MAKATI MEDICAL CENTER Ledesma Hall October 17, 2005 Hepatitis - Interactive Session Roel Leonardo R. Galang, M.D. Fellow, Philippine College of Physicians Diplomate, Philippine Society of Gastroenterology Diplomate, Philippine Society of Digestive Endoscopy Middle surface antigen Nucleocapsid DNApolymerase Envelope Genomic DNA Small surface antigen RNA primer Large surface antigen Hepatitis B virus HBV variants and mutants Pre-core and core mutations virulence immune escape response to interferon therapy Surface mutations detection vaccine escape HBIG immunoprophylaxis escape Polymerase mutations drug resistance Hepatitis B management guidelines GroupDatePublicationLeaders CASL ConsensusMar 1999Can J GastroSherman, Minuk Chinese ExpertMay 1999Chinese J HepatolZhang Ding Feng Guiding GroupSept 2000 Asia PacificJun 2000J Gastro HepatolFarrell, Liaw Consensus NIH2001GastroenterologyLok, Heathcote Hoofnagle NIH Nomenclature and terminology Evaluation and monitoring Therapy Hepatitis B management guidelines Nomenclature and terminology Avoid asymptomatic healthy carrier state Acceptable inactive carrier state HBsAg +ve, anti-HBe +ve, normal ALT HBV DNA less than 10 5 copies/ml Nomenclature and terminology: Category of responses Biochemical (BR) serum ALT w/in Normal range Virological (VR) - HBV DNA < 10 5 copies/ml - loss of HBeAg Histological (HR) - histology activity index by 2 points Complete (CR) - BR+/VR+ and loss of HBsAg Time of assessment On therapy: during therapy Maintained persist throughout the course of treatment End of treatment at end of defined course of therapy Off-therapy: after discontinuation of therapy Sustained - (SR-6) 6 months after therapy Sustained (SR-12) 12 months after therapy Evaluation of CHB should include: HBsAg, HBeAg, anti-HBe, anti-HDV HBV DNA LFTs Abdominal ultrasound Liver biopsy warranted if high ALT Liver biopsy Advantages Establish baseline disease Establish presence or absence of cirrhosis surveillance for HCC variceal bleed prevention Exclude co-existent liver disease Disadvantages Discomfort Discomfort Risk of bleeding etc Risk of bleeding etc Minimum - every 6 months ALT No need for HBV DNA HCC 6 monthly checks if high risk Cirrhosis Strong family history > 40 years Monitoring of CHB Therapy - mild disease Monitor Await future approaches eg. combination of antivirals NIH No treatment if normal ALT Asia Pacific No resistance Side effects Contraindications INTERFERONLAMIVUDINE V Resistance Well tolerated No contraindications Therapy - more severe disease Asia Pacific guidelines Consider if ALT >2 x ULN >5 x ULN - lamivudine 2-5 x ULN - lamivudine or IFN NIH Consider if ALT >2 x ULN >5 x ULN - monitor for 2-3 months 2-5 x ULN - lamivudine or IFN Therapy - HBeAg negative NIH If significant disease Consider long term lamivudine Therapy monitoring Asia Pacific During therapy 1-3 monthly ALT, HBeAg +/- HBV DNA End Therapy 3-6 monthly ALT, HBeAg +/- HBV DNA Stopping therapy Asia Pacific IFN 4-6 months therapy Lamivudine - stop if HBeAg seroconversion with HBV DNA loss on two separate occasions 1 month apart No consensus Non responders - ?? Prolonged therapy HBeAg negative Natural history of chronic HBV infection Acute Infection Chronic Carrier Resolution 3050 Years Chronic Hepatitis Stabilization Progression Cirrhosis Compensated Cirrhosis Liver Cancer Death Adapted from Feitelson, Lab Invest 1994 Decompensated Cirrhosis (Death) HBV vaccination - effect on incidence and mortality from HCC per children (6-14 yrs) per children (6-14 yrs) Chang M-H et al. N Engl J Med 1997; 336: per children (6-14 yrs) per children (6-14 yrs) Incidence Mortality Beginning of the program June 1984 Actuarial survival in end stage liver disease Historical Studies Cirrhosis 1 Decompensated cirrhosis 2 14% 55% Patients surviving (%) Years Weissberg et al, and De Jongh et al, Weissberg et al, and De Jongh et al, Treatment objectives for chronic hepatitis B Sustained suppression and eradication of HBV infection Improve clinical and biochemical profiles Improve/reverse liver inflammation and fibrosis Improve long-term prognosis reduce progression to cirrhosis and HCC improve survival improve long-term quality of life reduce long-term cost of medical care Therapies for Chronic Hepatitis B Antivirals Reduce HBV replication and improve liver disease, and allow recovery of HBV-specific immune response Lamivudine Immune modulators Stimulate immune system to attack HBV- infected cells and reduce associated liver disease Interferon-alpha Loss of viral replication with interferon Wong et al, Ann Intern Med 1993 Integrated analysis of 15 controlled studies N=837 p= p=0.001 Interferon therapy PROS Short treatment course >30% HBeAg loss 8-10% HBsAg loss No mutations Long term improvement CONS Substantial side effects Limited efficacy Asians Pre-Core mutants Decompensated Disease Immunocompromised Cost HBsAg envelopes Partially double- stranded DNA Lamivudine A(n) Infectious HBV virion (-)-DNA Infectious HBV virion mRNAcccDNA DNA pol RT Encapsidated pregenomic mRNA Lamivudine is a potent inhibitor of HBV replication Lai et al, J Med Virol 2000 Lamivudine rapidly suppresses serum HBV DNA HBeAg seroconversion after one year of therapy Seroconversion = HBeAg-ve and anti-HBe+ve PlaceboLamivudineIFNLamivudine + IFN Lai Dienstag Schalm *p12 months 37/4321/26 Korenman et al 1991 Schiff et al /31 Spontaneous Lok et al 1987 Guan et al 2000 HBeAg loss in different patient groups Major long term studies using lamivudine in HBeAg +ve CHB Asian 5yr study (B3018) Schiff et al, 2yr follow-on study (B3017) China 3yr study (B3026) HBeAg loss and HBeAg seroconversion (HBeAg-ve, anti-HBe+ve) (Modified ITT population) Year 1Year 2Year 3 Patients (%) HBeAg lossHBeAg seroconversion 38/400 33/400 60/400 46/400 81/400 69/400 HBeAg loss is increased in patients with higher baseline ALT (Modified ITT population) 10/18 5/18 12/18 Patients (%) 22/72 11/72 26/72 19/100 10/100 21/100 HBeAg seroconversion is increased in patients with higher baseline ALT (Modified ITT population) 13/100 14/72 6/18 10/100 8/72 5/18 19/100 20/72 11/18 Patients (%) HBeAg seroconversion = HBeAg negative, HBeAb positive Combination Therapy Schalm SW et al. RCT. Gut 2000 N = Lamivudine x 52 weeks 2. INF alpha x 16 weeks 3. Combination Findings: rate of HBeAg conversion at 52 weeks 18% vs 19% vs 29% Added benefit? Antiviral response to Interferon and Lamivudine with HBeAg +ve CHB Interferon Lamivudine wks Controls 52 wks Controls Loss of serum HBV DNA 37% 17% % 4-6% Loss of HBeAg 33% 12% 17-32% 6-11% HBeAg seroconversion difference of 18% 16-18% 4-6% Histologic improvement 49-56% 23-25% Normal ALT < 10% VR