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

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

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χ^2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,P=0.036)。HBeAg阴性组(n=66)感染者年龄高于HBeAg阳性组(n=176),差异有统计学意义(t=4.580,P<0.001),而HBV DNA载量、HBsAg水平均显著低于阳性组(t值分别为2.145、3.526,P值分别为0.033、0.001)。HBeAg阴性组感染者病程较阳性组长,GGT水平高于阳性组,差异均有统计学意义(U值分别为-2.561、-2.016,P值分别为0.010、0.044)。HBeAg阴性组感染者CHB人数所占比例低于阳性患者组,LC、HCC人数所占比例高于阳性组,差异有统计学意义(χ^2=20.609,P<0.001)。多因素logistic回归分析发现,ADV(比值比=5.493,95%可信区间:1.377~21.909)、不适当停药(比值比=5.945,95%可信区间:1.921~18.403)是HBV感染者发生耐药的独立危险因素(P值均<0.05)。结论江苏徐州地区HBV感染者以C基因型为主,耐药突变模式复杂多变。HBeAg阳性患者的HBV DNA复制较为活跃,建议HBV感染者初始选用高效低耐药抗病毒药物,并加强抗病毒治疗的依从性。

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,rtL180M+rtM204I/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 rtA181T/V in 16 patients(13.6%)and rtM204I/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 HBsAg level(t=2.145 and 3.526,P=0.033 and 0.001).The HBeAg-negative group had a significantly longer course of disease and a significantly higher level of gamma-glutamyl transpeptidase(GGT)than the HBeAg-positive group(U=-2.561 and-2.016,P=0.010 and 0.044).Compared with the HBeAg-positive group,the HBeAg-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(χ^2=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 HBeAg-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.