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

在探索肝脏疾病评估的非侵入性方法方面，非侵入性血清学和放射学方法评估纤维化的能力已在慢性乙肝(乙肝)和丙型肝炎(丙型肝炎)病毒感染中得到实质性验证。然而，对于这些工具在慢性丁型肝炎病毒(HDV)感染中的作用仍存在认识差距，这是一种双重病毒感染，特别是因为临床上有必要确定因进行性纤维化而需要治疗的个体或因肝硬变而需要额外医疗护理的个体。我们此前已经探索了丙型肝炎病毒(PMID：27813124)和振动控制瞬时弹性成像(PMID：31742822)中纤维化的血清学标志物的用途，并创造了一种新的HDV非侵入性纤维化评分(PMID：31837393)，并探索了横波弹性成像在丁型肝炎感染患者(PMID：36032402)中的应用。在一组慢性丁型肝炎、乙肝病毒和丙型肝炎患者中，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)中测量肝段体积比率和脾体积，以预测肝硬化和晚期纤维化(PMID：36204530)。 这些信息现在提供了另一种方式，一种可以自动化并广泛用于医学界评估HDV患者纤维化的方式。 在慢性HDV疗法领域，各种项目已经完成或正在进行中。2020年9月，完成了我们的临床治疗试验的受试者参与，题为：用氯那法尼、利托那韦和波长干扰素治疗慢性三角洲肝炎(NCT03600714)。这是一项2a期的开放标签研究，考察了26名患者在6个月内使用氯那法尼、利托那韦和Lambda干扰素三联疗法的安全性和抗病毒效果。给药后，所有患者在停药24周内接受监测。主要的治疗终点是治疗结束时HDV RNA病毒滴度下降2Logs。主要的安全终点是在整个疗程中耐受处方剂量的药物的能力。研究结束的结果于2020年11月在肝脏会议(AASLD)上公布，并在2022年6月的国际肝脏大会(EASL)上提交了使用该治疗组合根除病毒的数学模型。我们目前正在积极分析这些数据，并正在起草一份手稿，以供出版，以报告这项研究的结果。 一旦上述研究(NCT03600714)完成了积极的患者参与，就建立了一项新的研究，以继续探索HDV领域的治疗方法。这项研究获得了IRB的批准，完成了患者参与，然后于2023年5月结束(NCT03719313)。这是一项多中心的3期临床治疗试验，这是HDV领域的第一项试验，目的是评估洛那法尼和利托那韦与聚乙二醇干扰素α-2a或不与聚乙二醇干扰素-2a联合使用的有效性。我是美国国立卫生研究院临床中心的首席调查员，该中心将为患者治疗48周，然后再进行24周的非治疗监测。主要结果比较了服用氯那法尼和利托那韦的患者与服用安慰剂的患者在治疗结束时的综合病毒学和生化应答率，以及比较接受洛那昔布和利托那韦并或不使用聚乙二醇干扰素α-2a的患者在治疗结束时的综合病毒学和生化应答率。研究结束结果于2023年6月在国际肝病大会(EASL)上公布。正在进行积极的分析和手稿起草，以报告研究结果。 一旦上述研究(NCT03719313)完成，就建立了一项新的研究，以继续探索HDV领域的治疗方法。这项研究于2023年7月6日由IRB批准(NCT05953545)。这是一项开放标签的2a期临床试验，探索在慢性HDV感染患者中使用聚乙二醇干扰素lambda和Lonafarnib增强利托那韦48周的治疗。这项研究将治疗30名患有慢性HDV的成人患者，是先前完成的24周联合研究(NCT03600714)的后续研究，该研究显示了有希望的结果。假设是，在利托那韦的支持下，使用聚乙二醇干扰素lambda和Lonafarnib治疗将导致HDV RNA水平的显着下降。 除了这项正在进行的工作外，在本年度报告期间还完成了肝病方面的各种合作项目。这包括在各种同行评议期刊上发表的协作工作(PMID：36522461、37208598、37184208)。在HDV中，还发表了对核苷类似物治疗患者的不同组织学模式及其潜在影响的进一步探索(PMID：37089591)。最后，在本年度报告所涉期间出版了三份受邀审查手稿。这些综述可在题为《丁型肝炎感染的流行病学、表现和治疗方法》的《抗感染治疗专家评论》(PMID：36519386)、题为《丁型肝炎病毒的诊断：从病毒学到非侵入性纤维化标记物的国际肝病》(PMID：36621853)和《丁型肝炎：流行病学与治疗药物的最新进展》(PMID：36738087)中找到。

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).