# Atazanavir-induced lithiasis evidenced several years after drug discontinuation

Ralitsa Doncheva, Antoine Behr, Nadine Petitpain, Nathalie Massy, Benjamin Lefèvre

► To cite this version:

Ralitsa Doncheva, Antoine Behr, Nadine Petitpain, Nathalie Massy, Benjamin Lefèvre. Atazanavir-induced lithiasis evidenced several years after drug discontinuation. AIDS. Official journal of the international AIDS Society, 2024, 38 (10), pp.1604-1605. 10.1097/QAD.0000000000003951. hal-05029432

HAL Id: hal-05029432

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Submitted on 10 Apr 2025

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# Atazanavir-induced lithiasis evidenced several years after drug discontinuation

## Auteurs

Ralitsa Doncheva¹, Antoine Behr², Nadine Petitpain¹, Nathalie Massy³, Benjamin Lefevre⁴

1. Regional Pharmacovigilance Centre of Nancy, University Hospital of Nancy, 54511 Vandoeuvre les Nancy, France

2. Department of Urology, University Hospital of Nancy, 54511 Vandoeuvre les Nancy, France

3. Regional Pharmacovigilance Centre of Rouen, University Hospital of Rouen, 76031 Rouen, France

4. Department of Infectious Diseases, University Hospital of Nancy, 54511 Vandoeuvre les Nancy, France

## Corresponding author

Dr Nadine Petitpain, Regional Pharmacovigilance Centre of Nancy, University Hospital of Nancy, 54511 Vandoeuvre les Nancy, France ; Tel +33 383 6085 email crpv@chru-nancy.fr

**Keywords:** atazanavir, lithiasis, adverse reaction

**Declarations:** All authors disclose any conflict of interest with this paper. No funding was received.

**Word count:** 717
## Main text

Atazanavir (ATZ) is a protease inhibitor, used in combination therapy for highly active antiretroviral therapy (HAART) regimen. ATZ may cause stone deposition (lithiasis) at different sites such as urolithiasis [1,2], biliary lithiasis [3,4], sialolithiasis [5], as well as semicircular canals and parotid glands lithiasis [6]. The role of ATZ is not questionable since physical methods, infrared spectroscopy or X-ray diffraction, can demonstrate the presence of the drug or its metabolites within the calculi [1,7]. All cases and series published so far report on the occurrence of lithiasis during ATZ treatment, but we recently observed a case of renal calculi evidenced five years after ATZ discontinuation and revealed by renal colic. To highlight the possible delayed diagnosis of ATZ-induced lithiasis, we here describe this case and provide an analysis of similar cases from the French pharmacovigilance database.

Case report - A 62y-o woman had been treated with ATZ (boosted with ritonavir) and emtricitabine from August 2005 to October 2018 for HIV infection. Her medical history included hepatitis C, hemochromatosis treated with bloodletting, osteopenia and cannabis abuse. In 2007, ATZ plasma concentrations were high for two months, and normalized after ATZ and ritonavir dose reduction. Thereafter, ATZ varied from 0.017 to 0.723 mg/L (normal range 0.2 – 0.8 mg/L). In October 2007, she also had transient mild hypercalcemia with normal phosphatemia and normal 25-OH-vitamin D3. Vitamin D supplementation was discontinued and hypercalcemia did not reoccur. In May 2008, she was found with asymptomatic microscopic hematuria (10⁶ red blood cells/mL), discrete proteinuria (0.3 g/L), negative urine culture and decreased glomerular filtration rate (eGFR (Cockroft) 54 mL/min/1.73 sqm). In November 2009, she reported right lumbar intermittent pain, but urinary tract ultrasound and abdominal radiography did not evidence kidney lithiasis. Therefore, ATZ was continued under surveillance. In April 2018, because of asymptomatic but persisting decreased kidney function (eGFR 61 mL/min), ATZ was stopped and the treatment was switched to etravirine-raltegravir combination. In March 2023, in the setting of severe urinary tract infection, the patient underwent computed tomography which evidenced right obstructive ureterohydronephrosis due to a 10 mm subpyelic stone, associated with right pyelonephritis outbreaks. The patient received antibiotherapy and JJ stent placement. About two months later, cystoscopy under general anaesthesia allowed right ureteroscopic fragmentation of the stone. However, extraction was uncomplete due to an important ureteral spasm, and not allowing kidney revision. The infrared spectrometric analysis of the ureteral stone fragments revealed a 100% ATZ composition. In September 2023, a 6 mm ureteral stone was still present, and in November 2023, a new extraction was attempted but failed again due to pyeloureteral junction spasm. In March 2024, the JJ stent was removed, but the calculus was considered as not removable, and remained in place.
We searched for similar cases in the French Pharmacovigilance database. Our query, performed in March 2024, matching "atazanavir" and any MedDRA preferred terms containing the words « lithiasis » or « calcul », retrieved 236 lithiasis reports (179 renal, 49 biliary, 7 renal and biliary, 2 salivary). Of them, eight (3.4%) reports, including our case, and one published case[8] corresponded to a delayed diagnosis of renal lithiasis after ATZ discontinuation (table 1). In six patients, calculi analysis was available showing ATZ as unique or major component of the calculus. The only patient with mixed composition had prior history of lithiasis. Of note, our query did not retrieve any case of biliary or salivary lithiasis diagnosed lately after ATZ discontinuation.

ATZ calculi are usually described as small stones (0.5 – 6 mm in diameter) composed of pure ATZ base without metabolites, or ATZ and protein, beige to yellowish in color. The section analysis shows radial crystallization of ATZ crystals[9], and ATZ crystals are rod-like or peculiar needle-shaped, 100-200 µm in length[7,10].

In conclusion, ATZ induced urolithiasis occurring during treatment, may stay silent for a long time, even some years after discontinuation of ATZ, before being clinically significant. Thus, healthcare professionals and patients should be aware of such ATZ delayed complication, especially if clinical signs of urinary tract disorders occur, and perform stone analysis if applicable. Currently, ATZ is less prescribed, darunavir being preferred when a protease inhibitor is prescribed, and lithiasis may less often occur with these other protease inhibitors[7]. However, a case of urinary calculi containing raltegravir, ritonavir and darunavir has been reported in a woman with history urinary calculi with different anti-retroviral regimens[11].
References

1 Chang HR, Pella PM. **Atazanavir Urolithiasis**. *N Engl J Med* 2006; **355**:2158–2159.

2 De Lastours V, Ferrari Rafael De Silva E, Daudon M, Porcher R, Loze B, Sauvageon H, et al. **High levels of atazanavir and darunavir in urine and crystalluria in asymptomatic patients**. *J Antimicrob Chemother* 2013; **68**:1850–1856.

3 Courbon E, Laylavoix F, Soulie C, Le Beller C, Calvez V, Katlama C, et al. **Unexpected atazanavir-associated biliary lithiasis in an HIV-infected patient**. *J Antimicrob Chemother* 2012; **67**:250–251.

4 Rakotondravelo S, Poinsignon Y, Borsa-Lebas F, De La Blanchardiere A, Michau C, Jantzem H, et al. **Complicated Atazanavir-Associated Cholelithiasis: A Report of 14 Cases**. *Clin Infect Dis* 2012; **55**:1270–1272.

5 Le MP, Stitou H, Soulie C, Katlama C, Peytavin G. **Sialolithiasis in an HIV-1-infected patient treated with atazanavir/ritonavir monotherapy**. *J Antimicrob Chemother* 2013; **68**:727–729.

6 Pastori D, Esposito A, Cagliuso M, Conti V, Mezzaroma I. **Lithiasis of semicircular canals and parotid glands: unusual stones deposition in atazanavir-treated individuals**. *AIDS* 2009; **23**:2233–2234.

7 Daudon M, Frochot V, Bazin D, Jungers P. **Drug-Induced Kidney Stones and Crystalline Nephropathy: Pathophysiology, Prevention and Treatment**. *Drugs* 2018; **78**:163–201.

8 Brunel V, Massy N, Malval B. **Atazanavir urolithiasis without recent intake of atazanavir**. *Ann Biol Clin (Paris)* 2019; **77**:459–460.

9 Couzigou C, Daudon M, Meynard JL, Borsa-Lebas F, Higueret D, Escaut L, et al. **Urolithiasis in HIV-positive patients treated with atazanavir**. *Clin Infect Dis Off Publ Infect Dis Soc Am* 2007; **45**:e105-108.

10 Inagaki I, Adachi M, Ito H, Yasuda M, Tsurumi H, Deguchi T, et al. **Atazanavir-induced urine crystals demonstrated by infrared spectroscopic analysis**. *Urol Int* 2015; **94**:121–124.

11 Vassallo M, Dunais B, Naqvi A, Garaffo R, Durant J. **Raltegravir-induced nephrolithiasis: a case report**. *AIDS* 2012; **26**:1323–1324.