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Association of Preexisting Drug-Resistance Mutations and Treatment Failure in Hepatitis B Patients

The role of preexisting minority drug-resistance mutations in treatment failure has not been fully understood in chronic hepatitis B patients. To understand mechanisms of drug resistance, we analyzed drug-resistance mutations in 46 treatment-failure patients and in 29 treatment-naïve patients and de...

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Autores principales: Ma, Jie, Zhang, Yingchun, Chen, Xinyue, Jin, Yi, Chen, Dexi, Wu, Yun, Cui, Jing, Wang, Haitao, Liu, Jia, Li, Ning, Gao, Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728369/
https://www.ncbi.nlm.nih.gov/pubmed/23935839
http://dx.doi.org/10.1371/journal.pone.0067606
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author Ma, Jie
Zhang, Yingchun
Chen, Xinyue
Jin, Yi
Chen, Dexi
Wu, Yun
Cui, Jing
Wang, Haitao
Liu, Jia
Li, Ning
Gao, Feng
author_facet Ma, Jie
Zhang, Yingchun
Chen, Xinyue
Jin, Yi
Chen, Dexi
Wu, Yun
Cui, Jing
Wang, Haitao
Liu, Jia
Li, Ning
Gao, Feng
author_sort Ma, Jie
collection PubMed
description The role of preexisting minority drug-resistance mutations in treatment failure has not been fully understood in chronic hepatitis B patients. To understand mechanisms of drug resistance, we analyzed drug-resistance mutations in 46 treatment-failure patients and in 29 treatment-naïve patients and determined linkage patterns of the drug-resistance mutations in individual viral genomes using a highly sensitive parallel allele-specific sequencing (PASS) method. Lamivudine resistance (LAMr) mutations were predominant in treatment-failure patients, irrespective of the inclusion of LAM in the regimen. The primary LAMr mutations M204V and M204I were detected in 100% and 30% of the treatment-failure patients, respectively. Two secondary LAMr mutations (L180M and V173L) were also found in most treatment-failure patients (87% and 78%, respectively). The linkages containing these three mutations dominated the resistant viruses. Importantly, minority LAMr mutations present in <2% of the viral population were detected in 83% of the treatment-naïve patients. Moreover, the low-frequency same linked LAMr mutations (<0.15%) were detected in 24% of the treatment-naïve patients. Our results demonstrate that the selection of preexisting minority linked LAMr mutations may be an important mechanism for the rapid development of LAM resistance, caution the continuous use of LAM to treat drug-experienced and -naïve hepatitis B patients, and underline the importance of the detection of minority single and linked drug-resistance mutations before initiating antiviral therapy.
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spelling pubmed-37283692013-08-09 Association of Preexisting Drug-Resistance Mutations and Treatment Failure in Hepatitis B Patients Ma, Jie Zhang, Yingchun Chen, Xinyue Jin, Yi Chen, Dexi Wu, Yun Cui, Jing Wang, Haitao Liu, Jia Li, Ning Gao, Feng PLoS One Research Article The role of preexisting minority drug-resistance mutations in treatment failure has not been fully understood in chronic hepatitis B patients. To understand mechanisms of drug resistance, we analyzed drug-resistance mutations in 46 treatment-failure patients and in 29 treatment-naïve patients and determined linkage patterns of the drug-resistance mutations in individual viral genomes using a highly sensitive parallel allele-specific sequencing (PASS) method. Lamivudine resistance (LAMr) mutations were predominant in treatment-failure patients, irrespective of the inclusion of LAM in the regimen. The primary LAMr mutations M204V and M204I were detected in 100% and 30% of the treatment-failure patients, respectively. Two secondary LAMr mutations (L180M and V173L) were also found in most treatment-failure patients (87% and 78%, respectively). The linkages containing these three mutations dominated the resistant viruses. Importantly, minority LAMr mutations present in <2% of the viral population were detected in 83% of the treatment-naïve patients. Moreover, the low-frequency same linked LAMr mutations (<0.15%) were detected in 24% of the treatment-naïve patients. Our results demonstrate that the selection of preexisting minority linked LAMr mutations may be an important mechanism for the rapid development of LAM resistance, caution the continuous use of LAM to treat drug-experienced and -naïve hepatitis B patients, and underline the importance of the detection of minority single and linked drug-resistance mutations before initiating antiviral therapy. Public Library of Science 2013-07-30 /pmc/articles/PMC3728369/ /pubmed/23935839 http://dx.doi.org/10.1371/journal.pone.0067606 Text en © 2013 Ma et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Ma, Jie
Zhang, Yingchun
Chen, Xinyue
Jin, Yi
Chen, Dexi
Wu, Yun
Cui, Jing
Wang, Haitao
Liu, Jia
Li, Ning
Gao, Feng
Association of Preexisting Drug-Resistance Mutations and Treatment Failure in Hepatitis B Patients
title Association of Preexisting Drug-Resistance Mutations and Treatment Failure in Hepatitis B Patients
title_full Association of Preexisting Drug-Resistance Mutations and Treatment Failure in Hepatitis B Patients
title_fullStr Association of Preexisting Drug-Resistance Mutations and Treatment Failure in Hepatitis B Patients
title_full_unstemmed Association of Preexisting Drug-Resistance Mutations and Treatment Failure in Hepatitis B Patients
title_short Association of Preexisting Drug-Resistance Mutations and Treatment Failure in Hepatitis B Patients
title_sort association of preexisting drug-resistance mutations and treatment failure in hepatitis b patients
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728369/
https://www.ncbi.nlm.nih.gov/pubmed/23935839
http://dx.doi.org/10.1371/journal.pone.0067606
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