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. We propose to treat 21 adult patients with chronic delta hepatitis using the combination of the farnesyltransferase inhibitor (FTI) lonafarnib (LNF) and the protease inhibitor ritonavir (RTV). LNF has been shown to decrease serum quantitative HDV RNA in patients with chronic delta hepatitis infection, but dosing is limited by its side effects. RTV inhibits one of the cytochrome P-450 systems that metabolizes LNF leading to higher serum levels of LNF with minimal side effects. In this randomized, double-blinded, placebo-controlled study, there will be six groups of patients; Group 1(4 patients) will receive LNF/RTV 50/100 mg daily for 24 weeks, Group 2 (4 patients) will receive LNF/RTV 75/100mg daily for 24 weeks, Group 3 (4 patients) will receive LNF/RTV 100/100mg daily for 24 weeks, Group 4, 5 and 6 (3 patients for each group) will initially receive placebo for 12 weeks followed by either LNF/RTV 50/100 mg daily (3 patients) or LNF/RTV 75/100mg daily (3 patients) or LNF/RTV 100/100 mg daily (3 patients) for 12 weeks. After dosing, all patients will be monitored for 24 weeks off therapy. Nucleos(t)ide analogue therapy will be instituted during this study to prevent the possibility of hepatitis B virus reactivation/flare; Patients on pre-existing nucleos(t)ide analogues will be continued and patients not on pre-existing therapy will receive either entecavir or tenofovir for 48 weeks. Patients with quantifiable HDV RNA in serum and elevated aminotransferases will be enrolled. Before receiving therapy, patients will be evaluated for at least 3 visits with regular testing for HDV RNA quantitation and alanine aminotransferase (ALT) levels and will undergo Clinical Center admission for medical evaluation, timed blood draws and to start therapy. 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 ALT, aspartate aminotransferase , alkaline phosphatase, direct and total bilirubin, and albumin). At the end of the treatment, patients will undergo 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. Several secondary endpoints will be measured, including side effects, ALT levels, maintained virological response, undetectable HDV RNA in the serum, loss of HBsAg and symptoms. Therapy will be stopped for intolerance to lonafarnib and/or ritonavir (which will be carefully defined). This clinical trial is designed as a phase 2a study assessing the antiviral activity, safety and tolerance of three different doses of lonafarnib and ritonavir.