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: 10006720
• 负责人: Christopher Koh
• 金额: $ 54.06万
• 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/10006720
• 关键词: Adult; Annual Reports; Antiviral Agents; Antiviral Response; Biochemical; Blood Platelets; Blood Vessels; Chronic Hepatitis B; Chronic Hepatitis C; Chronic Hepatitis D; Chronic viral hepatitis; Clinic; Clinical; Clinical Trials; Disease; Dose; Effectiveness; Enrollment; FDA approved; Farnesyl Transferase Inhibitor; Fibrosis; Future; Gastroenterology; Goals; Hepatic; Hepatitis B; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatitis D; Hepatitis Delta Virus; Histologic; Homeostasis; Infection; Inflammation; Interferon-alpha; Interferons; Journals; Kinetics; Link; Liver; Liver diseases; Lonafarnib; Long-Term Effects; Manuscripts; Measurement; Measures; Methods; Monitor; National Institute of Diabetes and Digestive and Kidney Diseases; Pathogenesis; Patient Monitoring; Patients; Peer Review; Pharmaceutical Preparations; Phase; Platelet Count measurement; Portal Hypertension; Protease Inhibitor; Protocols documentation; Publishing; RNA; Randomized Clinical Trials; Research; Research Personnel; Ribavirin; Ritonavir; Safety; Serum; Sickle Cell Anemia; Spleen; Staging; Surrogate Markers; Therapeutic; Therapeutic Clinical Trial; Validation; Venous Pressure level; Viral; Viral hepatitis; Viremia; Virus Diseases; Work; base; chronic liver disease; co-infection; cohort; design; elastography; first-in-human; follow-up; indexing; novel therapeutics; nucleoside analog; open label; recruit; response; therapeutic development; tool; vibration; viral RNA

In exploring noninvasive methods of liver disease assessment, we have evaluated the utility of spleen and liver volumetrics as surrogate markers of hepatic venous pressure gradient (HVPG) measurements in patients with noncirrhotic portal hypertension (NCPH) (PMID:30094403). We identified that a positive linear correlation exists in patients with noncirrhotic portal hypertension pertaining to spleen/BMI and liver/BMI measurements and HVPG in contrast to patients with viral hepatitis related disease. Although further validation is needed, spleen and liver volumetrics may have clinical utility as a noninvasive measure of portal hypertension in patients with NCPH. Additionally, in chronic hepatitis B (CHB) infection, we have described the longitudinal effects of long term nucleoside analogue therapy for up to 17 years and have also evaluated the utility of non-invasive fibrosis markers in monitoring disease activity during treatment (PMID:31125632). In this work, we describe that both hepatic inflammation and fibrosis, assessed histologically, demonstrates the greatest improvement during the first year of therapy followed by a more linear improvement in subsequent years. In the assessment of noninvasive fibrosis markers, we corroborate findings from other CHB cohorts for the ability of the AST-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score to perform adequately in untreated CHB, as these scores were initially designed for chronic hepatitis C infection. Additionally, we identified that once on nucleoside analogue therapy for CHB, these noninvasive fibrosis scores do not perform well during the first 4 years of treatment, most likely due to early dynamic biochemical and histologic changes. Beyond 4 years of treatment, APRI and FIB-4 demonstrate significant correlations with histologic findings and may have clinical utility in monitoring patients. 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) and the use of vibration controlled transient elastography in sickle cell disease (PMID: 31218662) In a phase 2 randomized clinical trial exploring safety and antiviral response of 28 days of therapy with chlorcyclizine HCl (CCZ) plus ribavirin (RBV) versus chlorcyclizine HCl only, the primary results of the study were published in 2019 (PMID:30711416). In this study, 24 patients were treated and while the CCZ monotherapy group did not demonstrate any significant or sustained reduction in viremia, 58% of subjects treated with CCZ + RBV had a >3-fold decline in quantitively measured HCV RNA in serum. Subjects who responded demonstrated monophasic, biphasic or triphasic viral kinetic responses. Contrary to historical RBV monotherapy response, CCZ+RBV demonstrated a continued viral decline suggesting a possible synergistic effect of CCZ+RBV. In this first-in-humans for HCV clinical trial, CCZ demonstrated some anti-HCV effects suggesting that more potent CCZ derivatives with optimal PK features may be more suitable for future therapeutic development. In the field of chronic hepatitis D virus (HDV) infection, 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. After dosing, all patients will be monitored for 24 weeks off therapy. The primary therapeutic endpoint will be a decline in HDV RNA viral titer of 2 logs at the end of therapy. The primary safety endpoint will be the ability to tolerate the drugs at the prescribed dose for the full course of therapy. Per design, all 26 patients have been enrolled and dosed and are at various stages of on/off therapy protocol-based follow-up. 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: 30875937, 30695096, 30664876, 30982526). Finally, several invited review manuscripts have been published during the period that covers this annual report. These include a review in the journal Gastroenterology entitled Pathogenesis of and New Therapies for Hepatitis D (PMID: 30342789) and one in Clinics in Liver Disease entitled HBV/HDV Coinfection: A Challenge for Therapeutics (PMID: 31266627).

在探索无创肝病评估方法的过程中，我们评估了脾脏和肝脏体积作为非肝硬化门脉高压（NCPH）患者肝静脉压梯度（HVPG）测量的替代指标的实用性。我们发现，与病毒性肝炎相关疾病患者相比，非肝硬化门静脉高压症患者与脾脏/BMI和肝脏/BMI测量以及HVPG存在正线性相关。虽然还需要进一步的验证，但脾和肝容量可能作为NCPH患者门脉高压的无创测量具有临床应用价值。