Renal Tubular Transporter-Mediated Interactions of HIV Drugs: Implications for Patient Management

Interactions of drugs with renal transporters can reduce the tubular secretion of endogenous products and affect drug pharmacokinetics, efficacy, and toxicity. This review aims to understand the clinical implications of renal transporter-mediated interactions of HIV drugs. These interactions have been fully investigated for nucleoside/nucleotide reverse transcriptase inhibitors, particularly tenofovir disoproxil fumarate, and for some of the newer agents, such as rilpivirine, dolutegravir, and cobicistat. Interactions may include competition, inhibition, or induction of transporters, and interference with renal active secretion of creatinine, the most commonly used marker of renal function. Drug-drug interactions may result in an increased risk of drug toxicity. This interaction is more likely to occur with the protease inhibitors, particularly ritonavir, due to the inhibitory effects of these drugs on specific transporters involved in renal excretion of other drugs. Interactions with the transport of creatinine have been identified with rilpivirine, dolutegravir, and cobicistat. While rilpivirine and dolutegravir inhibit mainly the renal transporter OCT2 in the basolateral membrane of the proximal tubular cell, cobicistat predominantly inhibits the renal transporter MATE1 in the luminal membrane. These interactions can cause mild-to-moderate increases in serum creatinine concentrations and moderate reductions in estimated glomerular filtration rate that do not translate into real decreases in glomerular filtration. To use these drugs safely, clinicians must correctly interpret changes upon initiation of therapy to differentiate these spurious elevations in serum creatinine from clinically significant toxicity. In this article we propose a set of recommendations for clinical use of antiretroviral drugs that interfere with creatinine renal transporters.