高效抗逆转录病毒治疗对HBV/HIV共感染者HBV耐药基因突变影响的研究

The effect of highly active antiretroviral therapy(HAART) on the prevalence of HBV drug resistance mutations in HBV/HIV co-infected patients

目的了解高效抗逆转录病毒治疗(HAART)对HBV/HIV共感染者HBV耐药突变情况。方法收集123例未进行HAART的HBV/HIV共感染者(组1)和80例已接受HAART的HBV/HIV共感染者(组2)血清标本及其临床资料。对所有血清标本HBV DNA聚合酶基因进行巢式PCR扩增,对扩增产物进行电泳分析和测序,并构建基因进化树,通过单因素及多因素logistic回归模型分析耐药突变相关因素。结果有86例HBV DNA成功扩增并测序(组1有69例,组2有17例);组2耐药突变率(76.5%,95%CI:56.3%—96.7%)显著高于组1(1.4%,95%CI:-1.4%—4.2%),差异有统计学意义(χ~2=50.955,P<0.05)。两组患者中,耐拉米夫定的主要耐药突变形式是rtL180M+rtM204I+rtL80I(35.7%,95%CI:10.6%—60.8%);耐恩替卡韦的主要耐药突变形式是rtM204V+rtL180M(71.4%,95%CI:47.7%—95.1%);未发现替诺福韦酯耐药突变。组2有5例(6.3%)HBV病毒载量超过10×106拷贝/m L;其中1例治疗方案里含替诺福韦酯且已治疗4年。多因素Logistic回归分析发现,HAART是唯一与耐药突变发生有关的因素(P=0.000 1,OR=195.757,95%CI:14.14—2711.00)。结论抗HIV治疗可导致HBV/HIV共感染者HBV耐药突变率增高,在HAART治疗方案中替诺福韦酯不能完全抑制HBV复制。

Object To understand the effect of highly active antiretroviral therapy（HAART） on the prevalence of HBV drug resistance mutations in HBV/HIV co-infected patients. Methods Serum samples and clinic data were collected from HBV/HIV co-infected patients including 123 drug na？ve subjects（group 1） and 80 subjects on HAART（group 2）. The polymerase gene of HBV in serum of all study subjects was amplified and sequenced.Results DNA from 86 subjects was successfully amplified and sequenced, including 69 in group 1 and 17 in group 2.The prevalence of drug resistance mutations in group 2（76.5%, 95%CI： 56.3%-96.7%） was significantly higher than that in group 1（1.4%, 95%CI：-1.4%-4.2%）（χ^2=50.955, P0.05）. The major pattern of lamivudine-resistance mutations was L180 M＋ M204 I＋ L80 I（35.7%, 95%CI： 10.6%-60.8%）. The major pattern of entecavir resistance mutations was M204 V＋ L180 M（71.4%, 95%CI： 47.7%-95.1%）. No putative tenofovir resistance change was found. Five subjects（6.25%） in group 2 had HBV viral loads over 10×10^6 copies/ml. One of them has been treated with a regimen including tenofovir disoproxil fumarate for four years.Multivariate analysis showed that HAART was the only factor associated with the development of drug-resistant mutations（P = 0.000 1, OR=195.757, 95% CI： 14.14-2711.00）.Conclusions Treating HIV in HBV/HIV co-infection patients may increase the prevalence of HBV drug resistance mutations. TDF could not completely suppress HBV replication in these patients.