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Clonal evolution of multidrug resistant hepatitis B virus during entecavir rescue therapy

 Young E. Chon  ;  Bora Jin  ;  Sang H. Ahn  ;  Seungtaek Kim  ;  Nam D. Kim  ;  Jeon H. Park  ;  Chung M. Nam  ;  Kyun-Hwan Kim  ;  Sun P. Hong  ;  Sung H. Choi  ;  Do Y. Kim  ;  Jun Y. Park  ;  Kwang-Hyub Han 
 LIVER INTERNATIONAL, Vol.35(11) : 2370-2383, 2015 
Journal Title
Issue Date
Adenine/analogs & derivatives ; Adenine/therapeutic use ; Adult ; Antiviral Agents/therapeutic use* ; Clonal Evolution/genetics* ; DNA, Viral/genetics ; Drug Resistance, Viral/genetics* ; Drug Therapy, Combination ; Genotype ; Guanine/analogs & derivatives* ; Guanine/therapeutic use ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic/drug therapy* ; Humans ; Lamivudine/therapeutic use ; Male ; Middle Aged ; Mutation ; Organophosphonates/therapeutic use ; Viral Load
chronic hepatitis B ; clonal analysis ; colocation ; drug resistance ; entecavir ; hepatitis B virus ; multidrug resistance
BACKGROUND & AIMS: Analysing the mutation pattern of multidrug resistance (MDR) is important in the treatment of chronic hepatitis B (CHB). In this study, the evolutionary pattern of MDR mutations was investigated in patients receiving entecavir (ETV) rescue therapy.

METHODS: Eight CHB patients with lamivudine (LAM)- and adefovir (ADV)-resistant mutations showing suboptimal response to ETV and to subsequent ETV-plus-ADV therapy were enrolled. The clonal evolution of the mutation pattern was investigated through direct sequencing, multiplex restriction fragment mass polymorphism (RFMP), and clonal analysis and the utility of these methods was compared.

RESULTS: Among 160 clones at baseline, wild-type hepatitis B virus (HBV) was present in 62 (38.8%), LAM-resistant mutations in 92 (57.6%) and ADV-resistant mutations in 55 (34.4%). LAM-resistant mutations increased to 70.6% at the end of ETV therapy and increased to 74.4% at the 12th month of ETV-plus-ADV therapy. During the same time periods, ETV-resistant mutations were present in 46.3% and 38.8%, and ADV-resistant mutations were present in 3.1% and 9.4% respectively. When 256 nucleotides from 32 samples were examined for mutations, clonal analysis detected 93 mutations (36.3%), direct sequencing detected 36 mutations (14.1%) and RFMP detected 73 mutations (28.5%). The sensitivity (73.1%, 95% CI; 64.1-82.1%) and specificity (96.9%, 95% CI; 94.4-99.4%) of RFMP were high, showing a concordance rate of 88.3% with the results from clonal analysis. All mutations exceeding 40% of the total clones detected by clonal analysis were also detected by RFMP.

CONCLUSIONS: The clonal evolution of the mutation pattern in MDR HBV showed the selection of LAM-resistant (±ETV-resistant) HBV during ETV rescue therapy, which may be the primary reason for patients' suboptimal response. Multiplex RFMP is a useful method for detecting MDR mutations in clinical practice.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Preventive Medicine (예방의학교실) > 1. Journal Papers
Yonsei Authors
Kim, Do Young(김도영)
Kim, Seung Taek(김승택)
Nam, Chung Mo(남정모) ORCID logo https://orcid.org/0000-0003-0985-0928
Park, Jeon Han(박전한) ORCID logo https://orcid.org/0000-0001-9604-3205
Park, Jun Yong(박준용) ORCID logo https://orcid.org/0000-0001-6324-2224
Ahn, Sang Hoon(안상훈) ORCID logo https://orcid.org/0000-0002-3629-4624
Chon, Young Eun(전영은)
Han, Kwang-Hyub(한광협) ORCID logo https://orcid.org/0000-0003-3960-6539
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