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

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications & trials

Abstract

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) and volume quantification for ascites (PMID: 38900043). 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 in July 2023 (NCT05953545). This was an open label Phase 2a clinical trial exploring the use of peginterferon lambda and lonafarnib boosted ritonavir for 48 weeks of therapy in 30 patients with chronic HDV infection. The hypothesis was that therapy with peginterferon lambda and lonafarnib boosted with ritonavir will lead to a significant decline in HDV RNA levels. Prior to starting this study, the FDA placed a partial clinical hold on this study related to outside experiences with the use of peginterferon lambda which may place human subjects at significant risk of illness or injury. As such, this study was not started during FY24. As of current, the study was closed in FY25 without recruitment as the peginterferon lambda partial clinical hold still remains in place. Separate to this work, a secondary research study has been initiated to understand the genetic epidemiology of HDV in North America through the assessment of two large cohorts of HDV patients. As the NIH Clinical Center is one of the largest referral centers for HDV patients, we have the ability to study one of the largest cohorts of patients in North America. More recently (FY25), through collaborative work, we have a manuscript that is under peer review describing the genetic epidemiology of HDV in North America. The hope is that this information will help to shape therapeutic options for patients in North America with chronic HDV infection. In the area of drug induced liver injury (DILI), collaborative work has allowed for further investigation of the role of chemical analysis in causality assessment of herbal and dietary supplement (HDS)-induced liver injury (PMID:39354283). In this piece, we demonstrate the value of using HDS chemical analysis data in causality assessment for DILI as it has increased diagnostic confidence in over a third of the HDS cases collected. Separately, we identified that disulfiram is the leading cause of DILI among medications for alcohol use disorder (MAUD) and is associated with HLA-C*01:02 and DRB1*09:01 (PMID:39651750). Finally, we have described that cephalosporin induced liver injury can cause self-limited, mixed/cholestatic hepatitis that arises after a short course of therapy with a latency of up to 3 weeks. This liver injury is associated with the HLA-A*02:01 allele, which is linked to more severe liver injury at the onset of illness (PMID:40685563). 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: 40685563, 40645259, 38757950, 39168375, 39090843).