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 & patents

Abstract

In exploring noninvasive methods of liver disease assessment, clinically measurable platelet counts are a well-recognized surrogate marker for progression of liver disease. However, a specific cut-off for the identification of cirrhosis has not been established. With the increasing role of primary care providers in the management of chronic viral hepatitis, where cirrhosis is an indication to start therapy, the identification of a widely available and versatile tool for identifying patients with cirrhosis is clinically necessary. In a cohort of over 1,000 patients, we assessed the utility of routine laboratory markers that are used to characterize liver disease (AST, ALT, Alkaline Phosphatase, Prothrombin time, Albumin, Total Bilirubin) for their ability to identify patients with cirrhosis with chronic viral hepatitis B, C, or D infection (PMID: 34084591). Of the different clinical markers tested, platelets performed the best as a single marker at identifying cirrhosis and had similar performance characteristics as cumbersome subspecialist calculations (APRI and FIB-4). We also identified that the optimal platelet cutoff value for the detection of cirrhosis regardless of the type of chronic viral hepatitis infection is 143x109/L. Finally, in the analysis of individual chronic viral hepatitis infections, the cutoff value performs best in identifying cirrhosis in chronic hepatitis D infected patients. In a different cohort of patients with X-linked agammaglobulinemia (XLA), we described that nodular regenerative hyperplasia (NRH) is an underappreciated cause of noncirrhotic portal hypertension (PMID: 33027083). Specifically, we identified that platelet counts, in conjunction radiologic evidence of splenomegaly or hepatomegaly can serve as a diagnostic marker for the presence NRH. Also, on longitudinal follow-up, we demonstrate that declining platelet counts in the presence of hepatomegaly and splenomegaly can serve as a marker of progressive disease. Finally, we demonstrate that patients with XLA and NRH have worse outcomes than patients with XLA alone, therefore the early identification of subjects with NRH in XLA is paramount. In the field of chronic HDV, accurate U.S. estimations for the burden of disease is lacking and published data mostly pertains to intravenous drug users (IVDU). As such, testing recommendations by the American Association for the Study of Liver Diseases (AASLD) for the identification of HDV infection based on risk factors is mostly abstracted from European data. As the NIH serves as one of the largest referral centers for HDV therapies in North America, we examined our large population of HDV infected patients to identify risk factors that can aid in the diagnosis of active HDV infection (PMID: 33027083). In this piece, we found that risk factors for active HDV infection include a history of IVDU, baseline serum HBV-DNA <2000 IU/mL, ALT >40 U/L, and origination from an HDV endemic country. Our results not only confirm existing AASLD recommendations in a North American population, but they also provide added data to care providers as to whom and how to screen for HDV infection. 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 titled: 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 September 2020, the final patient completed the final visit for this study. The end-of-study results were presented in November 2020 at The Liver Meeting (AASLD). 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. 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 is IRB approved and is 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 this annual report. This includes collaborative work published in various peer reviewed journals (PMID: 34302839, 34048594). Finally, one invited review manuscript has been published during the period that covers this annual report. This review can be found in Drugs of Today and is titled Bulevirtide for HBV and HDV infections (PMID: 34268531).