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: 10932756
• 负责人: Christopher Koh
• 金额: $ 18.32万
• 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/10932756
• 关键词: Adult; Annual Reports; Anti-Infective Agents; Biochemical; Caring; Chronic Hepatitis B; Chronic Hepatitis C; Chronic Hepatitis D; Chronic viral hepatitis; Cirrhosis; Clinical; Clinical Trials; Combined Modality Therapy; Communities; Congresses; Data; Data Analyses; Diagnosis; Disease; Dose; Effectiveness; Enrollment; Epidemiology; FDA approved; Farnesyl Transferase Inhibitor; Fibrosis; Follow-Up Studies; Goals; Hepatitis B; Hepatitis C; Hepatitis C virus; Hepatitis D; Hepatitis Delta Virus; Hepatology; Histologic; Individual; Infection; Institutional Review Boards; Interferons; International; Journals; Knowledge; Liver; Liver diseases; Lonafarnib; Manuscripts; Measures; Medical; Methods; Modality; Monitor; National Institute of Diabetes and Digestive and Kidney Diseases; Outcome Study; Patient Participation; Patients; Pattern; Peer Review; Performance; Pharmaceutical Preparations; Phase; Placebos; Principal Investigator; Process; Protease Inhibitor; Publications; Publishing; Radiology Specialty; Reporting; Research; Research Personnel; Ritonavir; Safety; Scanning; Serology; Site; Spleen; Staging; Therapeutic; Therapeutic Agents; Therapeutic Trials; United States National Institutes of Health; Viral; Viral hepatitis; Virus Diseases; Work; X-Ray Computed Tomography; chronic liver disease; clinical center; cohort; deep learning model; elastography; mathematical model; meetings; novel; novel therapeutics; nucleoside analog; open label; peginterferon alfa-2a; primary outcome; response; serological marker; success; tool; treatment response; vibration; viral RNA; virology

In exploring noninvasive methods of liver disease assessment, the ability to assess fibrosis with non-invasive serologic and radiologic modalities has been substantially validated in chronic hepatitis B (HBV) and C (HCV) viral infection. However, there still exists a gap in knowledge regarding the utility of these tools in chronic hepatitis D virus (HDV) infection, which is a dual virus infection, especially since there is a clinical necessity to identify individuals who require therapy because of progressive fibrosis or those who require additional medical care because of cirrhosis. We have previously explored the utility of serologic markers of fibrosis in HDV (PMID: 27813124) and vibration-controlled transient elastography (PMID: 31742822) and have created a novel noninvasive fibrosis score for HDV (PMID: 31837393) and have explored the utility of sheer wave elastography (SWE) in hepatitis D infected patients (PMID: 36032402). In a cohort of patients with chronic HDV, HBV, and HCV, we evaluated the performance of deep learning models that measure the liver segmental volume ratio and spleen volumes in computed tomography (CT) scans to predict cirrhosis and advanced fibrosis (PMID: 36204530). This information now provides another modality, one that can be automated and widely available to the medical community for the assessment of fibrosis in HDV patients. In the field of chronic HDV therapeutics, various projects have been completed or are ongoing. In September 2020, subject participation was completed 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. The end-of-study results were presented in November 2020 at The Liver Meeting (AASLD) and mathematical modeling of viral eradication with this therapeutic combination was presented at the International Liver Congress (EASL) in June 2022. We are now actively analyzing the data and are in the process of drafting a manuscript for publication that will report the outcome of this study. Once the above-mentioned study (NCT03600714) completed active patient participation a new study was established to continue exploring therapeutics in the field of HDV. This study was IRB approved, completed patient participation, and then closed in May 2023 (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 principal 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 compared 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. The end-of-study results were presented in June 2023 at the International Liver Congress (EASL). Active analysis and manuscript drafting is ongoing to report the outcome of the study. Once the above-mentioned study (NCT03719313) was completed, a new study was established to continue exploring therapeutics in the field of HDV. This study was approved by the IRB on July 6, 2023 (NCT05953545). This is an open label Phase 2a clinical trial exploring the use of peginterferon lambda and lonafarnib boosted ritonavir for 48 weeks of therapy in patients with chronic HDV infection. This study will treat 30 adult patients with chronic HDV and is a follow-up study to the previous 24-week combination study that was previously completed (NCT03600714) which demonstrated promising results. The hypothesis is that therapy with peginterferon lambda and lonafarnib boosted with ritonavir will lead to a significant decline in HDV RNA levels. Aside from this ongoing work, various collaborative projects in liver disease have been completed during this annual report. This includes collaborative work published in various peer reviewed journals (PMID: 36522461, 37208598, 37184208). In HDV, further exploration of distinct histological patterns and its potential impact in patients with nucleoside analogue therapy was also published (PMID: 37089591). Finally, three invited review manuscripts have been published during the period that covers this annual report. These reviews can be found in Expert Review of Anti-Infective Therapy entitled Epidemiology, presentation, and therapeutic approaches for hepatitis D infections (PMID: 36519386), Liver International entitled Diagnosis of HDV: From virology to non-invasive markers of fibrosis (PMID: 36621853), and Hepatology entitled Hepatitis delta: epidemiology to recent advances in therapeutic agents (PMID: 36738087).

在探索非侵入性肝病评估方法的过程中，在慢性乙型肝炎（HBV）和丙型肝炎（HCV）病毒感染中，通过非侵入性血清学和放射学模式评估纤维化的能力已经得到了实质性的验证。然而，关于这些工具在慢性丁型肝炎病毒（HDV）感染（这是一种双重病毒感染）中的效用的知识仍然存在差距，特别是因为临床需要确定因进行性纤维化而需要治疗的个体或因肝硬化而需要额外医疗护理的个体。我们之前已经探索了HDV （PMID: 27813124）和振动控制瞬时弹性成像（PMID: 31742822）的纤维化血清学标志物的效用，并创建了一种新的HDV无创纤维化评分（PMID: 31837393），并探索了纯波弹性成像（SWE）在D型肝炎感染患者（PMID: 36032402）中的效用。在一组慢性HDV、HBV和HCV患者中，我们评估了深度学习模型的性能，该模型在计算机断层扫描（CT）中测量肝脏节段体积比和脾脏体积，以预测肝硬化和晚期纤维化（PMID: 36204530）。