Wang Yang, Liu Shuang, Chen Yu, Zheng Sujun, Zhou Li, Lu Fengmin, Duan Zhongping
1. Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
2. Department of Microbiology & Infectious Disease Center, Peking University Health Science Center, Beijing, China.
Int J Med Sci. 2015 May 15;12(5):416-22. doi: 10.7150/ijms.11687. eCollection 2015.
Entecavir (ETV) added to adefovir (ADV) is recommended in the consensus for management of patients with ADV resistance. However, little attention has been focused on the delayed reduction of HBV DNA and dynamics of ADV-resistant variants during ADV-ETV combination rescue therapy in the clinical setting. We characterized the dynamics of viral load and resistant variants in nucleos(t)ide analogues (NAs)-naïve chronic hepatitis B (CHB) patients during antiviral treatment with ADV monotherapy followed by ADV-ETV combination therapy.
A cohort of 55 CHB patients was enrolled in this study. Three NAs-naïve patients developed ADV-resistant variants during 24-33 months of ADV monotherapy, and then switched to ADV-ETV combination therapy. Thirty-five serial serum samples from these three patients were regularly collected during treatment. Ten mutants associated with commonly used antiviral drugs were detected by pyrosequencing.
HBV DNA decreased to the lowest level during ADV monotherapy at 6-18 months, with a decrease of 0.95-5.51 log10 copies/mL, whereas rtA181V or rtN236T gradually increased with extended therapy. HBV DNA decreased to below the detectable level during ADV-ETV combination therapy at 21-24 months, with a decrease of 4.19-4.65 log10 copies/mL. Resistant rtA181V and rtN236T were undetectable after 21-24 months of combination therapy. Moreover, no LAM-resistant rtM204I/V or ETV-resistant variants were detected during the 27-36 months of combination therapy.
Although ADV-resistant variants were suppressed, viral load reduction was delayed during ADV-ETV combination rescue therapy in patients with ADV-resistant HBV. The quantification of resistant variants by pyrosequencing may facilitate monitoring of antiviral therapy.
对于阿德福韦（ADV）耐药患者的管理，共识推荐在阿德福韦基础上加用恩替卡韦（ETV）。然而，在临床环境中，对于ADV-ETV联合挽救治疗期间HBV DNA的延迟下降以及ADV耐药变异株的动态变化关注较少。我们对初治的核苷（酸）类似物（NA）慢性乙型肝炎（CHB）患者在接受ADV单药治疗后序贯ADV-ETV联合治疗期间的病毒载量和耐药变异株动态变化进行了特征分析。
本研究纳入了55例CHB患者队列。3例初治患者在ADV单药治疗24至33个月期间出现ADV耐药变异株，随后换用ADV-ETV联合治疗。在治疗期间定期收集这3例患者的35份系列血清样本。通过焦磷酸测序检测与常用抗病毒药物相关的10种突变体。
HBV DNA在ADV单药治疗6至18个月期间降至最低水平，下降幅度为0.95至5.51 log10拷贝/mL，而rtA181V或rtN236T随着治疗时间延长逐渐增加。在ADV-ETV联合治疗21至24个月期间，HBV DNA降至检测水平以下，下降幅度为4.19至4.65 log10拷贝/mL。联合治疗21至24个月后，耐药的rtA181V和rtN236T未被检测到。此外，在联合治疗的27至36个月期间未检测到拉米夫定耐药的rtM204I/V或恩替卡韦耐药变异株。
尽管ADV耐药变异株受到抑制，但在ADV耐药的HBV患者中，ADV-ETV联合挽救治疗期间病毒载量下降延迟。通过焦磷酸测序对抗药变异株进行定量分析可能有助于监测抗病毒治疗。
