Atazanavir-Induced Severe Episodes of Kidney Stones in an HIV-1-Infected Subject Characterized by a CYP3A Poor Metabolizer Phenotype
Stefano Rusconi *
Infectious Diseases Unit, Department of Biomedical and Clinical Sciences “Luigi Sacco”, Università degli Studi di Milano, Milan, Italy.
Roberta Gagliardini
Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy.
Felicia Stefania Falvella
Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences “Luigi Sacco”, Università degli Studi di Milano, Milan, Italy.
Dario Cattaneo
Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences “Luigi Sacco”, Università degli Studi di Milano, Milan, Italy.
Valentina Di Cristo
Infectious Diseases Unit, Department of Biomedical and Clinical Sciences “Luigi Sacco”, Università degli Studi di Milano, Milan, Italy.
Andrea De Luca
University Division of Infectious Diseases, University of Siena, Siena, Italy.
Massimiliano Fabbiani
Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy.
Emilio Clementi
Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy and Unit of Clinical Pharmacology, CNR Institute of Neuroscience, Department of Biomedical and Clinical Sciences “Luigi Sacco”, Università degli Studi di Milano, 20157 Milan, Italy.
Massimo Galli
Infectious Diseases Unit, Department of Biomedical and Clinical Sciences “Luigi Sacco”, Università degli Studi di Milano, Milan, Italy.
Simona Di Giambenedetto
Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy.
*Author to whom correspondence should be addressed.
Abstract
Background: Atazanavir, an antiretroviral drug of the protease inhibitor class, is co-administered with ritonavir to inhibit atazanavir metabolism and decrease pharmacokinetic variability. Atazanavir is metabolised mainly by CYP3A4/5 enzymes. High CYP3A intersubject variability has been documented in most cases on a genetic basis. The CYP3A5*3 allele affects splicing defect and protein truncation. Recently a new intronic variant, CYP3A4*22, was found associated with reduced CYP3A4 activity. To assess whether an altered CYP3A activity impairs the metabolism of atazanavir, we investigated the two functional polymorphisms. To the best of our knowledge, this is the first case report showing that overexposure to ATV is associated with CYP3A poor phenotype and nephrolithiasis. Further study is needed in order to confirm this interesting observation.
Case Presentation: We describe the case of a 43 year-old HIV-1-infected man treated with atazanavir/ritonavir plus lamivudine who experienced early and recurrent severe episodes of kidney stones. Atazanavir plasma trough concentrations showed a value higher than the normal range, thus we investigated the two polymorphisms that are known to affect CYP3A4/5 activity. This analysis revealed that our patient was a CYP3A poor metabolizer since he carried CYP3A4*1/*22 and CYP3A5*3/*3 genotypes.
Conclusion: We suggest that screening of CYP3A functional variants is an appropriate approach, helping in treatment choice and potential dosage adjustment of protease inhibitors.
Keywords: Atazanavir, kidney stones, HIV-1, CYP3A, HAART