Disappearance of Renal Stones in an HIV-1-Infected Patient After Reduction of Atazanavir Dose

Abstract

Editor: Atazanavir/ritonavir administration has recently been shown to be a risk factor for symptomatic nephrolithiasis.¹ Atazanavir could promote kidney stones through mechanisms similar to indinavir-induced urolithiasis (drug crystallization and precipitation in the kidneys).¹ de Lastours and colleagues showed high levels of atazanavir and darunavir in urine with crystalluria in asymptomatic HIV-infected patients, with urinary atazanavir and darunavir concentrations significantly higher than plasma levels.²

We report the first case of an HIV-1-infected patient on atazanavir/ritonavir (300/100 mg daily) with recurrent kidney stone episodes, who benefited from an atazanavir dose reduction. A 30-year-old man (CDC A2), HIV infected since 2007, without hepatitis B or C virus (HBV or HCV) coinfections, came to our attention in October 2012. The patient had been taking tenofovir/emtricitabine and atazanavir/ritonavir (300/100 mg daily) since June 2011 (after 4 years of a fully suppressive first-line regimen of tenofovir/emtricitabine and efavirenz) with optimal adherence but was complaining of scleral icterus. His CD4⁺ T cell count was 903/mm³, HIV RNA <20 copies/ml, and total bilirubin 6.11 mg/dl. The family history was unremarkable for urolithiasis. Blood tests did not show any plasma lipid, kidney function (eGFR >90 ml/min/1.72 m²), or uric acid level abnormalities. He reported three kidney stone episodes in the past year (December 2011, May 2012, and September 2012) after starting an atazanavir-containing treatment. Renal echography showed thin bilateral stones (October 2012).

We decided to reduce the dose of atazanavir to 200 mg daily with 100 mg of ritonavir to reduce his discomfort due to atazanavir-related jaundice, collecting paired plasma and urine samples for pharmacokinetic analysis.³ Atazanavir C _trough was 1,017 ng/ml in plasma and 37,110 ng/ml in a urine sample before dose reduction. One month later (November 2012), his HIV RNA was still <20 copies/ml and his total bilirubin value decreased to 3.30 mg/dl. In June 2013, he did not report any episodes of renal stones, but the patient continued to report discomfort because of the persistent scleral icterus. His atazanavir dose was further reduced to 150 mg daily with 100 mg daily of ritonavir. In December 2013, his CD4 cell count was 660/mm³, his HIV RNA was not detectable, and his total bilirubin was 1.26 mg/dl, with the disappearance of the scleral icterus. After 13 months of follow-up, he no longer reported any sign of urolithiasis, and a renal echography did not show any radiological findings of renal stones.

At a second pharmacokinetics analysis, his atazanavir (ATV) C _trough was 160 and 4,683 ng/ml in plasma and urine, respectively. Nephrolithiasis has been reported in patients receiving ATV/r-containing antiretroviral therapy.^2,4 Several case reports documented high concentrations of ATV in renal stones, suggesting the involvement of ATV in nephrolithiasis.^4
–6 Hamada et al. recently reported in a single center cohort study that the incidence of renal stones is approximately 10 times higher among patients on ATV/r-containing antiretroviral therapy (ART) than those on other protease inhibitor-containing ART.¹ The mechanism of atazanavir/ritonavir-induced renal stone formation could be the crystallization of atazanavir, as in the case of indinavir-induced renal stones.⁶ Although in our case ATV concentrations were higher in urine than in plasma, as expected,² a dramatic decrease in urine concentration (by 88%) was shown after a dose reduction to boosted 150 mg daily, with the disappearance of symptoms and signs of renal stones. This finding confirms the need for a threshold of ATV urinary concentration to form precipitation in crystals.²

ATV plasma concentrations are known to correlate with serum bilirubin levels and a switch to unboosted ATV has been shown to reduce the risk of hyperbilirubinemia.⁷ Rockwood et al.⁸ found a close association between hyperbilirubinemia and the development of renal stones, supporting the association of both with plasma exposure, and, for the latter, with urinary exposure too. ATV crystalluria, in fact, has been shown to be related to the duration of ATV intake, but also to be more frequent in an ritonavir-boosted dose (300/100) as compared to those taking an unboosted 400 mg dose.² It is worth remembering that even in those taking indinavir, dose reduction and therapeutic drug monitoring were effective in case of renal stones.⁹

In our case, such an unconventional dose reduction made it possible to continue an ATV-containing effective regimen, with a clear improvement in tolerability, while maintaining virological efficacy. A dose decrease to boosted 150 mg/daily, in fact, was associated with an ATV C _trough still above the minimum effective concentration (MEC, 150 ng/ml). We could speculate that the ATV C _trough value of our patient dosed at 150 mg with 100 mg of ritonavir was in the expected range of unboosted ATV pharmacokinetics,⁸ and a switch to unboosted ATV has been shown to be effective in stable patients.⁸ However, we recently reported the efficacy of a maintenance reduced dose of atazanavir/ritonavir in a small cohort of virologically suppressed HIV-infected patients.¹⁰

In conclusion, a dose reduction of ATV in stable patients reporting the occurrence of ATV-related renal stones deserves further clinical evaluation as a strategy to improve the tolerability of this compound.

Footnotes

Acknowledgments

M. Lanzafame and S. Bonora have contributed equally to this work.

Author Disclosure Statement

No competing financial interests exist.

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