Combination Antiretroviral Therapy (cART) for PBC
Combination Antiretroviral Therapy (cART) for PBC
Placebo Controlled, double-blind randomized controlled trial (RCT) with 12 months Tenofovir
 Disoproxil and Raltegravir for primary biliary cholangitis (PBC) patients unresponsive to
 Ursodeoxycholic Acid (UDCA). Placebo patients will be offered 12 months open label therapy at
 unblinding. All patients will be offered an additional 12 months open label therapy.
 Observational, open label study will be performed in parallel using Emtricitabine
 (FTC)/Tenofovir Disoproxil (TDF) & Raltegravir in liver transplant recipients meeting all
 entry criteria except for use of immunosuppression.
Primary endpoint:

 Greater than 10% difference in mean percentage of alkaline phosphatase (ALP) reduction in
 cART vs. placebo at 6 and 12 months.

 Secondary endpoints:

 1. Serum biochemistries bilirubin, aspartate aminotransferase (AST), alanine
 aminotransferase (ALT) and gamma-glutamyltransferase (GGT) will be studied as continuous
 variables.

 2. 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.

 3. 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.

 4. 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].

 5. 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,

 -  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, 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.