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本帖最后由 StephenW 于 2020-8-25 21:58 编辑
LBO06
Response to discontinuation of long-term nucleos(t)ide analogue
treatment in HBeAg negative patients: Results of the Stop-NUC
trial
Florian van Bömmel1, Kerstin Stein2, Renate Heyne3, Hjördis Möller3,
Jörg Petersen4, Peter Buggisch4, Christoph Berg5, ChristophWerner5,
Stefan Zeuzem6, Andreas Herrmann7, Philipp Reuken7,
Martin Sprinzl8, Annette Grambihler8, Eckart Schott9,10,
Julia Benckert10, Anita Pathil11, Ulrike von Arnim12, Verena Keitel13,
Janina Trauth14, Simon Karl Georg15, Christian Trautwein16,
Andreas Trein17, Dietrich Hüppe18, Markus Cornberg19,
Frank Lammert20, Patrick Ingiliz21, Reinhart Zachoval22,
Holger Hinrichsen23, Alexander Zipprich24, Hartwig Klinker25,
Julian Schulze Zur Wiesch26, Oana Brosteanu27,
Anett Schmiedeknecht27, Thomas Berg28. 1University Hospital Leipzig,
Gastroenterology, Hepatology, Infectious Diseases and Peumology,
Leipzig, Germany; 2Hepatologie Magdeburg, Magdeburg, Germany;
3Leberzentrum am Checkpoint, Berlin; 4Medical Care Center Hamburg,
Hamburg, Germany; 5Universitätsklinik Tübingen, Medizinische Klinik
Innere Medizin I, Gastroenterologie, Gastrointestinale Onkologie,
Hepatologie, Infektiologie und Geriatrie, Tübingen, Germany;
6University Hospital Frankfurt, Medizinische Klinik 1 Gastroenterologie
und Hepatologie, Pneumologie und Allergologie, Endokrinologie und
Diabetologie sowie Ernährungsmedizin, Frankfurt am Main, Germany;
7University Hospital Jena, Klinik für Innere Medizin IV -
Gastroenterologie, Hepatologie, Infektiologie, Jena, Germany; 8Johannes
Gutenberg-Universitätsklinikum, I. Medizinische Klinik und Poliklinik,
Mainz, Germany; 9Helios Klinikum Emil von Behring, Klinik für Innere
Medizin II, Berlin, Germany; 10Charité Campus Virchow Clinic,
Hepatologie und Gastroenterologie, Berlin, Germany; 11University
Hospital Heidelberg, Abt. Innere Medizin IV, Heidelberg, Germany;
12Otto-von-Guericke-Universität Magdeburg, Klinik für
Gastroenterologie, Hepatologie und Infektiologie, Magdeburg, Germany;
13University Hospital of Düsseldorf, Clinic for Gastroenterology,
Hepatology and Infectiology, Düsseldorf, Germany;
14Universitätsklinikum Giessen, Gastroenterologie, Endokrinologie,
Stoffwechsel und klinische Infektiologie, Gießen, Germany;
15Gastroenterologie Leverkusen, Leverkusen, Germany; 16University
Hospital RWTH Aachen, Medizinische Klinik III - Gastroenterologie und
Stoffwechselkrankheiten, Aachen, Germany; 17Gemeinschaftspraxis für
Allgemeinmedizin und Innere Medizin, Stuttgart, Germany;
18Gastroenterologische Gemeinschaftspraxis Herne, Herne, Germany;
19Medizinische Hochschule Hannover (MHH), Klinik für
Gastroenterologie, Hepatologie und Endokrinologie, Hannover,
Germany; 20Saarland University Hospital, Klinik für Innere Medizin II,
Homburg, Germany; 21Zentrum für Infektiologie Berlin Prenzlauer Berg,
Berlin, Germany; 22LMU Klinikum der Universität München,
Medizinische Klinik und Poliklinik II, München, Germany;
23Gastroenterologisch-Hepatologisches Zentrum Kiel, Kiel, Germany;
24Universitätsklinik Halle, Universitätsklinik und Poliklinik für Innere
Medizin I, Halle, Germany; 25Universitätsklinikum Würzburg,
Medizinische Klinik II, Würzburg, Germany; 26Universitätsklinikum
Hamburg-Eppendorf, I. Medizinische Klinik und Poliklinik, Hamburg,
Germany; 27Universität Leipzig: Institut für Medizinische Informatik,
Statistik und Epidemiologie, Leipzig, Germany; 28University Hospital
Leipzig, Gastroenterology, Hepatology, Infectious Diseases and
Pulmonology, Leipzig, Germany
Email: [email protected].
Background and aims: Disc Discontinuation of long-term suppression
of HBV replication with nucleos(t)ide analogues (NUCs) can
result in durable immune control of hepatitis B virus (HBV)
replication in HBeAg negative patients. We have assessed the effect
of NUC discontinuation in HBeAg negative patients in a prospective,
multicenter, randomized trial (the Stop-NUC study).
Method: HBeAg-negative patients without cirrhosis who had
achieved suppressed HBV DNA for ≥4 years during NUC therapy
were randomly assigned to either stop (Arm A) or continue (Arm B)
treatment. The primary endpoint was sustained HBsAg loss at week
96. Secondary end points included HBsAg seroconversion, virologic
response (HBV DNA ≤20 IU/mL), biochemical response (alanine
aminotransferase (ALT) < upper level normal (ULN)) as well as
number of ALT flares (ALT >3 ULN) and time to re-therapy in the nontreatment
arm. All patients were observed for 96 weeks, with visits
including standard laboratory tests including HBV DNA levels,
quantitative HBsAg, alanine aminotransferase (ALT) and bilirubin
measurements, and adverse event reporting. In each arm 83 patients
were randomized. The full analysis set comprised 158 patients (79 vs
79), excluding eight patients who dropped out immediately after
randomization.
Results: At week 96 after NUC discontinuation, HBsAg loss or
seroconversionwere achieved in 8/79 (10%) and 6/79 (8%) patients in
Arm A and in no patient in Arm B, respectively (p = 0.006 and p =
0.028). After NUC discontinuation, all patients in Arm A and no
patient in Arm B experienced an HBV DNA flare >20 IU/mL, however,
atweek 96 HBV DNAwere levels ≤20 IU/mL in 24/79 (31%) patients in
Arm A and in all patients in Arm B (p < 0.001). ALT flare occurred in
28/79 (35%) patients in Arm A and in no patient in Arm B, and ALT
levels were within normal ranges in 69/79 (88%) patients in Arm A
and in 77/79 (97%) patients in Arm B at week 96 (p = 0.032). At week
96, NUC treatment had to be re-installed in 11/79 (14%) in Arm A
while 54/79 (68%) patients had no indication for treatment according
to current EASL recommendations. No patient in Arm A suffered
serious adverse event possibly related to NUC discontinuation.
Conclusion: This first large-scale randomized study demonstrates
the potential of discontinuation of long-term NUC treatment
for induction of durable immune control and functional cure in
patients with HBeAg negative chronic hepatitis B (EudraCT-Nr.: 2013-
004882-15). |
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