Treatment of Chronic Delta Hepatitis With Lonafarnib and Ritonavir
Treatment of Chronic Delta Hepatitis With Lonafarnib and Ritonavir
Background:

 - Chronic hepatitis D is a liver disease caused by the hepatitis D virus (HDV). It can be
 severe and progressive. Most people with hepatitis D will develop scarring and damage to the
 liver. There is no FDA approved drug to treat chronic hepatitis D. Researchers want to know
 if the drugs lonafarnib and ritonavir can help people with chronic hepatitis D.

 Objective:

 - To find out if treatment of hepatitis D with lonafarnib and ritonavir is safe and
 effective.

 Eligibility:

 - People 18 years of age and older with chronic hepatitis D. They must not have HIV or other
 major illnesses.

 Design:

 -  Participants will be screened with medical history, physical exams, and blood tests.

 -  Participants will have 24 weeks of treatment. They will then have 24 weeks of follow-up.

 -  Participants will be in 1 of 6 treatment groups. Those in each group will receive
 different doses of the study drugs. Some groups will start with placebo but will receive
 treatment after 3 months of placebo.

 -  Participants will also take drugs to treat hepatitis B.

 -  Participants will have many visits. These will include:

 -  One three-day stay at the Clinical Center

 -  Physical exams

 -  EKG: small sticky patches will be put on the chest, arms, and legs to trace heart rhythm

 -  Ultrasounds of the abdomen

 -  Urine and blood tests

 -  Stool samples

 -  Eye exams

 -  Evaluations by a reproductive endocrinologist (women) or urologist (men). Men may
 provide a sperm sample (optional).
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.
-  INCLUSION CRITERIA:

 1. Age 18 years or above, male or female.

 2. Serum alanine or aspartate aminotransferase (ALT or AST) activities above the
 upper limit of normal (ALT greater than or equal to 20 or AST greater than or
 equal to 20 U/L in females and ALT greater than or equal to 30 or AST greater
 than or equal to 30 U/L in males) on an average of three determinations taken
 during the previous 6 months at the NIH clinical center. The mean of the three
 determinations will be defined as baseline levels.

 3. Presence of anti-HDV in serum.

 4. Presence of quantifiable HDV RNA in serum.

 EXCLUSION CRITERIA:

 1. 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.

 2. Pregnancy, active breast-feeding, or inability to practice adequate contraception, in
 women of childbearing potential or in spouses of such women. Adequate contraception is
 defined as vasectomy in men, tubal ligation in women, or use of two barrier methods
 such as condoms and spermicide combination, birth control pills, an intrauterine
 device, Depo-Provera, or Norplant. In total, the participant and their partner must
 utilize two forms of contraception and one method must include a barrier method.

 3. 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), and active coronary artery disease.

 4. Systemic immunosuppressive therapy within the previous 2 months.

 5. 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, nonalcoholic steatohepatitis (but not
 steatosis), hemochromatosis, or alpha-1-antitrypsin deficiency).

 6. Active substance abuse, such as alcohol, inhaled or injection drugs within the
 previous year.

 7. Evidence of hepatocellular carcinoma.

 8. Evidence of concurrent hepatitis C infection with positive serum hepatitis c virus
 (HCV) RNA.

 9. Any experimental therapy or pegylated interferon therapy within 6 months prior to
 enrollment.

 10. Diagnosis of malignancy in the five years prior to the enrollment with exception
 granted to superficial dermatologic malignancies.

 11. Evidence of HIV co-infection; HIV 1/2 viral RNA or antigen on serum testing.

 12. Concurrent usage of statins as these drugs inhibits mevalonate synthesis, which
 reduces protein prenylation.

 13. Concurrent usage of moderate and strong cytochrome p450, family 3, subfamily A (CYP3A)
 inhibitors and inducers.

 14. Use of any prescription, nonprescription or natural medicine (herbal) medications
 unless the use of medication is medically necessary with appropriate monitoring.

 15. 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.

 16. Clinically significant baseline EKG abnormalities.

 17. Uncontrolled elevated triglycerides.

 18. History of pancreatitis as a result of hypertriglyceridemia.

 19. Inability to understand or sign informed consent.

 20. Any other condition, which in the opinion of the investigators would impede the
 patient s participation or compliance in the study.