抗病毒治疗对HBV准种进化的影响

tonychant

上海交通大学医学院附属瑞金医院感染科在国际顶级胃肠病学杂志 Gut (影响因子9.36)上发表了乙型肝炎病毒(HBV)准种进化与抗病毒治疗应答的最新研究成果，在国际上首次系统阐述了抗病毒治疗对HBV准种进化的影响。该研究由上海交通大学医学院检验系主任张欣欣教授指导，主要由博士研究生刘峰等完成。

慢性乙型病毒性肝炎是一种严重危害人类健康的常见病，目前尚无根治方法。抗病毒是治疗关键，可以显著改善预后。然而耐药及无应答患者预后差，其进展为肝硬化及肝癌的几率升高。早期预测抗病毒治疗应答及耐药发生可以对患者早期干预，从而改善预后。该研究运用分子克隆及生物信息学技术，从分子进化角度探讨了不同抗病毒药物治疗过程中HBV准种的早期进化特点，发现不同治疗应答患者其HBV准种进化模式明显不同：无应答患者的HBV准种进化较慢并且更复杂。HBV准种的早期进化特点可以准确预测抗病毒治疗的长期疗效。这一研究成果在国际上首次系统阐述了抗病毒治疗对HBV准种进化的影响，揭示了HBV准种与长期抗病毒治疗疗效的关系，并为耐药机制研究开辟了新的领域。该成果与新兴测序技术相结合，可以更早、更准确地预测长期治疗疗效，为临床抗病毒治疗的个体化提供决策依据。

本研究项目得到了国家“十一五”艾滋病和肝炎重大专项、国家自然基金、上海市优秀学科带头人资助项目等的资助。

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Gut doi:10.1136/gut.2010.226225

Evolutionary patterns of hepatitis B virus quasispecies under different selective pressures: correlation with antiviral efficacy

Feng Liu1, Li Chen1,2, De-Min Yu1, Lin Deng1, Rong Chen1, Yin Jiang3, Liang Chen3, Su-Yuan Huang1, Jia-Lun Yu1, Qi-Ming Gong1, Xin-Xin Zhang1

Objective 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.

Methods 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.

Results 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.

Conclusions 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.