Prior studies have linked exposure to protease inhibitors (PIs) with excess risk of chronic kidney disease (CKD). Whether such safety signals remain for more contemporary PIs, such as darunavir (DRV/r), remains unclear.
D:A:D participants with >3 estimated glomerular filtration rate (eGFR) measurements, were followed from their first eGFR>60 mL/min/1.73m[sup]2[/sup] after 1.1.2009 to the earliest of CKD (confirmed, >3 months apart, eGFR<60 mL/min/1.73m[sup]2[/sup]), last visit plus 6 months or 1.2.2015. Poisson regression was used to model associations between CKD and use of two contemporary PI’s (ritonavir boosted atazanavir (ATV/r) and DRV/r), adjusting for demographics, other antiretroviral treatment, renal and HIV-related risk factors.
Of 26,939 persons 1,209 developed CKD (incidence rate (IR) 8.6/1000 PYFU [95%CI 8.1-9.1]). 13.1% and 24.8% of the follow-up time (140,966 PYFU) was after starting DRV/r and ATV/r respectively. Median age at baseline was 44 (IQR 38-50) years, median CD4 count was 510 (IQR 370-700) cells/mm3, and 28.8%, 35.9% and 35.3% were at low, medium and high 5-year CKD risk estimated by the D:A:D CKD risk score. While the CKD IR was low in individuals unexposed to DRV/r or ATV/r and increased with increasing exposure, after adjustment, only ATV/r (adjusted IR ratio (aIRR) 1.86 [1.58-2.20]), but not DRV/r (1.29 [0.94-1.77]) exposure remained significantly associated with CKD after >4 years (figure). Further multivariate analysis excluding those unexposed to DRV/r showed no statistically significant association between increasing DRV/r exposure and CKD (aIRR 1.21/5 years [0.83-1.75]). After exclusion of those unexposed to ATV/r the CKD rate significantly increased with increasing ATV/r exposure (aIRR 1.24/5 years [1.01-1.52]). The results were similar for individuals at low, medium or high estimated CKD risk (p>0.05, test for interaction). The rate of discontinuing ATV/r, but not DRV/r, was associated with lower eGFR levels (aIRR 1.74 [1.36–2.22] for ATV/r and 1.24 [0.83-1.86] for DRV/r at eGFR<70 vs. >90).
In a large heterogeneous cohort of contemporarily treated HIV-positive persons with six years median follow-up, DRV/r discontinuation was eGFR unrelated and more extended DRV/r use was not significantly associated with excess CKD risk, although a similar association as seen with ATV/r could not be ruled out. The previously reported association between gradually increasing risks of CKD with longer use of ATV/r remained.