2019-2024年慢性HBV感染患者恩替卡韦耐药突变谱演变及其临床意义OA

Objective To analyze the detection characteristics of entecavir(ETV)genotypic resistance mutations in patients with chronic hepatitis B virus(HBV)infection from 2019 to 2024,aiming to elucidate the evolving patterns of ETV resistance and provide a basis for rational clinical antiviral therapy.Methods A total of 4697 chronic HBV-infected patients who underwent HBV resistance mutation testing and received nucleos(t)ide analogs(NAs)treatment at the Fifth Medical Center of Chinese PLA General Hospital between July 2019 and July 2024 were included in this retrospective study.Based on the detection of ETV resistance mutations,patients were divided into ETV-resistance mutation group(n=547)and non-ETV resistance mutation group(n=4150).Viral genomes were extracted from serum,and the HBV reverse transcriptase(RT)gene region was amplified using single-tube nested PCR,followed by Sanger sequencing to analyze NAs resistance-associated mutations.Clinical data were analyzed using logistic regression to identify risk factors for ETV resistance.Results ETV resistance mutations were detected in 547(11.6%)of the 4697 patients.These mutations were predominantly found in patients with prior NAs therapy,mainly those receiving lamivudine(LAM)-to-ETV sequential therapy(66.5%)or LAM-to-adefovir(ADV)-to-ETV therapy(20.0%).Among the 59 detected ETV resistance mutation patterns,mutations involving the rtS202 site were the most common(302 cases,55.2%),followed by those involving the rtT184 site(233 cases,42.6%),and the rtM250 site(71 cases,13.0%).Compared with non-ETV resistance mutation group,ETV-resistance mutation group had a significantly higher proportion of males,older age,elevated alanine aminotransferase(ALT)levels,higher HBV DNA loads,higher HBeAg positivity rate,higher prevalence of HBV genotype C,cirrhosis,and a history of LAM therapy(P<0.05).Multivariable analysis identified age≥45 years,HBeAg positivity,HBV DNA≥3.0 log10 IU/ml,HBV genotype C,cirrhosis,and prior LAM therapy as independent risk factors for ETV resistance.Among the 184 patients who received tenofovir disoproxil fumarate(TDF)/tenofovir alafenamide(TAF)-based rescue therapy and were followed up,148(80.4%)achieved virological response at week 48.Notably,two patients receiving a TAF+pegylated interferon α(PEG IFN-α)regimen achieved HBeAg seroconversion.Conclusions As a first-line potent oral nucleoside antiviral drug recommended by current guidelines,the clinical resistance pattern of ETV is evolving,with the rtS202G+rtL180M+rtM204V mutation combination becoming predominant.Older age,HBeAg positivity,high HBV DNA load,HBV genotype C,cirrhosis,and prior LAM therapy are key risk factors.For ETV-resistant patients,rescue therapy based on TDF/TAF in combination with PEG IFN-α may be an effective strategy to achieve a functional cure.