Treatment of Chronic Delta Hepatitis With Lonafarnib, Ritonavir and Lambda Interferon

Background: Infection with hepatitis D virus leads to a chronic liver disease with no effective treatment. Lonafarnib has improved hepatitis D virus levels in blood, but the medication still needs more research. Ritonavir makes other drugs more effective and is used with lonafarnib to make it more effective. Lambda interferon stimulates the body s response to viruses. Researchers want to see if combining these drugs fights hepatitis D and helps the liver. Objectives: To see if combining lonafarnib, ritonavir, and lambda interferon is safe and effective to treat chronic hepatitis D infection. Eligibility: Adults at least 18 years old with chronic hepatitis D infection Design: Participants will be screened with a physical exam, medical history, and blood and urine tests. Throughout the study, all participants will: * Follow rules for medicine, food, and contraception * Take hepatitis B medicine * Have weight checked * Have routine blood and urine tests * Give stool samples * Female participants will have pregnancy tests. Participants will have 3 visits before treatment. They will repeat screening tests and have a heart test and liver scan. Participants will have a 5-day inpatient stay. They will: * Baseline blood and urine tests * Have eye tests * Answer health questions * Have a liver sample taken and liver blood pressure measured. Participants will be sedated. * Have reproductive tests * Start the study drugs and have blood draws Over 24 weeks of treatment, participants will: -Take 2 study drugs by mouth every day and 1 as a weekly injection

Chronic delta hepatitis is a serious form of chronic liver disease caused by infection with the hepatitis D virus (HDV), a small RNA virus that requires farnesylation of its major structural protein (HDV antigen) for replication. Based on previous and ongoing clinical trials demonstrating effectiveness against HDV, we propose to treat 26 adult patients with chronic delta hepatitis using the combination of the farnesyltransferase inhibitor (FTI) lonafarnib (LNF), the protease inhibitor ritonavir (RTV) and peginterferon lambda-1a(lambda). In this phase 2a open label study, the safety and antiviral effects of triple therapy with LNF, RTV and lambda for a period of 6 months. After dosing, all patients will be monitored for 24 weeks off therapy. Nucleos(t)ide analogue therapy will be instituted/continued during this study to prevent the possibility of hepatitis B virus (HBV) reactivation/flare for the duration of participation in this clinical trial. Patients with quantifiable HDV RNA in serum will be enrolled. At each clinic visit, patients will be questioned about side effects, symptoms and quality of life, undergo focused physical examination, and have blood drawn for complete blood counts, HDV RNA, and routine liver tests (including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, direct and total bilirubin, and albumin). At the end of the treatment, patients will be admitted to the clinical center and will undergo repeat liver biopsy and hepatic venous pressure gradient (HVPG) measurements, repeat physical examination, assessment of symptoms (using a symptom scale questionnaire), complete blood counts, routine liver tests, and hepatitis B and D viral markers. The primary therapeutic endpoint will be a decline of 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. This clinical trial is designed as a phase 2a study assessing the antiviral activity, safety and tolerance of fixed doses of lonafarnib, ritonavir and peginterferon lambda.