恩替卡韦治疗肾功能不全患者的HBV

StephenW

August 9, 2019
Entecavir for Treatment of HBV in Patients With Renal Dysfunction
Gary Rothbard, MD, MS


In patients infected with hepatitis B virus (HBV) who had severe renal impairment, entecavir was found to be safe and effective for the treatment of HBV infection and did not have a negative impact on kidney function, according to a report published in Hepatology Research.

The nucleoside analogs tenofovir-disoproxil-fumarate, tenofovir-alafenamide, and entecavir are among the currently recommended first-line HBV therapies available to clinicians. However, the first medication carries known risks for nephrotoxicity, while the second is relatively new and unproven in patients with chronic kidney disease (CKD). This leaves entecavir as a potentially more suitable treatment for individuals infected with HBV who have serious renal dysfunction. Investigators sought to clarify the safety and efficacy of entecavir in this population, given the sparse data and limited evidence offered in the literature.

Between 2006 and 2018, a multicenter retrospective study enrolled 273 patients (median age, 57 years; 53.1% male) >20 years of age who had been treated with entecavir monotherapy (0.5 mg orally, given daily to weekly, depending on renal disease severity) for HBV infection for >1 year. Participants were evaluated at baseline and annually following initiation of therapy.

Primary outcomes included entecavir efficacy — assessed by viral load reduction rates, alanine transaminase normalization and virologic breakthrough rates — as well as renal function changes, according to baseline renal function. Participants were categorized by level of baseline renal dysfunction, with significant differences in baseline demographic and clinical characteristics existing between those with CKD stage G1/G2 and those with CKD stage G3/G4/G5 or who were on hemodialysis. Among all enrolled patients, at baseline there were 25 (9.2%), 5 (1.8%), and 10 (3.7%) people with CKD stage G3, stage G4/G5, and on hemodialysis, respectively. In the remainder of participants, kidney disease was categorized as stage G1/G2, with normal renal function and estimated glomerular filtration rates (eGFR) >60 mL/min/1.73 m2.

At 1, 2, and 3 years following entecavir therapy initiation, 84.2%, 94.0%, and 96.2% of patients, respectively, demonstrated substantial viral load reduction and disappearance of HBV-DNA. In people undergoing hemodialysis, entecavir had 100% efficacy and no virologic breakthrough after 1 year. A total of 7 individuals (2.5%) demonstrated virologic responses during the study. There were similar rates of HBV-DNA disappearance, virologic breakthrough, and alanine transaminase normalization (89.7%) over time seen in those with and without renal impairment.

Regarding impact on renal function, at 5 years after entecavir initiation, participants without baseline renal dysfunction had significant worsening of eGFR over time (P <.001), while those with CKD stage G3/G4/G5 showed nonsignificant improvements and a trend toward restoration of eGFR (P =.184). Entecavir was found to be safe over the course of the study, with no patients undergoing hemodialysis reporting serious adverse events that caused discontinuation.

Study strengths included a long median observation period, analysis of renal impact according to baseline renal function, and inclusion of several patients undergoing hemodialysis. Study limitations included a retrospective design with missing data, inability to track all co-administered medications, significant differences in baseline characteristics between groups, and a potentially insufficient treatment follow-up duration.

“In conclusion, [entecavir] for HBV-infected patients with moderate to severe renal dysfunction, including hemodialysis patients, is highly effective. [Entecavir] is indicated to be safe for patients with renal dysfunction,” noted the authors. They recommended that future research include longer studies involving more patients.

Funding and Conflicts of Interest Disclosures:

This study was supported in part by grants from the Japan Agency for Medical Research and Development (AMED; grant number grant number 19fk0210022h0103, 19fk0210018h0003, 19fk0310101s0503, 19fk0210048s0501, 19fk0210058h0001, 19fk0210047s04010401) and SPS KAKENHI; (Grant Number 19K0845819K08458).

Professor Naoya Sakamoto received lecture fees from Bristol Myers Squibb and Pharmaceutical K.K, grants and endowments from MSD K.K and Chugai Pharmaceutical Co., Ltd, and a research grant from Gilead Sciences, Inc. Dr. Goki Suda received research grants from Bristol Myers Squibb, MSD K.K, and Gilead Sciences. The other authors have nothing to disclose.

Reference

Suzuki K, Suda G, Yamamoto Y, et al. Entecavir treatment of hepatitis B virus‐infected patients with severe renal impairment and those on hemodialysis [published online July 1, 2019]. Hepatol Res. doi:10.1111/hepr.13399

StephenW

2019年8月9日
恩替卡韦治疗肾功能不全患者的HBV
Gary Rothbard，医学博士，硕士


根据Hepatology Research发表的一份报告，在感染了严重肾功能不全的乙型肝炎病毒（HBV）的患者中，恩替卡韦被发现对治疗HBV感染是安全有效的，并且对肾功能没有负面影响。

核苷类似物替诺福韦 - 地索普西 - 富马酸盐，替诺福韦 - 丙氨酰胺和恩替卡韦是目前推荐的临床医生可用的一线HBV疗法。然而，第一种药物具有已知的肾毒性风险，而第二种药物具有相对较新且未经证实的患有单一性奇异性的患者在文献中。

在2006年至2018年期间，一项多中心回顾性研究纳入了273例接受恩替卡韦单药治疗的患者（中位年龄57岁; 53.1％男性）> 20岁（口服0.5 mg，每日一次，每周一次，取决于肾脏疾病的严重程度）对于HBV感染> 1年。参与者在基线时和开始治疗后每年进行评估。

主要结果包括恩替卡韦疗效 - 根据基线肾功能，通过病毒载量减少率，丙氨酸转氨酶标准化和病毒学突破率以及肾功能改变进行评估。参与者按基线肾功能不全水平分类，基线人口统计学和CKD分期G1 / G2期患者和CKD分期G3 / G4 / G5患者或血液透析患者的临床特征存在显着差异。在所有入组患者中，基线时分别有25例（9.2％），5例（1.8％）和10例（3.7％）CKD分期G3期，G4期/ G5期和血液透析患者。在其余参与者中，肾脏疾病被归类为G1 / G2期，肾功能正常，估计肾小球滤过率（eGFR）> 60 mL / min / 1.73 m2。

恩替卡韦治疗开始后1年，2年和3年，分别有84.2％，94.0％和96.2％的患者表现出显着的病毒载量减少和HBV-DNA消失。在接受血液透析的人群中，恩替卡韦的疗效为100％，1年后无病毒学突破。在研究期间共有7个个体（2.5％）表现出病毒学应答。 HBV-DNA消失，病毒学突破和丙氨酸转氨酶正常化的发生率（89.7％）与有和无肾功能损害的患者相似。

关于对肾功能的影响，恩替卡韦开始后5年，没有基线肾功能不全的参与者随着时间的推移eGFR显着恶化（P <.001），而CKD分期G3 / G4 / G5的患者显示无显着改善和恢复趋势eGFR（P = .184）。在研究过程中发现恩替卡韦是安全的，没有接受血液透析的患者报告导致停药的严重不良事件。

研究优势包括长期中位观察期，根据基线肾功能分析肾脏影响，以及包括几名接受血液透析的患者。研究限制包括回顾性设计，缺失数据，无法跟踪所有共同给药的药物，组间基线特征的显着差异，以及可能不充分的治疗随访持续时间。

“总之，对于HBV感染的中重度肾功能不全患者，包括血液透析患者，[恩替卡韦]非常有效。[恩替卡韦]对肾功能不全患者是安全的，”作者指出。他们建议未来的研究包括涉及更多患者的更长研究。

资金和利益冲突披露：

该研究部分得到了日本医学研究和开发机构（AMED;资助号码授权号19fk0210022h0103,19fk0210018h0003,19fk0310101s0503,19fk0210048s0501,19fk0210058h0001,19fk0210047s04010401）和SPS KAKENHI的资助; （拨款号码19K0845819K08458）。

Naoya Sakamoto教授接受了Bristol Myers Squibb和Pharmaceutical KK的讲座费，MSD KK和Chugai Pharmaceutical Co.，Ltd的赠款和捐赠，以及Gilead Sciences，Inc。的研究经费.Goki Suda博士获得了Bristol Myers Squibb的研究经费， MSD KK和吉利德科学。其他作者没有透露任何内容。

参考

Suzuki K，Suda G，Yamamoto Y，et al。恩替卡韦治疗乙型肝炎病毒感染的严重肾功能不全患者和血液透析患者[在线发表于2019年7月1日]。 Hepatol Res。 DOI：10.1111 / hepr.13399