Treatment of Chronic Delta Hepatitis With Lonafarnib, Ritonavir and Lambda Interferon
Condition: Liver Disease; Hepatitis D
MeSH terms: Hepatitis A; Hepatitis D; Hepatitis D, Chronic; Hepatitis; Liver Diseases
Intervention: Peg-interferon lambda; Lonafarnib; Ritonavir
Intervention description: Peg-interferon Lambda is a covalent conjugate of human recombinant non- pegylated interferon (IFN) lambda and a 20-kDa linear pegylated (PEG) chain.; Oral prenylation inhibitor; Booster of lonafarnib action
Intervention MeSH terms: Interferons; Ritonavir; Lonafarnib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 26.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Hepatitis D; Hepatitis D Virus; Cirrhosis

Summary:

      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
    

Eligibility criteria:

        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.