Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial
Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial
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DOI：
10.1016/s2468-1253(17)30288-1
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发表时间：
2017-12-01
影响因子：
35.7
通讯作者：
Vaillant, Andrew
中科院分区：
文献类型：
--
作者：
Bazinet, Michel;Pantea, Victor;Vaillant, Andrew
背景REP 2139清除循环乙型肝炎病毒（HBV）表面抗原（HBsAg），通过免疫治疗增强HBV感染功能控制的恢复。我们评估了REP 2139和聚乙二醇化干扰素α -2a在慢性HBV和丁型肝炎病毒（HDV）合并感染患者中的安全性和有效性。方法：在这项开放标签、非随机、2期试验中，在摩尔多瓦基希讷乌的托马·乔巴传染病医院招募了年龄在18-55岁、未接受治疗、丁肝抗原[HBeAg]阴性、抗丁肝抗原[HDAg]阳性、HDV RNA阳性、血清HBsAg浓度大于1000 IU/mL、治疗前有6个月或更长时间的HDV感染史的患者。排除有HDV重复感染、HBV和HDV以外的肝脏感染或肝硬化的患者。患者接受500 mg静脉注射REP 2139，每周1次，持续15周，随后联合静脉注射250 mg REP 2139和180 μ g皮下聚乙二醇干扰素α -2a，每周1次，持续15周，然后180 μ g聚乙二醇干扰素α -2a单药治疗，每周1次，持续33周。治疗结束时评估的主要终点是治疗方案的安全性和耐受性，并在意向治疗人群中进行分析。次要结局包括血清HBsAg低于50 IU/mL的患者比例，抑制HBV DNA的患者比例，以及通过随访保持这些反应的患者比例。REP 301试验已在ClinicalTrials注册。网址：NCT02233075。我们还在治疗结束后1年进行了额外的随访，作为在ClinicalTrials注册的REP 301-LTF试验（计划持续3年）的中期分析。gov，编号NCT02876419，该项目正在进行中，但没有招募患者。在2014年9月8日至2015年1月27日期间，我们招募了12名患者进入REP 301研究。所有12例患者在治疗期间至少发生一次不良事件：2例（17%）患者出现贫血，8例（67%）中性粒细胞减少症，10例（83%）血小板减少症。5例（42%）患者丙氨酸转氨酶水平升高，4例（33%）患者天冬氨酸转氨酶水平升高，2例（17%）患者胆红素浓度升高。4例（33%）患者出现严重不良事件，12例（100%）患者出现治疗紧急实验室异常。6例患者治疗结束时HBsAg水平低于50 IU/mL（均< 0.05 IU/mL）；5例患者在1年随访结束时仍维持这一抑制水平。6例患者治疗结束时乙型肝炎表面抗体（anti-HBs）滴度高于10 mIU/mL（其中5例患者治疗期间抗- hbs浓度最高为7681-86 532 mIU/mL）， 5例患者1年随访结束时均维持该水平。在引入聚乙二醇化干扰素α -2a之前，丙氨酸和天冬氨酸转氨酶浓度升高和抗乙肝病毒滴度的显著升高仅限于HBsAg水平低于< 1 IU/mL的患者。9例患者在治疗结束时HBV DNA抑制（< 10 IU/mL）， 7例患者维持，8例患者在1年随访结束时新建立。11例患者在治疗期间变为HDV RNA阴性，治疗结束时仍有9例HDV RNA阴性；其中7名患者在1年随访结束时仍为HDV RNA阴性。1年随访结束时，12例患者中有9例血清转氨酶恢复正常。REP 2139联合聚乙二醇干扰素α -2a治疗是安全的，耐受性良好，并在治疗1年后建立了高比例患者HBV和HDV合并感染的功能控制和血清转氨酶正常化。这种联合治疗方法可能为HBV和HDV合并感染患者提供一种新的治疗选择。
Background REP 2139 clears circulating hepatitis B virus (HBV) surface antigen (HBsAg), enhancing the restoration of functional control of HBV infection by immunotherapy. We assessed the safety and efficacy of REP 2139 and pegylated interferon alfa-2a in patients with chronic HBV and hepatitis D virus (HDV) co-infection.Methods In this open-label, non-randomised, phase 2 trial, patients aged 18-55 years, who were treatment naive, hepatitis D antigen [HBeAg] negative, anti-hepatitis D antigen [HDAg] positive, and HDV RNA positive, with serum HBsAg concentrations of more than 1000 IU/mL, and a history of HDV infection for 6 months or more before treatment, were recruited at Toma Ciorba Hospital of Infectious Diseases in Chisinau, Moldova. Patients were excluded if they had HDV superinfection, liver infections other than HBV and HDV, or liver cirrhosis. Patients received 500 mg intravenous REP 2139 once per week for 15 weeks, followed by combined therapy with 250 mg intravenous REP 2139 and 180 mu g subcutaneous pegylated interferon alfa-2a once per week for 15 weeks, then monotherapy with 180 mu g pegylated interferon alfa-2a once per week for 33 weeks. The primary endpoints assessed at the end of treatment were the safety and tolerability of the treatment regimen, analysed in the intention-to-treat population. Secondary outcomes included the proportion of patients with serum HBsAg less than 50 IU/mL, the proportion of patients with suppressed HBV DNA, and the proportion of patients who maintained these responses through follow-up. The REP 301 trial is registered with ClinicalTrials. gov, number NCT02233075. We also did an additional follow-up at 1 year after the end of treatment, as an interim analysis of the REP 301-LTF trial (planned duration 3 years), registered with ClinicalTrials. gov, number NCT02876419, which is ongoing but not recruiting patients.Findings Between Sept 8, 2014, and Jan 27, 2015, we enrolled 12 patients into the REP 301 study. All 12 patients experienced at least one adverse event during treatment: two (17%) patients experienced anaemia, eight (67%) neutropenia, and ten (83%) thrombocytopenia. Five (42%) patients had raised alanine aminotransferase levels, four (33%) had raised aspartate aminotransferase levels, and two (17%) had increased bilirubin concentrations. Four (33%) patients had a serious adverse event, and 12 (100%) patients had treatment-emergent lab abnormalities. Six patients had HBsAg levels less than 50 IU/mL by the end of treatment (all < 0.05 IU/mL); five maintained this level of suppression at the end of 1 year follow-up. Six patients had hepatitis B surface antibody (anti-HBs) titres above 10 mIU/mL at the end of treatment (five had maximum anti-HBs concentrations of 7681-86 532 mIU/mL during treatment), which were maintained at the end of 1 year follow-up in these five patients. Elevated alanine and aspartate aminotransferase concentrations and profound elevations of anti-HBs titres were restricted to patients who had HBsAg levels of less than < 1 IU/mL before the introduction of pegylated interferon alfa-2a. Nine patients had suppressed HBV DNA (< 10 IU/mL]) at the end of treatment, which was maintained by seven patients and newly established in an eighth patient at the end of 1 year follow-up. 11 patients became HDV RNA negative during treatment, with nine remaining HDV RNA negative at the end of treatment; seven of these patients remained HDV RNA negative by the end of 1 year follow-up. By the end of 1 year follow-up, normalisation of serum aminotransferases occurred in nine of 12 patients.Interpretation Combined REP 2139 and pegylated interferon alfa-2a therapy is safe, well tolerated, and establishes functional control of HBV and HDV co-infection and normalisation of serum aminotransferases in a high proportion of patients 1 year after therapy. This combination therapy approach might provide a new treatment option for patients with HBV and HDV co-infection.