Darunavir and Ritonavir Total and Unbound Plasmatic Concentrations in HIV-HCV Co-Infected Patients with Hepatic Cirrhosis Compared to HIV Mono-Infected Patients

2015 Antimicrobial Agents and Chemotherapy In press;

OBJECTIVES: defining pharmacokinetic (PK) parameters of total and unbound darunavir and ritonavir in HIV-HCV co-infected patients with cirrhosis, as ritonavir-boosted darunavir is mainly metabolized in the liver and hepatic cirrhosis might modify darunavir/ritonavir concentrations. PATIENTS AND METHODS: Prospective, case-control, unicenter study. HIV-HCV co-infected patients with compensated cirrhosis (cases) and HIV mono-infected patients with normal liver function (controls) were included. Darunavir/ritonavir was given 800/100 mg once-daily. Patients were followed 24 weeks, assessing safety and efficacy. A steady-state 12-hours PK study was performed. Total and unbound concentrations were determined by Liquid Chromatography-tandem Mass Spectrometry. Unbound fraction was obtained by ultrafiltration. AUC and CL/F were assessed by non-compartmental models. RESULTS: Thirty patients (20 cases, 10 controls) were included. Amongst cirrhotic patients, Child-Pugh score was C in 4 cases, B in 1 and A in 15, median transient elastography values were 20 (14-26) kPa and 5 patients had prior clinical decompensations. There were no significant differences in darunavir PK parameters, between cases and controls except for longer Tmax and half-lives in cirrhotics. There were no significant differences in ritonavir total concentrations, but unbound concentrations were higher in cirrhotic patients. There were significant correlations between darunavir total and unbound concentrations both in cirrhotic patients and controls. There were no differences in PK parameters depending on Child-Pugh score, liver elasticity, gender or concomitant medications. CONCLUSIONS: In HIV-HCV patients with clinically compensated cirrhosis receiving darunavir/ritonavir 800/100 mg once-daily, darunavir total and unbound concentrations are similar to those observed in non-cirrhotic patients, and dose adjustments are not necessary.

Pubmed : 26282411