慢性丁型肝炎的布乐瑞肽 3 期随机临床试验。
A Phase 3, Randomized Trial of Bulevirtide in Chronic Hepatitis D.
机构信息
From Medizinische Hochschule Hannover, Excellence Cluster RESIST, and D-SOLVE Consortium (H.W., M.C.), Hannover, German Center for Infection Research (DZIF) Partner Site Hannover-Braunschweig, Braunschweig (H.W., M.C.), Clinical Pharmacology and Pharmacoepidemiology and DZIF Partner Site Heidelberg (A. Blank) and the Department of Internal Medicine IV (U.M.), Heidelberg University Hospital, Heidelberg, the Institute of Medical Virology (A. Berger, S.C.), the Department of Internal Medicine, University Hospital Frankfurt (S.Z.), DZIF (S.C.), and Fraunhofer Institute for Translational Medicine and Pharmacology ITMP (S.C.), Frankfurt, and Universitätsklinikum Hamburg-Eppendorf, Medizinische Klinik, and DZIF, Hamburg-Lübeck-Borstel-Riems, Hamburg (J.S.W.) - all in Germany; the Department of Infectious Diseases, Karolinska University Hospital, Karolinska Institutet, Stockholm (S.A.); the Department of Clinical and Experimental Medicine, University of Pisa, and the Hepatology Unit, Pisa University Hospital, Pisa (M.R.B.), the Division of Internal Medicine, University of Modena and Reggio Emilia, Modena (P.A.), and the Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, CRC "A. M. and A. Migliavacca" Center for Liver Disease, and the Department of Pathophysiology and Transplantation, University of Milan, Milan (P.L.) - all in Italy; M.F. Vladimirsky Moscow Regional Research and Clinical Institute (P.B.), National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health (V.C.), Sechenov University (V.C.), and the Clinic of Modern Medicine (T.S.), Moscow, the National Medical Research Center of Physiopulmonology and Infectious Diseases, Yekaterinburg (N.M.), Stavropol Regional Clinical Hospital, Stavropol (N.G.), Hepatolog, Samara (V.M.), and Southern Ural State Medical University, Chelyabinsk (O.S.) - all in Russia; and Gilead Sciences, Foster City, CA (D.M., V.S., Q.A., B.D., J.F., A.O., Y.L.).
出版信息
N Engl J Med. 2023 Jul 6;389(1):22-32. doi: 10.1056/NEJMoa2213429. Epub 2023 Jun 22.
BACKGROUND
Coinfection with hepatitis D virus (HDV) accelerates the progression of liver disease associated with chronic hepatitis B. Bulevirtide inhibits the entry of HDV into hepatocytes.
METHODS
In this ongoing phase 3 trial, patients with chronic hepatitis D, with or without compensated cirrhosis, were randomly assigned, in a 1:1:1 ratio, to receive bulevirtide subcutaneously at 2 mg per day (2-mg group) or 10 mg per day (10-mg group) for 144 weeks or to receive no treatment for 48 weeks followed by bulevirtide subcutaneously at 10 mg per day for 96 weeks (control group). Patients will complete 96 weeks of additional follow-up after the end of treatment. The primary end point was a combined response at week 48 of an undetectable HDV RNA level, or a level that decreased by at least 2 log IU per milliliter from baseline, and normalization of the alanine aminotransferase (ALT) level. The key secondary end point was an undetectable HDV RNA level at week 48, in a comparison between the 2-mg group and the 10-mg group.
RESULTS
A total of 49 patients were assigned to the 2-mg group, 50 to the 10-mg group, and 51 to the control group. A primary end-point response occurred in 45% of patients in the 2-mg group, 48% in the 10-mg group, and 2% in the control group (P<0.001 for the comparison of each dose group with the control group). The HDV RNA level at week 48 was undetectable in 12% of patients in the 2-mg group and in 20% in the 10-mg group (P = 0.41). The ALT level normalized in 12% of patients in the control group, 51% in the 2-mg group (difference from control, 39 percentage points [95% confidence interval {CI}, 20 to 56]), and 56% in the 10-mg group (difference from control, 44 percentage points [95% CI, 26 to 60]). Loss of hepatitis B virus surface antigen (HBsAg) or an HBsAg level that decreased by at least 1 log IU per milliliter did not occur in the bulevirtide groups by week 48. Headache, pruritus, fatigue, eosinophilia, injection-site reactions, upper abdominal pain, arthralgia, and asthenia were more common in the 2-mg and 10-mg groups combined than in the control group. No treatment-related serious adverse events occurred. Dose-dependent increases in bile acid levels were noted in the 2-mg and 10-mg groups.
CONCLUSIONS
After 48 weeks of bulevirtide treatment, HDV RNA and ALT levels were reduced in patients with chronic hepatitis D. (Funded by Gilead Sciences; MYR 301 ClinicalTrials.gov number, NCT03852719.).
背景
丁型肝炎病毒（HDV）合并感染可加速慢性乙型肝炎相关肝病的进展。Bulevirtide 可抑制 HDV 进入肝细胞。
方法
在这项正在进行的 3 期试验中，患有慢性丁型肝炎且无论是否伴有代偿性肝硬化的患者以 1:1:1 的比例随机分配，每天接受皮下注射 2 毫克（2 毫克组）或 10 毫克（10 毫克组）Bulevirtide，持续 144 周，或不接受治疗 48 周，然后每天皮下注射 10 毫克 Bulevirtide，持续 96 周（对照组）。患者在治疗结束后将完成 96 周的额外随访。主要终点是第 48 周时 HDV RNA 水平不可检测，或与基线相比下降至少 2 log IU/ml，以及丙氨酸氨基转移酶（ALT）水平正常。关键次要终点是在第 48 周时 HDV RNA 水平不可检测，比较 2 毫克组和 10 毫克组。
结果
共有 49 名患者被分配到 2 毫克组，50 名患者被分配到 10 毫克组，51 名患者被分配到对照组。2 毫克组患者中有 45%达到主要终点反应，10 毫克组患者中有 48%达到主要终点反应，对照组患者中有 2%达到主要终点反应（与对照组相比，每个剂量组的 P<0.001）。第 48 周时，2 毫克组 12%的患者 HDV RNA 水平不可检测，10 毫克组 20%的患者 HDV RNA 水平不可检测（P=0.41）。对照组有 12%的患者 ALT 水平正常，2 毫克组有 51%的患者（与对照组相比，差异为 39 个百分点[95%置信区间{CI}，20 至 56]），10 毫克组有 56%的患者（与对照组相比，差异为 44 个百分点[95%置信区间，26 至 60]）。第 48 周时，Bulevirtide 组未发生乙型肝炎表面抗原（HBsAg）丢失或 HBsAg 水平下降至少 1 log IU/ml。头痛、瘙痒、疲劳、嗜酸性粒细胞增多、注射部位反应、上腹痛、关节痛和乏力在 2 毫克和 10 毫克组比对照组更常见。未发生与治疗相关的严重不良事件。在 2 毫克和 10 毫克组中均观察到胆汁酸水平的剂量依赖性升高。
结论
在接受 48 周 Bulevirtide 治疗后，慢性丁型肝炎患者的 HDV RNA 和 ALT 水平降低。（由吉利德科学公司资助；登记号：MYR 301；ClinicalTrials.gov 编号，NCT03852719。）
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