Combination antiretroviral therapy improves recurrent primary biliary cholangitis following liver transplantation

Abstract

Recurrent primary biliary cholangitis (rPBC) is frequent following liver transplantation and associated with increased morbidity and mortality. It has been argued that rPBC behaves like an infectious disease because more potent immunosuppression with tacrolimus is associated with earlier and more severe recurrence. Prophylactic ursodeoxycholic acid is an established therapeutic option to prevent rPBC, whereas the role of second line therapies, such as obeticholic acid and bezafibrate in rPBC, remains largely unexplored. To address the hypothesis that a human betaretrovirus plays a role in the development of PBC, we have tested antiretroviral therapy in vitro and conducted randomised controlled trials showing improvements in hepatic biochemistry. Herein, we describe the utility of combination antiretroviral therapy to manage rPBC in two patients treated with open label tenofovir/emtricitabine‐based regimens in combination with either lopinavir or raltegravir. Both patients experienced sustained biochemical and histological improvement with treatment, but the antiretroviral therapy was associated with side effects.

Apples to Apples? A Comparison of Real-World Tolerability of Antiretrovirals in Patients with Human Immunodeficiency Virus Infection and Patients with Primary Biliary Cholangitis

“…Several ART agents used to treat PLWH have been repurposed for patients with PBC. Specifically, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) have been tested in vitro, in animal models and in clinical trials with PBC patients, either alone or in combination with the protease inhibitor (PI) combination ritonavir-boosted lopinavir (LPV/r) or the integrase strand transfer inhibitor (INSTI) raltegravir (RAL) [ 8 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

“…A comparative analysis of several dual NRTI regimens with and without LPV/r revealed that the combination of TDF/FTC with LPV/r had the optimal biochemical and histological impact and reduced MMTV RNA levels in the liver [ 36 ]. Then, a cART regimen with TDF/FTC and LPV/r was used to treat a young patient with severe recurrent PBC following liver transplantation [ 8 ]. Biochemical and histological improvements were observed, but LPV/r inhibited the metabolism of tacrolimus to such an extent that the patient only required 0.5 mg tacrolimus weekly to maintain adequate immunosuppression levels ( Figure 1 ).…”

“…Biochemical and histological improvements were observed, but LPV/r inhibited the metabolism of tacrolimus to such an extent that the patient only required 0.5 mg tacrolimus weekly to maintain adequate immunosuppression levels ( Figure 1 ). The commencement of cART was also associated with biochemical hepatitis [ 8 ].…”

“…Indeed, recurrent PBC after liver transplantation remains a common and clinically important issue, and the potential to treat an infectious cause of PBC remains a priority. It is therefore of interest that combination antiretroviral therapy (cART) has shown some utility in reversing cholangitis in patients with PBC who experience disease recurrence following liver transplantation ( Figure 1 ) [ 8 ].…”

“…Consequently, we previously conducted interventional studies with repurposed ART to address the hypothesis that HBRV infection is central to PBC and, at the same time, perform proof-of-principle studies to assess whether clinical improvement corresponds to a reduction in virologic load [ 8 , 28 , 29 , 30 , 31 , 32 , 33 ]. While the use of ART was associated with demonstrable biochemical and histological improvement, treatment with HIV protease inhibitors was associated with clinically significant side effects.…”