慢性HBV相关肝病患者HBV基因型和耐药突变位点与疾病进展的关系

Relationship of HBV genotypes and drug-resistant mutation sites to disease progression in patients with HBV-related chronic liver diseases

目的探讨慢性HBV相关肝病患者HBV基因型和耐药突变位点检测与疾病进展的关系。方法选取230例经核苷(酸)类似物(NAs)治疗的慢性HBV相关肝病患者作为研究对象,检测其外周血HBV基因型和RT区氨基酸序列耐药突变情况。结果 230例慢性HBV相关肝病患者中100例(43.47%)检出NAs耐药突变,以LAM/LdT耐药最多见(30.00%,69/230)、ADV耐药次之(7.83%,18/230)、ETV耐药最少(5.65%,13/230),比较差异有统计学意义(χ^(2)=67.392,P<0.01)。在LAM/LdT耐药中,单点耐药55例(79.71%),以rtM204V/I突变多见(17.39%,40/230);多点耐药14例(20.29%),以rtL180M+rtM204V/I突变多见(5.65%,13/230)。在ADV耐药中,以单点耐药为主(11例,占61.11%),rtA181T是其主要突变位点(3.91%,9/230)。在ETV耐药中,均为多点耐药,以rtM204V/I+rtA181T+rtS202G/I突变为主(突变率为3.04%,7/230)。230例慢性HBV相关肝病患者均为B基因型和C基因型,未检测到A、D、E、F、G、H、J基因型,其中B基因型患者162例(70.43%);C基因型患者68例(29.57%)。HBV B基因型和C基因型在rt180突变率和rt181突变率上比较,差异均有统计学意义(χ^(2)=11.545、4.845,均P<0.05),但在其他位点突变上差异无统计学意义(P>0.05)。慢性乙型肝炎组、乙型肝炎相关肝硬化组HBV基因型分布差异有统计学意义(χ^(2)=25.012,P<0.01)。慢性乙型肝炎组、乙型肝炎相关肝硬化组和乙型肝炎相关肝癌组rt204耐药位点突变率比较,差异有统计学意义(P=0.015),但其他位点突变率差异无统计学意义(P>0.05)。结论本地区慢性HBV相关肝病患者基因型以B型和C型为主,NAs主要耐药突变点检出率较高,其中不同基因型疾病进展情况和耐药突变情况存在差异,而在不同疾病阶段rt204耐药位点突变率亦存在差异。

Objective To explore the relationship of hepatitis B virus(HBV)genotypes and drug resistance mutation sites to disease progression in patients with HBV-related chronic liver diseases.Methods Two hundred and thirty patients with HBV-related chronic liver diseases treated with nucleos(t)ide analogues(NAs)were selected as study subjects.HBV genotypes and drug-resistant mutations within reverse transcriptase(RT)region were detected.Results Among the 230 patients with HBV-related chronic liver disease,100 cases(43.47%)were found to have NA-resistant mutations,with lamivudine(LAM)/telbivudine(LdT)resistance being the most common(30.00%,69/230),adefovir(ADV)resistance being the second(7.83%,18/230),entecavir(ETV)resistance being the least(5.65%,13/230),and there was statistically significant difference among them (χ^(2)=67.392,P<0.001).Among the cases with LAM/LdT-resistant mutations,55 were single-point mutant(79.71%),most being rtM204V/I mutations(17.39%,40/230);14 were multipoint mutant(20.29%),most being rtL180M+rtM204V/I mutations(5.65%,13/230).Among the cases of ADV resistant mutations,most were single-point mutant(61.11%,11/18),Rta181 t mutations being the most prevalent(3.91%,9/230).And all cases of ETV-resistant mutations were multi-point mutant,most being rtm204 v/I+rta181 t+rts202 g/I mutations(3.04%,7/230).In all the patients with HBV-related chronic liver diseases,HBV genotypes were B(70.43%,162/230)and C(29.57%,68/230),with no genotype A,D,E,F,G,H or J.There was significant difference in mutation rates of rt180 and rt181 between genotype B and C of HBV (χ^(2)=11.545,P=0.001;χ^(2)=4.845,P=0.028),no significant difference in rates of other mutations(P>0.05).The distribution of HBV genotypes was statistically different between chronic hepatitis B group and hepatitis B-related cirrhosis group (χ^(2)=25.012,P<0.001).The rate of rt204 mutation was significantly different among chronic hepatitis B group,hepatitis B-related cirrhosis group and hepatitis B-related liver cancer group(P=0.015),and rates of other mutations were not(P>0.05).Conclusion The genotypes of HBV in this area are mainly B and C,and the detection rate of main resistant mutations against NAs is relatively high.The disease progression and resistant mutations in patients infected with HBV of different genotypes are different,and the rate of rt204 mutation is different in different disease stages.It is suggested that patient infected with HBV should be routinely tested for HBV genotypes and resistance against NAs for individualized treatment and improvement of disease progression.