Wang Yang, Liu Shuang, Chen Y U, Zheng Sujun, Zhou L I, Lu Fengmin, Duan Zhongping
Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China.
Department of Microbiology and Infectious Diseases, Peking University Health Science Center, Beijing 100083, P.R. China.
Exp Ther Med. 2016 Jun;11(6):2293-2299. doi: 10.3892/etm.2016.3230. Epub 2016 Apr 6.
Adefovir (ADV) sequential monotherapy was included in the 2005 Asia-Pacific guidelines for the management of patients with lamivudine (LAM) resistance. However, following the development of ADV resistance, the proportion of resistant variants during combined rescue therapy with ADV and entecavir (ETV) were unknown. The present study characterized the dynamics of resistant variants in patients with chronic hepatitis B (CHB) and LAM-resistant variants during antiviral therapy consisting of ADV monotherapy followed by ADV-ETV combination therapy. A total of 3 patients were selected from a cohort of 55 patients with CHB due to developing ADV resistance. The patients had been previously treated with LAM (100 mg daily) for 21-24 months. At the initiation of sequential monotherapy with ADV, LAM-resistant variants (rtM204V/I and rtL180M) were detected in the three patients. These patients developed ADV resistance during 19-30 months of ADV sequential monotherapy, and then switched their antiviral regimen to ADV-ETV combination therapy. During ADV monotherapy and ADV-ETV combination therapy, the patients were monitored every 3 months for the first year of therapy, and then every 6 months thereafter. A total of 30 serum samples were collected from the patients throughout the monitoring period. In total, 10 mutants that were associated with commonly-used antiviral drugs were detected by pyrosequencing. During ADV sequential monotherapy, LAM-resistant variants were gradually decreased, whereas ADV-resistant rtA181V/T and rtN236T variants gradually increased in the viral population. During 30-41 months of ADV-ETV combination therapy, viral load reduction was 2.59-3.28 log copies/ml; ADV-resistant variants rtA181T/V and rtN236T were undetectable following 11-24 months of combination therapy; and rtL180M and rtM204I/V remained dominant in the viral population. In conclusion, the results of the present study suggested that, in patients with LAM and ADV-resistant variants that developed during LAM-ADV sequential monotherapy, ETV-ADV combination therapy may partially inhibit the replication of HBV DNA; however, LAM-resistant rtL180M and rtM204I/V variants remained predominant following 30-41 months combination therapy.
阿德福韦酯（ADV）序贯单药治疗被纳入2005年亚太地区拉米夫定（LAM）耐药患者管理指南。然而，在ADV耐药发生后，ADV与恩替卡韦（ETV）联合挽救治疗期间耐药变异体的比例尚不清楚。本研究对慢性乙型肝炎（CHB）患者及LAM耐药变异体在由ADV单药治疗随后进行ADV-ETV联合治疗的抗病毒治疗过程中耐药变异体的动态变化进行了特征分析。从55例CHB患者队列中选取了3例因发生ADV耐药的患者。这些患者此前接受LAM（每日100mg）治疗21 - 24个月。在开始ADV序贯单药治疗时，3例患者均检测到LAM耐药变异体（rtM204V/I和rtL180M）。这些患者在ADV序贯单药治疗19 - 30个月期间出现ADV耐药，随后将抗病毒方案转换为ADV-ETV联合治疗。在ADV单药治疗及ADV-ETV联合治疗期间，治疗的第一年每3个月对患者进行监测，此后每6个月监测一次。在整个监测期间共从患者采集了30份血清样本。通过焦磷酸测序共检测到10种与常用抗病毒药物相关的突变体。在ADV序贯单药治疗期间，LAM耐药变异体逐渐减少，而ADV耐药的rtA181V/T和rtN236T变异体在病毒群体中逐渐增加。在ADV-ETV联合治疗30 - 41个月期间，病毒载量降低了2.59 - 3.28 log拷贝/ml；联合治疗11 - 24个月后，未检测到ADV耐药变异体rtA181T/V和rtN236T；rtL180M和rtM204I/V在病毒群体中仍占主导地位。总之，本研究结果表明，在LAM-ADV序贯单药治疗期间出现LAM和ADV耐药变异体的患者中，ETV-ADV联合治疗可能部分抑制HBV DNA复制；然而，联合治疗30 - 41个月后，LAM耐药的rtL180M和rtM204I/V变异体仍占优势。
