恩替卡韦与其他核苷类似物可长期治疗慢性HBV感染相当

StephenW

Entecavir Is Comparable to Other Nucleoside Analogues for Long-Term Treatment of Chronic HBV Infection
Gary Rothbard, MD, MS


Entecavir was safe, effective and comparable to other commonly used nucleoside analogues in terms of malignancy rates and disease progression, with a superior virologic response compared with nonentecavir medications, in patients with chronic hepatitis B (CHB) who were followed for up to 10 years, according to a report published in Clinical Gastroenterology and Hepatology.

Although entecavir has proved efficacious for treating people chronically infected with the hepatitis B virus (HBV), achieving viral replication suppression and effectively reducing disease progression, successful management may entail lifelong therapy. On the basis of preclinical findings of malignancies associated with entecavir, investigators sought to comparatively assess the long-term safety and efficacy profiles of entecavir vs similar nonentecavir medications used to combat CHB.


Between 2007 and 2009, the REALM study (ClinicalTrials.gov identifier: NCT00388674) was an international, multicenter, prospective, randomized trial that enrolled 12,378 participants (median age, 39.0 years; 75.8% male; 84.2% Asian) with CHB who were randomly assigned 1:1 to receive entecavir (n=6216) or another nonentecavir nucleoside analogue (n=6162) and followed-up every 6 months for 7 to 10 years. Alternate nonentecavir formulations included adefovir (71.7%), telbivudine (10.7%), and lamivudine (7.2%). A China subcohort of individuals treated with entecavir (n=2659) or nonentecavir medication (n=2646) evaluated patient virologic response over time, as measured by HBV DNA analysis (HBV DNA <50 IU/mL for at least 2 consecutive visits).

Primary outcomes were times to adjudicated clinical outcome events, including malignancies, HBV disease progression, and death, and rates of serious adverse events and clinical outcome events. Secondary outcomes included rates of hepatocellular carcinoma (HCC), malignant neoplasms, and nonhepatocellular carcinoma malignancies. In the China cohort, virologic response and its relationship to the clinical outcome events was the key endpoint. Cox proportional hazard modeling was used to calculate relative risk of being in the entecavir vs nonentecavir group, using hazard ratios (HRs) and 95% CIs.

There was no significant difference between the entecavir and nonentecavir groups in clinical outcome event timing for any of the primary endpoints, such as overall malignancies (HR, 0.93; 95% CI, 0.800-1.084; P =.36), disease progression (HR, 0.89; 95% CI, 0.769-1.030; P =.12), and death (HR, 0.85; 95% CI, 0.713-1.012; P =.068): No significant differences existed between groups in terms of secondary endpoints. Treatment-related serious adverse events were reported by 12 (0.2%) and 50 (0.8%) entecavir and nonentecavir patients, respectively.

For the China cohort subanalysis, a sustained virologic response was seen in 79.7% and 60.8% of the entecavir and nonentecavir groups, respectively. Viral suppression was associated with a reduction in the risk for hepatocellular carcinoma (HR, 0.03; 95% CI, 0.009-0.113) and liver-related CHB disease progression (HR, 0.09; 95% CI, 0.038-0.221), irrespective of treatment group.

Study limitations included unavailability of HBV DNA data outside of China and a relatively young study population that precluded comparing malignancies by age.

“These findings confirm the long-term safety of entecavir and its appropriateness for long-standing therapy of CHB as recommended by current guidelines,” noted the authors.

Disclosures: This study was sponsored by Bristol-Myers Squibb, with partial support by the Ministry of Science and Technology of China (2018ZX10301202 and 2017ZX10202202) and the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01S131). Please see the original reference for a full list of authors’ disclosures.

Reference

Hou J-L, Zhao W, Lee C, et al. Outcomes of long-term treatment of chronic HBV infection with entecavir or other agents from a randomized trial in 24 countries [published online July 12, 2019]. Clinical Gastroenterol Hepatol. doi:10.1016/j.cgh.2019.07.010

StephenW

恩替卡韦与其他核苷类似物可长期治疗慢性HBV感染相当
Gary Rothbard，医学博士，硕士


恩替卡韦在恶性率和疾病进展方面是安全，有效和可与其他常用核苷类似物相比，与非恩替卡韦药物相比具有优异的病毒学应答，对于随访长达10年的慢性乙型肝炎（CHB）患者，据临床胃肠病学和肝病学杂志发表的一份报告。

恩替卡韦已被证明对治疗慢性感染乙型肝炎病毒（HBV）的人有效，实现病毒复制抑制和有效减少疾病进展，成功的管理可能需要终身治疗。根据与恩替卡韦相关的恶性肿瘤的临床前研究结果，研究人员寻求比较评估恩替卡韦与用于对抗CHB的类似非恩替卡韦药物的长期安全性和有效性。


在2007年至2009年期间，REALM研究（ClinicalTrials.gov标识符：NCT00388674）是一项国际性，多中心，前瞻性随机试验，共纳入12,378名参与者（中位年龄39.0岁; 75.8％男性; 84.2％亚洲人）随机选择CHB分配1：1接受恩替卡韦（n = 6216）或另一种非恩替卡韦核苷类似物（n = 6162），每6个月随访7至10年。替代非恩替卡韦制剂包括阿德福韦（71.7％），替比夫定（10.7％）和拉米夫定（7.2％）。使用恩替卡韦（n = 2659）或非恩替卡韦药物（n = 2646）治疗的中国亚组，通过HBV DNA分析（HBV DNA <50 IU / mL至少连续2次访视）测量，评估患者的病毒学应答随时间的变化。

主要结果是判定临床结果事件的时间，包括恶性肿瘤，HBV疾病进展和死亡，以及严重不良事件和临床结果事件的发生率。次要结果包括肝细胞癌（HCC），恶性肿瘤和非肝细胞癌恶性肿瘤的发生率。在中国队列中，病毒学应答及其与临床结果事件的关系是关键终点。 Cox比例风险模型用于计算恩替卡韦组与非恩替卡韦组的相对风险，使用风险比（HRs）和95％CI。

恩替卡韦组和非恩替卡韦组在任何主要终点的临床结果事件发生时间上没有显着差异，如总体恶性肿瘤（HR，0.93; 95％CI，0.800-1.084; P = .36），疾病进展（HR） ，0.89; 95％CI，0.769-1.030; P = .12）和死亡（HR，0.85; 95％CI，0.713-1.012; P = .068）：在次要终点方面，各组之间没有显着差异。治疗相关的严重不良事件分别由12名（0.2％）和50名（0.8％）恩替卡韦和非恩替卡韦患者报告。

对于中国队列亚组分析，恩替卡韦和非恩替卡韦组分别有79.7％和60.8％的持续病毒学应答。病毒抑制与肝细胞癌风险降低（HR，0.03; 95％CI，0.009 -0.113）和肝脏相关CHB疾病进展（HR，0.09; 95％CI，0.038-0.221）有关，与治疗无关组。

研究的局限性包括中国以外的HBV DNA数据不可用以及相对年轻的研究人群，这些人群不能按年龄比较恶性肿瘤。

“这些研究结果证实了恩替卡韦的长期安全性及其对CHB长期治疗的适当性，正如现行指南所推荐的那样，”作者指出。

披露：本研究由Bristol-Myers Squibb赞助，得到了中国科学技术部（2018ZX10301202和2017ZX10202202）的部分支持以及广东珠江人才计划（2017BT01S131）的地方创新和研究团队项目。有关作者披露的完整列表，请参阅原始参考。

参考

侯JL，赵伟，李C，等。恩替卡韦或其他药物长期治疗慢性HBV感染的结果来自24个国家的随机试验[在线发表于2019年7月12日]。临床Gastroenterol Hepatol。 doi：10.1016 /j.cgh.2019.07.010

小牡丹

恩替卡韦的安全性和副作用已经有定论。TAF是目前最需要研究的，尤其与恩替卡韦相比，其副作用大小如何。很快，TAF将在中国乙肝人群的应用比例大于百分之五十。不能早日得出TAF长期应用的优缺点，将是医学科研的污点。眼看着对TAF的商业炒作愈演愈烈，希望有靠谱的科普知识发表。