Chronicle hepatitis B (C.H.B.) Definition: Seropositivity for surface antigen of Hepatitis B (HbsAg) for more than 6 months Baku 2014 DR. W. te Winkel

Four phases of infection a. Immune tolerant phase: HbeAg + ALAT: n HBV-DNA > 1x10 e 5 HBV-DNA > 1x10 e 5 b. Immune active phase: HBV-DNA lower ALAT higher HbeAg:- HbeAg:- c. Inactive phase: HBV-DNA < 1,0 x 10 e 4 ALAT =n ALAT =n d. Reactivation (immune suppression R)

Epidemiology - worldwide: 400 million chronicle infected - Mortality HBV related liver disease (cirrhosis, H.C.C.) - the Netherlands: 0,2% chronic carrier 2,1% has been infected 2,1% has been infected - Endemic:Sub-Sahara South East Asia 10-15% seropositieve China

- Virus: small DNA virus - Surface: HbsAg - Core: Hepatitis B core antigen HbeAg (also free in blood) - Parenteral route of transistor - Replication liver - H.B.V. replication: HbeAg, HBV-DNA

- Route of transmission blood, Horizontal (child-child) - High risk groups : - sexual contacts - i.v. drugs use - i.v. drugs use - maternal infant - maternal infant - medical risk - medical risk (personal, transfusion, hemodialysis etc.) - Natural course: asymptomatic < 5% CHB < 5% CHB

Clinical symptoms, diagnosis - History: Fatigue, anorexia, icterus, joint pain, transfusion, i.v. drugs. transfusion, i.v. drugs. - Physical examination: Signs of chronic liver disease - yaundice- caput medusa - erythema palmaris - spider naevi - ascites- hepatomegaly - gynaecomastia

- Laboraty test: liver enzymes liverfunctiontest liverfunctiontest - Virological investigations - replicative state: quantitative HBV-DNA HbeAg - anti Hbe HbeAg - anti Hbe - viral co-infections - H B V genotype - Ultra sound : signs of cirrhosis portal hypertension - Liver biopsy (when indication for R) - necro inflammation - liver fibrosis - Gastroscopy / varices

Complications of CHB - Cirrhosis : 20% five years cumulative - Screening monthly by echo for HCC - Incidence Asië : HCC 3,2 % (by cirrhohic) Africa Africa Alpha foetproteïn: cavé false positive - Hepatitis A: immunity for HAV, when no immunity : vaccination when no immunity : vaccination

Indications for treatment - Great percentage of patients needs no R a. Active replication HBV HBV-DNA > 10 copies/ml 2,0 x 10 IU/ml 2,0 x 10 IU/ml b. ALAT 2 x upper limit months c. Liver biopsy :interface hepatitis Fibrosis Fibrosis - Compensated liver cirrhosis HBV-DNA > 1 x 10 - Decompensated ; HBV-DNA 1000/ml (pregnancy, profylactic chemotherapy) (pregnancy, profylactic chemotherapy)5 4 4

No treatment indication - Not fulfilling trias criteria - inactive carrier - immune tolerant - Risk on reactivation - control 3-6 monthly high HBV-DNA - control 3-6 monthly low HBV-DNA HbeAg + HbeAg + - control 6-12 monthly HbeAg-

Goal of antiviral treatment - Prevent complications (cirrhosis, H.C.C.) - sAg seroconversion (sAg - antiHbs+) Seldom! Other end point: - HbeAg seroconversion (antiHbe) - HBV-DNA low viral concentration (below PCR def.) - Biochemical respons: normal ALAT - Improved liver histology To induce inactive phase

Response Response a. Permanent response Active immune response HbeAg - HbsAg seroconversion HbsAg seroconversion b. Therapeutic maintained response - suppression DNA without active immune response immune response PEG : permanent response Nucleoside analogues: therapeutic maintained response maintained response

Antiviral therapy PEG interferon - Interferon alfa -since 1980 For eAg+ eAg - CHB Natural cytokines - Polyethylene glycol molecule PEG High action High action - Doses 1 x a week 180 ug s.c. for 48 weeks PEG interferon alfa 2 a 2 b

PEG Interferon HbeAg + : seroconversie 40% HbeAg - : Not detectibel HBV 63% HbsAg seroconversic 7% HbsAg seroconversic 7% - HBV genotype: A.B - > - C.D HbeAg loss - Disadvantage: subcutaneous route - Side effect : local injection place Trombopenia, neutropenia Trombopenia, neutropenia Psychical, neurological Psychical, neurological Fluelike symptoms Fluelike symptoms

No PEG interferon: with cirrhosis Psychiatric Psychiatric Cardial problem Cardial problem Then Nucleoside analogues - Mode of action: reduction viral polymerase Low viral replication - Disadvantage:long term treatment Low percentage sustained response Antiviral resistance

Lamivudine1999 Adefovir2003 Entecavir2006 Telbivudine2007 Tenofovir 2008 Lamivudine 100 mg/day Result: HbeAg serocon 16-22%1 year (HBV-DNA < 1 x 10 e 5) 47 %4 year (HBV-DNA < 1 x 10 e 5) 47 %4 year HbeAg-HBV-DNA < %1 year 39%4 year 39%4 year Forming of antiviral resistance (71% 5 year)

Adefovir wildtype - lamivudine resistance H.B.V. - dose: 10 mg/day 1 year 3 years 1 year 3 years a. HeAg + e Ag seroconversic 12 %43% HBV < 10 21% 56% HBV < 10 21% 56% 5 years 5 years b. HbeAg -HBV-DNA< 1 x 10 51% 67% ALAT 72% 69% ALAT 72% 69% Less resistance then lamivudine (28% 5 years) 3 3

Entecavir2006 Guanine analog 0,5 mgr/day - Entecavir more virus reduction then lamivudine 1 year 3 years 1 year 3 years - HbeAg+ : seroconversion 21% 39% HBV-DNA < 30067% 82% ALAT n68% 90% - HbeAg - : HBV-DNA

Telbivudine same group nucleoside analogue as Lamivudine - dose 600 mgr/day 1 year 2 years 1 year 2 years Result: HbeAg+ seroconversion 22% 29% HBV-DNA < % 54% HBV-DNA < % 54% Seroconversion still in 80% persistent 35 weeks HbeAg -HBV-DNA < % 79% Resistance: 2-3 % 1 years, 7-27% 2 years

Tenofovir nucleotide reverse transcriptase inhibitor - dose 245 mgr/dail 1 year2 years - HbeAg+ : seroconversion21 %34 % HBV_DNA

Choice, duration initial treatment - PEG interferon first choice, no contra indication - High sustained response after stop R - Short treatment course Disadvantage: s.c., side effects Disadvantage: s.c., side effects - Nucleoside analogues: when contra indications PEG - oral, less side effect - disadvantage; long treatment resistance

Long term inactive phase PEG interferon HbeAg +: % HbeAg - : 1 -25% Sustained response: 85% eAg+,40% eAg- Therapy: 1 year Nucleosides after stop treatment 40% recurrence eAg+ 90% recurrence eAg- patients

Entecavir highest antiviral potention Tenovofir Entecavir lowest resistance Tenovofir Tenovofir Duration treatment: HbeAg seroconversion 6 months HBV-DNA < 400 copies/ml HBV-DNA < 400 copies/ml HbeAg patients not clear when to stop R

Control / Follow up PEG inj: monthly lab (neutropenia, liver functiontrombopenia) Virus serologic3 monthly Nucleosides:3 monthly lab (kreatine) Virus serologic: 3 monthly (HbsAg, antiHbs, HbeAg, antiHbe Kwantitatieve HBV.DNA) Kwantitatieve HBV.DNA)

Dose reduction PEG: neutrof. granulocytes < 0,75 x 10 9/l Trombocytes< 50 x 10 9/l Lower 25% dose Stop Rneutrof. < 0,50 trombocytes

Antiviral resistance - Nucleoside analogues 6 months R HBV-DNA < factor 100 reduction reduction Treatment Failure: a. antiviral resistance b. compliance patient b. compliance patient First sign resistance higher serum HBV-DNA later ALAT Change in tenofovir

Control after treatment course - PEG interferon: 3-6 months after stop HBV-DNA HBV-DNA HBV-serolog HBV-serolog HbeAg - patients 1 year HBV-DNA < 10 ALAT = n ALAT = n Control yearly ALAT for 3 years Control yearly ALAT for 3 years HbsAg- antiHbs+only control immunosupp R - Nucleoside analogues 3 monthly 5