L’hépatite chronique D (HVD) est la plus sévère des hépatites virales, avec un risque plus élevé de développer une cirrhose et/ou un carcinome hépato-cellulaire. Le traitement de référence par interféron pégylé (PegIFN) conduit à environ 20% de réponse virologique (ARN VHD indétectable), mais les rechutes son fréquentes. Le Bulevirtide (BLV) 2mg/sc a l’autorisation de mise sur le marché en Europe. L’objectif de l’étude était d’évaluer l’efficacité et la sécurité du BLV en association avec le PegIFN chez des patients atteints d’HCD, à 48 semaines (48S) après la fin du traitement.

L’association due la combinaison BLV 10 mg + PegIFN pour une durée de 48 semaines suivi de BLV en monothérapie 48 semaines, permet une réponse virologique (ARN VHD indétectable) maintenue 24 et 48 semaines après  la fin du traitement, chez pratiquement un patient sur deux, supérieure au traitement de référence 48 semaines par PegIFN, au bulevirtide seul ou à la combothérapie selon le même schéma PegINF/ BLV 2mg. Cette combinaison permet un traitement à durée déterminée de 96 semaines pour les patients atteints d’HDV.

Abstract

BACKGROUND

In a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear.

METHODS

In this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 μg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 μg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group.

RESULTS

A total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity.

CONCLUSIONS

The combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment.

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