徐州地区HBV感染者逆转录聚合酶区基因耐药变异特点及耐药影响因素分析

李莎; 彭华彬; 李淑芹; 周静; 汪莉萍

doi:10.3969/j.issn.1001-5256.2020.06.012

徐州地区HBV感染者逆转录聚合酶区基因耐药变异特点及耐药影响因素分析

DOI: 10.3969/j.issn.1001-5256.2020.06.012

徐州医科大学附属医院感染性疾病科

基金项目:

中国肝炎防治基金会天晴肝病研究基金(CTHPC20132140)；

详细信息

中图分类号: R512.62
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出版历程
- 出版日期: 2020-06-20

Drug resistance mutations in polymerase region and related influencing factors in patients with hepatitis B virus infection

Research funding:

摘要

摘要:
目的探讨江苏徐州地区HBV感染者逆转录聚合酶区（RT）基因耐药变异模式及与临床特征的关系,并分析影响耐药的相关因素。方法收集2014年5月-2019年4月于徐州医科大学附属医院感染科行HBV RT区检测的242例HBV感染者的临床资料,比较不同基因型、HBeAg状态患者的临床特征。既往有明确核苷（酸）类药物用药史的HBV感染者164例,其中发生已知耐药位点变异118例,未发生已知耐药位点变异46例,两组患者行影响HBV RT区耐药变异危险因素分析。计量资料采用独立样本t检验或Mann-Whitney U检验。计数资料组间比较采用χ2检验。采用logistic回归分析筛选影响患者耐药的危险因素。结果江苏徐州地区HBV感染者RT区耐药突变模式以rtL180M+rtM204I/V/S（25例,21. 2%）、rtA181T/V（16例,13. 6%）、rtM204I/V/S（15例,12. 7%）多见。242例患者中B基因型13例（5. 4%）,C基因型229例（94. 6%）,未发现其他基因型。B基因型感染者ALT水平高于C基因型,差异有统计学意义（U=-2. 096...
- 乙型肝炎病毒 /
- 突变 /
- 抗病毒药 /
- 核苷(酸)类药物
Abstract:
Objective To investigate the pattern of drug resistance mutations of the genes in the reverse transcriptase( RT) region and its association with clinical features in patients with hepatitis B virus( HBV) infection in Xuzhou,Jiangsu,China,as well as the influencing factors for drug resistance. Methods A total of 242 patients with HBV infection who underwent the detection of the HBV RT region in Department of Infectious Diseases,The Affiliated Hospital of Xuzhou Medical University,from May 2014 to April 2019 were enrolled,and the clinical features were compared between the patients with different genotypes and HBeAg statuses. Of all patients,164 had a clear medication history of nucleos( t) ide analogues( NAs),among whom 118 had known mutations at drug resistance loci and 46 did not have such mutations,and the risk factors for drug resistance mutations in the HBV RT region were analyzed for the two groups. The independent samples t-test or the Mann-Whitney U test was used for comparison of continuous data between groups; the chi-square test was used for comparison of categorical data between groups; a logistic regression analysis was used to investigate the risk factors for drug resistance. Results Among the patients with HBV infection in Xuzhou,rtL180 M + rtM204 I/V/S was the most common pattern of drug resistance mutation in the RT region and was observed in 25 patients( 21. 2%),followed by rtA181 T/V in 16 patients( 13. 6%) and rtM204 I/V/S in 15 patients( 12. 7%). Of all 242 patients,13( 5. 4%) had genotype B and 229( 94. 6%) had genotype C,and no other genotypes were found. The patients with genotype B had a significantly higher level of alanine aminotransferase( ALT) than those with genotype C( U =-2. 096,P =0. 036). Compared with the HBeAg-positive group,the HBeAg-negative group had a significantly older age( t = 4. 580,P < 0. 001) and significantly lower HBV DNA load and HBs Ag level( t = 2. 145 and 3. 526,P = 0. 033 and 0. 001). The HBe Ag-negative group had a significantly longer course of disease and a significantly higher level of gamma-glutamyl transpeptidase( GGT) than the HBe Ag-positive group( U =-2. 561 and-2. 016,P = 0. 010 and 0. 044). Compared with the HBe Ag-positive group,the HBe Ag-negative group had a significantly lower proportion of patients with chronic hepatitis B and a significantly higher proportion of patients with liver cirrhosis or hepatocellular carcinoma( χ2= 20. 609,P < 0. 001). The multivariate logistic regression analysis showed that administration of lamivudine + adefovir dipivoxil( OR = 0. 080,95% CI: 0. 008-0. 748,P < 0. 05),administration of adefovir dipivoxil( OR = 5. 493,95% CI: 1. 377-21. 909,P < 0. 05),and improper drug withdrawal( OR = 5. 945,95% CI: 1. 921-18. 403,P < 0. 05) were independent risk factors for drug resistance in patients with HBV infection. Conclusion Most of the patients with HBV infection in Xuzhou are infected with HBV genotype C,with a complex and diverse pattern of drug resistance mutations. HBV DNA replication is active in HBe Ag-positive patients,and therefore,it is recommended to initially select antiviral drugs with high efficiency and low resistance and strengthen the compliance with antiviral therapy.
- hepatitis B virus /
- mutation antiviral agents /
- nucleoside(acid) analogues /

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参考文献(24)

[1] CALIGIURI P,CERRUTI R,ICARDI G,et al. Overview of hepatitis B virus mutations and their implications in the management of infection[J]. World J Gastroenterol,2016,22(1):145-154.

[2] SONG JE,LEE CH,KIM BS. Efficacy of long-term tenofovir disoproxil fumarate therapy in chronic hepatitis B patients with partial virologic response in real practice[J]. Korean J Intern Med,2019,34(4):802-810.

[3] Chinese Society of Infectious Disease,Chinese Medical Association; Chinese Society of Hepatology,Chinese Medical Association. Guidelines for the prevention and treatment of chronic hepatitis B(version 2019)[J]. J Clin Hepatol,2019,35(12):2648-2669.(in Chinese)中华医学会感染病学分会，中华医学会肝病学分会．慢性乙型肝炎防治指南(2019年版)[J]．临床肝胆病杂志，2019,35(12):2648-2669.

[4] MANTOVANI N,CICERO M,SANTANA LC,et al. Detection of lamivudine-resistant variants and mutations related to reduced antigenicity of HBsAg in individuals from the cities of Santos and So Paulo,Brazil[J]. Virol J,2013,10:320.

[5] ORLANDO R,TOSONE G,PORTELLA G,et al. Prolonged persistence of lamivudine-resistant mutant and emergence of new lamivudine-resistant mutants two years after lamivudine withdrawal in HBs Ag-positive chronic hepatitis patient:A case report[J]. Infection,2008,36(5):472-474.

[6] Chinese Society of Hepatology and Chinese Society of Infectious Diseases Chinese,Medical Association. The guideline of prevention and treatment for chronic hepatitis B:A 2015 update[J]. J Clin Hepatol,2015,31(12):1941-1960.(in Chinese)中华医学会肝病学分会，中华医学会感染病学分会．慢性乙型肝炎防治指南(2015年更新版)[J]．临床肝胆病杂志，2015,31(12):1941-1960.

[7] JIANG M,GONG X,XIAO XQ,et al. Expression of serum miRNA-122-3p in patients with CHB treated with PEG-interferon-alpha 2b[J]. Int J Virol,2019,26(5):293-298.(in Chinese)蒋敏，龚兴，肖新强，等．血清miRNA-122-3p在聚乙二醇干扰素-α2b治疗CHB患者中表达的研究[J]．国际病毒学杂志，2019,26(5):293-298.

[8] ZHANG HY,LIU LG,YE CY,et al. Evolution of drug-resistant mutations in HBV genomes in patients with treatment failure during the past seven years(2010-2016)[J]. Virus Genes,2018,54(1):41-47.

[9] QIAN F,QIN J,LI D,et al. Monitoring of genotypic resistance profile in chronic hepatitis B patients receiving nucleos(t)ide analogues in Huzhou,China[J]. J Infect Dev Ctries,2016,10(9):996-1002.

[10] Experts Attending the Disscussion on Hepatitis B Virus Drug Resistance. Drug resistance to nucleoside and nucleotide analogs in chronic hepatitis B and its management[J]. J ClinHepatol,2013,29(1):10-17.(in Chinese)参加乙型肝炎耐药讨论会专家．核苷和核苷酸类药物治疗慢性乙型肝炎的耐药及其管理[J]．临床肝胆病杂志，2013,29(1):10-17.

[11] LIU Y,ZHOU Y,LI X,et al. Hepatitis B virus mutation pattern rt L180M+A181C+M204V may contribute to entecavir resistance in clinical practice[J]. Emerg Microbes Infect,2019,8(1):354-365.

[12] LEE CI,KWON SY,KIM JH,et al. Efficacy and safety of tenofovir-based rescue therapy for chronic hepatitis B patients with previous nucleo(s/t)ide treatment failure[J]. Gut Liver,2014,8(1):64-69.

[13] SVAROVSKAIA ES,CURTIS M,ZHU Y,et al. Hepatitis B virus wild-type and rt N236T populations show similar early HBV DNA decline in adefovir refractory patients on a tenofovirbased regimen[J]. J Viral Hepat,2013,20(2):131-140.

[14] YEH CT,CHEN T,HSU CW,et al. Emergence of the rt A181T/s W172*mutant increased the risk of hepatoma occurrence in patients with lamivudine-resistant chronic hepatitis B[J]. BMC Cancer,2011,11:398.

[15] TERRAULT NA,LOK A,MCMAHON BJ,et al. Update on prevention,diagnosis, and treatment of chronic hepatitis B:AASLD 2018 hepatitis B guidance[J]. Hepatology,2018,67(4):1560-1599.

[16] European Association for the Study of the Liver,European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection[J]. J Hepatol,2017,67(2):370-398.

[17] LIVINGSTON SE,SIMONETTI JP,MCMAHON BJ,et al. Hepatitis B virus genotypes in Alaska Native people with hepatocellular carcinoma:Preponderance of genotype F[J]. J Infect Dis,2007,195(1):5-11.

[18] WANG LP,CHENG X,LI CY,et al. Relationship between pre-existing resistance mutations and HBV genotype in patients with HBV related liver cirrhosis[J]. World Chin J Dig,2017,25(10):891-896.(in Chinese)汪莉萍，程笑，李春杨，等．乙型肝炎肝硬化患者HBV预存耐药变异与基因型的关系[J]．世界华人消化杂志，2017,25(10):891-896.

[19] BAO T,HU QG,YE J,et al. Value of HBs Ag level in dynamic monitoring of disease progression in patients with chronic HBV infection[J]. J Clin Hepatol,2017,33(8):1475-1478.(in Chinese)鲍腾，胡庆刚，叶珺，等．HBsAg水平在慢性HBV感染者疾病进展中的动态监测价值[J]．临床肝胆病杂志，2017,33(8):1475-1478.

[20] HU GF,LI XP,WU ZP,et al. Clinical features of acute-onchronic liver failure induced by withdrawl of nucleos(t)ide analogues[J]. J Clin Hepatol,2017,33(7):1320-1323.(in Chinese)胡高飞，李小鹏，吴振平，等．停用核苷和核苷酸类药物抗HBV后诱发慢加急性肝衰竭的临床特征[J]．临床肝胆病杂志，2017,33(7):1320-1323.

[21] HA NB,HA NB,GARCIA RT,et al. Medication nonadherence with long-term management of patients with hepatitis B e antigen-negative chronic hepatitis B[J]. Dig Dis Sci,2011,56(8):2423-2431.

[22] LEE HW,PARK JY,LEE JW,et al. Long-term efficacy of tenofovir disoproxil fumarate monotherapy for multidrug-resistant chronic HBV infection[J]. Clin Gastroenterol Hepatol,2019,17(7):1348-1355. e2.

[23] LIM YS,GWAK GY,CHOI J,et al. Monotherapy with tenofovir disoproxil fumarate for adefovir-resistant vs. entecavir-resistant chronic hepatitis B:A 5-year clinical trial[J]. J Hepatol,2019,71(1):35-44.

[24] SHIRVANI-DASTGERDI E,WINER BY,CELI-TERRASSA T,et al. Selection of the highly replicative and partially multidrug resistant rt S78T HBV polymerase mutation during TDF-ETV combination therapy[J]. J Hepatol,2017,67(2):246-254.

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