Department of Medicine, Stanford University, CA, United States.
Antiviral Res. 2010 Dec;88(3):269-75. doi: 10.1016/j.antiviral.2010.09.012. Epub 2010 Sep 25.
Drug resistance resulting from reverse transcriptase (RT) mutations is one of the main obstacles to successful hepatitis B virus (HBV) therapy. Indeed, HBV treatment guidelines recommend HBV genotypic resistance testing for patients receiving nucleos(t)ide RT inhibitors (N(t)RTIs) who develop virological failure. N(t)RTI-resistance mutations at 10 RT positions have been well characterized in phenotypic studies, however, data are lacking on the relative frequency of these mutations in N(t)RTI-treated and untreated individuals. There are also few published data on the extent of amino acid variation at most of the 344 positions of HBV RT and the extent to which this variation is influenced by N(t)RTI treatment. We retrieved 23,871 HBV RT sequences from GenBank and reviewed the published reports of these sequences to ascertain the number of individuals from whom the sequences were obtained, the N(t)RTI treatments of these individuals, and the year and region of virus sampling. We then used these data to populate a relational database we named HBVrtDB. As of July 2010, HBVrtDB contained 6811 sequences from 3869 individuals reported in 281 references. Among these 3869 individuals, 73% were N(t)RTI-naïve and 27% received one or more N(t)RTIs. Among the 10 well-characterized N(t)RTI-resistance mutations, L80I/V, V173L, L180M, A181T, T184S, S202G and M204I/V were significantly associated with treatment with lamivudine, an l-nucleoside analog, and A181S/T/V and N236T were significantly associated with treatment with adefovir, an acyclic nucleoside phosphonate. A similar analysis of ten additional less well-characterized resistance mutations demonstrated a significant association with N(t)RTI treatment for four of the mutations: L82M, S85A, A200V, and Q215S. We also created an interactive program, HBVseq, to enable users to identify mutations in submitted sequences and retrieve the prevalence of these mutations in HBVrtDB according to genotype and N(t)RTI treatment. HBVrtDB and HBVseq are available at http://hivdb.stanford.edu/HBV/releaseNotes/.
耐药性是乙型肝炎病毒（HBV）治疗失败的主要原因之一，而耐药性主要由逆转录酶（RT）突变引起。事实上，HBV 治疗指南建议对接受核苷（酸）类似物逆转录酶抑制剂（N(t)RTIs）治疗后出现病毒学失败的患者进行 HBV 基因耐药性检测。在表型研究中，已对 10 个 RT 位置的 N(t)RTI 耐药突变进行了很好的描述，但是，缺乏关于 N(t)RTI 治疗和未治疗个体中这些突变相对频率的数据。关于 HBV RT 344 个位置中大多数位置的氨基酸变异程度以及 N(t)RTI 治疗对这种变异的影响程度，也仅有少数发表的数据。我们从 GenBank 中检索了 23871 个 HBV RT 序列，并查阅了这些序列的已发表报告，以确定获得序列的个体数量、这些个体的 N(t)RTI 治疗情况以及病毒采样的年份和区域。然后，我们使用这些数据填充了一个名为 HBVrtDB 的关系数据库。截至 2010 年 7 月，HBVrtDB 包含了 6811 个来自 3869 个个体的序列，这些个体分别来自 281 个参考文献。在这 3869 个个体中，73%是 N(t)RTI 初治者，27%接受过一种或多种 N(t)RTI 治疗。在 10 种特征明确的 N(t)RTI 耐药突变中，L80I/V、V173L、L180M、A181T、T184S、S202G 和 M204I/V 与拉米夫定（一种 l-核苷类似物）治疗显著相关，A181S/T/V 和 N236T 与阿德福韦酯（一种无环核苷膦酸酯）治疗显著相关。对另外 10 种不太明确的耐药突变进行的类似分析表明，其中 4 种耐药突变与 N(t)RTI 治疗显著相关：L82M、S85A、A200V 和 Q215S。我们还创建了一个交互式程序 HBVseq，允许用户识别提交序列中的突变，并根据基因型和 N(t)RTI 治疗在 HBVrtDB 中检索这些突变的流行率。HBVrtDB 和 HBVseq 可在 http://hivdb.stanford.edu/HBV/releaseNotes/ 上获得。
