Author information

• ¹Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Liebigstrasse 20, 04103 Leipzig, Germany. Electronic address: florian.vanboemmel@medizin.uni-leipzig.de.
• ²Praxis Hepatologie - Magdeburg, Breiter Weg 228m, 39104 Magdeburg, Germany.
• ³Leberzentrum Checkpoint, Bergmannstraße 5-7, 10961 Berlin, Germany.
• ⁴Leberzentrum Hamburg an der Asklepios Klinik St. Georg, Lohmühlenstraße 5, 20099 Hamburg, Germany.
• ⁵Universitätsklinikum Tübingen, Medizinische Klinik I, Otfried-Müller-Straße 10, 72076 Tübingen, Germany.
• ⁶Universitätsklinikum Frankfurt, Medizinische Klinik 1, Theodor-Stern-Kai, 60590 Frankfurt am Main, Germany.
• ⁷Universitätsklinikum Jena, Klinik für Innere Medizin IV, Am Klinikum 1, 07747 Jena, Germany.
• ⁸Universitätsmedizin Mainz, I. Medizinische Klinik und Poliklinik. Johannes Gutenberg Universität, Langenbeckstrasse 1, 55131, Mainz, Germany.
• ⁹Charité-Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany; Klinik für Innere Medizin II, Helios Klinikum Emil von Behring, Walterhöferstrasse 11, 14165 Berlin, Germany.
• ¹⁰Universitätsklinikum Frankfurt, Medizinische Klinik 1, Theodor-Stern-Kai, 60590 Frankfurt am Main, Germany; Universitätsklinikum Heidelberg, Innere Medizin IV, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
• ¹¹Universitätsklinikum Magdeburg AöR, Leipziger Str. 44, 39120 Magdeburg, Germany.
• ¹²Universitätsklinikum Magdeburg AöR, Leipziger Str. 44, 39120 Magdeburg, Germany; Universitätsklinikum Düsseldorf, Klinik für Gastroenterologie, Hepatologie und Infektiologie, Moorenstr. 5, 40225, Düsseldorf, Germany.
• ¹³Universitätsklinikum Gießen, Medizinische Klinik II, Klinikstraße 33, 35385 Gießen, Germany.
• ¹⁴MVZ Gastroenterologie Leverkusen, Franz-Kail-Str. 2, 51375 Leverkusen, Germany.
• ¹⁵Universitätsklinikum RWTH Aachen, Medizinische Klinik III, Pauwelsstraße 30, 52074 Aachen, Germany.
• ¹⁶Gemeinschaftspraxis Schwabstrasse 59, 70197 Stuttgart, Germany.
• ¹⁷Gastroenterologische Gemeinschaftspraxis Herne, Wiescherstr. 20, 44623 Herne, Germany.
• ¹⁸Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Carl-Neuberg-Straße 1, 30625 Hannover, Germany; Centre for Individualised Infection Medicine (CiiM), Hannover, Germany.
• ¹⁹Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Carl-Neuberg-Straße 1, 30625 Hannover, Germany; Universitätsklinikum des Saarlandes, Klinik für Innere Medizin II, Kirrberger Straße 100, 66421 Homburg, Germany.
• ²⁰Zentrum für Infektiologie (zibp) Berlin, Driesener Str. 20, 10439 Berlin, Germany; Henri Mondor Universitary Hospital, Hepatology Department, Creteil, France.
• ²¹LMU Klinikum Großhadern, Medizinischen Klinik und Poliklinik II, Marchioninistraße 15, 81377 München, Germany.
• ²²Gastroenterologisch-Hepatologisches Zentrum Kiel, Goethestr. 11, 24116 Kiel, Germany.
• ²³Universitätsklinikum Jena, Klinik für Innere Medizin IV, Am Klinikum 1, 07747 Jena, Germany; Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, Germany.
• ²⁴Universitätsklinikum Würzburg, Medizinische Klinik II, Oberdürrbacher Straße 697080 Würzburg, Germany.
• ²⁵Universitätsklinikum Hamburg-Eppendorf, I. Medizinische Klinik und Poliklinik, Martinistraße 52, 20246 Hamburg, Germany.
• ²⁶Clinical Trial Centre, Leipzig, Germany.
• ²⁷Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Liebigstrasse 20, 04103 Leipzig, Germany.

Abstract

Background & aims: Nucleos(t)ide analogues (NUCs) are the standard and mostly lifelong treatment for chronic HBeAg-negative hepatitis B, as functional cure (loss of HBsAg) is rarely achieved. Discontinuation of NUC treatment may lead to functional cure; however, to date, the evidence for this has been based on small or non-randomized clinical trials. The STOP-NUC trial was designed with the aim of increasing the HBsAg loss rate using a NUC treatment interruption approach.

Methods: In this multicenter, randomized-controlled trial, 166 HBeAg-negative patients with chronic hepatitis B on continuous long-term NUC treatment, with HBV DNA <172 IU/ml (1,000 copies/ml) for ≥4 years, were randomized to either stop (Arm A) or continue NUC treatment (Arm B) for a 96-week observation period. In total, 158 patients were available for final analysis, 79 per arm. The primary endpoint was sustained HBsAg loss up to week 96.

Results: Our study met its primary objective by demonstrating HBsAg loss in eight patients (10.1%, 95% CI 4.8%-19.5%) in Arm A and in no patient in Arm B (p = 0.006). Among patients with baseline HBsAg levels <1,000 IU/ml, seven (28%) achieved HBsAg loss. In Arm A, re-therapy was initiated in 11 (13.9%) patients, whereas 32 (40.5%) patients achieved sustained remission. A decrease of HBsAg >1 log IU/ml was observed in 16 patients (20.3%) in Arm A and in one patient (1.3%) in Arm B. No serious adverse events related to treatment cessation occurred.

Conclusions: Cessation of NUC treatment was associated with a significantly higher rate of HBsAg loss than continued NUC treatment, which was largely restricted to patients with end of treatment HBsAg levels <1,000 IU/ml.

Impact and implications: As HBeAg-negative patients with chronic hepatitis B on nucleos(t)ide analogues (NUCs) rarely achieve functional cure, treatment is almost always lifelong. The STOP-NUC trial was conducted to investigate whether discontinuing long-term NUC treatment can increase the cure rate. We found that some patients achieved functional cure after stopping NUCs, which was especially pronounced in patients with HBsAg levels <1,000 at the end of NUC treatment, and that many did not need to resume therapy. The results of the Stop-NUC trial provide evidence for the concept of stopping NUC treatment as a therapeutic option that can induce functional cure.