Xu Yan, Wang Xu, Liu Zhenhua, Zhou Changyu, Qi Wenqian, Jiao Jian, Yu Fan, Guo Honghua, Zhao Ping, Wang Jiangbin
Department of Gastroenterology, China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, 130033, China.
BMC Gastroenterol. 2017 Aug 30;17(1):102. doi: 10.1186/s12876-017-0657-y.
Current treatments for chronic hepatitis B (CHB) include pegylated interferon alpha (PEG-IFN-α) which is an immune modulator, and nucleos(t)ide analogs (NAs) which directly inhibit HBV DNA polymerase. With the limited efficacy of PEG-IFN-α and prolonged treatment periods associated with NAs, there is an urgent need for novel therapeutic strategies, especially for patients with a poor early response to anti-viral therapy.
In this study, 178 patients with chronic hepatitis B (n = 131) and compensated (n = 47) HBV-induced cirrhosis were enrolled, 120 patients with HBeAg (+). All the patients were treated for 12 weeks with PEG-IFN-α. Among them, a total of 138 patients with a poor virological response after 12 weeks were treated for an additional 48 weeks with Peg-IFNα-2a (control) (n = 43), with Peg-IFNα-2a + entecavir (ETV) (n = 49), or Peg-IFNα-2a + adefovir dipivoxil (ADV) (n = 46), and were followed for 48 weeks after therapy. Early virological response was defined as undetectable HBV DNA after anti-viral therapy for 12 weeks. Sustained virological response (SVR) was defined as no change in therapeutic effectiveness after 6 months follow-up, and no recurrence.Therapeutic efficacy was determined by evaluating HBV DNA levels, serum and liver HBsAg levels, liver function tests and liver histology.
Patients in the Peg-IFNα-2a + ETV and Peg-IFNα-2a + ADV groups showed a significantly greater decrease in HBV DNA levels over time, and a significantly higher SVR compared to patients receiving Peg-INFα-2a monotherapy (both P values <0.05). Although patients receiving combination therapy had a significantly higher change in serum HBsAg levels compared to the monotherapy group, there was no significant difference in liver HBsAg levels between the three treatment groups.
This study demonstrated that in patients with a poor virological response after 12 weeks of treatment with Peg-IFNα-2a alone, addition of ADV or ETV significantly reduced HBV DNA levels, serum HBsAg levels, and increased SVR. Individualization of anti-viral therapy would ensure that only patients who do not respond to Peg-IFNα-2a would receive combination therapy. Our data have important implications for the treatment of CHB patients who fail to show an early response to Peg-IFNα-2a monotherapy.
This trial was retrospectively registered on 2012 May 24 at the China Clinical Trials Registry (ChiCTR-OCC-12002196).
慢性乙型肝炎（CHB）的现有治疗方法包括作为免疫调节剂的聚乙二醇化干扰素α（PEG-IFN-α）以及直接抑制乙肝病毒（HBV）DNA聚合酶的核苷（酸）类似物（NAs）。鉴于PEG-IFN-α疗效有限且NAs治疗周期长，迫切需要新的治疗策略，尤其是针对抗病毒治疗早期反应不佳的患者。
本研究纳入了178例慢性乙型肝炎患者（n = 131）和代偿期（n = 47）HBV诱导的肝硬化患者，其中120例HBeAg阳性。所有患者接受PEG-IFN-α治疗12周。其中，138例12周后病毒学反应不佳的患者分别接受Peg-IFNα-2a单药治疗（对照组）（n = 43）、Peg-IFNα-2a联合恩替卡韦（ETV）（n = 49）或Peg-IFNα-2a联合阿德福韦酯（ADV）（n = 46）治疗48周，并在治疗后随访48周。早期病毒学反应定义为抗病毒治疗12周后检测不到HBV DNA。持续病毒学反应（SVR）定义为随访6个月后治疗效果无变化且无复发。通过评估HBV DNA水平、血清和肝脏HBsAg水平、肝功能检查及肝脏组织学来确定治疗效果。
与接受Peg-INFα-2a单药治疗的患者相比，Peg-IFNα-2a联合ETV组和Peg-IFNα-2a联合ADV组患者的HBV DNA水平随时间显著下降，SVR显著更高（P值均<0.05）。尽管联合治疗组患者血清HBsAg水平变化显著高于单药治疗组，但三组治疗组肝脏HBsAg水平无显著差异。
本研究表明，对于单独使用Peg-IFNα-2a治疗12周后病毒学反应不佳的患者，加用ADV或ETV可显著降低HBV DNA水平、血清HBsAg水平，并提高SVR。抗病毒治疗个体化可确保仅对Peg-IFNα-2a无反应的患者接受联合治疗。我们的数据对治疗未能对Peg-IFNα-2a单药治疗显示早期反应的CHB患者具有重要意义。
本试验于2012年5月24日在中国临床试验注册中心（ChiCTR-OCC-12002196）进行回顾性注册。
