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Urolithiasis (kidney stones) in HIV-Positive Patients Treated with Atazanavir
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Clinical Infectious Diseases Sept Epub 2007;45:000
Carine Couzigou,1 Michel Daudon,2 Jean Luc Meynard,3 Francoise Borsa-Lebas,4 Denise Higueret,5 Lelia Escaut,1 David Zucman,1 Jean-Yves Liotier,1 Jean-Louis Quencez,1 Karine Asselah,1 Thierry May,7 Didier Neau,6 and Daniel Vittecoq1
1Service des Maladies Infectieuses et Tropicales, AP-HP, Hopital Paul Brousse, Villejuif, 2Laboratoire de Biochimie, AP-HP, Hopital Necker, and 3Service des Maladies Infectieuses et Tropicales, AP-HP, Hopital Saint-Antoine, Paris, 4Service des Maladies Infectieuses et Tropicales, Centre Hospitalo-Universitaire, Rouen, 5Laboratoire de Biochimie and 6Federation des Maladies Infectieuses et Tropicales, Hopital Pellegrin, Bordeaux, and 7 Service des Maladies Infectieuses et Tropicales, Centre Hospitalo-Universitaire, Nancy, France
ABSTRACT. Among protease inhibitors, atazanavir has not been associated with urolithiasis in clinical studies. We describe 11 cases of atazanavir-associated urolithiasis in patients with human immunodeficiency virus (HIV) infection. Patients with low water intake, high urinary pH, and a prior history of urinary stones may have a higher risk of atazanavir-associated urine crystallization.
Atazanavir sulfate is a protease inhibitor used in combination with other antiretroviral agents for the treatment of HIV infection. In the European Union, atazanavir was approved for use in treatment-experienced patients in March 2004, at a once-daily dose of 300 mg boosted with 100 mg of ritonavir. Atazanavir has the major advantages of being simple to administer and having fewer undesirable effects on the lipid profiles of patients, with no loss of relative potency [1]. Urolithiasis has not been associated with atazanavir in clinical studies.
We conducted a retrospective study, including data for all HIV-infected patients who developed urolithiasis as a result of atazanavir therapy and received a diagnosis at 1 of 7 participating HIV units. The total number of patients treated with atazanavir from March 2004 through February 2007 was documented in the local HIV database in each participating unit.
Several variables were studied, including age; CD4+ cell count; HIV load; other blood factors (e.g., creatinine clearance, calcemia, and phosphoremia); medical history; duration of atazanavir treatment, antiretroviral therapy, and other associated treatments; symptoms; urinary pH; stone composition; and outcome.
Case series. A total of 1134 patients were treated with atazanavir at the participating units from March 2004 through February 2007. Eleven of these patients received a diagnosis of atazanavir-associated urolithiasis. The main demographic and clinical characteristics of these patients are given in table 1. The mean age of the patients (±SD) was 45 ± 6.2 years (range, 30-52 years). Five of the patients had HIV-hepatitis C virus (HCV) coinfection. None of the coinfected patients had hepatic insufficiency or cirrhosis. The rate of HIV-HCV coinfection among patients treated with atazanavir in the participating units was 14%.
Two patients (patients 4 and 6) had chronic moderate renal failure before receiving a diagnosis of atazanavir-associated urolithiasis. Four patients had a prior history of urinary stones before receipt of atazanavir therapy. The mean CD4+ cell count (±SD) was 579 ± 251 cells/mm3 (range, 154-990 cells/mm3), and the HIV RNA level was undetectable in all patients (<50 copies/mL). All patients received atazanavir (300 mg/day) plus ritonavir (100 mg/day) once daily, combined with 1 or 2 nucleoside reverse-transcriptase inhibitors. Plasma atazanavir concentrations, which were available for patients 4, 5, 10, and 11 (2334, 2890, 2500, and 1200 ng/mL, respectively; measurements were obtained 12, 14, 12, and 23 h after the last drug intake, respectively), were in the normal range of concentrations for boosted atazanavir. The mean time (±SD) between atazanavir introduction and urolithiasis was 22.9 ± 5.6 months (range, 15.6-30.9 months). No patient was receiving other lithogenic medications.
Ten patients experienced an episode of acute renal colic, and 1 patient described intermittent dull lumbar pain. Three patients had bilateral nephrolithiasis and, at present, continue to require sessions of lithotripsy.
Calcemia and phosphoremia were in the normal range for all patients for whom data were recorded (calcemia and phosphoremia data were not recorded for patient 4, and phosphoremia data were not recorded for patient 8). The mean urinary pH was 6.75. Diagnosis of atazanavir-associated urolithiasis was determined by infrared spectrophotometry. Analysis revealed that stones contained crystals of atazanavir base but did not contain metabolites. One patient had 2 stones (patient 5). Eight stones had an atazanavir core (pure atazanavir or atazanavir associated with protein), and 4 stones had a calcium oxalate core. Stone sizes were 0.5-6 mm in diameter. Stones of pure atazanavir and stones composed of atazanavir and protein were beige to yellowish in color, friable, and radiolucent, and they resembled stones associated with uric acid. In most cases, the stone section presented a radial crystallization growth made of atazanavir crystals formed into thin rods.
Boosted atazanavir therapy was withdrawn and replaced for 5 patients, whereas it was maintained for 6 patients, who were instructed to increase their oral fluid intake and to drink more acidic drinks (such as carbonated beverages). One of the 6 patients experienced a urinary atazanavir stone recurrence 10 months later. None of the patients developed severe renal impairment.
Discussion.
Among antiretroviral agents, indinavir is well known to induce kidney stones [2]. Kidney stones attributable to saquinavir [3], nelfinavir [4], and lopinavir [5] have also been reported in clinical cases.
The overall prevalence of atazanavir-associated urolithiasis in our study was 0.97%. Atazanavir has not been associated with urolithiasis or crystalluria in clinical studies, and only 2 cases have been reported recently [6, 7]. Thus, to date, incidences of atazanavir-associated urolithiasis appear to be low, given that atazanavir has been administered to thousands of people worldwide.
One case report described a patient with interstitial nephritis and reversible acute renal failure, but the patient did not experience urolithiasis [8]. Acute renal failure was not observed in our study.
In our study, all patients were symptomatic, and atazanavir-associated urolithiasis occurred 23 months after starting atazanavir treatment. The mechanism of developing atazanavir stones is unknown. It is, however, probably linked to urinary precipitation of pure atazanavir, as has been described for indinavir stones [9]. Indeed, the pharmacological profile of atazanavir is similar to that of indinavir. Atazanavir is mainly metabolized and eliminated by the liver. However, in healthy subjects, up to 7% of the drug is excreted unchanged in the urine following a single 400-mg dose [1]. Like indinavir, atazanavir is slightly soluble in water (4-5 mg/mL) and has a pH-dependent solubility (with maximal solubility at pH 1.9). In our study, a high urinary pH may have favored atazanavir precipitation.
Based on the pharmacokinetics of atazanavir, maintenance of a high urinary output and urine acidification may be helpful in preventing atazanavir crystallization and urolithiasis recurrence. Urine acidification may, however, be poorly tolerated and possibly harmful, especially for patients receiving concomitant treatment with sulphonamide derivatives. No recurrence occurred in 5 of the 6 patients who continued to receive atazanavir therapy in our series.
Other factors may have influenced the occurrence of atazanavir-associated urolithiasis. Patients with a history of urinary stones may have a higher risk for developing such complications while taking atazanavir.
The high HIV-HCV coinfection rate in our study (45%) was not explained by a high HIV-HCV coinfection rate among patients treated with atazanavir in the participating units (the HIV-HCV coinfection rate in the participating units was only 14%). One explanation for the high HIV-HCV coinfection rate in our study might be that chronic active HCV infection may have impaired liver clearance of atazanavir, leading to greater atazanavir renal elimination (thereby favoring crystallization). However, in our case series, none of the HIV-HCV-coinfected patients had hepatic insufficiency or cirrhosis. Furthermore, recent data suggest that plasma concentrations of boosted atazanavir are not elevated in HIV-HCV-coinfected patients and do not correlate with liver stiffness [10]. Further studies are required to determine whether HCV infection is a contributing factor to atazanavir-associated urolithiasis.
In our case series, recorded biological factors (calcemia and phosphoremia) were normal, and the associated medications were nonlithogenic. Finally, other factors predisposing to urolithiasis (such as nutritional risk factors), which may have influenced the occurrence of atazanavir-associated urolithiasis, were not explored in this study.
Six patients continued to receive atazanavir therapy despite urolithiasis; of these, only 1 patient experienced urolithiasis recurrence. Therefore, we believe that patients experiencing a first episode of urolithiasis secondary to atazanavir therapy may continue to be treated with the drug if the episode is resolved and if they are able to maintain adequate hydration. In conclusion, atazanavir use must be considered to be a possible cause of urolithiasis in HIV-infected patients, and clinicians should be aware of this new stone type.
Potential conflicts of interest. All authors: no conflicts.
Atazanavir-associated nephrolithiasis: cases from the US Food and Drug Administration's Adverse Event Reporting System
[Research Letters]
Chan-Tack, Kirk M; Truffa, Melissa M; Struble, Kimberly A; Birnkrant, Debra B
Division of Antiviral Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
AIDS:Volume 21(9)31 May 2007p 1215-1218
Abstract
The risk of nephrolithiasis associated with atazanavir is not well characterized. The US Food and Drug Administration's Adverse Event Reporting System was searched for reports of nephrolithiasis in HIV-infected patients taking an atazanavir-based regimen. Thirty cases were identified. Many patients required hospitalization for management, including lithotripsy, ureteral stent insertion, or endoscopic stone removal. Some cases of nephrolithiasis resulted in atazanavir discontinuation. Healthcare professionals and patients should be informed that nephrolithiasis is a possible adverse event with atazanavir.
Two cases of nephrolithiasis due to atazanavir (ATV) were recently described in the literature [1,2]. The risk of nephrolithiasis associated with the use of ATV is not well characterized.
The Adverse Event Reporting System (AERS) of the US Food and Drug Administration (FDA) is a voluntary reporting system. This database contains spontaneous reports generated by health professionals, consumers, and manufacturers from the United States and other countries [3]. The AERS was searched for reports of nephrolithiasis in HIV-infected patients taking an atazanavir-based regimen. The search was conducted using the Medical Dictionary for Regulatory Activities high level term 'renal lithiasis'. This term includes three preferred terms: 'nephrolithiasis', 'nephrocalcinosis', and 'stag horn calculus'. Data on demographics, co-morbidities, concurrent medications, atazanavir exposure (defined as the time between atazanavir initiation and the onset of signs or symptoms of nephrolithiasis), diagnostic evaluation (radiology, laboratory results, stone analysis), patient management, and clinical outcomes were reviewed for each case [4,5].
From December 2002 to January 2007, 30 cases of nephrolithiasis in HIV-infected patients taking an atazanavir-based regimen were reported in the AERS database, including the published cases [1,2]. The clinical characteristics of these patients are shown in Table 1. Twenty-one patients were men, five patients were women, and four patients had no sex reported. Five patients (17%) had underlying liver disease: four patients had hepatitis C (one with cirrhosis), and one patient had hepatitis B with cirrhosis. Three patients had pre-existing renal disease and five patients (17%) had a history of nephrolithiasis.
Of the 20 cases reporting complete antiretroviral information (medications and doses), 13 patients received concomitant tenofovir and 17 patients received 100 mg ritonavir. Among 14 cases reporting stone analysis, 12 had atazanavir confirmed by infrared spectrophotometry or other analysis. In six cases with available data, atazanavir concentrations in the stone ranged from 40 to 100%. In 17 cases with complete atazanavir treatment history, the median time between atazanavir initiation and the onset of nephrolithiasis was 1.7 years (range 5 weeks to 6 years).
Among the 30 patients, 18 required hospitalization, seven received outpatient care, and five lacked data. Interventions for stone removal were performed in eight patients (27%). Two patients required lithotripsy only, one patient underwent both lithotripsy and ureteral stent insertion, one patient needed nephrostomy tube placement for the relief of severe hydronephrosis because of ureteral obstruction by the calculus, two patients had ureteral stent insertion and endoscopic surgical extraction of the stone, and two patients needed endoscopic surgical extraction of the stone. In addition to clinical symptoms associated with nephrolithiasis, some patients also reported concurrent laboratory and radiological abnormalities [4,5]. Five patients developed renal insufficiency (four with acute renal insufficiency and one with a worsening of baseline chronic renal insufficiency) at the time of nephrolithiasis. In all four cases of acute renal insufficiency, renal function returned to baseline after stone removal and atazanavir discontinuation. In the patient who developed a worsening of baseline chronic renal insufficiency, renal function improved but had not returned to its previous baseline after stone removal. Three patients had radiological documentation of hydronephrosis. Of the 30 cases, atazanavir was reported as discontinued in nine cases (30%) after nephrolithiasis was diagnosed.
Data submitted to a voluntary reporting system such as the AERS are often limited by the absence of detailed and pertinent information, such as demographics, weight (only available for seven patients in the study), medical co-morbidities (particularly conditions that predispose to nephrolithiasis [4,5]), duration of atazanavir exposure, continuation of atazanavir after nephrolithiasis was diagnosed (only available for 15 patients), atazanavir drug levels (only available for one patient [1]), doses of any concurrent medications, diagnostic evaluation, patient management, and clinical outcome. As these adverse drug events are obtained voluntarily from a population of unknown size, the ability to make reliable estimates in frequency or establish a causal relationship with drug exposure is not always possible. Despite these limitations, our study findings from the AERS database suggest that atazanavir can be associated with nephrolithiasis. In the AERS database, 30 cases were identified, of which 12 cases had confirmed atazanavir by infrared spectrophotometry or other analysis. Only two of the confirmed cases (patients 18 and 23) have been reported in the literature [1,2]. In addition to the 12 confirmed atazanavir-associated cases, five cases were excluded that could have been confirmed as atazanavir-associated cases with better follow-up information. Three patients had reports that stated 'kidney stones observed through lab work', but provided no details regarding the composition of the stones (patients 8, 9, and 10). Furthermore, two patients had stone analysis but incomplete characterization of the stone metabolite (patient 25) or possible inaccurate reporting of the data (patient 30). It is conceivable that, with better follow-up information, some or all of these five cases could also be confirmed as being associated with the use of atazanavir.
The mechanism for the development of atazanavir-associated nephrolithiasis is unknown. Further information is needed to determine whether patients with pre-existing hepatic or renal impairment or a history of nephrolithiasis are at an increased risk of this event. Data are not currently available to determine whether increased atazanavir exposures or prolonged atazanavir use is associated with these events.
Nephrolithiasis associated with atazanavir can cause significant morbidity, including renal dysfunction and hydronephrosis. Many cases required hospitalization for management and symptom relief. Lithotripsy, ureteral stent insertion, nephrostomy tube placement, or endoscopic stone removal was needed in a subset of cases. Some cases of nephrolithiasis resulted in the discontinuation of atazanavir. Healthcare professionals and patients should be informed that nephrolithiasis is a possible adverse event with the use of atazanavir. If signs or symptoms of nephrolithiasis occur, healthcare providers should consider temporary interruption or discontinuation of atazanavir therapy.
Atazanavir-containing renal calculi in an HIV-infected patient
[Correspondence]
AIDS:Volume 21(8)11 May 2007p 1060-1062
Anderson, Peter La; Lichtenstein, Kenneth Ab,c; Gerig, Nel Ec; Kiser, Jennifer Ja; Bushman, Lane Ra
aSchool of Pharmacy, Department of Pharmaceutical Sciences, USA
bSchool of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado, USA
cRose Medical Center, Denver, Colorado, USA.
Approximately 7% of an atazanavir (Reyataz; Bristol-Myers Squibb, Princeton, New Jersey, USA) dose is excreted as unchanged drug in the urine and the solubility of atazanavir increases with acidity [1]. These properties are similar to those of indinavir, which is more soluble in acid solutions and of which 19% is excreted as unchanged drug in the urine. Indinavir is associated with precipitation in the urine and clinical sequelae in 4-43% of patients [2-4]. Conversely, there have been only two recent case reports of atazanavir-associated urolithiasis in the literature [5,6]. We report here another case of renal calculi containing significant amounts of atazanavir in an HIV-infected patient.
The patient was a 51-year-old man who was found to be HIV positive in 1989. His antiretroviral history included: zidovudine from January 1993 to July 1994; stavudine from July 1994 to April 1996; and triple therapy with stavudine, lamivudine, and indinavir beginning in April 1996. Ritonavir was added to indinavir in March 1999 (800 mg/100 mg twice a day). In November 2003, the patient switched from boosted indinavir to atazanavir/ritonavir (300 mg/100 mg) because of patches of dry and scaly skin and flank discomfort (although no kidney stones). From December 2003 to March 2005, his flank discomfort and skin problems resolved, and he had no new medication-related complaints. His HIV markers were stable over the course of this medical treatment. His CD4 cell nadir was 399 cells/ƒÊl in January 1995. Since then and up to now his CD4 cell count has ranged between 400 and 700 cells/ƒÊl. His viral load has been undetectable since starting triple drug therapy in April 1996. His other medications and concomitant health issues include cetirizine10 mg as needed for allergy symptoms and oxycodone/acetaminophen and sumatriptan nasal spray as needed for migraines.
The history of the present nephrolithiasis episode began in March 2005, 1.5 years after indinavir was stopped and atazanavir-ritonavir was begun. The patient presented with severe right flank pain requiring hospitalization. His urine pH was 6 and urinalysis was unremarkable. A non-contrast computed tomography scan of the abdomen and pelvis demonstrated right hydroureteronephrosis with some perinephric stranding, but no calculi. As a result of continuing pain, an intravenous pyelogram was obtained. This also showed right-sided hydroureteronephrosis with dilation to the distal ureter, but no stones or filling defects could be seen. Shortly after this examination he passed seven calculi, measuring 2-5 mm each. Chemical analysis of these stones revealed 'crystals of undetermined origin'. The patient continued to pass stones for the next 10 months, and he complained of urinary urgency, frequency and nocturia. Repeat chemical analyses showed 'organic matter consistent with cellulose'. The stones did not contain critical amounts of calcium, uric acid, cystine, or struvite. In January 2006, the patient was diagnosed with gout. Allopurinol (300 mg/day) was begun and his urine was alkalinized with oral UroCitK (potassium citrate). His production of stones increased on this regimen.
In February 2006, we considered that atazanavir might be precipitating in the urine based on the increase in stone production with urine alkalinization and the factors mentioned in the introduction. We asked the patient to save several stones for the analysis of atazanavir (Fig. 1).
We separately analysed three stones for their atazanavir content. Briefly, each stone was weighed (mg) and placed into a centrifuge tube. Methanol was added to create a volume ratio of 1 mg/ml. This stone/methanol mixture was sonicated for 30 min and the residual debris was removed by centrifugation. The stone solution was injected onto our validated high-performance liquid chromatography-ultraviolet method for protease inhibitors. This method undergoes twice-yearly proficiency testing.
The initial total weights of the three stones were 4.53, 6.72, and 9.20 mg. Each stone contained a significant amount of atazanavir by weight (41, 44, and 49%). Ritonavir was also present in the stones at less than 1%. Initially, it appeared that indinavir might be present in trace amounts that were below the quantifiable limit. We verified the presence of each protease inhibitor by liquid chromatography-mass spectrometry, however, and indinavir was not detectable whereas atazanavir and ritonavir were confirmed.
On the basis of these results, the patient replaced atazanavir/ritonavir with efavirenz. By May 2006, his rate of stone passage had decreased substantially.
In summary, the substantial level of atazanavir in the renal calculi of this patient (approximately 40-50% by weight) plus the reduction in stone passage after switching from atazanavir to efavirenz suggests that atazanavir played an important role in the presence of these stones [4]. This is the third case report of atazanavir-containing renal calculi in an HIV-infected patient [5,6]. One other report suggested that atazanavir caused a case of acute interstitial nephritis, which was considered a hypersensitivity-like reaction to the drug [7]. Given the rarity of atazanavir-associated renal problems, we speculate that our patient had an unusual physical or biochemical predisposition that led to these stones. The history of indinavir use and the presence of gout stand out as possible factors contributing to this potential predisposition.
Sponsorship: This study received grant support from the National Institutes of Health RO1-AI64029, RO1-AI33835, and P30-AI054907.
Atazanavir Urolithiasis
NEJM Nov 16, 2006
To the Editor: Atazanavir sulfate, a protease inhibitor, is indicated in combination with other antiretroviral agents for the treatment of HIV type 1 (HIV-1) infection.1 Among the antiretroviral agents that are currently in use, only indinavir is known to cause kidney stones.2 We describe a patient who had hydronephrosis and a ureteral stone composed mainly of atazanavir metabolites.
A 44-year-old man with HIV infection presented with abdominal pain, chills, nausea and vomiting, and a decreased oral intake of fluids. His CD4 count was 70 cells per cubic millimeter, and his HIV-1 RNA level was less than 75 copies per milliliter. He was receiving treatment with highly active antiretroviral therapy (HAART), consisting of atazanavir, ritonavir, lamivudine, and tenofovir. His HAART had been withheld for 2 weeks before admission, owing to lactic acidosis.
The patient reported that he had passed a kidney stone without any gross hematuria a week before admission. He also had a history of renal insufficiency, with a baseline creatinine level of 1.4 to 1.6 mg per deciliter; nonischemic dilated cardiomyopathy; chronic obstructive pulmonary disease; and adrenal insufficiency (for which he was receiving long-term corticosteroid therapy). His blood pressure was 101/65 mm Hg, his heart rate was 73 beats per minute, and he was afebrile. Physical examination revealed dehydration and diffuse abdominal discomfort. His serum creatinine level was 1.6 mg per deciliter. Urinalysis revealed no protein, blood, or white cells. Blood and urine cultures were negative.
Computed tomography revealed a right ureteral stone with hydronephrosis. The patient underwent cystoscopy with right ureteroscopic extraction of the stone and stent placement. The ureteral stone (0.7 by 0.5 by 0.3 cm) was sent for analysis to the Laboratory for Stone Research in Newton, Massachusetts. The patient's condition subsequently improved, and he was discharged home.
Analysis of the ureteral stone revealed that it was composed of a mixture of 60% atazanavir metabolite and 40% calcium phosphate (carbonate apatite). The stone contained atazanavir crystals and not metabolites adsorbed into the apatite. Examination was initially done with the use of polarized light microscopy. The drug crystals were clearly birefringent needles, whereas carbonate apatite did not transmit the polarized light. Subsequently, the identity of atazanavir metabolite was ascertained by infrared spectroscopy. Atazanavir is metabolized and excreted mainly through the liver, and only 13% of a single radiolabeled 400-mg dose was recovered in the urine, of which 7% constituted unchanged drug.1 To our knowledge, there have been no previous reports that atazanavir can form crystals in the urine. This case suggests that atazanavir needs to be considered among the possible causes of urolithiasis in patients with HIV infection who are receiving HAART.
Hernan R. Chang, M.D.
Jacksonville Infectious Diseases
Jacksonville, FL 32216
Atazanavir urinary stones in an HIV-infected patient
[Correspondence]
Pacanowski, Jeromea; Poirier, Jean-Marieb; Petit, Isabellec; Meynard, Jean-Luca; Girard, Pierre-Mariea
aService des Maladies Infectieuses et Tropicales, France
bLaboratoire de Pharmacologie, Hopital Saint-Antoine, Universite Pierre et Marie Curie, Paris VI, France
cLaboratoire LCL, Paris, France.
Indinavir has rapidly been shown to cause urinary stones, an adverse effect not so far reported with other protease inhibitors. We report what we believe to be the first case of atazanavir-induced urolithiasis.
Case report
A 38-year-old French man of Caucasian origin was found to be HIV-1 seropositive in June 2003. At the time of diagnosis he was being managed for liver cirrhosis caused by hepatitis B virus. He had a history of urinary calcium oxalate stones, diagnosed in 1988 and 2000. He was first prescribed antiretroviral treatment, consisting of didanosine, tenofovir and efavirenz, in September 2003. As a result of neurological adverse effects of efavirenz and the hepatitis B, he was switched to emtricitabine, tenofovir and ritonavir-boosted atazanavir (100/300 mg a day) in September 2004. Renal colics occurred approximately once a month from October 2005, and every 2 weeks from March 2006, and were not relieved by non-steroidal anti-inflammatory drugs or urinary alkalinization. Renal ultrasonography showed calculi in the right kidney, with no signs of hydronephrosis. He was referred to a consultant urologist after a new episode of renal colic. Ureteroscopic stone extraction and JJ ureteral stenting were performed in June 2006. Infrared spectrophotometry of two calculi, one discharged spontaneously and the second retrieved by endoscopic basketing, demonstrated that they were composed of pure atazanavir, with no evidence of calcium oxalate or urate crystals. The urinary pH was 5.5. Trough and peak plasma atazanavir concentrations measured 24.25 h and 3.5 h, respectively, after the last drug intake were 580 and 4624 ng/ml, in the normal range of concentrations reported after boosted atazanavir administration combined with tenofovir.
Plasma and urine levels of calcium and urate were normal. Boosted atazanavir was withdrawn and replaced by boosted fosamprenavir.
Indinavir is mainly metabolized by the liver, with minor renal excretion. Indinavir tends to crystallize in alkaline urine, leading to renal colic in approximately 8% of patients [1]. In a series of indinavir-treated patients with urolithiasis [2], 29% of patients had indinavir stones whereas the others had calcium oxalate or urate stones caused by classic metabolic abnormalities. Hyperhydratation and urinary acidification reduce the risk of renal colic caused by indinavir. Four poorly documented cases of renal colic have been reported in patients taking lopinavir [3]. Atazanavir, a new azapeptide HIV-1 protease inhibitor, is already widely prescribed for its good safety profile and once-a-day administration. After oral administration, atazanavir is largely bound to serum proteins and is mainly metabolized by isoenzyme CYP3A4 into free or glucuronidated metabolites excreted in bile. Dose-related hyperbilirubinemia is a very common adverse effect of atazanavir, because of the competitive inhibition of the enzymatic uridine diphosphate glucuronosyl transferase pathway of bilirubin glucuronidation. Crystallization in urine has not previously been reported, although the summary of product characteristics mentions renal colic as a rare adverse event. In healthy individuals, 7% of the atazanavir dose is excreted unchanged in the urine. Like indinavir, the solubility of atazanavir is increased in acid fluids. The effects of hepatic impairment on the pharmacokinetics of ritonavir-boosted atazanavir are not known. In our patient, impaired hepatic metabolism caused by cirrhosis might have led to the increased renal elimination of atazanavir, thereby favouring its crystallization.
Clinicians should thus be aware that urolithiasis may occur in patients on ritonavir-boosted atazanavir. When a patient on atazanavir presents with renal colic, the stones should be analysed by infrared spectrophotometry in order to distinguish those composed of calcium oxalate or urate from those composed of atazanavir crystals, as the treatment options may differ.
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