Dynamics of creatinine estimated glomerular filtration rate using one or more antiretrovirals that inhibit creatinine tubular secretion

Abstract

Background Cobicistat, dolutegravir and rilpivirine are all modest inhibitors of proximal tubular creatinine secretion (IPTCrS) and hence a moderate and early non-progressive creatinine estimated glomerular filtration rate (Cr-eGFR) reduction has been observed in clinical trials. Data regarding the impact of combination of those drugs on Cr-eGFR, in the clinical practice, are scarcely known. Methods Changes in Cr-eGFR after starting darunavir/cobicistat alone or in combination with dolutegravir and/or rilpivirine were studied in a nationwide retrospective cohort study of consecutive HIV-infected patients initiating darunavir/cobicistat. The relationship between Cr-eGFR changes over time and the use of darunavir/cobicistat alone or darunavir/cobicistat plus dolutegravir and/or rilpivirine adjusted by different HIV patient’s characteristics, socio-demographics, HIV severity and use of tenofovir concomitant medication other than antiretrovirals was explored through univariate and multivariate analyses. Results The analysis included 725 patients. At 48 weeks, the combination of two or more IPTCrS (darunavir/cobicistat with rilpivirine and/or dolutegravir) was associated with higher decreases in Cr-eGFR [adjusted median difference (±SD) –3.5 ± 1.6 (95% CI –6.6 to –0.3), P = 0.047], and a decrease up to or higher than 15 mL/min/1.73 m2 was more frequent [adjusted OR 3.233 (95% CI 1.343–7.782), P = 0.009], with respect to darunavir/cobicistat alone. The Cr-eGFR changes between darunavir/cobicistat and darunavir/cobicistat with rilpivirine and/or dolutegravir showed more significant decreases in patients taking two or more IPTCrS at 12, 24 and 48 weeks. (ClinicalTrials.gov: NCT03042390). Conclusions Concomitant use of darunavir/cobicistat plus IPTCrS dolutegravir, rilpivirine, or both produced an additive effect in the expected Cr-eGFR decrease.

Renal adverse drug reactions

“…Whether using one or more antiretrovirals that inhibit different renal transporters of creatinine has a greater impact on eGFR is unclear. In a retrospective cohort analysis in Spain, changes in eGFR after starting darunavir/cobicistat alone, or in combination with either dolutegravir or rilpivirine were evaluated in 725 patients [37 ▪ ]. Cobicistat acts primarily on multidrug and toxin extrusion protein (MATE)-1, while dolutegravir and rilpivirine mainly affect organic cation transporter (OCT)-2.…”

Cystatin C in addition to creatinine for better assessment of glomerular renal function decline in people with HIV receiving antiretroviral therapy

“…As a current hypothesis, overestimation of plasma creatinine because of ICS exposure would erroneously decrease the eGFR. antiretroviral drugs such as DTG, RPV, COBI, and RTV are reported as effective ICS through interaction with PTC transporters leading to a bias in the estimation of kidney function [8][9][10] with a potential additive effect when using multiple ICS in the antiretroviral drug strategy [33]. Indeed, after initiation of darunavir/ COBI in combination with DTG and/or RPV, a decrease of eGFRcreat more than 15 ml/min per 1.73 m 2 could be observed [33].…”

“…antiretroviral drugs such as DTG, RPV, COBI, and RTV are reported as effective ICS through interaction with PTC transporters leading to a bias in the estimation of kidney function [8][9][10] with a potential additive effect when using multiple ICS in the antiretroviral drug strategy [33]. Indeed, after initiation of darunavir/ COBI in combination with DTG and/or RPV, a decrease of eGFRcreat more than 15 ml/min per 1.73 m 2 could be observed [33]. In our study using cystatin C equation for eGFR determination is mainly associated with higher eGFR compared to creatinine CKD-EPI equation.…”