Aude Desnoyer1, Dan Pospai2, Minh Patrick Lê3, Anne Gervais4, Alexandra Heurgué-Berlot5, Achour Laradi6, Stanislas Harent4, Adriana Pinto4, Dominique Salmon7, Sophie Hillaire8, Hélène Fontaine9, David Zucman10, Anne-Marie Simonpoli11, Patrice Muret12, Lucile Larrouy13, Brigitte Bernard Chabert5, Diane Descamps13, Yazdan Yazdanpanah4, Gilles Peytavin14. 1. Pharmaco-Toxicology Department, Bichat-Claude Bernard Hospital, APHP, Paris, France. Electronic address: audedesnoyer@gmail.com. 2. Gastroenterology Department, Bichat-Claude Bernard Hospital, APHP, Paris, France. 3. Pharmaco-Toxicology Department, Bichat-Claude Bernard Hospital, APHP, Paris, France. 4. Infectious Diseases & Tropical Department, Bichat-Claude Bernard Hospital, APHP, Paris, France. 5. Gastroenterology Department, Robert Debré Hospital, Reims, France. 6. Nephrology Department, ECHO-CMCM, Le Mans, France. 7. Internal Medicine Department, Cochin Hospital, APHP, Paris Descartes University, Sorbonne Paris Cité, Paris, France. 8. Gastroenterology Department, Foch Hospital, Suresnes, France. 9. Gastroenterology Department, Cochin Hospital, APHP, Paris Descartes University, Sorbonne Paris Cité, Inserm U1016, Paris, France. 10. Infectious Diseases Department, Foch Hospital, Suresnes, France. 11. Internal Medicine Department, Louis-Mourier Hospital, APHP, Colombes, France. 12. Clinical Pharmaco-Toxicology Department, University Hospital of Besançon, INSERM U1098, Besançon, France. 13. Virology Department, Bichat-Claude Bernard Hospital, APHP, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, IAME, INSERM UMR 1137, Paris, France. 14. Pharmaco-Toxicology Department, Bichat-Claude Bernard Hospital, APHP, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, IAME, INSERM UMR 1137, Paris, France.
Abstract
BACKGROUND & AIMS: Hepatitis C virus (HCV) infection is an independent risk factor for chronic kidney disease and leads to faster liver disease progression in patients requiring hemodialysis than in those with normal renal function. Little is known about the use of a sofosbuvir-containing regimen for infected patients on hemodialysis. We aimed to describe the pharmacokinetics, safety and efficacy of sofosbuvir in 2 dosing regimens and associated antiviral agents in HCV-infected patients requiring hemodialysis. METHODS: Multicenter, prospective and observational study of patients receiving sofosbuvir, 400mg once daily (n=7) or 3 times a week (n=5), after hemodialysis with simeprevir, daclatasvir, ledipasvir or ribavirin was conducted. Drug plasma concentrations were determined by liquid chromatography-tandem mass spectrometry before and after a 4h hemodialysis and 1.5h after last drug intake at the end of hemodialysis. RESULTS: Plasma concentrations of sofosbuvir or its inactive metabolite sofosbuvir-007 did not accumulate with either regimen between hemodialysis sessions or throughout the treatment course. Sofosbuvir-007 extraction ratio (52%) was consistent with historical data. In one patient receiving the once daily regimen, sofosbuvir-007 half-life was slightly higher (38h) than for patients with normal renal function receiving a full dose. Hemodialysis did not remove any other associated anti-HCV agents. Clinical and biological tolerance was good for all patients. Two relapses occurred with the 3 times a week regimen and none with the once daily. CONCLUSIONS: A regimen including sofosbuvir, 400mg once daily, could be proposed for HCV-infected patients requiring hemodialysis and should be associated with close clinical, biological, cardiovascular, and therapeutic drug monitoring. LAY SUMMARY: Hepatitis C Virus (HCV) infection in hemodialysis patients is prevalent and aggressive. Effective anti-HCV treatment in these patients may stabilize their renal disease. However, sofosbuvir, the cornerstone of most anti-HCV-containing regimens, should not be administered to these patients until more data is available. In this pharmacokinetic study, sofosbuvir full dose (400mg once daily) administered every day with another direct antiviral agent did not accumulate in hemodialysis patients and was safe and effective.
BACKGROUND & AIMS:Hepatitis C virus (HCV) infection is an independent risk factor for chronic kidney disease and leads to faster liver disease progression in patients requiring hemodialysis than in those with normal renal function. Little is known about the use of a sofosbuvir-containing regimen for infectedpatients on hemodialysis. We aimed to describe the pharmacokinetics, safety and efficacy of sofosbuvir in 2 dosing regimens and associated antiviral agents in HCV-infectedpatients requiring hemodialysis. METHODS: Multicenter, prospective and observational study of patients receiving sofosbuvir, 400mg once daily (n=7) or 3 times a week (n=5), after hemodialysis with simeprevir, daclatasvir, ledipasvir or ribavirin was conducted. Drug plasma concentrations were determined by liquid chromatography-tandem mass spectrometry before and after a 4h hemodialysis and 1.5h after last drug intake at the end of hemodialysis. RESULTS: Plasma concentrations of sofosbuvir or its inactive metabolite sofosbuvir-007 did not accumulate with either regimen between hemodialysis sessions or throughout the treatment course. Sofosbuvir-007 extraction ratio (52%) was consistent with historical data. In one patient receiving the once daily regimen, sofosbuvir-007 half-life was slightly higher (38h) than for patients with normal renal function receiving a full dose. Hemodialysis did not remove any other associated anti-HCV agents. Clinical and biological tolerance was good for all patients. Two relapses occurred with the 3 times a week regimen and none with the once daily. CONCLUSIONS: A regimen including sofosbuvir, 400mg once daily, could be proposed for HCV-infectedpatients requiring hemodialysis and should be associated with close clinical, biological, cardiovascular, and therapeutic drug monitoring. LAY SUMMARY:Hepatitis C Virus (HCV) infection in hemodialysis patients is prevalent and aggressive. Effective anti-HCV treatment in these patients may stabilize their renal disease. However, sofosbuvir, the cornerstone of most anti-HCV-containing regimens, should not be administered to these patients until more data is available. In this pharmacokinetic study, sofosbuvir full dose (400mg once daily) administered every day with another direct antiviral agent did not accumulate in hemodialysis patients and was safe and effective.