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Effect of Highly Active Antiretroviral Therapy on Tacrolimus Pharmacokinetics in Hepatitis C Virus and HIV Co-Infected Liver Transplant Recipients in the ANRS HC-08 Study

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Abstract

Objective

To characterise the interactions between tacrolimus and antiretroviral drug combinations in hepatitis C virus-HIV co-infected patients who had received a liver transplant.

Design

An observational, open-label, multiple-dose, two-period, one-sequence design clinical trial in which patients received tacrolimus as an immunosuppressive therapy during the postoperative period and then had an antiretroviral drug regimen added. Tacrolimus pharmacokinetics were evaluated at steady state during these two periods.

Methods

Fourteen patients participated in the study and seven participated in the intensified pharmacokinetic protocol. Patients were included if they had undergone liver transplantation for end-stage chronic hepatitis C, absence of opportunistic infection, a CD4 cell count of >150 cells/μL and an undetectable HIV plasma viral load (<50 copies/mL) under highly active antiretroviral therapy. During the posttransplantation period, the tacrolimus dose was adjusted according to blood concentrations. When liver function and the tacrolimus dose were stable, antiretroviral therapy was reintroduced.

Results

When lopinavir/ritonavir were added to the tacrolimus regimen (seven patients), the tacrolimus dose was reduced by 99% to maintain the tacrolimus concentration within the therapeutic range. Only two patients were treated with nelfinavir, which led to a wide variation in inhibition of tacrolimus metabolism. When efavirenz (four patients) or a nucleoside analogue combination (one patient) was added, very little change in tacrolimus dosing was required.

Conclusion

The lopinavir/ritonavir combination markedly inhibited tacrolimus metabolism, whereas the effect of efavirenz was small. Tacrolimus dosing must be optimised according to therapeutic drug monitoring and the antiretroviral drug combination.

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Acknowledgements

This study was presented in part at the 12th Conference on Retroviruses and Opportunistic Infections (abstract no. 662), 22–25 February 2005, Boston, MA, USA. The study was sponsored by the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS), Paris, France.

The authors thank Abbott Laboratories for providing lopinavir, ritonavir and the internal standard; Roche for providing nelfinavir; and Bristol-Myers Squibb for providing efavirenz for analytical assays.

The authors have no conflicts of interest that are directly relevant to the content of this study.

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Correspondence to Anne-Marie Taburet.

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Teicher, E., Vincent, I., Bonhomme-Faivre, L. et al. Effect of Highly Active Antiretroviral Therapy on Tacrolimus Pharmacokinetics in Hepatitis C Virus and HIV Co-Infected Liver Transplant Recipients in the ANRS HC-08 Study. Clin Pharmacokinet 46, 941–952 (2007). https://doi.org/10.2165/00003088-200746110-00002

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