Urinary stones a rare side-effect of atazanavir

Urinary stones (urolithiasis) are a rare side-effect of atazanavir (Reyataz) therapy, warn French doctors in the October 15^th edition of Clinical Infectious Diseases. They found that approximately 1% of atazanavir-treated patients developed stones in their urine an average of 23 months after starting treatment with the drug. A low fluid intake and a prior history of urinary stones appeared to be risk factors for the side-effect.

Atazanavir is a protease inhibitor which was approved in Europe for use by treatment-experienced patients in early 2004. The approved once-daily dose of atazanavir is 300mg, boosted by 100mg of ritonavir. Once-daily dosing and the infrequency of gastrointestinal side-effects has made the drug an attractive option for many patients.

It has however been associated with hyperbilirubinaemia in a small number of patients. This side-effect is not dangerous, but can involve a distressing yellowing of the skin. There were no reports of urinary stones in the clinical trials conducted before the approval of atazanavir.

But doctors in France conducted a retrospective study and found eleven cases of urinary stones in 1134 patients who were treated with the drug between 2004 and February 2007. This provided a prevalence of just under 1%. The patients received their care at seven centres, and all took once-daily ritonavir-boosted atazanavir with two nucleoside/nucleotide reverse transcriptase inhibitors.

The investigators gathered data on CD4 cell count, viral load, age, levels of calcium, creatinine and phosphorus in blood, medical history, and duration of atazanavir and other antitroviral therapy, to see if they could find any factors associated with urinary stones.

The mean age of patients developing urinary stones was 45 years ,mean CD4 cell count was 579 cells/mm³ and all the patients had an undetectable viral load.

Five (45%) individuals were coinfected with hepatitis C virus, a significantly higher prevalence than that seen in the entire cohort (14%).

Two patients had a history of chronic moderate kidney failure before receiving their diagnosis of urinary stones, and four individuals had previously had urinary stones before treatment with atazanavir.

Plasma levels of atazanavir were within the normal range in all eleven patients and the mean duration of treatment with the drug before urinary stones developed was 23 months.

Severe pain in the kidneys (renal colic) was reported by ten patients and one individual complained of intermittent dull lumbar pain. Three patients also developed kidney stones for which they are receiving ongoing therapy.

Calcium and phosphorus levels were within normal ranges, but the investigators did observe that patients with urinary stones had high urinary pH (mean, 6.75).

Stones were between 0.5 – 6mm in diameter and tended to resemble stones or uric acid. In most cases they had a rod-like shape.

Treatment with boosted atazanavir was stopped in five patients. The remaining six patients were instructed to increase their fluid intake, and to drink more carbonated, acidic fluids. One patient had a recurrence of urinary stones, but none of the individuals developed severe renal impairment.

“The mechanism of developing atazanavir stones is unknown” comment the investigators, but they suggest that it could be linked to “urinary precipitation of pure atazanavir, as has been described with indinavir stones.” Although atazanavir is metabolised by the liver, up to 70% of the drug is excreted by the body in urine. Atazanavir is best dissolved in urine with a pH of 1.9 – but the investigators found that patients with atazanavir urine stones had an unusually high urine pH of 6.75.

Although hepatitis C coinfection was more common amongst patients with urinary stones, the investigators note that none of the coinfected patients had hepatic insufficiency or cirrhosis. In addition, there is no evidence that levels of boosted atazanavir are increased in coinfected patients with liver problems.

“We believe that patients experiencing a first episode of urolithiasis secondary to atazanavir therapy may continue to be treated with the drug and if the episode is resolved and they are able to maintain adequate hydration”, conclude the investigators, but caution, “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.”