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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.

SUBMITTER: Lytvyak E

PROVIDER: S-EPMC8362166 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Combination antiretroviral therapy improves recurrent primary biliary cholangitis following liver transplantation.

Lytvyak Ellina E Niazi Mina M Pai Rohit R He Daniel D Zhang Guangzhi G Hübscher Stefan G SG Mason Andrew L AL

Liver international : official journal of the International Association for the Study of the Liver 20210608 8

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, re ...[more]

PMID: 34008271

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Project description:BackgroundThere is a wealth of data documenting the epidemiology of primary biliary cholangitis (PBC) globally; however, the epidemiology of PBC has not been as well studied in Canada. Our study characterized the Canadian prevalence of PBC and the number of liver transplantations because of PBC.MethodsFor this retrospective cohort study we used national hospital administrative records from the Canadian Institute for Health Information, with the exception of Quebec for the prevalence estimate and Quebec and British Columbia for the transplant analysis. Prevalent patients were identified through a diagnostic code for PBC of the Canadian version of the 10th revision of the International Classification of Diseases. PBC transplant patients were identified from their transplant record. Descriptive statistics were used to summarize the characteristics of the study cohorts.ResultsIn 2015, 8680 patients with PBC were identified in Canada, translating to a prevalence of 318 cases per million. Annual prevalence by province varied, ranging from 283 (95% confidence interval [CI] 269-297) cases per million to 465 (95% CI 426-504) cases per million, and the 6-year PBC liver transplantation rate ranged from 3.17 (95% CI 1.27-6.54) to 5.92 (95% CI 3.71-9.08) per million. The Atlantic provinces exhibited the highest PBC prevalence and close to the highest 6-year liver transplantation rate (465 [95% CI 426-504] cases per million and 5.70 [95% CI 426-504, 3.19-9.56] cases per million, respectively). We observed the lowest PBC prevalence (283 [95% CI 269-297] cases per million) and the second lowest 6-year liver transplantation rate in Ontario (3.37 [95% CI 2.47-4.50] cases per million).InterpretationThe prevalence of PBC that we found in Canada is similar to the prevalence reported in other studies, but our work also indicates geographic variation within this country. Given our finding of geographic clustering of PBC across Canada, we hypothesize that environmental and genetic factors contribute to the pathogenesis of this condition.

Project description:Background & aimsTacrolimus has been associated with recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT), which in turn may reduce survival. This study aimed to assess the association between the type of calcineurin inhibitor used and long-term outcomes following LT in patients with PBC.MethodsSurvival analyses were used to assess the association between immunosuppressive drugs and graft or patient survival among adult patients with PBC in the European Liver Transplant Registry. Patients who received a donation after brain death graft between 1990 and 2021 with at least 1 year of event-free follow-up were included.ResultsIn total, 3,175 patients with PBC were followed for a median duration of 11.4 years (IQR 5.9-17.9) after LT. Tacrolimus (Tac) was registered in 2,056 (64.8%) and cyclosporin in 819 (25.8%) patients. Following adjustment for recipient age, recipient sex, donor age, and year of LT, Tac was not associated with higher risk of graft loss (adjusted hazard ratio [aHR] 1.07, 95% CI 0.92-1.25, p = 0.402) or death (aHR 1.06, 95% CI 0.90-1.24, p = 0.473) over cyclosporin. In this model, maintenance mycophenolate mofetil (MMF) was associated with a lower risk of graft loss (aHR 0.72, 95% CI 0.60-0.87, p <0.001) or death (aHR 0.72, 95% CI 0.59-0.87, p <0.001), while these risks were higher with use of steroids (aHR 1.31, 95% CI 1.13-1.52, p <0.001, and aHR 1.34, 95% CI 1.15-1.56, p <0.001, respectively).ConclusionsIn this large LT registry, type of calcineurin inhibitor was not associated with long-term graft or recipient survival, providing reassurance regarding the use of Tac post LT in the population with PBC. Patients using MMF had a lower risk of graft loss and death, indicating that the threshold for combination treatment with Tac and MMF should be low.Impact and implicationsThis study investigated the association between immunosuppressive drugs and the long-term survival of patients with primary biliary cholangitis (PBC) following donation after brain death liver transplantation. While tacrolimus has previously been related to a higher risk of PBC recurrence, the type of calcineurin inhibitor was not related to graft or patient survival among patients transplanted for PBC in the European Liver Transplant Registry. Additionally, maintenance use of mycophenolate was linked to lower risks of graft loss and death, while these risks were higher with maintenance use of steroids. Our findings should provide reassurance for physicians regarding the continued use of Tac after liver transplantation in the population with PBC, and suggest potential benefit from combination therapy with mycophenolate.

Project description:Following the characterization of a human betaretrovirus in patients with primary biliary cirrhosis (PBC), pilot studies using antiretroviral therapy have been conducted as proof of principal to establish a link of virus with disease and with the eventual aim to find better adjunct therapies for patients unresponsive to ursodeoxycholic acid. In the first open label pilot study, the reverse transcriptase inhibitor lamivudine had little demonstrable biochemical or histological effect after 1 year. Whereas, lamivudine in combination with zidovudine was associated with a significant reduction in alkaline phosphatase as well as improvement in necroinflammatory score, cholangitis and ductopenia over a 12 mo period. A double blind, multi-center randomized controlled trial using lamivudine with zidovudine for 6 mo confirmed a significant reduction in alkaline phosphatase, ALT and AST in patients on antiviral therapy. However, none of the patients achieved the stringent endpoint criteria for normalization of alkaline phosphatase. Furthermore, some patients developed biochemical rebound consistent with drug resistance. A major fault of these studies has been the inability to measure the viral load in peripheral blood and therefore, provide a direct correlation between improvement of hepatic biochemistry and reduction in viral load. Nevertheless, viral mutants to lamivudine with zidovudine were later characterized in the NOD.c3c4 mouse model of PBC that has been used to test other antiretroviral regimens to betaretrovirus. The combination of tenofovir and emtricitabine reverse transcriptase inhibitors and the HIV protease inhibitor, lopinavir were found to abrogate cholangitis in the NOD.c3c4 mouse model and the same regimen normalized the liver tests in a PBC patient with HIV and human betaretrovirus infection. This combination antiretroviral therapy has now been used in a double blind randomized controlled crossover study for patients with PBC followed by an open label extension study. Only a third of the PBC patients were able to tolerate the lopinavir but those maintained on tenofovir, emtricitabine and lopinavir experienced sustained and clinically meaningful reduction in hepatic biochemistry. While we await the histological and virological evaluation, it is clear that better tolerated regimens of antiretroviral treatment will be required in future clinical trials.

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Combination antiretroviral therapy improves recurrent primary biliary cholangitis following liver transplantation.

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Combination antiretroviral therapy improves recurrent primary biliary cholangitis following liver transplantation.

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