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

点击翻译按钮获取中文摘要

In exploring noninvasive methods of liver disease assessment, we have evaluated the clinical utility of vibration controlled transient elastography (VCTE) for the detection of cirrhosis in chronic hepatitis D infection (PMID: 31742822). While the use of VCTE has revolutionized the management of chronic hepatitis B virus and hepatitis C virus infections, VCTE has not been studied in HDV infection and its accuracy remains a question due to the significant hepatic inflammation associated with HDV. In this work, we compared the performance of VCTE in HDV patients with monoinfected HBV and HCV patients in addition to comparing the performance of VCTE against noninvasive serologic markers of fibrosis (i.e.: AST-to-platelet ratio index (APRI), Fibrosis-4 (FIB-4), AST-to-ALT ratio (AAR), and red cell distribution width (RDW)-to-platelet ratio (RPR)). We describe that VCTE has better diagnostic accuracy in detecting cirrhosis in HDV patients compared to noninvasive serologic markers of fibrosis. Additionally, we describe that despite significantly increased levels of histologic inflammation, the performance of VCTE in HDV is comparable to that of HBV and HCV. Finally, we provide a new cut-off VCTE value for use in HDV patients which optimizes the ability to detect cirrhosis. In follow-up to the above described work in HDV, we have also taken the opportunity to create a novel noninvasive fibrosis score, called the Delta-4 fibrosis score (D4FS), which can be utilized in daily clinical practice (PMID: 31837393). In this piece, a training cohort of patients was utilized to identify the four clinical parameters (gamma-glutamyl transpeptidase (GGT), platelet count, alanine aminotransferase (ALT), and liver stiffness measurements (LSM) via VCTE) that were associated with the presence of histologically confirmed cirrhosis to create the D4FS. The performance of the D4FS in identifying patients with histologic cirrhosis was then evaluated against VCTE alone, FIB-4, APRI and AAR in a validation cohort. Notably, the D4FS outperformed all of the other noninvasive tests with an area under the receiver operating curve (AUROC) of 0.94. These impressive results should be confirmed in additional HDV cohorts and may provide clinicians with new tools in identifying cirrhosis with noninvasive means in HDV. 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), the use of VCTE in sickle cell disease (PMID: 31218662), identification of a viral exposure signature that defines early onset hepatocellular carcinoma (PMID: 32526205) and expanding the clinical description of autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) associated hepatitis (PMID:32557834). 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 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. As of August 2020, the final patient completed the final visit for this study. Interim end-of-treatment results were presented in November 2019 at The Liver Meeting and in August 2020 at the International Liver Congress. We are now actively analyzing the data and intend on publishing the final results in the near future. 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 has been IRB approved and is now 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 the course of this annual report. This includes collaborative work published in various peer reviewed journals (PMID: 31872446, 32389361). Finally, several invited review manuscripts have been published during the period that covers this annual report. These include a review in the World Journal of Gastroenterology titled Chronic hepatitis delta: A state-of-the-art review and new therapies (PMID: 31528088) and one in Gastroenterology Reports titled Hepatitis D Infection: from initial discovery to current investigational therapies (PMID: 32477569).