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

INCLUSION CRITERIA: * Age 18 years or above, male or female. * Presence of anti-HDV in serum. * Presence of quantifiable HDV RNA in serum at three time pre-treatment points with a mean HDV RNA level \>2 log10 above the lower limit of quantification (LLOQ) of the HDV RNA assay. * Demonstration of chronicity as evidenced by the presence of HDV RNA in serum for \>/= 6 months, or presence of Anti-HDV antibody \>/= 6months. EXCLUSION CRITERIA: * Decompensated liver disease, defined by bilirubin \>4mg/dL, albumin \<3.0 gm/dL, prothrombin time \>2 sec prolonged, or history of bleeding esophageal varices, ascites or hepatic encephalopathy. Laboratory abnormalities that are not thought to be due to liver disease may not necessarily require exclusion. Patients with ALT levels greater than 1000 U/L (\>25 times ULN) will not be enrolled but may be followed until three determinations are below this level. Patients with an absolute neutrophil count \<1000/dL and platelets \<75,000/dL will be excluded from the study as well. * Pregnancy, active breast-feeding, or inability to practice adequate contraception, in women of childbearing potential or in partners of such women. Adequate contraception is defined as vasectomy in male sexual partners of female participants, tubal ligation in women, or use of two contraceptive methods such as condoms and spermicide combination with an intrauterine device or Depo-Provera, or Norplant. * Significant systemic or major illnesses other than liver disease, including, but not limited to, congestive heart failure, renal failure (eGFR \<50 ml/min), organ transplantation, serious psychiatric disease or depression (only if felt to be at high risk by the NIH psychiatric consultation service), or active coronary artery disease. * Systemic immunosuppressive therapy within the previous 2 months before enrollment. * Evidence of another form of liver disease in addition to viral hepatitis (for example autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson disease, alcoholic liver disease, ongoing drug induced liver disease, nonalcoholic steatohepatitis (but not steatosis), hemochromatosis, or alpha-1-antitrypsin deficiency). * Active substance abuse, such as alcohol, inhaled or injection drugs within the previous year. * Evidence of hepatocellular carcinoma. This will be determined on the basis of imaging with ultrasound/ CT scan or MRI performed a maximum of 6 months prior to enrollment. Elevated alpha fetoprotein (AFP) levels will be evaluated clinically and further imaging may be performed if felt necessary. * Evidence of concurrent hepatitis C infection with positive serum hepatitis C virus (HCV) RNA. * Any experimental therapy or pegylated interferon therapy within 6 months prior to enrollment. * Active, serious autoimmune disease such as systemic lupus erythematosus, ulcerative colitis, Crohn s disease or rheumatoid arthritis, that is in the opinion of the investigators might be exacerbated by therapy with lambda interferon. This will be evaluated at baseline and during follow-up laboratory testing (including blood and urine studies) in addition to described symptoms at each outpatient visit. * Diagnosis of malignancy in the five years prior to the enrollment with exception granted to superficial dermatologic malignancies. * Evidence of HIV co-infection; HIV 1/2 antibody positivity on serum testing. * Concurrent usage of statins as these drugs inhibits mevalonate synthesis, which reduces protein prenylation. * Concurrent usage of moderate and strong CYTOCHROME P-450 CYP3A (CYP3A) inhibitors and inducers. * Concurrent usage of alpha 1 adrenoreceptor antagonist, antiarrhythmic, pimozide, sildenafil, sedative and hypnotics, ergot and St. John s Wort due to possible effect of ritonavir on hepatic metabolism of these drugs resulting in potentially life-threatening side effects. * Clinically significant baseline EKG abnormalities such as corrected QT (QTc) interval \>450 ms and/or prolonged PR interval. * Uncontrolled elevated triglycerides (\>500 mg/dL). Patients on lipid lowering therapy other than statins will be eligible for this study. * History of pancreatitis from causes other than gallstone pancreatitis. Subjects with a baseline amylase and/or lipase level \>3 ULN will be excluded from the study. * Inability to understand or sign informed consent. * Any other condition, which in the opinion of the investigators would impede the patient s participation or compliance in the study.