title: High levels of atazanavir and darunavir in urine and crystalluria in asymptomatic patients.
abstract: OBJECTIVE
  Atazanavir has been associated with kidney stones and renal failure. We measured urine and plasma concentrations of recent protease inhibitors (PIs) and searched for PI crystals in the urine of asymptomatic patients.
  
  
  METHODS
  A cross-sectional analysis of HIV-infected patients taking ritonavir-boosted atazanavir 300 mg/day (ATV300/r), unboosted atazanavir 400 mg/day (ATV400), ritonavir-boosted darunavir at either 800 mg/day (DRV800/r) or 1200 mg/day (DRV1200/r) or ritonavir-boosted lopinavir 800 mg/day was performed. Plasma and urine were collected and PI levels measured using HPLC. Crystals were detected and identified in urine using polarized microscopy.
  
  
  RESULTS
  PI levels were measured in 266 patients, 142 of whom were assessed for urinary crystals. Their mean age was 46 years. The mean duration of HIV infection was 10.5 years and the mean duration of the current PI-containing regimen was 22.5 months. The mean CD4 cell count was 494 cells/mm(3); 74% showed controlled HIV replication. Median urinary PI levels were 22.3, 14.3, 26.9 and 29.7 mg/L for ATV300/r, ATV400, DRV800/r and DRV1200/r, respectively, significantly higher than plasma levels, which were all <5 mg/L (P < 0.001). In contrast, median urinary lopinavir concentrrations did not significantly differ from plasma concentrations (4.2 and 6.4 mg/L, respectively; P = 0.7) and were significantly lower than those of other PIs (P < 0.001). Atazanavir crystals were found in 7/78 patients receiving ATV300/r (8.9%; 95% CI = 2.6%-15.2%) and darunavir crystals were found in 4/51 patients receiving darunavir (7.8%; 95% CI = 0.4%-15.2%). Longer exposure to atazanavir was the only risk factor associated with the presence of atazanavir crystalluria (P = 0.04).
  
  
  CONCLUSIONS
  Unlike lopinavir, atazanavir and darunavir reached high concentrations in urine. Urinary crystals were found in a few patients receiving ritonavir-boosted atazanavir or darunavir and may favour nephrolithiasis.
authors.affiliation: Infectious Diseases Department, St Louis Hospital, APHP and Sorbonne Paris Cité, University Paris Diderot, Paris, France. vdelastours@hotmail.com
authors.forename: Victoire
authors.initials: V
authors.lastname: de Lastours
authors.forename: Erika
authors.initials: E
authors.lastname: Ferrari Rafael De Silva
authors.forename: Michel
authors.initials: M
authors.lastname: Daudon
authors.forename: Raphaël
authors.initials: R
authors.lastname: Porcher
authors.forename: Benedicte
authors.initials: B
authors.lastname: Loze
authors.forename: Hélène
authors.initials: H
authors.lastname: Sauvageon
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Molina
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000652:urine*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D000069446:Atazanavir Sulfate; D002851:Chromatography, High Pressure Liquid; D003430:Cross-Sectional Studies; D003460:Crystallization; D000069454:Darunavir; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008859:Microscopy, Polarization; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood / Q000652:urine*; D010949:Plasma / Q000737:chemistry; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000652:urine*; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000652:urine*; D014556:Urine / Q000737:chemistry; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D009842:Oligopeptides; D011725:Pyridines; D013449:Sulfonamides; D000069446:Atazanavir Sulfate; D000069454:Darunavir
keywords: HIV drug toxicity; antiretrovirals; urolithiasis