Abstract：
Bulevirtide is a first-in-class peptidic entry inhibitor for hepatitis B virus (HBV) and hepatitis D virus infection. In July, 2020, bulevirtide 2 mg received conditional marketing authorisation by the European Medical Agency for treatment of chronic hepatitis D virus infection. We investigated the antiviral activity of bulevirtide in patients chronically infected with HBV and hepatitis D virus.
MYR202 (ClinicalTrials.gov, NCT03546621; EudraCT, 2016-000395-13) was a multicentre, parallel-group, randomised, open-label, phase 2 trial. Adults (aged 18-65 years) with chronic hepatitis D virus infection, including patients with cirrhosis and patients who had contraindications to PegIFNα treatment or for whom treatment did not work, were eligible and were enrolled from four hospitals in Germany and 12 hospitals in Russia. Patients were randomly assigned (1:1:1:1) to receive 2 mg (n=28), 5 mg (n=32), or 10 mg (n=30) subcutaneous bulevirtide once per day with tenofovir disoproxil fumarate (TDF; 245 mg once per day orally) or TDF alone (245 mg once per day orally; n=30) for 24 weeks. Randomisation was done using a digital block scheme with stratification, consisting of 480 randomisation numbers separated into 30 blocks. The primary endpoint was undetectable hepatitis D virus RNA or 2 log10 IU/mL or higher decline in hepatitis D virus RNA at week 24, which was analysed in the modified intention-to-treat population, including patients who received study medication at least once after randomisation. Hepatitis D virus RNA concentrations were monitored until week 48. Safety was assessed for all patients who received at least one dose of bulevirtide or TDF.
Between Feb 16, 2016, and Dec 8, 2016, 171 patients with chronic hepatitis D virus infection were screened; 51 were ineligible based on the exclusion criteria and 120 patients (59 with cirrhosis) were enrolled. At week 24, 15 (54%, 95% CI 34-73) of 28 patients achieved undetectable hepatitis D virus RNA or a 2 log10 IU/mL or more decline in hepatitis D virus RNA (p<0·0001 vs TDF alone) with 2 mg bulevirtide, 16 (50%, 32-68) of 32 with 5 mg bulevirtide (p<0·0001), and 23 (77%, 58-90) of 30 with 10 mg bulevirtide (p<0·0001), versus one (4%, 0·1-18) of 28 with TDF alone. By week 48 (24 weeks after bulevirtide cessation), hepatitis D virus RNA concentrations had rebounded, with median changes from week 24 to week 48 of 1·923 log10 IU/mL (IQR 0·566-2·485) with 2 mg bulevirtide, 1·732 log10 (0·469-2·568) with 5 mg bulevirtide, and 2·030 log10 (1·262-2·903) with 10 mg bulevirtide. There were no deaths associated with treatment. Three (9%) patients in the bulevirtide 5 mg group, two (7%) patients in the bulevirtide 10 mg group, and one (4%) patient in the TDF group had serious adverse events. Common treatment-emergent adverse events included asymptomatic bile salt increases and increases in alanine aminotransferase and aspartate aminotransferase.
Bulevirtide induced a significant decline in hepatitis D virus RNA over 24 weeks. After cessation of bulevirtide, hepatitis D virus RNA concentrations rebounded. Longer treatment durations and combination therapies should be investigated.
Hepatera LLC, MYR GmbH, and the German Centre for Infection Research, TTU Hepatitis.
MYR202 (ClinicalTrials.gov, NCT03546621; EudraCT, 2016-000395-13) was a multicentre, parallel-group, randomised, open-label, phase 2 trial. Adults (aged 18-65 years) with chronic hepatitis D virus infection, including patients with cirrhosis and patients who had contraindications to PegIFNα treatment or for whom treatment did not work, were eligible and were enrolled from four hospitals in Germany and 12 hospitals in Russia. Patients were randomly assigned (1:1:1:1) to receive 2 mg (n=28), 5 mg (n=32), or 10 mg (n=30) subcutaneous bulevirtide once per day with tenofovir disoproxil fumarate (TDF; 245 mg once per day orally) or TDF alone (245 mg once per day orally; n=30) for 24 weeks. Randomisation was done using a digital block scheme with stratification, consisting of 480 randomisation numbers separated into 30 blocks. The primary endpoint was undetectable hepatitis D virus RNA or 2 log10 IU/mL or higher decline in hepatitis D virus RNA at week 24, which was analysed in the modified intention-to-treat population, including patients who received study medication at least once after randomisation. Hepatitis D virus RNA concentrations were monitored until week 48. Safety was assessed for all patients who received at least one dose of bulevirtide or TDF.
Between Feb 16, 2016, and Dec 8, 2016, 171 patients with chronic hepatitis D virus infection were screened; 51 were ineligible based on the exclusion criteria and 120 patients (59 with cirrhosis) were enrolled. At week 24, 15 (54%, 95% CI 34-73) of 28 patients achieved undetectable hepatitis D virus RNA or a 2 log10 IU/mL or more decline in hepatitis D virus RNA (p<0·0001 vs TDF alone) with 2 mg bulevirtide, 16 (50%, 32-68) of 32 with 5 mg bulevirtide (p<0·0001), and 23 (77%, 58-90) of 30 with 10 mg bulevirtide (p<0·0001), versus one (4%, 0·1-18) of 28 with TDF alone. By week 48 (24 weeks after bulevirtide cessation), hepatitis D virus RNA concentrations had rebounded, with median changes from week 24 to week 48 of 1·923 log10 IU/mL (IQR 0·566-2·485) with 2 mg bulevirtide, 1·732 log10 (0·469-2·568) with 5 mg bulevirtide, and 2·030 log10 (1·262-2·903) with 10 mg bulevirtide. There were no deaths associated with treatment. Three (9%) patients in the bulevirtide 5 mg group, two (7%) patients in the bulevirtide 10 mg group, and one (4%) patient in the TDF group had serious adverse events. Common treatment-emergent adverse events included asymptomatic bile salt increases and increases in alanine aminotransferase and aspartate aminotransferase.
Bulevirtide induced a significant decline in hepatitis D virus RNA over 24 weeks. After cessation of bulevirtide, hepatitis D virus RNA concentrations rebounded. Longer treatment durations and combination therapies should be investigated.
Hepatera LLC, MYR GmbH, and the German Centre for Infection Research, TTU Hepatitis.
摘要：
背景：Bulevirtide是乙型肝炎病毒（HBV）和丁型肝炎病毒感染的一类肽进入抑制剂。七月,2020年，丁维肽2mg获得欧洲医学机构有条件的上市许可，用于治疗慢性丁型肝炎病毒感染。我们调查了慢性乙型肝炎病毒和丁型肝炎病毒感染患者的抗病毒活性。
方法：MYR202(ClinicalTrials.gov，NCT03546621;EudraCT,2016-000395-13)是一个多中心，平行组，随机化，开放标签，第二阶段试验。成人（年龄18-65岁）患有慢性丁型肝炎病毒感染，包括肝硬化患者和有PegIFNα治疗禁忌症或治疗无效的患者，符合资格，并从德国的四家医院和俄罗斯的12家医院注册。患者被随机分配（1：1：1：1）接受2毫克（n=28），5毫克（n=32），或10mg（n=30）每天一次皮下丁韦韦肽与富马酸替诺福韦酯（TDF;245mg每天一次口服）或TDF单独（245mg每天一次口服；n=30），持续24周。随机化是使用带有分层的数字块方案进行的，由480个随机数组成，分为30个块。主要终点是在第24周时检测不到丁型肝炎病毒RNA或2log10IU/mL或更高的丁型肝炎病毒RNA下降，在改良的意向治疗人群中进行了分析，包括随机分组后至少接受过一次研究药物治疗的患者.监测D型肝炎病毒RNA浓度直至第48周。对所有接受至少一个剂量的bulevirtide或TDF的患者进行安全性评估。
结果：在2016年2月16日至2016年12月8日之间，筛选了171例慢性丁型肝炎病毒感染患者;根据排除标准，51例不合格，120例患者（59例肝硬化）入选。在第24、15周（54%，95％CI34-73）的28例患者获得了无法检测到的丁型肝炎病毒RNA或2log10IU/mL或更多的丁型肝炎病毒RNA下降（p<0·0001vsTDF单独），16（50%，32-68）的32个，含5毫克丁韦韦肽（p<0·0001），和23（77%，58-90）的30与10毫克的bulevirtide（p<0·0001），与一个(4%，0·1-18）单独使用TDF的28。到第48周（戒毒后24周），丁型肝炎病毒RNA浓度有所回升,从第24周到第48周的中位数变化为1·923log10IU/mL（IQR0·566-2·485），使用2mg丁韦肽，1·732log10（0·469-2·568）含5毫克丁维肽，和2·030log10（1·262-2·903）和10mgbulevirtide。没有与治疗相关的死亡。3例（9%）患者在布勒韦肽5mg组中，丁维肽10mg组中有两名（7％）患者，和一个（4％）的TDF组患者有严重的不良事件。常见的治疗引起的不良事件包括无症状的胆汁盐增加和丙氨酸氨基转移酶和天冬氨酸氨基转移酶的增加。
结论：Bulevirtide在24周内诱导了丁型肝炎病毒RNA的显著下降。停止丁维肽后，丁型肝炎病毒RNA浓度反弹。应研究更长的治疗持续时间和联合治疗。
背景：HepateraLLC，MYRGmbH,和德国感染研究中心，TTU肝炎。
方法：MYR202(ClinicalTrials.gov，NCT03546621;EudraCT,2016-000395-13)是一个多中心，平行组，随机化，开放标签，第二阶段试验。成人（年龄18-65岁）患有慢性丁型肝炎病毒感染，包括肝硬化患者和有PegIFNα治疗禁忌症或治疗无效的患者，符合资格，并从德国的四家医院和俄罗斯的12家医院注册。患者被随机分配（1：1：1：1）接受2毫克（n=28），5毫克（n=32），或10mg（n=30）每天一次皮下丁韦韦肽与富马酸替诺福韦酯（TDF;245mg每天一次口服）或TDF单独（245mg每天一次口服；n=30），持续24周。随机化是使用带有分层的数字块方案进行的，由480个随机数组成，分为30个块。主要终点是在第24周时检测不到丁型肝炎病毒RNA或2log10IU/mL或更高的丁型肝炎病毒RNA下降，在改良的意向治疗人群中进行了分析，包括随机分组后至少接受过一次研究药物治疗的患者.监测D型肝炎病毒RNA浓度直至第48周。对所有接受至少一个剂量的bulevirtide或TDF的患者进行安全性评估。
结果：在2016年2月16日至2016年12月8日之间，筛选了171例慢性丁型肝炎病毒感染患者;根据排除标准，51例不合格，120例患者（59例肝硬化）入选。在第24、15周（54%，95％CI34-73）的28例患者获得了无法检测到的丁型肝炎病毒RNA或2log10IU/mL或更多的丁型肝炎病毒RNA下降（p<0·0001vsTDF单独），16（50%，32-68）的32个，含5毫克丁韦韦肽（p<0·0001），和23（77%，58-90）的30与10毫克的bulevirtide（p<0·0001），与一个(4%，0·1-18）单独使用TDF的28。到第48周（戒毒后24周），丁型肝炎病毒RNA浓度有所回升,从第24周到第48周的中位数变化为1·923log10IU/mL（IQR0·566-2·485），使用2mg丁韦肽，1·732log10（0·469-2·568）含5毫克丁维肽，和2·030log10（1·262-2·903）和10mgbulevirtide。没有与治疗相关的死亡。3例（9%）患者在布勒韦肽5mg组中，丁维肽10mg组中有两名（7％）患者，和一个（4％）的TDF组患者有严重的不良事件。常见的治疗引起的不良事件包括无症状的胆汁盐增加和丙氨酸氨基转移酶和天冬氨酸氨基转移酶的增加。
结论：Bulevirtide在24周内诱导了丁型肝炎病毒RNA的显著下降。停止丁维肽后，丁型肝炎病毒RNA浓度反弹。应研究更长的治疗持续时间和联合治疗。
背景：HepateraLLC，MYRGmbH,和德国感染研究中心，TTU肝炎。
