Fanconi Syndrome Accompanied by Renal Function Decline with Tenofovir Disoproxil Fumarate: A Prospective, Case-Control Study of Predictors and Resolution in HIV-Infected Patients

• Authors: Samir K. Gupta, Indiana University School of Medicine; Albert Anderson, Emory University; Ramin Ebrahimi, Gilead Sciences, Inc.; Todd Fralich, Gilead Sciences, Inc.; Hiba Graham, Gilead Sciences, Inc.; Valeska Scharen-Guivel, Gilead Sciences, Inc.; John F. Flaherty, Gilead Sciences, Inc.; Claude Fortin, University of Montreal; Robert C. Kalayjian, Metrohealth Medical Center; Anita Rachlis, University of Toronto; Christina M. Wyatt, Icahn School of Medicine at Mount Sinai
• Journal Title: PLoS ONE
• Volume: Volume 9, Number 3
• Publisher: Public Library of Science | 2014-03-20, Pages e92717-e92717
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1371/journal.pone.0092717
• Subjects: Health Sciences, Pathology; Biology, Virology
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; ANTIRETROVIRAL-EXPERIENCED PATIENTS; THERAPY; DYSFUNCTION; REVERSIBILITY; IMPAIRMENT; CLEARANCE; REGIMENS; COHORT

Abstract

Objective: The predictors of Fanconi syndrome (FS) accompanied by renal function decline with use of the antiretroviral tenofovir disoprox il fumarate (TDF) have not been assessed. In addition, the natural history of renal recovery from FS after TDF discontinuation is not well-described. Design: We prospectively enrolled HIV-infected patients receiving TDF with newly identified FS (defined as at least two markers of proximal tubulopathy and either a > 25% decline in creatinine clearance (CrCl) from pre-TDF values or a CrCl < 60 mL/min in those without a known pre-TDF CrCl) in a multicenter observational study. These case participants were matched 1:2 to controls; characteristics between the two groups were compared. Case participants with known pre-TDF CrCl values were then followed over 48 weeks to assess renal recovery. Results: Nineteen cases and 37 controls were enrolled. In multivariable analysis, previous or concurrent use of lopinavir/ritonavir [OR 16.37, 95% CI (2.28, 117.68); P = 0.006] and reduced creatinine clearance prior to initiation of TDF [OR 1.44 for every 5 mL/min reduction, 95% CI (1.09, 1.92); P = 0.012; OR 19.77 for pre-TDF CrCl lower than 83 mL/min, 95% CI (2.24, 174.67); P = 0.007] were significantly associated with FS. Of the 14 cases followed for resolution, 7 (50%) achieved at least partial resolution (defined as recovering CrCl > 70% of pre-TDF values) although most participants had full normalization of proximal tubulopathy markers within two months of TDF discontinuation. Conclusions: FS, defined by specific CrCl decreases and markers of tubulopathy, is more likely in those who have received or are currently receiving concomitant lopinavir/ritonavir or who had lower CrCl prior to TDF initiation. Half of those with protocol-defined FS had CrCl recover to near pre-TDF values during the first year after TDF discontinuation.