Nucleos(t)ide analogues altered quasispecies composition of hepatitis B virus (HBV)-resistant mutations in serum HBV DNA and serum HBV RNA

Liao，Hao1,2; Zhang，He2; Shao，Jinman3; Li，Xiaoyong2; Zheng，Wei V.1; Li，Le4; Yu，Guangxin5; Si，Lanlan4; Zhou，Tao1; Yao，Zengtao4; Dai，Jiuzeng4; Xu，Dongping4; Cheng，Guanxun1; Qu，Jiuxin2; Liu，Yan4; Chen，Junhui1; Lu，Fengmin5

2023-03-01

10.1002/jmv.28612

Journal of medical virology   Impact Factor & Quartile

0146-6615

1096-9071

Serum hepatitis B virus (HBV) RNA is a new serological indicator reflecting viral replication with good clinical application prospects. This study aimed to clarify the dynamic changes of serum HBV RNA levels and the quasispecies of HBV RNA virus-like particles in nucleos(t)ide analogues (NAs)-experienced chronic hepatitis B (CHB) patients harboring NAs-resistant mutations and their identifiable effects on NAs resistance. We included CHB patients who were on long-term NAs treatment and with HBV DNA rebound. The longitudinally dynamics of serum HBV RNA levels were quantitatively detected, and the quasispecies differences between serum HBV DNA and serum HBV RNA were compared by high-throughput sequencing. The effect of NAs concentration pressure on altering the resistance mutations quasispecies proportion of HBV DNA and HBV RNA in cell supernatant was analyzed in vitro. A total of 447 serum samples from 36 CHB patients treated with NAs were collected. The median follow-up period was 47 months (about 4 years), and the longest follow-up period was 117 months (about 10 years). Our results showed that HBV RNA could reflect virological breakthrough in 23 (64%, 23/36) patients, and serum HBV RNA rebound earlier than HBV DNA in 12 (52%, 12/23) patients. However, serum HBV RNA remained at a consistently high level and did not fluctuate significantly with the HBV DNA rebound in 6 of 36 patients. In addition, serum HBV RNA was not consistently detectable in 7 of the 36 patients, and their serum HBV RNA was undetectable even after HBV DNA had rebounded. The proportion of drug-resistant mutations in HBV DNA was higher than that of HBV RNA by high-throughput sequencing. The results of in vitro experiments showed that the viral strains with drug-resistant mutation in HBV DNA in cell supernatants gradually become the dominant strains with the increase of NAs concentrations. Serum HBV RNA levels can reflect virological breakthrough in most NAs- treated CHB patients, but there are certain limitations. NAs alter the quasispecies composition of serum HBV DNA and serum HBV RNA, resulting in a higher detection rate of drug-resistant mutations in serum HBV DNA than in serum HBV RNA.

hepatitis B virus hepatitis B virus RNA nucleos(t)ide analogues resistant mutation virologic breakthrough

SCI

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China Postdoctoral Science Foundation[2019TQ0206];National Natural Science Foundation of China[81721002];

Virology

Virology

WOS:000960340500009

WILEY

MICROBIOLOGY

2-s2.0-85151168411

Scopus

1.Intervention and Cell Therapy Center,Peking University Shenzhen Hospital,Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center,Shenzhen,China
2.Department of Clinical Laboratory,Shenzhen Third People's Hospital,National Clinical Research Center for Infectious,Southern University of Science and Technology,Shenzhen,China
3.Comprehensive Internal Medicine Department,Beijing Xiaotangshan Hospital,China
4.Department of Infectious Diseases,Fifth Medical Center of Chinese PLA General Hospital,China
5.Department of Microbiology & Infectious Disease Center,School of Basic Medical Sciences,Peking University Health Science Center,China

Liao，Hao,Zhang，He,Shao，Jinman,et al. Nucleos(t)ide analogues altered quasispecies composition of hepatitis B virus (HBV)-resistant mutations in serum HBV DNA and serum HBV RNA[J]. Journal of medical virology,2023,95(3).

Liao，Hao.,Zhang，He.,Shao，Jinman.,Li，Xiaoyong.,Zheng，Wei V..,...&Lu，Fengmin.(2023).Nucleos(t)ide analogues altered quasispecies composition of hepatitis B virus (HBV)-resistant mutations in serum HBV DNA and serum HBV RNA.Journal of medical virology,95(3).

Liao，Hao,et al."Nucleos(t)ide analogues altered quasispecies composition of hepatitis B virus (HBV)-resistant mutations in serum HBV DNA and serum HBV RNA".Journal of medical virology 95.3(2023).