Highly Active Antiretroviral Therapy for Patients With Primary Biliary Cirrhosis (HAART)

Randomized Controlled Pilot Study of Highly Active Anti-Retroviral Therapy for Patients With Primary Biliary Cirrhosis

Patients with primary biliary cirrhosis (PBC) develop progressive liver disease and often require liver transplantation. The cause of disease is unknown. It is thought to occur as a result of an infection in subjects that are more susceptible to disease than others. The investigators found evidence of retrovirus infection in patients with primary biliary cirrhosis. The investigators found that most patients with PBC have evidence of viral infection. Since then the investigators have conducted clinical studies using anti-viral therapy. The investigators found that PBC patients treated with combination anti-retrovirus therapy experienced significant reversal of the disease process. However, the changes were not substantial and the investigators are now looking for better antiviral regimens. Now the investigators have found a mouse model with a similar virus infection that develops a similar biliary disease. Importantly, the investigators found that antiviral therapy blocks the development of the disease in this mouse. The investigators have used this model to find safer and more effective antiviral treatments for patients with PBC. The investigators have now found out that a combination of highly active antiretroviral therapy with Truvada and Kaletra stops disease in the mouse and plan to use this combination to see if it works in patients with PBC.

Study Overview

• Status: Terminated
• Conditions: Primary Biliary Cirrhosis
• Intervention / Treatment: Drug: Placebo; Drug: TDF/FTC/LPV/r

Detailed Description

6 months therapy with blinded Kaletra and Truvada vs. 6 months therapy with blinded placebo followed by 6 months open label therapy with Kaletra and Truvada

18 month extension study with open label Kaletra and Truvada in patients completing 6 months of therapy with Kaletra and Truvada with biochemical endpoint

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B2
      • University of Alberta

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients 18 years old of either sex will be recruited for this study.
2. Elevated ALP after 6 months UDCA therapy ≥ 2 x upper limit of normal or abnormal bilirubin.
3. Positive serum AMA or Liver biopsy histology compatible with PBC.
4. Maintained on UDCA at a dose of 13-15 mg/kg for 6 or more months.
5. Patients must read and sign informed consent form

Exclusion Criteria:

1. Subjects with baseline AST or ALT > 5 x ULN.
2. Patients who have altered dose of any medications used to treat PBC (such as UDCA) or the use of colchicine, corticosteroids, azathioprine, chlorambucil, methotrexate, or D-penicillamine within the last 6 months.
3. Advanced liver disease or esophageal varices, INR > 1.2 (upper limit of normal), Albumin < 35 g/L (lower limit of normal), platelets < 120,000/mm3, Childs Pugh class B or C cirrhosis, presence of varices or previous variceal hemorrhage, spontaneous encephalopathy, ascites or need for liver transplantation.
4. Patients with a secondary diagnosis such as HIV, viral hepatitis, drug induced liver injury, extrahepatic biliary obstruction, primary sclerosing cholangitis, metabolic liver diseases or alcoholic liver disease Regular use of more than 30 g of alcohol per day in the last year. Clinically apparent pancreatitis or with a predicted survival of less than 3 years from malignant or other potentially life threatening disease.
5. An ultrasound showing a hepatic mass consistent with hepatocellular carcinoma within the last year in patients with cirrhosis.
6. Previous allergic reaction to study medications.

7. Creatinine clearance less than < 70 mL/min using the Cockcroft Gault equation:

   Creatinine clearance (mL/min) = (140 - age) x body wt (Kg) x 0.85 (if female)/serum creatinine in mol/l

8. Pregnancy or breast-feeding a child. Young sexually active patients not using contraception
9. Young sexually active patients not using contraception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Identical Placebo Tablets. Duration: 6 months therapy with blinded placebo followed by 6 months open label therapy (Truvada and Kaletra). Following, there is an option for an 18-month extension study.	Drug: Placebo; 6 months therapy with blinded placebo followed by 6 months open label therapy with Kaletra and Truvada.; Other Names: Truvada; Tenofovir; Emtricitabine; lopinavir; ritonavir
Active Comparator: TDF/FTC/LPV/r; TDF/FTC/LPV/r One tablet of Truvada a day at standard dose of Tenofovir 300mg and Emtricitabine 200mg and four tablets of Kaletra once a day for a total dose of lopinavir 800mg and ritonavir 200mg for 6 months, or less if adverse events occur. Duration: 6 months of therapy with the option of open label for additional 18-month extension study.	Drug: TDF/FTC/LPV/r; one tablet of Truvada a day at standard dose of Tenofovir 300mg and Emtricitabine 200mg and four tablets of Kaletra once a day for a total dose of lopinavir 800mg and ritonavir 200mg for 6 months or less if adverse events occur; Other Names: Truvada; Kaletra; Tenofovir; Emtricitabine; lopinavir; ritonavir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Reduction of ALP to 1.67x ULN	The outcomes will be measured are from 12 to 24 weeks at the end of the study
normalization of bilirubin.	The outcomes will be measured are from 12 to 24 weeks at the end of the study

Secondary Outcome Measures

Outcome Measure	Time Frame
Reduction of human betaretrovirus.	The outcomes will be measured are from 12 to 24 weeks in RCT; and 6 monthly to 2 years for the extension study
Symptoms with changes in PBC-40	The outcomes will be measured are from 12 to 24 weeks in RCT; and 6 monthly to 2 years for the extension study
Changes in AMA and immunoglobulin levels	The outcomes will be measured are from 12 to 24 weeks in RCT; and 6 monthly to 2 years for the extension study
Biochemistry: GGT, AST and ALT	The outcomes will be measured are from 12 to 24 weeks in RCT; and 6 monthly to 2 years for the extension study
Histology in extension study	The outcomes will be measured are from 12 to 24 weeks in RCT; and 6 monthly to 2 years for the extension study

Collaborators and Investigators

• Sponsor: University of Alberta
• Collaborators: Canadian Institutes of Health Research (CIHR); Gilead Sciences; Abbott
• Investigators: Principal Investigator: Andrew Mason, University of Alberta

Publications and helpful links

General Publications

• Schembri G, Schober P. Killing two birds with one stone. Lancet. 2011 Jan 1;377(9759):96. doi: 10.1016/S0140-6736(10)61343-8. No abstract available.

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: April 25, 2011
• First Submitted That Met QC Criteria: June 6, 2012
• First Posted (Estimated): June 7, 2012

Study Record Updates

• Last Update Posted (Actual): November 21, 2024
• Last Update Submitted That Met QC Criteria: November 20, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: PBC
• Additional Relevant MeSH Terms: Pathologic Processes; Digestive System Diseases; Biliary Tract Diseases; Liver Diseases; Bile Duct Diseases; Cholestasis, Intrahepatic; Cholestasis; Fibrosis; Liver Cirrhosis; Liver Cirrhosis, Biliary; Viral Protease Inhibitors; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Protease Inhibitors; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors; Antiviral Agents; Cytochrome P-450 Enzyme Inhibitors; Reverse Transcriptase Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Tenofovir; Emtricitabine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Ritonavir; Lopinavir
• Other Study ID Numbers: HAART Study