Behandeling van chronische hepatitis. Hans Van Vlierberghe Dienst Gastro-hepatologie UZ Gent

Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Hepatitis G TTV

Chronische hepatitis C. Prevalentie in België: 0,9 %. Mild gestoorde transaminasen. 20% evolutie naar cirrose ---> HCC.

HCV virologie RNA virus ( flaviviridiae) Choo et al. 1989 op basis van nucleotide sequencies: => 6 genotypes en 80 subtypes + quasispecies multipele genotypes veroorzaken verschil in: * respons op therapie (Ib) * virus-gastheer interaktie

Schematische voorstelling HCV-genoom 37

Epidemiologie Prevalentie Naar schatting 100.000 personen in België = 1% van de bevolking Regionale verschillen Wetenschappelijke Instituut voor Volksgezondheid Louis Pasteur, België (1998)

Posttransfusion Hepatitis C All volunteer donors HBsAg Donor Screening for HIV Risk Factors Anti-HIV ALT/Anti-HBc Anti-HCV Improved HCV Tests Adapted from HJ Alter and Tobler and Busch, Clin Chem 1997

Epidemiologie HCV (3) Huidige risico factoren voor HCV infectie: * IV drug gebruik: 60% * transfusie van bloed en bloedprodukten: 5-10% (voor 1990: 60%) => risico: 0.01-0.001% per eenheid bloed * hemodialyse: 20% * hoog risico sexueel gedrag, promiscuïteit: 20%

Epidemiologie HCV (4) * tatoeage, body piercing, acupunctuur? * gezondheidssector * orgaantransplantatie van HCV + donor * sporadisch: 30%

HCV Prevalence by Selected Groups United States Hemophilia Injecting drug users Hemodialysis STD clients Gen population adults Surgeons, PSWs Pregnant women Military personnel Average Percent Anti-HCV Positive

Estimated Burden of Hepatitis C in different National Models U.S.A. (Davis et al, Hepatology 1998) Cirrhosis  61% HCC  68% by year 2008 Liver related death  233% FRANCE (Deuffic et al, Hepatology 1999) HCC related mortality Men  150% by year 2020 Women  233% Not only is the disease a burden to patients. As the disease progresses to cirrhosis and HCC, this public health issue will have large financial implications on healthcare resources. Projections over the next decade suggest an important % increase in the numbers of cases of cirrhosis, HCC and liver related deaths AUSTRALIA (Law et al, J Hepatol Gastroenterol 1999) Cirrhosis  102% HCC  150% by year 2020

Natuurlijk verloop van de ziekte Cirrotische decompensatie Cirrose Adler M. Interface Infectiology, n°1 (September 1998)

Progression of fibrosis METAVIR F rapid intermediate 4 slow 3 2 1 10y 20y 30y 40y 50y Duration of infection Poynard, Lancet 1997

Progression of fibrosis METAVIR F Male, > 50y, alcohol > 50g/day 4 Female, < 50y, alcohol< 50g/d 3 2 1 10y 20y 30y 40y 50y Duration of infection Poynard, J Hepatol 2001

Factors affecting the course of HCV Co-factors Host Age at infection Race Male gender Steatosis > 30% ALT > 2N Glycemia > 110 mg% BMI > 28 HLA DR4 B8 ? Hemochromatosis gene? Immunity (HIV, Tx) Alcohol HBV HIV Fe ++ ? tobacco HGV: no Fibrosis Cirrhosis Virus Genotype: no Viral load: ? Alberti, J Hepatol 1999

Acute hepatitis C!!!! Acute hepatitis C wordt chronisch in 80% van de gevallen. ( bv. Prikaccident). Follow up: onmiddellijk: ALT, HCV Al, spijtserum voor HCV RNA na 2-4 weken: HCV RNA (optioneel) na 3 maanden: ALT, HCV Al Therapie: IFN: 5MU IE SC/ dag gedurende 8 weken: SR in 8O %!

CHC en behandeling. Indicaties tot therapie: gestegen ALT (?) Leverbiopsie toont chronische hepatitis HIV negatief (?)

PCR

1. Klassieke Behandeling Alfa Interferon: antiviraal, antiproliferatief, immuno-modulerend IFN alfa: 3 MU SC 3x per week Ribavirine: nucleoside analoog, in monotherapie niet efficiënt Ribavirine: 1000-1200 mg PO dagelijks of ten minste 10.6 mg/kg/d

Ribavirine. Breed spectrum oraal antiviraal middel. Dosis: 1000-1200 mg per dag in monotherapie: daling van ALT, doch geen effect op HCVRNA en histologie Neveneffecten: hemolytische anemie gastro-intestinale last verstopte neus

Beperkingen klassieke behandeling Dal Piek

2. Kunnen we beter scoren: PEG-IFN? Interferon alfa met PEG ( polyethyleenglycol): macromolecule Langer half leven => minder snel geelimineerd Administratie 1x per week SC

Structuur van PEGASYS® Slide 33. PEGASYS® (Peginterferon Alfa-2a [40KD]) PEGASYS® (peginterferon alfa-2a [40KD]) is a pegylated form of recombinant Escherichia coli–expressed IFN alfa-2a (ROFERON®-A) that is formed by the covalent attachment of a 40-kDa PEG branched moiety to the IFN alfa-2a molecule by means of a stable amide bond. The PEG moiety 40kDa,1 and 19 kDa2 IFN alfa-2a molecule together yield a total molecular mass of approximately 59 kDa for the pegylated molecule. PEGASYS® is indicated for the treatment of histologically proven CHC in adults who have elevated transaminases and who are positive for serum HCV RNA, including patients with compensated cirrhosis. PEGASYS® can be used alone or in combination with ribavirin (RBV) in IFN-naïve patients or in those who have previously responded to IFN therapy and have relapsed posttreatment.3 Pegylation of the IFN alfa-2a molecule clearly enhances the absorption, distribution, and clearance of IFN. The pharmacokinetics of PEGASYS® in healthy individuals are characterized by an absorption half-life of 50 hours,4 a terminal half-life of 77 hours (compared with 5.1 hours for IFN alfa-2a),2,5 and a 10-fold decrease in systemic clearance compared with the conventional IFN alfa-2a molecule,4 resulting in antiviral serum concentrations that are constant and sustained throughout the entire 1-week (168 hours) dosing period.5 1. Biopharma. Interferon alpha-2a, rDNA, PEG. 2. ROFERON® -A. PDR ®. 56th ed. 2002. 3. EMEA. PEGASYS®. 4. Reddy KR. Ann Pharmacother. 2000;34:915-923. 5. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288. IFN Large branched-chain PEG Stable amide bond

Pharmacokinetiek van het interferon IFN -2a tiw 2 4 6 8 10 12 14 25 50 75 100 125 150 Xu et al. Hepatology 1982, 28 (suppl): 702A.

Klassieke Pegylatie PEG-IFN -2a (5KD, lineair) 0,0 0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 25 50 75 100 125 150 Hours ng/mL Mon Tue Wed Thu Fri Sat Sun Nieforth KA, et al. Clin Pharmacol Ther. 1996;59:636-646.

Klassieke Pegylatie PEG-IFN -2b (12KD, lineair) 0.5 µg/kg 1.0 µg/kg 1500 pg/mL 1000 0.5 µg/kg 1.0 µg/kg 1.5 µg/kg 500 24 48 72 96 120 144 Adapted from Glue P et al. Clin Pharmacol Ther. 2000;68:556-567.

PEGASYS® Pegylatie van nieuwe generatie PEG-IFN -2a (40KD, vertakt) 5 10 15 20 25 50 75 100 125 150 ng/mL Hours Mon Tue Wed Thu Fri Sat Sun Modi et al., AASLD 2000, Abstract

PEG interferon: Resultaten (1) Mans M. Lancet 2001 SVR * *: p < 0.02 *

PEG interferon: Resultaten (2) SVR Fried M. NEJM 2002 * * p < 0.05 * * * * *

Optimalisatie van de behandeling Genotype 1 52% 42% 41% SVR (%) 29% Optimal arm provides 51% SVR in genotype 1 When using a lower dose of ribavirin, SVR falls by a fifth !! n=101 n=118 n=250 n=271 PEGASYS® RBV 800 PEGASYS® RBV 1000/1200 PEGASYS® RBV 800 PEGASYS® RBV 1000/1200 24 weeks 48 weeks Hadziyannis J. 37th EASL, Madrid 2002, Abstract #1. Marcellin P. Expert report on the NV15942 Study. Data on file. F.Hoffmann-La Roche, Basel, Switzerland.

Optimalisatie van de behandeling Genotype 2 en 3 84% 81% 79% 80% SVR (%) Optimal arm provides 51% SVR in genotype 1 When using a lower dose of ribavirin, SVR falls by a fifth !! n=96 n=144 n=99 n=153 PEGASYS® RBV 800 PEGASYS® RBV 1000/1200 PEGASYS® RBV 800 PEGASYS® RBV 1000/1200 24 weeks 48 weeks Marcellin P. Expert report on the NV15942 Study. Data on file. F.Hoffmann-La Roche, Basel, Switzerland.

Early prediction response in patients with genotype 1. Early Response SVR Yes 86% (n = 390) 65% Week 12 HCV RNA neg or drop of 2 log10 PCR (n = 453) No NPV = 97% 14% (n = 63) 3% Fried et al. NEJM 2002

Side effects of PEG-interferon. Similar to interferon alfa Mind : more leucopenia more thrombopenia long half life.

Leukocytes and neutrophil counts Mean counts (109/l) Neutrophils Leukocyte and neutrophil counts were somewhat lower in the PegIntron 1.5 g/kg QW+ Ribavirin 800mg daily group Treatment Weeks

Platelet values (x 109 / l) over time Mean Platelet (X109/L) Platelets levels were similar between the .5somewhat lower in the PegIntron 1.5 g/kg QW+ Ribavirin 800mg daily group Treatment Weeks

CHC en combinatietherapie. Follow up: Start: ALT, HCV RNA, genotype, kwantitatief RNA, leverbiopsie. 6 maand therapie: HCV RNA log 2 reductie op week 12 ETR: HCV RNA, ALT 6 maand FU: HCV RNA, ALT

Atypische hepatitis C. Acute hepatitis C normale transen kinderen cryoglobulinemie/glomerulonefritis HIV/HCV HCV levertransplantpatient HCV positieve hemodialyse patient

Toekomst HCV behandeling. PEG - interferon therapeutisch vaccin nieuwere nucleoside analogen

Antisense Oligonucleotides Future Possibilities Ribozymes Protease Ribavirin- like drugs Antisense Oligonucleotides Helicase Antifibrotic Therapy RNA Interference Polymerase Therapeutic Vaccines