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

 INCLUSION 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 AFP levels will be evaluated clinically and further imaging may be performed
 if felt necessary.

 -  Evidence of concurrent hepatitis C infection with positive serum 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 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 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.