UZ Gasthuisberg KULeuven HBV Frederik Nevens Hepatologie UZ Gasthuisberg KULeuven WKBV september 2004

I. Epidemiology in Belgium (1) Incidence Acute Hepatitis B*: 1982-84: 25/100.000 - year 1991-92: 6/100.000 - year Age: 20 – 49 y Sex: 73% males * Devroey D et al.; Int. J. Infect. Dis. 1997

I. Epidemiology in Belgium (2) Prevalence HBsAg+* Pregnant women: 0,67% (14-20% HBeAg+)(1) Flanders (1993-1994): 0,7%(2) Cidex screening (2001): 0,4% (81/18.315) *Development of chronic hepatitis B: 10% Tormans G et al. Soc Sci Med. 1993 Beutels M et al. Eu J Epidemiol. 1997

II. Infectiology in Belgium Mode of transmission* sexual activity travel endemic area: 27% IV drug abuse: 18% → Vaccination * Van Damme P. et al., Arch. Public Health 1998

Prof. Leroux-Roels

III. Natural History and Treatment of Chronic Hepatitis B

Cirrhosis (F4)

Wie moet behandeld worden = patiënten met risico op cirrose → Chronische hepatitis (=ALT↑)* → HBsAg + en ALT↑ en HBV DNA > 20.000 IU/ml * Risico op cirrose +/- 30% na 10 jaar

Wie moet niet behandeld worden = HBsAg: + ALT: nl HBV DNA PCR - neg: blijvend risico op HCC? - pos: kans op reactivatie* → risico op HCC → noodzaak tot follow-up *Heropflakkering bij steroidwithdrawel cytostatica

Doel van de behandeling = blijvende normalisatie ALT* ≠ eradicatie HBV (intrahepatisch ccc DNA) Cfr. HBsAg- HBcAs+ lever →20% reactivatie na OLT! * Grootste kans indien HBeAg- HBeAs+ (seroconversie)

Welke behandeling HBeAg+ 1) INFα: 5-10 MU 3/w sc 4-6m(1) 2) Lamivudine(2)(Zeffix®): 100 mg/dag tot HBeAS+(30%)(kan jaren duren) HBeAg- 1) Lamivudine tot HBsAg- (10%) 2) INFα 1 – 1 ½ jaar. Nucleoside analoog – DNA polymerase remmer 20% meer kans tot seroconversie met PEG INF

Resistensie op Lamivudine - > 50% na 5 jaar - ↑ HBV DNA < 1 log - ↑ ALT Adefovir (nucleoside analoog): 10mg/dag - bij cirrose overlap 3 maanden - trager antiviraal effect - resistensie na 3 jaar: enkele % - aanpassen interval bij nierfunctiebeperking

Study 437 at 48 Weeks Regression of Cirrhosis ADV 10 mg Patients (%) PLB ADV 10 mg PLB (F3 to F4) (F4 to F3)

HBeAg clearance predicts survival Niederau C, N Engl J Med, 1996

Spontaneous HBeAg clearance Age at infection: - Immune tolerant phase: 15% after 20 years - Immune clearence phase: 70% after 10 years Higher rate of HBeAg clearence: - older age - elevated ALT - female gender - genotype B McMahon, Ann Intern Med, 2001 Huang & Lok, Clin Liver Dis, 2003

Study 437 Efficacy through 72 Weeks: ALL ADV 10 mg* Patients (%) At 48 weeks patients on 30 mg were re-randomized to placebo, patients on placebo were re-randomized to 10 mg and patients on 10 mg were re-randomized to 10 mg or placebo in a 1:1 fashion Blinded study terminated due to a misallocation of dosing during the second year; all data presented censored at the first mis-allocated dose The data presented in the following section presents patients that received at least one dose of ADV 10 mg either in the first or second 48 weeks referred to as (ALL ADV 10 mg, n = 309 patients) Patient have varying amounts of follow-up beyond 48 weeks. For this analysis, the median time of additional treatment beyond 48 wk was 16.1 wk (interquartile range of 8.1 – 27.3 wk) We report 72 week data in the ALL ADV 10 mg group from Kaplan-Meier analyses of HBV DNA, ALT normalization, HBeAg loss, and HBeAg seroconversion HBV DNA <400 copies/mL ALT normalization HBeAg loss HBeAg seroconversion *Kaplan-Meier estimates. Marcellin, P, et al. Hepatology. 2002; Vol. 36, #840.

Addendum: Interpretatie HB serologie (1) HBsAg- HBCAs- HBsAs- → … HBCAs- HBsAs+ → … HBCAs+ HBsAs+ → … HBCAs+ HBsAs- → …

Addendum: Interpretatie HB serologie (2) HBsAg+ ALT nl → … ALT↑ → …