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French study investigates crystals in urine
<p>Sean R. Hosein</p>
December 1, 2012

In the era of modern anti-HIV therapy (commonly called ART or HAART), treatments are generally well tolerated, particularly for people starting ART for the first time.

In the mid-to-late 1990s, one anti-HIV drug, a protease inhibitor called indinavir (Crixivan), was associated with an increased risk for developing kidney stones—a very distressing and painful condition. To reduce the risk of developing this problem, healthcare professionals encouraged indinavir users to drink at least 1.5 litres of water every day, in addition to whatever other fluid they drank. Drinking this volume of fluid every day may not be easy for some people at first. However, many indinavir users adapted to help reduce their risk for kidney stones.

Researchers in Paris, France, have been conducting analyses of the urine of HIV-positive people who used modern protease inhibitors such as atazanavir (Reyataz), darunavir (Prezista) and a co-formulation of lopinavir-ritonavir (Kaletra). Atazanavir is of particular concern because it is somewhat similar in shape to indinavir. Moreover, there have been isolated reports of kidney stones developing in some users of atazanavir.

Preliminary reports from France suggest that atazanavir and darunavir, compared to lopinavir-ritonavir, tend to reach relatively high concentrations in the urine. Moreover, the French researchers found crystals of atazanavir and darunavir in the urine of a small number of participants. The significance of this finding is explored later in this report.

Study details

Researchers recruited 146 participants whose average profile was as follows:

  • 85% men, and 15% women
  • age – 47 years
  • length of time HIV positive – 11 years
  • CD4+ count – 522 cells
  • proportion with an HIV viral load less than 400 copies – 81%
  • length of time taking protease inhibitors – 2 years

The following combinations of protease inhibitors were being taken in the study:

  • atazanavir 300 mg + ritonavir 100 mg – 59 participants
  • atazanavir 400 mg – 19 participants
  • darunavir 800 mg + ritonavir 100 mg – 38 participants
  • darunavir 1,200 mg + ritonavir 200 mg – 13 participants
  • lopinavir-ritonavir – 13 participants

Blood and urine samples were collected and subjected to analysis.

Results

Technicians found crystals in the urine of 32 participants; in 11 cases, analysis revealed that these crystals were made from the following protease inhibitors:

  • atazanavir – crystals of this drug were found in the urine samples from seven of 78 participants taking this drug. In all seven cases, participants were taking ritonavir, which boosts the concentration of atazanavir in the blood.
  • darunavir – crystals of this drug were found in the urine samples from four of 51 participants taking this drug. Three of them were taking darunavir 800 mg + ritonavir 100 mg while the fourth was taking darunavir 1,200 mg + ritonavir 200 mg.
  • lopinavir-ritonavir – no cases of crystals were found in urine samples

Caution needed

The present study’s findings are somewhat surprising when it comes to darunavir; crystals of this drug in the urine have not been reported previously.

The study is interesting but due to several of the following weaknesses, its results need to be taken with caution:

  • This was not a randomized study and we have no information why some participants were prescribed certain regimens and not others. It is thus possible that this lack of randomization could have inadvertently biased the interpretation of the results.
  • Direct assessments of the fluid intake of participants were not done. We therefore have no idea of how much fluid they drank on a daily basis. This could have had an impact on the formation of crystals in the urine.
  • We do not know the medical history of the patients, specifically if they or close family members had a history of kidney stones or kidney dysfunction. Such a history could have predisposed some people to having crystals of anti-HIV drugs in the urine.
  • There was no data on vitamin D levels in the blood or that of parathyroid hormone. The body sometimes produces elevated levels of parathyroid hormone to compensate for low intake or absorption of calcium (caused in part by low vitamin D levels). Elevated levels of parathyroid hormone are associated with an increased risk for kidney stones.

A note about crystals

Crystals act as seeds, forming a core that attracts more substances and, in some cases, eventually leading to the formation of kidney stones. This is why it is important for adults to drink large amounts of fluid—between 1.5 and 2 litres of water daily, in addition to other fluids that are consumed throughout the day.

Darunavir is a widely used drug with a very good record of safety and effectiveness. It has not been associated with kidney stones. Therefore, the findings from the present study are not by themselves a cause for alarm.

—Sean R. Hosein

REFERENCES:

1. de Lastours V, Silva E, Daudon M, et al. Atazanavir and darunavir crystalluria and high atazanavir and darunavir concentrations in urine of asymptomatic patients receiving atazanavir- and darunavir-based regimens. In: Program and abstracts of the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy, 9-12 September 2012. San Francisco, California. Abstract H-889.

2. Asplin JR, Coe FL, Favus MJ. Chapter 287. Nephrolithiasis. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012.

3. Rockwood N, Mandalia S, Bower M, et al. Ritonavir-boosted atazanavir exposure is associated with an increased rate of renal stones compared with efavirenz, ritonavir-boosted lopinavir and ritonavir-boosted darunavir. AIDS. 2011 Aug 24;25(13):1671-3.

4. Chan-Tack KM, Truffa MM, Struble KA, et al. Atazanavir-associated nephrolithiasis: cases from the US Food and Drug Administration's Adverse Event Reporting System. AIDS. 2007 May 31;21(9):1215-8.



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