乙型肝炎病毒基因型耐药检测和临床因素分析

Drug resistance detection of virus genotype in hepatitis B and analysis of its clinical factors

目的探讨乙型肝炎病毒（HBV）耐药的相关因素和临床意义。方法回顾性分析该院2011~2013年的153例慢性乙型肝炎（CHB）患者的临床资料,对已知4种核苷（酸）类似物拉米夫定、阿德福韦酯、恩替卡韦和替比夫定的8个病毒耐药位点使用双脱氧末端终止法（Sanger法）直接测序,检测耐药;统计分析病毒基因型耐药的相关临床因素,分析预后与耐药的相关性。结果 CHB患者共有47例（29.8%）出现了病毒基因型耐药,常见的变异位点为204M-I（18例）、204M-V（8例）、181A-T（10例）、181A-V（5例）、180L-M（14例）。有家族史、HBeAg阳性,既往使用核苷（酸）类似物、基线丙氨酸氨基转移酶（ALT）≥5倍患者病毒耐药比例显著增加,发生率分别为38.8%,34.8%,34.6%和50.0%。COX多因素回归还发现HBV-DNA基因型耐药增加进展为肝硬化的风险,OR值为4.704（95%CI：1.199~18.454）。结论 Sanger法直接测序是HBV-DNA基因型耐药的可靠方法。有乙型肝炎家族史、HBeAg阳性以及使用过核苷（酸）类似物、基线ALT≥5倍患者中病毒耐药比例显著增加;HBV-DNA基因型耐药还增加进展为肝硬化的风险。

Objective To explore the related factors of hepatitis B virus（HBV）drug resistance and their clinical significance.Methods The retrospective analysis was performed on the dinical data in 153 cases of CHB in our hospital during 2011-2013.The8 viral drug resistance loci of 4known nucleosides analogues lamivudine,adefovir ester,entecavir and telbivudine were performed the direct sequencing by using the double DNA end termination method（Sanger method）;the related clinical factors of drug-resistant virus genotypes were statistically analyzed and the correlation between prognosis and drug resistance was analyzed.Results Among 153 patients with CHB,47 cases（29.8%）appeared virus genotype drug-resistant,the common sites were 204M-I（18 cases）,204M-V（8 cases）,followed by 181A-T（10cases）,181A-V（5cases）,then 180L-M（14 cases）.The proportion of viral drug resistance in the patients with family history,HBeAg positive,using the nucleotide analogues in the past and the baseline ALT≥5times was significantly increased,the incidence rates were 38.8%,34.8%,34.6% and 50.0% respectively.The multivariable COX regression found that HBV-DNA genetic drug resistance increased the risk of progression to cirrhosis of the liver,the ORvalue was4.704（95%CI：1.199-18.454）.Conclusion the Sanger method for direct sequencing is reliable and accurate method of HBVDNA genotype drug resistance.The proportion of viral drug resistance in the patients with a family history of hepatitis B,HBeAg positive,using nucleotide analogues and baseline ALT≥5times is significantly increased;HBV-DNA genotype drug resistance also increases the risk of progression to cirrhosis of the liver.