标题: EASL 2018 PS-162 丁型肝炎病毒RNA和抗原强烈肝内下降 用Myrcludex B [打印本页] 作者: StephenW 时间: 2018-4-3 11:27 标题: EASL 2018 PS-162 丁型肝炎病毒RNA和抗原强烈肝内下降 用Myrcludex B
EASL 2018 PS-162
Strong intrahepatic decline of hepatitis D virus RNA and antigen
after 24weeks of treatment with Myrcludex B in combinationwith
Tenofovir in chronic HBV/HDV infected patients: Interim results
from a multicenter, open-label phase 2b clinical trial
L. Allweiss1, C. Dettmer1, T. Volz1, K. Giersch1, A. Alexandrov2,
H.Wedemeyer3,4, S. Urban4,5, J.-H. Bockmann1,4, M. Luetgehmann4,6,
M. Dandri1,4. 1University Medical Center Hamburg-Eppendorf, I.
Department of Internal Medicine, Hamburg, Germany; 2MYRGmbH, Bad
Homburg, Germany; 3Hannover Medical School, Department of
Gastroenterology, Hepatology and Endocrinology, Hannover, Germany;
4German Center for Infection Research (DZIF), Hannover, Heidelberg and
Hamburg-Lübeck-Borstel Partner Sites; 5University Hospital Heidelberg,
Department of Infectious Diseases, Molecular Virology; 6University
Medical Center Hamburg-Eppendorf, Department of Medical
Microbiology, Virology and Hygiene, Hamburg, Germany
Email: [email protected]
Background and Aims: Besides interferon alpha there is no approved
treatment for patients chronically infected with hepatitis delta virus
(HDV). Myrcludex B (MyrB) is a first-in-class entry inhibitor which
blocks the HBV/HDV receptor sodium taurocholate co-transporter
NTCP. Interim results of this phase 2b clinical trial on chronically HBV/
HDV co-infected individuals receiving MyrB daily in combination
with TDF demonstrated a dose-dependent HDV RNA decline in
serum, which was accompanied by ALT reduction and normalization
in some patients (Wedemeyer et al., Hepatology 2017, DOI: 10.1002/
hep.29500). Here we investigated the efficacy of MyrB treatment in
reducing HDV intrahepatically using paired liver biopsies obtained at
baseline (BL) and week 24.
Method: 120 HBeAg-negative patients with chronic Hepatitis Dwere
randomized in 4 treatment arms. TDF treatment (245mg/day) started
at least 12w prior to MyrB. MyrBwas administered s.c. once daily at 2
(A), 5 (B) or 10 (C) mg for 24w. Patients in arm D received TDF alone.
BL biopsies were available for 31 patients, paired liver biopsies for 22
patients. Virological parameters were assessed by qPCR and
immunohistochemistry. Expression of inflammatory genes was
determined by qPCR.
Results: At w24, intrahepatic HDV RNA declined in all MyrB arms
with median reductions from BL by 0.78 log in A (n = 7), 1.07 log in B
(n = 5) and by 1.34 log in C (n = 7). TDF treatment (D) showed modest
HDV RNA reductions (0.30 logIU/ml, n = 3). Median HBV infection
levels at BL (n = 31) were 0.23 HBV DNA copies/cell, 0.03 cccDNA
copies/cell, 2.5 total HBV RNA/GAPDH; among paired biopsies, the
strongest median reduction of HBV RNA (0.4 log) and total HBV DNA
(0.6log) was determined in group C. Of note, immunohistochemistry
revealed a substantial and dose-dependent decrease of HDAg+ cells.
Accordingly, transcriptional levels of inflammatory chemokines
decreased (e.g. CXCL10 median 0.45 Δlog 10) and such reduction
was more pronounced in patients with intrahepatic HDV RNA decline
of ≥1 log10.
Conclusion: Intrahepatic levels of HDV RNA and of HDAg+ cells
strongly declined after 24 weeks of MyrB treatment in a dosedependent
manner. The concomitant ALT reduction and decrease of
inflammatory cytokines suggests that the drop of HDV infection can
diminish liver inflammation. Because of the strong decline of
intrahepatic HDV infection levels induced by blocking HDV entry
and turnover, HDV clearance might be achievable upon prolonged
treatment durations.