慢性乙型肝炎患者停用核苷（酸）類似物後的嚴重不良事件

StephenW

慢性乙型肝炎患者停用核苷（酸）類似物後的嚴重不良事件：一項系統評價和薈萃分析
Cheng-Hao Tzeng 1 2 3、Tzu-Haw Chen 1 2 3、Jia-Ling Wu 4、Teng-Yu Lee 5 6、John A Borghi 7、Jaw-Town Lin 2、Mindie H Nguyen 8 9、Yao-Chun Hsu 1 2 3 10 11
隸屬關係
隸屬關係

     1個
     台灣高雄義大腫瘤醫院消化內科和肝病科。
     2個
     台灣高雄義大醫院消化內科和肝病科。
     3個
     台灣高雄義守大學醫學院醫學院。
     4個
     國立成功大學醫學院公共衛生學系，台南，台灣。
     5個
     台灣台中市台中榮民總醫院內科消化內科和肝病科。
     6個
     台灣台中中山醫學大學醫學院。
     7
     美國加利福尼亞州帕洛阿爾托市斯坦福大學萊恩醫學圖書館和知識管理中心。
     8個
     美國加利福尼亞州帕洛阿爾托市斯坦福大學醫學中心胃腸病學和肝病學部。
     9
     美國加利福尼亞州帕洛阿爾托市斯坦福大學醫學中心流行病學和人口健康系。
     10
     國立陽明交通大學生物醫學信息學研究所，台北，台灣。
     11
     輔仁大學附屬醫院/輔仁大學消化內科，新北，台灣。

     PMID：36466989 PMCID：PMC9708915 DOI：10.1016/j.jhepr.2022.100617

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抽象的

背景和目的：慢性乙型肝炎患者停用核苷（酸）類似物 (NUC) 後出現嚴重臨床結果的風險仍未得到充分錶徵。 本系統評價和薈萃分析旨在評估當前關於該問題的文獻。

方法：我們在 PubMed、Embase 和 Web of Science 中搜索了 NUC 停止研究，這些研究記錄了 2006 年 1 月 1 日至 2022 年 8 月 18 日期間發表的臨床結果。我們進行了元研究分析，以檢查報告的結果與研究設計和特徵之間的關係 並且還匯總了非重疊人群的研究，以提供 (1) 嚴重肝炎發作或肝功能失代償或 (2) 肝炎發作相關死亡或肝移植的比例的風險估計。

結果：元研究分析包括 50 項具有高度異質性設計和特徵的研究。 我們發現，根據結果定義、隨訪持續時間和样本量，安全結果的報告差異很大。 只有 10 項研究將安全事件預先指定為研究結果，只有 4 項研究的結果定義包括肝功能不全、隨訪時間 >12 個月和样本量 >100 名患者。 我們進一步匯總了 15 項涉及 4,525 人的研究，估計重度肝炎發作或失代償的發生率為 1.21%（95% CI 0.70-2.08%），具有顯著異質性（I 2 = 54%，p <0.01），而肝炎發作- 相關死亡或肝移植的發生率為 0.37% (95% CI 0.20-0.67%)，無顯著異質性 (I 2 = 0.00%，p = 1.00)。

結論：目前關於 NUC 停用後嚴重臨床結果風險的文獻非常有限且異質性很大。 對可用數據的匯總分析發現，大約 1% 的停止使用 NUC 的患者出現了嚴重的疾病發作或肝功能失代償。

影響和意義：當前有關慢性乙型肝炎患者停用 NUC 的安全性問題的文獻有限，而且在設計和特徵上存在異質性，因此應謹慎解讀。 根據目前可用的數據，發生嚴重肝炎發作或肝功能失代償的患者比例估計為 1.21%，與發作相關的死亡或肝移植的患者比例估計為 0.37%。 我們的研究結果對於接受核苷（酸）類似物治療乙型肝炎病毒感染的個體很重要，因為我們不僅匯集了當前可用的數據來估計治療停止後發生嚴重臨床不良事件的風險，而且還發現了現有文獻關於安全性的關鍵局限性 有限療法。

關鍵詞：ALT，丙氨酸轉氨酶； CHB，慢性乙型肝炎； 慢性乙型肝炎； ETV，恩替卡韋； HBV，乙型肝炎病毒； HBeAg，乙型肝炎e抗原； HBsAg，乙型肝炎表面抗原； NUC，核苷（酸）類似物； PT，凝血酶原時間； TDF，富馬酸替諾福韋二吡呋酯； 有限療法； 核苷（酸）類似物； 結果研究。

© 2022 作者。
利益衝突聲明

CHT：發言人：Abbvie、Bristol-Myers Squibb、Gilead Sciences、Merck Sharp & Dohme 和 Bayer。 TYL：研究資助：Gilead Sciences、Merk Sharp & Dohme 和 Roche。 諮詢/諮詢委員會/發言人：吉利德科學、Merk Sharp & Dohme、羅氏、艾伯維、百時美施貴寶、拜耳、楊森和衛材。 MHN：研究資助：輝瑞、Glycotest、Enanta、吉利德、國家癌症研究所、Vir、BK Kee 基金會； 諮詢/諮詢委員會：Novartis、Spring Bank、Janssen、Gilead、Exact Sciences、Intercept、Eli Lilly、Bayer、Eisai、Laboratory of Advanced Medicine。 YCH：研究資助：Gilead Sciences； 諮詢/諮詢委員會：Gilead Sciences； 演講者：Abbvie、Bristol-Myers Squibb、Gilead Sciences、Merck Sharp & Dohme 和 Novartis。 所有其他作者：無需透露。 詳情請參閱隨附的 ICMJE 披露表格。

StephenW

Serious adverse events after cessation of nucleos(t)ide analogues in individuals with chronic hepatitis B: A systematic review and meta-analysis
Cheng-Hao Tseng  1   2   3 , Tzu-Haw Chen  1   2   3 , Jia-Ling Wu  4 , Teng-Yu Lee  5   6 , John A Borghi  7 , Jaw-Town Lin  2 , Mindie H Nguyen  8   9 , Yao-Chun Hsu  1   2   3   10   11
Affiliations
Affiliations

    1
    Division of Gastroenterology and Hepatology, E-DA Cancer Hospital, Kaohsiung, Taiwan.
    2
    Division of Gastroenterology and Hepatology, E-DA Hospital, Kaohsiung, Taiwan.
    3
    School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan.
    4
    Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
    5
    Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
    6
    School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
    7
    Lane Medical Library & Knowledge Management Center, Stanford University, Palo Alto, CA, USA.
    8
    Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA.
    9
    Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, CA, USA.
    10
    Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan.
    11
    Division of Gastroenterology, Fu-Jen Catholic University Hospital/Fu-Jen Catholic University, New Taipei, Taiwan.

    PMID: 36466989 PMCID: PMC9708915 DOI: 10.1016/j.jhepr.2022.100617

Free PMC article
Abstract

Background & aims: The risk of serious clinical outcomes following cessation of nucleos(t)ide analogues (NUCs) in individuals with chronic hepatitis B remains poorly characterized. This systematic review and meta-analysis aimed to evaluate current literature on this issue.

Methods: We searched PubMed, Embase, and Web of Science for NUC stop studies that noted clinical outcomes published between January 1, 2006 and August 18, 2022. We performed meta-research analyses to examine the relationships of reported outcomes with study designs and characteristics and also pooled studies with non-overlapping populations to provide risk estimates for the proportions of (1) severe hepatitis flares or hepatic decompensation or (2) hepatitis flare-related death or liver transplantation.

Results: The meta-research analysis included 50 studies of highly heterogeneous designs and characteristics. We found that reporting of safety outcomes varied widely according to outcome definition, follow-up duration, and sample size. Only ten studies prespecified safety events as the study outcome, and only four had an outcome definition to include hepatic insufficiency, a follow-up duration >12 months, and a sample size >100 patients. We further pooled 15 studies with 4,525 individuals and estimated that severe hepatitis flares or decompensation would occur in 1.21% (95% CI 0.70-2.08%), with significant heterogeneity (I 2 = 54%, p <0.01), while hepatitis flare-related death or liver transplantation would occur in 0.37% (95% CI 0.20-0.67%), without significant heterogeneity (I 2 = 0.00%, p = 1.00).

Conclusions: Current literature on the risk of serious clinical outcomes following NUC cessation is very limited and highly heterogeneous. Pooled analyses of available data found approximately 1% of patients who stopped NUCs developed severe flares or hepatic decompensation.

Impact and implications: Current literature regarding the safety concerns surrounding NUC cessation for individuals with chronic hepatitis B is limited and heterogeneous in designs and characteristics, and thus should be interpreted with great caution. Based on currently available data, the proportion of patients that develop severe hepatitis flares or hepatic decompensation was estimated at 1.21% and that of flare-related death or liver transplantation at 0.37%. Our findings are important for individuals receiving nucleos(t)ide analogues for hepatitis B virus infection because we not only pooled currently available data to estimate the risk of serious clinical adverse events following treatment cessation but also uncovered critical limitations of existing literature regarding the safety of finite therapy.

Keywords: ALT, alanine transaminase; CHB, chronic hepatitis B; Chronic hepatitis B; ETV, entecavir; HBV, hepatitis B virus; HBeAg, hepatitis B e-antigen; HBsAg, hepatitis B surface antigen; NUC, nucleos(t)ide analogues; PT, prothrombin time; TDF, tenofovir disoproxil fumarate; finite therapy; nucleos(t)ide analogue; outcome research.

© 2022 The Author(s).
Conflict of interest statement

CHT: Speaker: Abbvie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, and Bayer. TYL: Research grant: Gilead Sciences, Merk Sharp & Dohme, and Roche. Consulting/advisory board/speaker: Gilead Sciences, Merk Sharp & Dohme, Roche, Abbvie, Bristol-Myers Squibb, Bayer, Janssen, and Eisai. MHN: Research grant: Pfizer, Glycotest, Enanta, Gilead, National Cancer Institute, Vir, BK Kee Foundation; Consulting/advisory board: Novartis, Spring Bank, Janssen, Gilead, Exact Sciences, Intercept, Eli Lilly, Bayer, Eisai, Laboratory of Advanced Medicine. YCH: Research grant: Gilead Sciences; Consulting/advisory board: Gilead Sciences; Speaker: Abbvie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, and Novartis. All other authors: Nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details.

StephenW

http://www.jhep-reports.eu/article/S2589555922001896/pdf