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EASL 2018 FRI-324
Modeling serum HBsAg, HBV DNA and transaminase kinetics
during REP 2139 monotherapy in chronic HBeAg+ HBV infection
L. Shekhtman1,2, N. Borochov1, S. Cotler1, L. Hershkovich1,
S. Uprichard1, M. Al-Mahtab3, M. Bazinet4, A. Vaillant4, H. Dahari1.
1Loyola University Medical Center, United States; 2Bar-Ilan University,
Israel; 3Bangabandhu Sheikh Mujib Medical University, Dhaka,
Bangladesh; 4Replicor Inc., Canada
Email: [email protected]
Background and Aims: Nucleic acid polymers (NAPs) block the
secretion of HBV subviral particles (SVPs) without affecting secretion
of Dane particles or intracellular levels of HBsAg (Blanchet et al. J
Hepatol.2017;66:S257). In HBeAg+ chronic HBV infection, NAP
monotherapy is associated with almost complete removal of
circulating HBsAg and substantial reductions in serum HBV DNA
(Al-Mahtab et al., PLOS One 2016;11:e0156667). Here we provide a
mathematical model that predicts HBV DNA, HBsAg and transaminase
kinetic parameters against HBV during REP 2139 monotherapy in
the REP 102 protocol (NCT02646189).
Methods: Twelve HBeAg+ chronically infected HBV patients received
weekly 500 mg IV infusions of REP 2139 for 20–40weeks (Al-Mahtab
et al., idem). HBV DNA (viral load, VL), HBsAg and alanine
aminotransferase (ALT(levels were measured every 1–2 weeks
during treatment. A model that includes proliferation of uninfected
and infected cells and accounts for HBV DNA, HBsAg and ALT
dynamics was developed.
Results: Mean baseline VL, ALT and HBsAg were 7.9 ± 1.3Log copies/
ml, 79 ± 36IU/l and 4.5 ± 0.7 logIU/ml, respectively. Three nonresponders
with no decline in VL or HBsAg were excluded. VL and
HBsAg significantly declined from baseline levels during therapy.
At the end of NAP monotherapy, mean ALT was lower than baseline
(61 ± 29 IU/l) however ALT flares (>3-fold increase) were observed in
4 patients between 4 and 9 weeks after initiation of therapy. Model
fits indicate that HBsAg and VL declines started 36 ± 32 days after
introduction of REP 2139 and estimate a mean REP 2139 efficacy of
96.7% ± 4.4% in blocking HBsAg secretion. Assuming that REP 2139-
mediated reductions in HBsAg allow for restoration of immune
function, modeling projects a mean increase in the rate of viral
clearance of 541-fold per day (range increase of 0.2–4544 fold per
day) with mean maximum fold enhancement of 3.2. ± 1.2 logs within
110 ± 35 days post therapy initiation. The model reproduces the
observed ALT kinetics in the 5 patients without an ALT flare.
Conclusions: Modeling fits indicated a potent efficacy/enhancement
in blocking HBsAg secretion and associated viral clearance. The delay
observed before HBsAg and VL decline after introduction of REP 2139
was variable among patients and in some cases was decoupled,
suggesting a variable state of immune function participating in the
clearance of HBsAg versus HBV DNA. Further modeling efforts to
refine the understanding of the modes of action of NAPs against HBV
and the nature of ALT flares are ongoing.
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发表于 2018-4-5 05:55
