Peginterferon Lambda and Lonafarnib Boosted With Ritonavir 48-Week Combination Therapy for Delta Hepatitis

Background: Chronic hepatitis D is a serious liver disease caused by a virus. Currently, no medications are approved to treat chronic hepatitis D. Objective: To test a combination of 3 drugs in people with chronic hepatitis D. Eligibility: People 18 years or older with chronic hepatitis D. Design: Participants will be in the study about 2 years. They will have 3 inpatient stays of 3 to 5 days. Participants will be screened. They will have a physical exam with blood tests. They will have a test of their heart function and an ultrasound: a wand that uses sound waves to create images of the liver will be rubbed over the skin on their torso. Participants will stay in the clinic for a 3-day baseline visit. They will have imaging scans, an eye exam, and a visit with a reproductive specialist. They will have a liver biopsy: about 1 inch of liver tissue will be removed, either with a tube inserted through a vein in the neck, or with a needle inserted through the participant s side. Participants will take the study drugs for 48 weeks. Two of them are tablets taken twice a day at home; 1 is a shot administered once a week. Participants will begin taking the drugs during a 5-day stay in the clinic. Then they will have 15 outpatient visits while taking the drugs and 7 more after they finish. The last 3-day clinic stay will be 6 months after participants finish taking the drugs. The liver biopsy, imaging scans, and other tests will be repeated.

Study Description: This is an open-label clinical trial treating 30 adult patients with chronic delta hepatitis with peginterferon lambda and lonafarnib boosted with ritonavir for 48 weeks. This is a follow up study to the previous 24-week combination study we had previously completed which demonstrated promising results. We hypothesize that therapy with peginterferon lambda and lonafarnib boosted with ritonavir will lead to a significant decline in hepatitis D virus RNA levels. Objectives: Primary Objective: The goal of this study is to assess the therapeutic response to 48 weeks of treatment with peginterferon lambda and lonafarnib boosted with ritonavir in patients with chronic hepatitis D. Secondary Objectives: * Evaluation of the hepatitis D viral response to treatment during the treatment period and 24 weeks after the end of study. * Evaluation of the hepatitis B viral response to treatment during the treatment period and 24 weeks after the end of study. * Comparison of the patients liver parenchyma before and after treatment. * Comparison of the patients liver biochemistry before, during and after treatment. * Comparison of the patients hepatic venous pressure measurements before and after treatment. * Evaluation of the patients bone density changes during therapy. * Evaluation of changes in the patients fecal microbiome before, during and after treatment. * Evaluation of the patients quality of life before, during and after treatment. Tertiary Objective: 1\. Comparison of the patients immune response before, during and after treatment. Endpoints: Primary Endpoint: * Number of patients with HDV RNA levels \< Lower Limit of Quantification (LLOQ), target not detected (TND) and the number of patients with HDV RNA levels \<LLOQ, target detected (TD) in serum at 24 weeks after a 48-week treatment course of Peginterferon Lambda and Lonafarnib boosted Ritonavir. * The ability to tolerate peginterferon lambda and lonafarnib boosted with ritonavir therapy for 48 weeks. Discontinuation of the medication by the clinical team or patient will be considered a failure to tolerate the medicine. Secondary Endpoints: * Sustained undetectable HDV RNA in serum at 48 weeks of treatment. * Decrease of HDV RNA by \>2 log from baseline at 48 weeks of therapy and 24 weeks post treatment. * Determine the proportion of subjects with serum HDV RNA\<LLOQ, TND with ALT normalization and \<LLOQ, TD with ALT normalization. * Reduction in histologic inflammatory scores (modified HAI) by at least two points with no progression in histologic fibrosis (Ishak) at week 24 post-treatment follow-up. * Normalization of serum ALT (per reference lab) at the end of therapy and at week 24 of post-therapy follow-up, OR reduction in serum ALT by \>50% of baseline at the end of therapy and week 24 of post therapy follow up. * Reduction in hepatic venous pressure gradient (HVPG) measurements by \>25% of baseline OR normalization of HVPG (\<5 mm Hg) at week 24 post-treatment measurement. * Reduction in Fibroscan(R) transient elastography values by \>25% of baseline at study end. * Loss of HBsAg from the serum at the end of therapy or at week 24 of post-therapy follow-up. * Changes in quantitative HBsAg levels at the end of therapy and at week 24 of post therapy follow up, compared to baseline. * Changes in bone density measurements by Dual-Energy X-ray Absorptiometry (DEXA). * Changes in symptom scale measurements and quality of life before, during and after therapy. * Changes in the fecal microbiome before, during and after treatment. Tertiary endpoint: -Changes in the patients peripheral blood mononuclear cell (PBMC) response to HDV during and following therapy in comparison to baseline. Changes in the phenotype and transcriptome of the intrahepatic immune cell infiltrate prior to and 24 weeks post end of therapy.