Management and Treatment of Chronic Delta Hepatitis Infection and other Liver Diseases

慢性丁型肝炎感染和其他肝脏疾病的管理和治疗

• 批准号: 10250259
• 负责人: Christopher Koh
• 金额: $ 65.09万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10250259
• 关键词: Adult; Alanine Transaminase; Annual Reports; Antiviral Agents; Area; Biochemical; Blood Platelets; Blood Vessels; Chronic; Chronic Hepatitis B; Chronic Hepatitis C; Chronic Hepatitis D; Chronic viral hepatitis; Cirrhosis; Clinical; Clinical Trials; Congresses; Data Analyses; Detection; Disease; Dose; Effectiveness; Erythrocytes; FDA approved; Farnesyl Transferase Inhibitor; Fibrosis; Future; Gamma-glutamyl transferase; Gastroenterology; Goals; Hepatic; Hepatitis; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatitis D; Hepatitis Delta Virus; Histologic; Homeostasis; Infection; Inflammation; Institutional Review Boards; Interferon-alpha; Interferons; International; Investigational Therapies; Journals; Link; Liver; Liver diseases; Lonafarnib; Manuscripts; Measurement; Methods; Monitor; National Institute of Diabetes and Digestive and Kidney Diseases; Patient Participation; Patients; Peer Review; Performance; Pharmaceutical Preparations; Phase; Placebos; Platelet Count measurement; Polyglandular Autoimmune Syndrome Type I; Primary carcinoma of the liver cells; Protease Inhibitor; Publishing; Reporting; Research; Research Personnel; Ritonavir; Safety; Sickle Cell Anemia; Site; Staging; State-of-the-Art Reviews; Testing; Therapeutic; Therapeutic Clinical Trial; Training; United States National Institutes of Health; Validation; Viral; Viral hepatitis; Visit; Width; Work; base; chronic liver disease; clinical center; clinical practice; cohort; diagnostic accuracy; early onset; elastography; follow-up; indexing; meetings; novel; novel therapeutics; open label; peginterferon alfa-2a; primary outcome; recruit; response; serological marker; tool; vibration; viral RNA; virology

In exploring noninvasive methods of liver disease assessment, we have evaluated the clinical utility of vibration controlled transient elastography (VCTE) for the detection of cirrhosis in chronic hepatitis D infection (PMID: 31742822). While the use of VCTE has revolutionized the management of chronic hepatitis B virus and hepatitis C virus infections, VCTE has not been studied in HDV infection and its accuracy remains a question due to the significant hepatic inflammation associated with HDV. In this work, we compared the performance of VCTE in HDV patients with monoinfected HBV and HCV patients in addition to comparing the performance of VCTE against noninvasive serologic markers of fibrosis (i.e.: AST-to-platelet ratio index (APRI), Fibrosis-4 (FIB-4), AST-to-ALT ratio (AAR), and red cell distribution width (RDW)-to-platelet ratio (RPR)). We describe that VCTE has better diagnostic accuracy in detecting cirrhosis in HDV patients compared to noninvasive serologic markers of fibrosis. Additionally, we describe that despite significantly increased levels of histologic inflammation, the performance of VCTE in HDV is comparable to that of HBV and HCV. Finally, we provide a new cut-off VCTE value for use in HDV patients which optimizes the ability to detect cirrhosis. In follow-up to the above described work in HDV, we have also taken the opportunity to create a novel noninvasive fibrosis score, called the Delta-4 fibrosis score (D4FS), which can be utilized in daily clinical practice (PMID: 31837393). In this piece, a training cohort of patients was utilized to identify the four clinical parameters (gamma-glutamyl transpeptidase (GGT), platelet count, alanine aminotransferase (ALT), and liver stiffness measurements (LSM) via VCTE) that were associated with the presence of histologically confirmed cirrhosis to create the D4FS. The performance of the D4FS in identifying patients with histologic cirrhosis was then evaluated against VCTE alone, FIB-4, APRI and AAR in a validation cohort. Notably, the D4FS outperformed all of the other noninvasive tests with an area under the receiver operating curve (AUROC) of 0.94. These impressive results should be confirmed in additional HDV cohorts and may provide clinicians with new tools in identifying cirrhosis with noninvasive means in HDV. Other collaborative work in exploring noninvasive methods of liver disease assessment that have been completed during this annual report include exploring the link between platelet counts and vascular homeostasis across early and late stages of fibrosis in hepatitis C (PMID: 31407130), the use of VCTE in sickle cell disease (PMID: 31218662), identification of a viral exposure signature that defines early onset hepatocellular carcinoma (PMID: 32526205) and expanding the clinical description of autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) associated hepatitis (PMID:32557834). In the field of chronic HDV therapeutics, various projects have been completed or are ongoing. In July 2018, recruitment was open for our clinical therapeutic trial entitled: Treatment of chronic delta hepatitis with lonafarnib, ritonavir and lambda interferon (NCT03600714). This is a phase 2a open label study examining the safety and antiviral effects of triple therapy with lonafarnib, ritonavir and lambda interferon for a period of 6 months in 26 patients. After dosing, all patients were monitored for 24 weeks off therapy. The primary therapeutic endpoint is a decline in HDV RNA viral titer of 2 logs at the end of therapy. The primary safety endpoint is the ability to tolerate the drugs at the prescribed dose for the full course of therapy. As of August 2020, the final patient completed the final visit for this study. Interim end-of-treatment results were presented in November 2019 at The Liver Meeting and in August 2020 at the International Liver Congress. We are now actively analyzing the data and intend on publishing the final results in the near future. As the above-mentioned study (NCT03600714) has completed active patient participation a new study has been established to continue exploring therapeutics in the field of HDV. This study has been IRB approved and is now open for recruitment (NCT03719313). This is a multi-centered phase 3 clinical therapeutic trial, the first in the field of HDV, with the intent of assessing the utility of the combination of lonafarnib and ritonavir with or without peginterferon alfa-2a. I am the primary investigator at the NIH Clinical Center site which will treat patients for 48 weeks followed by off-therapy monitoring for an additional 24 weeks. The primary outcomes will be to compare the composite virologic and biochemical response rate at the end of therapy in patients who receive lonafarnib and ritonavir versus placebo and to compare the composite virologic and biochemical response rate at the end of treatment in patients who receive lonafarnib, ritonavir with or without peginterferon alfa-2a. Aside from this ongoing work, various collaborative projects in HDV have been completed during the course of this annual report. This includes collaborative work published in various peer reviewed journals (PMID: 31872446, 32389361). Finally, several invited review manuscripts have been published during the period that covers this annual report. These include a review in the World Journal of Gastroenterology titled Chronic hepatitis delta: A state-of-the-art review and new therapies (PMID: 31528088) and one in Gastroenterology Reports titled Hepatitis D Infection: from initial discovery to current investigational therapies (PMID: 32477569).

在探索肝脏疾病评估的非侵入性方法中，我们评估了振动控制瞬态弹性成像（VCTE）检测慢性丁型肝炎感染（PMID：31742822）肝硬化的临床效用。 虽然VCTE的使用已经彻底改变了慢性B型肝炎病毒和丙型肝炎病毒感染的管理，但VCTE尚未在HDV感染中进行研究，并且由于与HDV相关的显著肝脏炎症，其准确性仍然是一个问题。 在这项工作中，我们比较了VCTE在HDV患者与单一感染HBV和HCV的患者中的性能，以及VCTE针对纤维化的非侵入性血清学标志物的性能（即：AST与血小板比率指数（APRI）、纤维化-4（FIB-4）、AST与ALT比率（AAR）和红细胞分布宽度（RDW）与血小板比率（RPR））。 我们描述了VCTE在检测HDV患者肝硬化方面比无创性纤维化血清学标志物具有更好的诊断准确性。 此外，我们描述了尽管组织学炎症水平显著增加，但HDV中VCTE的性能与HBV和HCV相当。 最后，我们为HDV患者提供了一个新的临界VCTE值，该值优化了检测肝硬化的能力。 在上述HDV研究的后续工作中，我们还借此机会创建了一种新的非侵入性纤维化评分，称为Delta-4纤维化评分（D4 FS），可用于日常临床实践（PMID：31837393）。 在这篇文章中，利用患者的训练队列来确定与组织学证实的肝硬化相关的四个临床参数（γ-谷氨酰转肽酶（GGT），血小板计数，丙氨酸氨基转移酶（ALT）和通过VCTE的肝硬度测量值（LSM）），以创建D4 FS。 然后在验证队列中针对单独的VCTE、FIB-4、APRI和AAR评估D4 FS在识别具有组织学肝硬化的患者中的性能。 值得注意的是，D4 FS优于所有其他非侵入性测试，其受试者工作曲线下面积（AUROC）为0.94。 这些令人印象深刻的结果应该在其他HDV队列中得到证实，并可能为临床医生提供新的工具，以非侵入性方式识别HDV肝硬化。 在本年度报告中完成的探索肝脏疾病评估的非侵入性方法的其他合作工作包括探索丙型肝炎纤维化早期和晚期血小板计数与血管稳态之间的联系（PMID：31407130），VCTE在镰状细胞病中的应用（PMID：31218662），确定定义早发性肝细胞癌的病毒暴露特征（PMID：32526205）和扩展自身免疫性多内分泌病念珠菌病外胚层营养不良（APECED）相关肝炎（PMID：32557834）的临床描述。 在慢性HDV治疗领域，各种项目已经完成或正在进行中。 2018年7月，我们的临床治疗试验开始招募，该试验名为：用洛那法尼、利托那韦和λ干扰素治疗慢性丁型肝炎（NCT 03600714）。 这是一项2a期开放标签研究，在26名患者中检查了使用洛那法尼、利托那韦和λ干扰素的三联疗法的安全性和抗病毒效果，为期6个月。 给药后，所有患者均接受24周停药监测。 主要治疗终点是治疗结束时HDV RNA病毒滴度下降2 log。 主要安全性终点是在整个治疗过程中耐受处方剂量药物的能力。 截至2020年8月，最终患者完成了本研究的最终访视。 中期治疗结束结果于2019年11月在肝脏会议上和2020年8月在国际肝脏大会上公布。我们正在积极分析数据，并打算在不久的将来公布最终结果。 由于上述研究（NCT 03600714）已经完成了患者的积极参与，因此建立了一项新的研究，以继续探索HDV领域的治疗方法。 本研究已获得IRB批准，目前开放招募（NCT 03719313）。 这是一项多中心的3期临床治疗试验，是HDV领域的第一项试验，目的是评估洛那法尼和利托那韦与或不与聚乙二醇干扰素α-2a联合使用的效用。 我是NIH临床中心的主要研究者，该中心将对患者进行48周的治疗，然后再进行24周的停药监测。 主要结局将是比较接受洛那法尼和利托那韦与安慰剂的患者在治疗结束时的复合病毒学和生化应答率，并比较接受洛那法尼、利托那韦联合或不联合聚乙二醇干扰素α-2a的患者在治疗结束时的复合病毒学和生化应答率。 除了这项正在进行的工作外，在本年度报告期间还完成了HDV的各种合作项目。 这包括在各种同行评审期刊上发表的合作工作（PMID：31872446，32389361）。 最后，在本年度报告所涉期间，发表了几份特邀评论稿。 其中包括一篇发表在《世界胃肠病学杂志》（World Journal of Gastroenterology）上的题为《慢性丁型肝炎：最先进的综述和新疗法》（PMID：31528088）的综述，以及一篇发表在《胃肠病学报告》（Gastroenterology Reports）上的题为《丁型肝炎感染：从最初发现到目前的研究性疗法》（PMID：32477569）的综述。