Tenney Daniel J, Rose Ronald E, Baldick Carl J, Pokornowski Kevin A, Eggers Betsy J, Fang Jie, Wichroski Michael J, Xu Dong, Yang Joanna, Wilber Richard B, Colonno Richard J
Bristol-Myers Squibb Company Research and Development, Wallingford, CT 06492, USA.
Hepatology. 2009 May;49(5):1503-14. doi: 10.1002/hep.22841.
Patients with chronic hepatitis B virus (HBV) infection who develop antiviral resistance lose benefits of therapy and may be predisposed to further resistance. Entecavir (ETV) resistance (ETVr) results from HBV reverse transcriptase substitutions at positions T184, S202, or M250, which emerge in the presence of lamivudine (LVD) resistance substitutions M204I/V +/- L180M. Here, we summarize results from comprehensive resistance monitoring of patients with HBV who were continuously treated with ETV for up to 5 years. Monitoring included genotypic analysis of isolates from all patients at baseline and when HBV DNA was detectable by polymerase chain reaction (> or = 300 copies/mL) from Years 1 through 5. In addition, genotyping was performed on isolates from patients experiencing virologic breakthrough (> or = 1 log(10) rise in HBV DNA). In vitro phenotypic ETV susceptibility was determined for virologic breakthrough isolates, and for HBV containing novel substitutions emerging during treatment. The results over 5 years of therapy showed that in nucleoside-naïve patients, the cumulative probability of genotypic ETVr and genotypic ETVr associated with virologic breakthrough was 1.2% and 0.8%, respectively. In contrast, a reduced barrier to resistance was observed in LVD-refractory patients, as the LVD resistance substitutions, a partial requirement for ETVr, preexist, resulting in a 5-year cumulative probability of genotypic ETVr and genotypic ETVr associated with breakthrough of 51% and 43%, respectively. Importantly, only four patients who achieved < 300 copies/mL HBV DNA subsequently developed ETVr.
Long-term monitoring showed low rates of resistance in nucleoside-naïve patients during 5 years of ETV therapy, corresponding with potent viral suppression and a high genetic barrier to resistance. These findings support ETV as a primary therapy that enables prolonged treatment with potent viral suppression and minimal resistance.
慢性乙型肝炎病毒（HBV）感染患者若出现抗病毒耐药性，将失去治疗益处，且可能更容易产生进一步耐药。恩替卡韦（ETV）耐药（ETVr）是由HBV逆转录酶在T184、S202或M250位点发生替换所致，这些替换在出现拉米夫定（LVD）耐药替换M204I/V +/- L180M的情况下出现。在此，我们总结了对持续接受ETV治疗长达5年的HBV患者进行全面耐药监测的结果。监测包括对所有患者基线时以及第1年至第5年通过聚合酶链反应可检测到HBV DNA（>或 = 300拷贝/毫升）时的分离株进行基因分型分析。此外，对出现病毒学突破（HBV DNA升高>或 = 1 log(10)）的患者的分离株进行基因分型。对病毒学突破分离株以及治疗期间出现新替换的HBV进行体外ETV表型敏感性测定。5年治疗结果显示，在初治核苷类药物患者中，基因型ETVr以及与病毒学突破相关的基因型ETVr的累积概率分别为1.2%和0.8%。相比之下，在LVD难治性患者中观察到耐药屏障降低，因为LVD耐药替换是ETVr的部分必要条件，其预先存在，导致基因型ETVr以及与突破相关的基因型ETVr的5年累积概率分别为51%和43%。重要的是，只有4例HBV DNA达到< 300拷贝/毫升的患者随后出现了ETVr。
长期监测显示，初治核苷类药物患者在5年ETV治疗期间耐药率较低，这与有效的病毒抑制和较高的耐药遗传屏障相对应。这些发现支持ETV作为一种一线治疗药物，可实现长期有效的病毒抑制治疗且耐药性最小。
