Combination Antiretroviral Therapy (cART) for PBC

Primary endpoint:

Change in mean percentage of alkaline phosphatase (ALP) reduction in cART vs. placebo at 6 and 12 months.

Secondary endpoints:

• Serum biochemistries bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) will be studied as continuous variables.
• Composite endpoint used for the POISE study [A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis]: (i) reduction of ALP to < 1.67 upper limit of normal, (ii) normalization of bilirubin within upper limit of normal (ULN) and (iii) reduction of ALP by > 15% at 6 and 12 months.
• Symptomatic evaluation performed using the PBC-40 to assess five symptom domains relating to fatigue, itch, cognitive symptoms, social and emotional symptoms, and other symptoms.
• Histological change in grade and stage of PBC using the Nakanuma scoring system for a subgroup of patients undergoing liver biopsy [liver biopsy not compulsory for study].
• Serial human betaretrovirus measurement in peripheral blood and cellular immune response to viral peptides.

Inclusion criteria

• over 18 years old of either sex,
• Anti-mitochondrial antibody +ve or liver histology compatible with PBC,
• stable UDCA dose of 13-15 mg/kg for > 12 months or intolerant to UDCA,
• ALP at least 1.67 x ULN or abnormal bilirubin less than 2x ULN
• able to read and sign informed consent form.

Exclusion criteria

• subjects with baseline total bilirubin > 2 x ULN,(patients meeting inclusion criteria stabilized on second line therapies including obeticholic acid or bezafibrate over 12 months or more may be enrolled).
• use of non-standard or experimental therapy within the last 6 months,
• advanced liver disease: INR > 1.2 ULN, Albumin < 35 g/L lower limit of normal, platelets < 120,000/microL unless varices with risk of bleeding excluded by endoscopy within the last 6 months, Childs Pugh class B or C cirrhosis, presence of grade 2 varices or previous variceal hemorrhage, encephalopathy, ascites or need for liver transplantation within the next two years;
• secondary diagnosis such as HIV, viral hepatitis, drug induced liver injury, extrahepatic biliary obstruction, primary sclerosing cholangitis, metabolic liver - regular use of > 30g alcohol/day in the last year;
• a predicted survival of less than 3 years from malignant or other life threatening disease;
• hepatic mass consistent with hepatocellular carcinoma ;
• previous allergic reaction to study medications;
• Glomerular Filtration Rate less than < 30 mL/min as measured Cockcroft-Gault formula;
• pregnancy, breast-feeding or pre-menopausal patients not using contraception.