Quantification of HBsAg and HBV-DNA during Therapy with Peginterferon alpha-2b plus Lamivudine and Peginterferon alpha-2b Alone in a German Chronic Hepatitis B Cohort

Zusammenfassung

Hintergrund: Peginterferon alpha-2b (PEG-IFNa2b) und Lamivudin sind effektive Behandlungsoptionen bei einer chronischer Hepatitis-B-Infektion. Es gab Hinweise, dass die Kombinationstherapie von PEG-IFNα-2b und Lamivudin im Vergleich zur Monotherapie eine höhere Rate an HBeAg-Serokonversion induziert sowie eine stärkere Suppression der HBV-DNA- und der HBsAg-Produktion erreichen kann. Patienten und Methodik: 59 Patienten mit chronischer Hepatitis B wurden in die Studie eingeschlossen. Es erfolgte die Randomisation in eine 9-monatige Therapie mit PEG-IFNα-2b 1,5 µg/kg o. i. w. (n = 27) oder PEG-IFNα-2b plus Lamivudin 100 mg (n = 32). Die Nachbeobachtungszeit betrug 24 Wochen. Das primäre Zielkriterium war der Verlust der HBV-DNA 24 Wochen nach Ende der Therapie. HBV-DNA (PCR) und HBsAg (Axsym, Abbott) wurden zu Beginn, am Ende der Therapie und am Ende der Nachbeobachtungszeit quantitativ bestimmt, während die HBeAg (Axsym, Abbott) Bestimmung zu den gleichen Zeitpunkt qualitativ erfolgte. Die Bestimmung der HBV-Genotypen erfolgte mit dem Innolipa Assay (Innogenetics). Resultate: Es wurden lediglich 32 Patienten in die Gruppe der Kombinationstherapie und 27 Patienten in die Gruppe der Monotherapie randomisiert. Der Abfall der HBV-DNA (4,60 log vs. 2,41 log; p = 0,003) war signifikant stärker unter Kombinationstherapie. Der Anteil der Patienten mit ALT-Normalisierung, viraler Suppression (HBV-DNA < 400 copies/mL) und einer HBeAg Serokonversion war jedoch ohne Unterschied zwischen den Behandlungsgruppen. Der HBV-Genotyp hatte keinen Einfluss auf die Zielparameter. In einer Post-hoc-Analyse wurden bei 29 Patienten zusätzlich HBsAg-Spiegel bestimmt. Hierbei zeigte die Kombinationstherapie sowohl während (– 0,7 ± 1,17 log IU/mL vs. –0,26 ± 0,61 log IU/mL; p = 0,35) als auch nach der Behandlung (– 0,68 ± 1,29 log IU/mL vs. – 0,24 ± 0,56 log IU/mL; p = 0,82) einen stärkeren, aber nicht signifikanten Abfall des HBsAg. Zwei von 3 Patienten mit 2 log HBsAg-Abfall unter 100 IU/mL erreichten in der Langzeitnachbeobachtung einen HBsAg-Verlust. Diskussion: Aufgrund geringer Rekrutierungszahlen erreichte die Studie nicht den primären Studienendpunkt. Jedoch zeigte sich in einer Post-hoc-Analyse ein mehr als 2-fach stärkerer HBsAg-Abfall in der Kombinationstherapie, wobei nach Absetzen des Lamivudins kein Wiederanstieg des HBsAg beobachtet wurde. Dieses Ergebnis kann auf einen Nutzen zukünftiger Kombinationstherapien hinweisen, bei denen die Nucleos(t)idtherapie fortgeführt wird.

Abstract

Background: Peginterferon alpha-2b (PEG-IFNa2b) and lamivudine are efficient treatment options for chronic hepatitis B virus (HBV) infection. We assumed that a combination therapy of PEG-IFNα-2b plus lamivudine will be more effective than PEG-IFNα-2b alone concerning loss of HBV-DNA, HBeAg seroconversion, and HBsAg reduction. Patients and Methods: Patients with chronic hepatitis B were randomised to nine months treatment with PEG-IFNα-2b 1.5 µg/kg o. i. w. or PEG- IFNα-2b plus lamivudine 100 mg/d. The study was designed with 60 patients per treatment arm. The primary endpoint was defined as loss of HBV-DNA (< 400 copies/mL) 24 weeks after the end of therapy. HBV-DNA (PCR), HBsAg (Architect, Abbott), and HBeAg (Axsym, Abbott) were determined prior to and at the end of treatment as well as at follow-up. HBV-genotypes were determined by Innolipa (Innogenetics). Results: Only 32 patients were randomised to combination therapy and 27 individuals to monotherapy due to low recruitment rates. On treatment reduction of HBV-DNA was significantly higher during combination therapy compared to PEG-IFNa-2b monotherapy (– 4.60 ± 2.71 vs. – 2.41 ± 2.17 log; p = 0.003). However, there was no difference in the number of cases achieving HBV-DNA < 400 copies/mL, ALT normalisation, or HBeAg seroconversion at follow-up. None of the parameters was significantly related to HBV-genotypes. In a post-hoc analysis serum HBsAg levels were analysed as an additional prognostic parameter for treatment response (n = 29). Combination therapy showed a stronger, but not significant HBsAg decline during (– 0.7 ± 1.17 log IU/mL vs. – 0.26 ± 0.61 log IU/mL; p = 0.35) and after therapy (– 0.68 ± 1.29 log IU/mL vs. – 0.24 ± 0.56 log IU/mL; p = 0.82). Two of three cases with a 2-log HBsAg decline to HBsAg levels < 100 IU/mL eliminated HBsAg during long-term follow-up. Conclusion: The study was underpowered with respect to the primary endpoint due to low recruitment rates. However, in the post-hoc analysis HBsAg decline was over two-fold stronger at the end of treatment and follow-up after combination therapy and did not rebound after lamivudine withdrawal. These results may indicate the usefulness of future combination therapies without discontinuation of nucleos(t)ide analogues.

Schlüsselwörter

chronische Hepatitis B - Virushepatitis - Leber - Therapie - HBsAg quantitativ

Key words

chronic hepatitis B - viral hepatitis - liver - therapy - HBsAg quantitative

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