29th Viral Hepatitis Prevention Board Meeting Madrid, November 2006 Treatment of chronic hepatitis B José M. Sánchez-Tapias Liver Unit Hospital Clínic University of Barcelona Spain
CHRONIC HBV INFECTION THE DISEASE Highly heterogeneous at presentation Variable outcome on long-term Long-term prognosis uncertain THE TREATMENT Valuable therapies available but Limited efficacy Prolonged administration Viral resistance High cost CLINICAL MANAGEMENT DIFFICULT
CHRONIC HEPATITIS B VIRUS INFECTION IS A VERY HETEROGENEOUS CONDITION Immuno-tolerant carriers Inactive (healthy) carriers Active carriers
Active HBV carriers Defined by: ElevatedALT Increased serum HBV-DNA Liver inflammation and fibrosis: Mild Moderate Severe Outcome: Potentially (but not necessarily) progressive disease Spontaneous remission possible Should all active carriers be treated?
Prognostic determinants for chronic hepatitis B in Asians: Therapeutic implications CUMULATIVE RISK OF DEVELOPMENT OF COMPLICATIONS 15 Risk of complications (%) 12 9 6 3 Good therapies for more seriously ill patients are available Number of patients 0 0 30 60 90 120 150 180 Months of follow-up 3203 1562 921 579 300 152 39 Yuen et al. Gut 2005
Lamivudine for patients with chronic hepatitis B and advanced liver disease Progression of the disease 1 according to therapy Disease progresion (% of patients) 25 20 15 10 5 0 0 6 12 18 20 30 36 Months Placebo Lamivudine 1: Includes worsening of Child score, clinical decompensation and HCC. Liaw et al., NEJM 2004
Lamivudine for patients with chronic hepatitis B and advanced liver disease Progression of the disease according to therapy and development of resistance to lamivudine Disease progresion (% of patients) 25 20 15 10 5 0 0 6 12 18 20 30 36 Months Placebo 21% YMDD 13% Wild type 5% Liaw et al., NEJM 2004
Which patients should be treated? Therapy should be reserved for those who need to be treated those with active disease examplified by raised serum aminotransferases, by clinical or histological evidence of progressive disease, or both. The decision to start therapy should not be made on the basis of HBV-DNA levels alone.. Jay H. Hoofnagle NEJM, March 2006
CRITERIA FOR TREATMENT Chronic infection HBsAg positive Serum HBV-DNA > 10 5 copies/ml Increased ALT Liver inflamation (HAI >4) AASLD, EASL, APASLD Consensus Conferences
Treatment of chronic hepatitis B Drugs LICENSED: Interferons (alfa-interferon, pegylated α-2a interferon) Nucleos(t)ide analogues: Lamivudine, adefovir, entecavir, tenofovir (HIV). ON THE WAY: Telbivudine, clevudine, emtricitabine, pradefovir, valtorcitabine, ANA380. Combinations FAR AWAY: Immunostimulants, therapeutic vaccines, gene therapy
Advantages and disadvantages of available agents Advantages INTERFERON Disadvantages Finite duration of treatment Durable response Loss of HBsAg No resistance Side effects. Injection Low response rate Expensive ANALOGUES Excellent tolerance Oral administration Potent inhibition of viral replicacation Less expensive than IFN Long or indefinite treatment duration Drug resistance Low rate of HBsAg clearance Expensive if administered long-term
Peginterferon in HBeAg-positive chronic hepatitis B Three large controlled trials (1-3) More efficient than lamivudine (48 weeks), but less well tolerated HBe seroconversion in 30% Response sustained in 90% of responders HBsAg seroconversion in 3% More efficacy in patients with higher ALT, lower serum HBV- DNA and genotype A or B 1) Janssen et al, Lancet 2005 2) Lau et al, NEJMed 2005 3) Yuen-Chan, Ann Intern Med 2005.
Peginterferon alfa-2a in patients with HBeAg-negative chronic hepatitis B Patients (%) 100 80 60 40 81 43 63 End of treatment (48 weeks) End of follow up (24 weeks) 20 0 < 20,000 c./ml HBV-DNA 19 < 400 c./ml Marcellin et al. N Engl J Med 2004; 351:1206-17
Peginterferon alfa-2a in patients with HBeAg-negative chronic hepatitis B 116 patients With biochemical response* after 24 weeks on no therapy. Followed for an additional 18 months (24 months off-therapy) Normal ALT: 44 (38%) (25%)** ALT <50 IU/L HBV-DNA < 100x10 3 c./ml : 47 (41%) (27%)** HBsAg seroconversion: 6 ( 5%) ( 3%)** *: Defined by ALT below 50 IU/L **: Percent of the whole treated population Marcellin et al. EASL 2006 (Abstract 743)
NUCLEOS(t)IDE ANALOGUES Activity: Block HBV-DNA polymerase Chain termination Effects of one year therapy: Marked reduction (suppression) of viral replication Improved ALT, histology and liver function Well tolerated Benefits usually not sustained after discontinuation Prolonged therapy is necessary For how long? Resistance may occur
Consequences of viral resistance Virologic and biochemical breakthrough Loss of initial virologic, biochemical, and histologic response Hepatitis flares, hepatic decompensation, and death
Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine 100 89% Virological response 1 Virological Breakthrough 2 % patients 80 60 40 63% 37% 48% 52% 39% 61% 20 0 11% 1 year 2 years 3 years 4 years 1. HBV DNA < 10 5 copies/ml by Digene Hybrid Capture II or bdna Bayer assay 2. Reappearance of HBV DNA by non PCR assay or > 10 5 copies/ml by PCR assay AISF Lamivudine Study Group Di Marco et al. Hepatology 2004; 40: 883-91
Long term therapy with Adefovir dipivoxil for HBeAg negative chronic hepatitis B % patients 100 80 60 40 73% 68% 78% 71% 88% 79% 20 0 6% 0% 3% Week 48 Week 96 Week 144 Biochemical response Virological response 1 Genotypic resistance 2 1. HBV DNA < 1000 copies/ml by Roche Amplicor Monitor PCR assay 2. Detection of ADV-resistance associated mutations Hadziyannis et al. NEJM 2005
SUSTAINED BIOCHEMICAL AND VIROLOGICAL REMISSION AFTER DISCONTINUATION OF 4 TO 5 YEARS OF ADEFOVIR DIPIVOXIL TREATMENT IN HBeAg-NEGATIVE CHRONIC HEPATITIS B 33 Patients with HBeAg neg chronic hepatitis B (genotype D) In sustained remission under Normal LFT Undetectable HBV-DNA No genotypic resistance Improved histology ADV therapy for 4-5 years Followed for 18 months after treatment withdrawal 22 (67%) maintained remission (Inactive HBV carriers) 11 (33%) relapsed witin 3 months. Responded to re-treatment Hadziyannis et al., AASLD 2006, (Abst 114)
Efficacy of one year therapy with nucleosid(t)e analogues for Hepatitis B Undetectable HBV DNA (< 400 copies/ml) ALT Normalization (%) 100 91 (%) 100 80 69 60 51 73 80 60 48 68 60 72 78 71 40 38 40 20 21 20 0 HBeAg + Patients HBeAg - Patients 0 HBeAg + Patients HBeAg - Patients Adefovir Entecavir Lamivudine Adefovir Entecavir Lamivudine
Entecavir in HBeAg(-) Patients: Week 96 Cumulative Response Outcomes Percentage of Patients 100 80 60 40 20 P <.0001 90 72 P <.0001 94 77 P =.045 78 71 P =.05 89 84 Entecavir Lamivudine 0 Wk 48 Wk 96 Wk 48 Wk 96 HBV DNA < 300 copies/ml ALT 1 x ULN Shouval D, et al. EASL 2006. Abstract 45.
CURRENT TREATMENT OF CHRONIC HBV INFECTION Still evolving Effective therapies available Optimal therapeutic options partially identified Many questions pending