Association Between Antiretroviral Exposure and Renal Impairment Among HIV-Positive Persons With Normal Baseline Renal Function: the D:A:D Studya

Abstract

Background. Several antiretroviral agents (ARVs) are associated with chronic renal impairment, but the extent of such adverse events among human immunodeficiency virus (HIV)–positive persons with initially normal renal function is unknown. Methods. D:A:D study participants with an estimated glomerular filtration rate (eGFR) of ≥90 mL/min after 1 January 2004 were followed until they had a confirmed eGFR of ≤70 mL/min (the threshold below which we hypothesized that renal interventions may begin to occur) or ≤60 mL/min (a value indicative of moderately severe chronic kidney disease [CKD]) or until the last eGFR measurement during follow-up. An eGFR was considered confirmed if it was detected at 2 consecutive measurements ≥3 months apart. Predictors and eGFR-related ARV discontinuations were identified using Poisson regression. Results. Of 22 603 persons, 468 (2.1%) experienced a confirmed eGFR of ≤70 mL/min (incidence rate, 4.78 cases/1000 person-years of follow-up [95% confidence interval {CI}, 4.35–5.22]) and 131 (0.6%) experienced CKD (incidence rate, 1.33 cases/1000 person-years of follow-up [95% CI, 1.10–1.56]) during a median follow-up duration of 4.5 years (interquartile range [IQR], 2.7–6.1 years). A current eGFR of 60–70 mL/min caused significantly higher rates of discontinuation of tenofovir (adjusted incidence rate ratio [aIRR], 1.72 [95% CI, 1.38–2.14]) but not other ARVs compared with a current eGFR of ≥90 mL/min. Cumulative tenofovir use (aIRR, 1.18/year [95% CI, 1.12–1.25]) and ritonavir-boosted atazanavir use (aIRR, 1.19/year [95% CI, 1.09–1.32]) were independent predictors of a confirmed eGFR of ≤70 but were not significant predictors of CKD whereas ritonavir-boosted lopinavir use was a significant predictor for both end points (aIRR, 1.11/year [95% CI, 1.05–1.17] and 1.22/year [95% CI, 1.16–1.28], respectively). Associations were unaffected by censoring for concomitant ARV use but diminished after discontinuation of these ARVs. Conclusions. Tenofovir, ritonavir-boosted atazanavir, and ritonavir-boosted lopinavir use were independent predictors of chronic renal impairment in HIV-positive persons without preexisting renal impairment. Increased tenofovir discontinuation rates with decreasing eGFR may have prevented further deteriorations. After discontinuation, the ARV-associated incidence rates decreased.