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ICAAC 2012: Atazanavir Linked to Kidney Stones in People with HIV

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HIV positive people taking ritonavir-boosted atazanavir (Reyataz) are more likely to develop kidney stones than those using other antiretroviral medications, according to study data presented at the recent 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012) in San Francisco and published in the November 1, 2012 issue of Clinical Infectious Diseases. Another study suggested that darunavir (Prezista) may also raise the risk.

Not long after the advent of combination antiretroviral therapy (ART) using protease inhibitors, clinicians began reporting an increased incidence of kidney or renal stones among people using one of the first drugs in this class, indinavir (Crixivan). Newer protease inhibitors are generally better tolerated, but their association with kidney stones has not been extensively studied.

Atazanavir

Yohei Hamada from the National Center for Global Health and Medicine in Tokyo and colleagues compared the frequency of kidney stones between individuals who started antiretroviral regimens containing atazanavir/ritonavir versus those taking other protease inhibitors. Boosting with ritonavir (Norvir) allows other drugs to reach higher levels in the body.

This retrospective study included 1240 people receiving ART a single center in Japan between 2004 and 2010. Within this group, 38% received atazanavir/ritonavir.

Results

  • 31 out of 465 participants (6.7%) taking atazanavir/ritonavir were diagnosed with kidney stone, for a rate of 23.7 cases per 1000 person-years.
  • In comparison, only 4 out of 775 people (0.5%) taking other protease inhibitors developed kidney stones, a 10-fold lower rate of 2.2 cases per 1000 person-years.
  • In a multivariate analysis, use of atazanavir/ritonavir remained significantly associated with development of kidney stones (adjusted hazard ratio [HR]10.4, or more than 10 times higher risk).
  • The increased risk was similar in an analysis controlling for other risk factors such as age, sex, body weight, baseline GFR and uric acid levels, and prior exposure to indinavir (adjusted HR 10.8).
  • Atazanavir/ritonavir was a significant risk factor for kidney stones in all subgroups analyzed.
  • Elevated bilirubin -- a known side effect of atazanavir -- was not associated with development of kidney stones.
  • Among the 31 patients taking atazanavir/ritonavir who developed kidney stones, this occurred a median of 24.5 months after starting the drug.
  • 6 of the 18 participants (33%) who continued to use atazanavir/ritonavir despite a diagnosis of kidney stones experienced recurrences, versus none of those who discontinued atazanavir/ritonavir.
  • Kidney function declined more among patients who developed kidney stones compared with those who did not.

"The incidence of renal stones was substantially higher among patients in the [atazanavir/ritonavir] group, compared with patients in the other protease inhibitors group," the investigators concluded. "Continuation of [atazanavir/ritonavir] after diagnosis of renal stones was associated with a high rate of recurrence. Switching [atazanavir/ritonavir] to other antiretrovirals is warranted in patients who develop renal stones."

"[T]he development of renal stones is a risk factor for chronic kidney disease," they elaborated in their discussion. "Thus, [atazanavir/ritonavir] should be carefully introduced in patients with concomitant predisposing risk factors for chronic kidney disease."

Another recent analysis of more than 3 million people in the general population in Alberta, Canada -- described in the August 29, 2012, British Medical Journal -- found that development of even a single kidney stone was associated with a significant increase in the likelihood of adverse kidney outcomes including end-stage renal disease, which can necessitate dialysis or transplantation. The absolute risk, however, remained small.

"I am not surprised by these findings because when you are passing a stone through a kidney, there is definitely the potential for permanent damage," lead study author R. Todd Alexander stated in a university press release.

"It's important to note that the vast majority of people with kidney stones won't develop permanent kidney damage," added co-author Marcello Tonelli. "But a few will, and that's why it's important for people with stones to get proper follow-up care -- to reduce their risk of another stone, and to detect kidney damage if it has occurred."

Drug Crystals

Kidney stones can develop when drug crystals build up in the kidneys. In a related study presented at ICAAC, French researchers measured urine and blood plasma concentrations of newer protease inhibitors and looked for drug crystals in the urine of asymptomatic patients.

The analysis included 266 participants on stable (for an average of 22 months) antiretroviral therapy that included 300 mg/day ritonavir-boosted atazanavir, 400 mg/day unboosted atazanavir, boosted 800 or 1200 mg/day darunavir, or 800 mg/day lopinavir/ritonavir (Kaletra). Most were men, the average age was about 46 years, the mean CD4 T-cell count was about 500 cells/mm3, and three-quarters had HIV viral load < 400 copies/mL.

The researchers found that atazanavir -- whether boosted or not -- and boosted darunavir both resulted in significantly more drug crystals in urine compared with lopinavir; 7 patients (9%) taking atazanavir had measurable atazanavir crystals, while 4 people (8%) taking darunavir had detectable urine darunavir crystals.

"Atazanavir and darunavir concentrate highly in the urine of asymptomatic patients, which is not the case for lopinavir," they concluded. "Atazanavir crystals but also darunavir crystals (which have never yet been described) were evidenced in the urine of a few asymptomatic patients receiving atazanavir- and darunavir-based regimens...Attention should be paid towards the potential renal toxicity of darunavir as well as atazanavir.

10/23/12

References

Y Hamada, TNishijima, K Watanabe, et al. High Incidence of Renal Stones Among HIV-Infected Patients on Ritonavir-Boosted Atazanavir Than in Those Receiving Other Protease Inhibitor-Containing Antiretroviral Therapy. Clinical Infectious Diseases 55(9):1262-1269. November 1, 2012.

Y Hamada, TNishijima, K Watanabe, et al. High Incidence of Renal Stones in HIV-infected Patients on Ritonavir-boosted Atazanavir- than in Those on Other Protease Inhibitors-containing Antiretroviral Therapy. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012). San Francisco. September 9-12, 2012. Abstract H-888.

V de Lastours, ESilva, M Daudon, et al. High ATZ and DRV Urine Concentrations and Cristalluria in Asymptomatic Patients Receiving ATV and DRV-Based Regimens. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012). San Francisco. September 9-12, 2012. Abstract H-889.

RT Alexander, BR Hemmelgarn, N Wiebe, et al. Kidney stones and kidney function loss: a cohort study. British Medical Journal 345:e5287. August 29, 2012.

Other Sources

ICAAC/American Society for Microbiology. Ritonavir-Boosted Atazanavir Is a Significant Risk Factor for Kidney Stones. Press release. September 10, 2012.

University of Alberta. U of A Medical Researchers Draw Link Between Kidney Stones and Kidney Failure. Press release. September 6, 2012.