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2015 ; 5
(ä): 17123
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Composition and Interactions of Hepatitis B Virus Quasispecies Defined the
Virological Response During Telbivudine Therapy
#MMPMID26599443
Zhou B
; Dong H
; He Y
; Sun J
; Jin W
; Xie Q
; Fan R
; Wang M
; Li R
; Chen Y
; Xie S
; Shen Y
; Huang X
; Wang S
; Lu F
; Jia J
; Zhuang H
; Locarnini S
; Zhao GP
; Jin L
; Hou J
Sci Rep
2015[Nov]; 5
(ä): 17123
PMID26599443
show ga
Reverse transcriptase (RT) mutations contribute to hepatitis B virus resistance
during antiviral therapy with nucleos(t)ide analogs. However, the composition of
the RT quasispecies and their interactions during antiviral treatment have not
yet been thoroughly defined. In this report, 10 patients from each of 3 different
virological response groups, i.e., complete virological response, partial
virological response and virological breakthrough, were selected from a
multicenter trial of Telbivudine treatment. Variations in the drug
resistance-related critical RT regions in 107 serial serum samples from the 30
patients were examined by ultra-deep sequencing. A total of 496,577 sequence
reads were obtained, with an average sequencing coverage of 4,641X per sample.
The phylogenies of the quasispecies revealed the independent origins of two
critical quasispecies, i.e., the rtA181T and rtM204I mutants. Data analyses and
theoretical modeling showed a cooperative-competitive interplay among the
quasispecies. In particular, rtM204I mutants compete against other quasispecies,
which eventually leads to virological breakthrough. However, in the absence of
rtM204I mutants, synergistic growth of the drug-resistant rtA181T mutants with
the wild-type quasispecies could drive the composition of the viral population
into a state of partial virological response. Furthermore, we demonstrated that
the frequency of drug-resistant mutations in the early phase of treatment is
important for predicting the virological response to antiviral therapy.