/mL 9

10 Curing Hepatitis B Special Issues Treating immunotolerant patients Preventing reactivation Preventing HCC Recognizing malignant transformation at a molecular level Raymond Schinazi Robert Gish Anna Lok 10