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Ritonavir-boosted atazanavir exposure is associated with an increased rate of renal stones compared with efavirenz, ritonavir-boosted lopinavir and ritonavir-boosted darunavir
24 August 2011
Research Letters

Rockwood, Neesha; Mandalia, Sundhiya; Bower, Mark; Gazzard, Brian; Nelson, Mark epartment of HIV Medicine, Chelsea and Westminster Hospital, London, UK.
Correspondence to Dr Neesha Rockwood, SpR HIV/GUM, Department of HIV Medicine, St Stephens Centre, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. Tel: +44 020 8465625; e-mail:

Although there have been case reports of the development of nephrolithiasis in individuals receiving antiretroviral (ARV) therapy including ritonavir-boosted atazanavir (ATZ/r) [1-5], there have been no data presented on the relative rates of the development of renal stones in those receiving ATZ when compared with other commonly used ARVs. Although primarily metabolized by the liver, approximately 7% of an ATZ/r dose is excreted unchanged in the urine and its solubility decreases with an increased alkalinity of urine [6]. When renal calculi do develop, they have been reported to contain 40-100% of ATZ by weight [3,4].

The mechanism of development of ATZ-associated renal stones is unknown, although there have been reports of ATZ intratubular crystal precipitation which have been confirmed by renal biopsy [4].

ATZ-associated renal stones may lead to obstructive uropathy and acute renal failure needing interventional management. Prior case series have suggested an association with viral hepatitis co-infection, prior renal stones and baseline chronic renal impairment [1,4,5,7]. We retrospectively compared the rate of development of renal stones in a large cohort of HIV-infected individuals exposed to ARV regimens containing ATZ/r with a second group exposed to efavirenz (EFV), ritonavir-boosted lopinavir (LPV/r) and ritonavir-boosted darunavir (DRV/r) over a 45-month study period from May 2006 to February 2010.

The departmental computer database, which holds data on clinical, therapeutic and investigations of all those attending the HIV unit, was used to identify individuals who developed renal stones. To ensure full case ascertainment, this was cross-checked with a separate database held in the radiology department of all individuals who had undergone an abdominal radiograph, a renal ultrasound scan, a computed scan of the abdomen or a pelvis or intravenous urogram at the Chelsea and Westminster Hospital. Diagnosis of renal stones was made only on a radiological basis. As ARV-associated renal stones are often radiolucent, abnormalities in the collecting systems compatible with obstruction or dilatation secondary to a recently passed stone were included as evidence of stones, but only in the context of an appropriate clinical history.

Rate of renal stones for each ARV studied was calculated using Poisson regression model in which total duration on each individual ARV was used as a denominator. In order to keep the coefficient of the denominator constant, this was loge-transformed and used as an offset in the Poisson model. The data were analysed using the Genmod procedure in SAS, version 9.1 (SAS Institute, Cary, North Carolina, USA) with loge link and Poisson error distributions. This fits generalized linear models allowing time-dependent measures of probability. Data are presented as renal stone rate per 1000 patient-years with 95% confidence interval (CI) and statistical significance was evaluated by comparing the ATZ/r group with those receiving combined EFV/LPV/r/DRV/r. A subanalysis was performed, excluding individuals who developed renal stones during the study period with previous ritonavir-boosted IND (IND/r) or ATZ/r exposure.

The total number of individuals in the cohort was 5655. The rate of nephrolithiasis in the ATZ/r group (n = 1206) compared with the EFV/LPV/r/DRV/r combined group (n = 4449) was 7.3 (95% CI 4.7-10.8] per 1000 patient-years and 1.9 (95% CI 1.2-2.8] per 1000 patient-years (P < 0.001), respectively. After adjusting for previous IND/r exposure in the ATZ/r group, and previous ATZ/r/IND/r exposure in the EFV/LPV/r/DRV/r combined group, the renal stone rate was in the ATZ/r group (n = 1000) compared with the EFV/LPV/r/DRV/r group cohort (n = 3293) was 5.67 (95% CI 3.6-9.36) per 1000 patient-years and 1.51 (95% CI 0.85-2.4) per 1000 patient-years (P < 0.001) (Table 1), respectively.

The median bilirubin at renal stones diagnosis in the ATZ/r group, compared with the recent bilirubin measurement in all remaining patients on ATZ/r who attended during the study period and who had at the time not developed renal stones, was 50.5 [interquartile range (IQR) 32-65] and 23 μmol/l (IQR 9-44) (P < 0.001), respectively.

In our study, 42% of cases of ATZ/r-associated renal stones had baseline chronic renal impairment with an estimated glomerular filtration rate of less than 60 ml/min per 1.73 m2 at the start of the study period. This was significantly higher than that in 4.5% of cases with baseline chronic renal impairment, as defined above in those on ATZ/r who did not develop clinical evidence of renal stones (P < 0.001). Forty percent of cases of ATZ/r-associated renal stones with chronic baseline renal impairment had a history of renal stones prior to the beginning of the study period. The proportion of ATZ/r-associated stone formers with chronic viral hepatitis B or C co-infection was 8% and did not significantly differ from rates of 4.2% in those on ATZ/r who did not form stones.

In the 24 individuals who developed renal stones while receiving ATZ/r, the median time from commencement of ATZ/r to developing a renal stone was 30 months (IQR 13-49). Twenty-one (87.5%) of the 24 individuals were switched from ATZ to an alternative protease inhibitor, six of whom had a further episode associated with nephrolithiasis. One individual who developed renal stones on DRV/r with a previous history of ATZ/r exposure had evidence of ATZ/r on stone analysis 21 months after stopping ATZ/r. Eight individuals with ATZ/r-associated renal stones required interventional management with stenting or nephrostomy insertion.

Our data have shown that the incidence of renal stones in those exposed to ATZ/r is greater than that with other commonly utilized ARV regimens, with and without adjusting for prior ATZ/r and IND/r exposure. The significantly higher median bilirubin in the group of ATZ/r-associated renal stone formers suggests that individuals with a pharmacogenetic predisposition to slower metabolization of ATZ/r may have an increased risk of stone formation due to associated higher levels of ATZ/r.

There are limitations to our study, including its retrospective nature. Although the rate of ATZ/r-associated renal stones was found to be 7.3 per 1000 patient-years, this is likely to be an underestimation of the true incidence of ATZ/r-associated renal stones, as we utilized a radiological diagnosis within our own hospital to calculate rates. Clearly, individuals may have presented to other hospitals for investigation. Only 13% of individuals with confirmed renal stones had stone composition analysis with infrared sphectrophotometry; thus, we cannot confirm that those developing renal stones on ATZ were indeed related to this therapy.

ATZ/r-associated renal stones should, thus, be considered as a potential comorbidity when making the choice of a suitable protease inhibitor for individual patients.

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