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SAT375
HBeAg seroconversion during treatment with peginterferonalfa2a
(PEG-IFN) is preceded by selection of hepatitis B virus basal
core promoter and pre-core variants which are associated with
decreased HBV replication
Maria Pfefferkorn1, Carolin Hahn1, Karen Rother1, Danilo Deichsel1,
Cynthia Wat2, Thomas Berg1, Florian van Bömmel1. 1Division of
Hepatology, University Clinic Leipzig, Clinic and Policlinic for
Gastroenterology, Hepatology, Infectiology, and Pneumology, Leipzig,
Germany; 2Roche Products Ltd. Welwyn, United Kingdom
Email: [email protected].
Background and Aims: Variants in the basal core promoter (BCP,
nt1743-1849) of the HBV genome (the mutations A1762Tand G1764A
[BCP++]) and a stop mutation at position 1896 (PC) in precore-region
have been described to be associated with response to treatment with
PEG-IFN.We have investigated the development of BCP++/PC variants
during treatment with PEG-IFN.Method: A total of 31 HBeAg positive(+) patients with (n = 19) or
without (w/o, n = 12) subsequent HBeAg seroconversion (SC)
matched by age, HBsAg levels and HBV genotype, who received
PEG-IFN (180 μg/week) for 48 weeks in a prospective randomized
study (Roche, WV16241), were retrospectively analyzed. In serum
samples derived from baseline (BL), weeks 12, 24, 48 and 72 the HBV
markers HBeAg, HBsAg, HBV DNA and HBV RNA were quantified. BCP
and PC-stop regions were analyzed at all time points by direct
sequencing of the region nt1690-2337 on either HBV DNA, or if HBV
DNA was unavailable, on HBV RNA basis.
Results: At BL, 10/19 (52%) patients with subsequent HBeAg SC
showed a BCP++ or PC stop mutation. Until the end of treatment all
patients with HBeAg SC developed a mutation in the BCP/PC region.
In contrast, only 2/12 (16%) patients w/o HBeAg SC showed a
mutation before treatment, whereas additionally 5 patients developed
a BCP/PC mutation during treatment (58%, p = 0.003). Analysis
of the different HBV marker kinetics revealed a strong association of
the occurrence of BCP or PC mutations and decreasing HBV RNA and
HBeAg, but not HBsAg and HBV DNA levels during treatment. Thus,
median HBV RNA levels decreased from 6.1 (0–8) log cp/mL before
treatment to 3.3 (0–6.0) log cp/mL after 12 weeks of treatment and
became (in median) subsequently undetectable in patients with
HBeAg SC. Interestingly, in a few patients with persisting wildtype
BCP/PC sequences (n = 3), HBV RNA levels remained unchanged in
this patient group. Accordingly, patients w/o HBeAg SC who
developed a BCP or PC mutation during treatment (n = 3/5), showed
a strong decrease of HBV RNA levels from 7.6 (7.7–8.6) log cp/mL
before treatment to 0.0 (0–4.3) log cp/mL after 48 weeks.
Conclusion: BCP and PC variants are being selected during PEG-IFN
treatment, especially in patients with subsequent HBeAg SC.
Irrespective of HBeAg SC, the occurrence of these variants leads to a
decrease in HBV replication as measured by HBV RNA. The role of
BCP/PC mutations in the process of HBeAg SC needs to be studied and
our results to be confirmed in a larger population. |
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发表于 2020-8-26 19:32