Subscribe to RSS
DOI: 10.1055/s-2004-824872
© Georg Thieme Verlag Stuttgart · New York
Neue Ansätze in der Hepatitis B-Therapie
New advances in the treatment of hepatitis BPublication History
eingereicht: 8.9.2003
akzeptiert: 26.2.2004
Publication Date:
21 July 2004 (online)

Zusammenfassung
Eine Interferontherapie über 6 Monate gilt weiterhin als Standardtherapie für chronisch Hepatitis B-Virus (HBV) infizierte Patienten mit günstigen prognostischen Faktoren und fehlenden Kontraindikationen. Ob pegyliertes Interferon (PEG-IFN) verglichen mit herkömmlichen Interferon (IFN), ähnlich wie bei der Therapie der Hepatitis C auch bei der Hepatitis B die Ansprechrate steigern kann, ist derzeit noch unklar. Bei Kontraindikationen gegen Interferon oder ungünstiger klinischer Konstellation sollte Lamivudin gegeben werden. Diese Therapie hat ein günstiges Nebenwirkungsprofil, muss jedoch bei vielen Patienten als Dauertherapie gegeben werden. Unter einer Langzeitbehandlung kommt es gehäuft zur Resistenzentwicklung und damit Wirkungsabschwächung. Das kürzlich in Deutschland zur Behandlung der chronischen HBV-Infektion zugelassene Adefovir stellt eine Alternative besonders bei Lamivudinresistenz dar. Spezifische Mutationen unter der Therapie mit Adefovir wurden bislang nur in Einzelfällen beobachtet. Tenofovir und Emtricitabine sind Substanzen, die zur Human Immunodeficiency Virus (HIV)-Therapie zugelassen sind, und darüber hinaus gute Wirksamkeit gegen HBV zeigen. Weitere Nukleotid- bzw. Nukleosidanaloga mit teilweise sehr hoher inhibitorischer Potenz sind Entecavir, Clevudine und L-Thymidine (L-dT). Die Wirksamkeit gegen Lamivudin-resistente HBV-Stämme ist bisher für Adefovir, Tenofovir, Entecavir und ACH 126 - 443 (ß-L-Fd4C) nachgewiesen.
Insgesamt stehen damit nunmehr mehrere hochaktive Substanzen zur Therapie der chronischen HBV-Infektion zur Verfügung bzw. befinden sich kurz vor der Zulassung. Wahrscheinlich werden in Zukunft Kombinationstherapien, bestehend aus verschiedenen Substanzen oder Substanzklassen, ähnlich wie bei der HIV-Therapie, weitere Fortschritte in der Behandlung der chronischen HBV-Infektion bringen.
Summary
In patients with chronic hepatitis B virus infection and suitable serologic characteristics treatment of choice is interferon alpha for a duration of 6 months. It is as yet unproven whether pegylated interferon improves response rates in comparison to standard-IFN, as in the treatment of hepatitis C virus infection. Patients with cotraindications for IFN-therapy or with prognostic unfavourable characteristics should be treated with lamivudine. This therapy is tolerated well but has to be given for many years. Drug resistance against lamivudine is common and increases with duration of therapy. Adefovir is a new agent which has recently been approved for the treatment of HBV infection and is the treatment of choice in patients with resistance against lamivudine. Adefovir associated mutations have been demonstrated only rarely. Tenofovir and Emtricitabine are substances which are approved for the therapy of HIV infection and exibit strong antiviral activity against HBV. Further agents with inhibitory activity against HBV are Entecavir, Clevudine, and L-dt. Different clinical trials with these promising new compounds are in progress. Agents effective against Lamivudine-resistant strains are Adefovir, Tenofovir, Entecavir, and ß-L-Fd4C.
In conclusion, there are many agents highly active for treatment of chronic HBV infection. Combination regimen including different substances, similar to therapy in HIV infected individuals, might lead to even higher response rates in the treatment of chronic HBV infection in the near future.
Literatur
- 1
Afdhal N H, O’Brien C B, Oshana S C.
Potent anti-HBV activity of ACH-126,443 correlated with 14-day pharmacokinetics
and safety: Predictions for activity against YMDD mutant strains.
Hapatology.
2002;
36
372A
MissingFormLabel
- 2
Angus P, Vaughan R, Xiong S. et al .
Resistance to adefovir dipivoxil therapy associated with the selection of a
novel mutation in the HBV polymerase.
Gastroenterology.
2003;
125
292-297
MissingFormLabel
- 3 Bochet M, Tubiana R, Benhamou R. et al .Tenofovir disoproxil fumarate suppresses lamivudine-resistant HBV replication
in patients co-infected with HIV/HBV. 9th Conference on Retroviruses and Opportunistic Infections 2002: 675-M
MissingFormLabel
- 4
Buti M, Esteban R.
Adefovir dipivoxil.
Drugs Today.
2003;
39
127-135
MissingFormLabel
- 5
Bryant M L, Bridges E, Placidi L. et al .
Antiviral L-nucleosides specific for hepatitis B virus infection.
Antimicrob Agents Chemother.
2001;
45
229-235
MissingFormLabel
- 6
Chang T T, Hadziyannis S, Cianciara J. et al .
Sustained viral load and ALT reduction following 48 weeks of entecavir treatment
in subjects with chronic hepatitis B who have failed lamivudine.
Hepatology.
2002;
36
300A
MissingFormLabel
- 7
Cooksley W GE, Piratvisuth T, Lee S D. et al .
Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B
e antigen-positive chronic hepatitis B.
J Viral Hepat.
2003;
10
298-305
MissingFormLabel
- 8
de Franchis R, Meucci G, Vecchi M. et al .
The natural history of asymptomatic hepatitis B surface antigen carriers.
Ann Intern Med.
1993;
118
191-194
MissingFormLabel
- 9
de Man R A, Marcellin P. et al .
A randomized, placebo-controlled study to evaluate the efficacy of 12-month
famciclovir treatment in patients with chronic hepatitis B e antigen-positive
hepatitis B.
Hepatology.
2000;
32
413-417
MissingFormLabel
- 10
Deres K, Schroder C H, Paessens A. et al .
Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids.
Science.
2003;
299
893-896
MissingFormLabel
- 11
Dienstag J L, Schiff E R, Wright T L. et al .
Lamivudine as initial treatment for chronic hepatitis B in the United States.
N Engl J Med.
1999;
341
1256-1263
MissingFormLabel
- 12
Erhardt A, Reineke U, Blondin D. et al .
Mutations of the core promoter and response to interferon treatment in chronic
replicative hepatitis B.
Hepatology.
2000;
31
716-725
MissingFormLabel
- 13
Fattovich G.
Progression of hepatitis B and C to hepatocellular carcinoma in Western countries.
Hepatogastroenterology.
1998;
45
1206-1213
(Suppl 3)
MissingFormLabel
- 14
Gerken G, Gomes J, Lampertico P, Colombo M. et al .
Clinical evaluation and applications of the Amplicor HBV Monitor test, a quantitative
HBV DNA PCR assay.
J Virol Methods.
1998;
74
155-165
MissingFormLabel
- 15
Gish R, Leung N, Wang C, Sacks S. et al .
Antiviral activity, safety, and incidence of resistance in chronically infected
hepatitis B patients (CHB) given once daily emtricitabine for 2 years.
Hepatology.
2002;
36
372A
MissingFormLabel
- 16
Guan R, Lai C L, Liaw Y F, Lim S G, Lee C M.
Efficiacy and safety of 5 years lamivudine treatment of Chinese patients with
chronic hepatitis B.
Gastroenterol Hepatol.
2001;
16
A60
MissingFormLabel
- 17
Hadziyannis S J, Tassopoulos N C, Heathcote E J. et al .
Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic
hepatitis B.
N Engl J Med.
2003;
348
800-807
MissingFormLabel
- 18 Hadziyannis S J, Tassopoulus N, Heathcote E J. et al .96 weeks of Adefovir dipivoxil in HbeAg negative CHB: significant virological,
biochemical and histological improvement. EASL 2003
MissingFormLabel
- 19
Kane M.
Global programme for control of hepatitis B infection.
Vaccine.
1995;
13
(Suppl 1)
S47-S49
MissingFormLabel
- 20
Klein C, Bock C T, Wedemeyer H. et al .
Inhibition of hepatitis B virus replikation in vivo by nucleoside analogues
and siRNA.
Gastroenterology.
2003;
125
9-18
MissingFormLabel
- 21
Korba B E, Schinazi R F, Cote P, Tennant B C, Gerin J L.
Effect of oral administration of emtricitabine on woodchuck hepatitis virus
replication in chronically infected woodchucks.
Antimicrob Agents Chemother.
2000;
44
1757-1760
MissingFormLabel
- 22
Lai C L, Chien R N, Leung N W. et al .
A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine
Study Group.
N Engl J Med.
1998;
339
61-68
MissingFormLabel
- 23
Lai C L, Myers M W, Pow M D, Lee Y M, Yuen M F, Lim S G.
Safe and potent suppresion of hepatitis B virus (HBV) with L-deoxythymidine
(LDT): results of a dose escalation trial.
Hepatology.
2001;
34
321A
MissingFormLabel
- 24
Leung N W, Lai C L, Chang T T. et al .
Extended lamivudine treatment in patients with chronic hepatitis B enhances
hepatitis HBe antigen serocoversion rates: Results after 3 years of therapy.
Hepatology.
2001;
33
1527
MissingFormLabel
- 25
Leung N, Gish R G, Wang C. et al .
A randomized, double-blind comparison of 3 doses of emtricitabine (FTC) in patients
with chronic hepatitis B (CHB) given 48 weeks of treatment (FTCB-102).
Hepatology.
2001;
34
349A
MissingFormLabel
- 26
Liaw Y D, Tai C, Chu T, Chen T.
The development of cirrhosis in patients with chronic type B hepatitis: A prospective
study.
Hepatology.
1998;
8
493-496
MissingFormLabel
- 27
Lin S M, Sheen I S, Chien R N, Chu C M, Liaw Y F.
Long-term beneficial effect of interferon therapy in patients with chronic hepatitis
B virus infection.
Hepatology.
1999;
29
971-975
MissingFormLabel
- 28
Marcellin P, Chang T T, Lim S G. et al .
Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic
hepatitis B.
N Engl J Med.
2003;
348
808-816
MissingFormLabel
- 29 Marcellin P, Lau G KK, Mommeja-Marin H. et al .A phase I/II dose escalating trialevaluating safety, tolerability, pharmacokinetics
and antiviral activity of clevudine in patients chronically infected with
HBV. EASL 2003
MissingFormLabel
- 30
Maynard J E.
Hepatitis B: global importance and need for control.
Vaccine.
1990;
8
(Suppl)
S18-20
MissingFormLabel
- 31 Nelson M, Portsmouth S D, Stebbing J. et al .Tenofovir in the treatment of individuals co-infected with HIV-1 and Hepatitis
B. International AIDS Conference Barcelona 2002: B7302
MissingFormLabel
- 32
Niederau C, Heintges T, Lange S. et al .
Long-term follow-up of HBeAg-positive patients treated with interferon alfa
for chronic hepatitis B.
N Engl J Med.
1996;
334
1422-1427
MissingFormLabel
- 33
Perrillo R P, Wright T, Rakela J. et al .
Multicenter united states canadian trial to assess lamivudine monotherapy before
and after liver transplantation for chronic hepatitis B.
Hepatology.
2001;
33
424-432
MissingFormLabel
- 34
Perrillo R P, Lai C L, Liaw Y F. et al .
Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B.
Hepatology.
2002;
36
186-194
MissingFormLabel
- 35
Sagir A, Heintges T, Erhardt A, Kirschberg O, Häussinger D.
Daily interferon alfa 2a dosing improves response rates in patients with chronic
hepatitis B dramatically.
Hepatology.
2002;
36
624A
MissingFormLabel
- 36
Schalm S W.
Clinical implications of lamivudine resistance by HBV.
Lancet.
1997;
349
3-4
MissingFormLabel
- 37
Schalm S W, Heathcote J, Cianciara J. et al .
Lamivudine and alpha interferon combination treatment of patients with chronic
hepatitis B infection: A randomised trial.
Gut.
2000;
46
562-568
MissingFormLabel
- 38
Sung J JY, Lai J K, Zeuzem S. et al .
A randomised double-blind phase II study of Laminvudine (LAM) compared to Lamivudine
plus Adefovir Dipivoxil (ADV) for treatment naive patients with chronic Hepatitis
B (CHB): week 52 analysis.
J Hepatol.
2003;
38
25-26
MissingFormLabel
- 39
Tassopoulos N C, Volpes R, Pastore G. et al .
Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis
B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore
Mutant Study Group.
Hepatology.
1999;
29
889-896
MissingFormLabel
- 40
Thomas H C, Karayiannis P, Brook G.
Treatment of hepatitis B virus infection with interferon. Factors predicting
response to interferon.
J Hepatol.
1991;
13
(Suppl 1)
4-7
MissingFormLabel
- 41
Villeneuve J P, Condray L D, Willems B. et al .
Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatits
B.
Hepatology.
2000;
31
207-210
MissingFormLabel
- 42
Yalcin K, Degertekin H, Yildiz F, Celik Y.
Comparison of 12-month courses of interferon-alpha-2b-lamivudine combination
therapy and interferon-alpha-2b monotherapy among patients with untreated chronic
hepatitis B.
Clin Infect Dis.
2003;
36
1516-1522
MissingFormLabel
Priv.-Doz. Dr. med. T. Heintges
Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum
Düsseldorf
Moorenstraße 5
40225 Düsseldorf
Phone: 0211/8118939
Fax: 0211/8119123
Email: heintges@uni-duesseldorf.de