Department of Infectious Diseases, Institute of Infectious & Respiratory Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Er Rd, Shanghai 200025, China.
Gut. 2011 Sep;60(9):1269-77. doi: 10.1136/gut.2010.226225. Epub 2011 Feb 2.
To investigate the evolution of hepatitis B virus (HBV) quasispecies (QS) within the reverse transcriptase (RT) region during the early stage of entecavir treatment and its impact on virological response, and to compare evolutionary patterns under different selective pressures.
31 patients with chronic hepatitis B receiving entecavir (17 responders and 14 partial responders according to the HBV DNA levels at week 48) and 25 patients receiving lamivudine (14 responders and 11 non-responders) as controls were included. An average of 26 clones (2892 total from both groups) spanning the RT region per sample was sequenced.
QS complexity and diversity, in addition to alanine aminotransferase and HBV DNA levels, were comparable between responders and partial responders at baseline. However, QS complexity in responders at week 4 was statistically lower than that in partial responders at the nucleotide level (0.6494 vs. 0.7723, p=0.039). Net changes in diversity as well as the viral nucleotide substitution rate of responders were higher than those of partial responders, and both correlated with virological responses at both week 48 and the final visit (mean: 28 months). A preliminary model of QS evolution variables predicted 16 of 17 responders and 13 of 14 partial responders in the entecavir group. Despite significant differences between responders to entecavir and responders to lamivudine at week 4, the characteristics of QS were quite similar between partial responders to entecavir and non-responders to lamivudine.
The evolutionary patterns of HBV RT QS differ between responders and partial responders during the early stage of entecavir treatment. Characteristics of HBV QS evolution during the first 4 weeks contribute to the prediction of long-term virological responses. The similar patterns of HBV RT QS in partial responders and non-responders receiving different nucleoside analogues may imply a novel mechanism of drug resistance, which warrants further investigation.
研究恩替卡韦治疗早期乙型肝炎病毒（HBV）准种（QS）在逆转录酶（RT）区的演变及其对病毒学应答的影响，并比较不同选择压力下的进化模式。
纳入 31 例接受恩替卡韦治疗的慢性乙型肝炎患者（根据第 48 周 HBV DNA 水平，17 例为应答者，14 例为部分应答者）和 25 例接受拉米夫定治疗的患者（14 例为应答者，11 例为无应答者）作为对照。对每个样本的 RT 区进行了平均 26 个克隆（两组共 2892 个）的测序。
应答者和部分应答者在基线时的 QS 复杂性和多样性，以及丙氨酸氨基转移酶和 HBV DNA 水平均相似。然而，应答者在第 4 周时的 QS 复杂性在核苷酸水平上明显低于部分应答者（0.6494 比 0.7723，p=0.039）。应答者的多样性净变化以及病毒核苷酸取代率均高于部分应答者，且均与第 48 周和最终随访时的病毒学应答相关（平均：28 个月）。QS 进化变量的初步模型预测了恩替卡韦组 17 例应答者中的 16 例和 14 例部分应答者中的 13 例。尽管恩替卡韦应答者和拉米夫定应答者在第 4 周时存在显著差异，但恩替卡韦部分应答者和拉米夫定无应答者的 QS 特征非常相似。
在恩替卡韦治疗早期，应答者和部分应答者的 HBV RT QS 进化模式不同。第 4 周内 HBV QS 进化的特征有助于预测长期病毒学应答。接受不同核苷类似物治疗的部分应答者和无应答者的 HBV RT QS 相似模式可能暗示了一种新的耐药机制，值得进一步研究。
