Antiretroviral Drug Interactions: Overview of Interactions Involving New and Investigational Agents and the Role of Therapeutic Drug Monitoring for Management

Abstract

Antiretrovirals are prone to drug-drug and drug-food interactions that can result in subtherapeutic or supratherapeutic concentrations. Interactions between antiretrovirals and medications for other diseases are common due to shared metabolism through cytochrome P450 (CYP450) and uridine diphosphate glucuronosyltransferase (UGT) enzymes and transport by membrane proteins (e.g., p-glycoprotein, organic anion-transporting polypeptide). The clinical significance of antiretroviral drug interactions is reviewed, with a focus on new and investigational agents. An overview of the mechanistic basis for drug interactions and the effect of individual antiretrovirals on CYP450 and UGT isoforms are provided. Interactions between antiretrovirals and medications for other co-morbidities are summarized. The role of therapeutic drug monitoring in the detection and management of antiretroviral drug interactions is also briefly discussed.

Managing drug interactions in HIV-infected adults with comorbid illness

“…Both the efficacy and the toxicity of non-HIV medications can be drastically affected by the coadministration of antiretrovirals. 2,10 It is also important for HIV care providers to appreciate the bidirectional nature of HIV drugdrug interactions. Many antiretroviral agents have a narrow therapeutic window.…”

“…Excessively high plasma concentrations can increase toxic effects and reduce tolerability, whereas low plasma concentrations lead to reduced virologic control and emergence of drug-resistant strains of the virus. 2,10 In either case, the ability to ensure long-term, durable control of HIV infection is compromised. Thus, HIV-infected pa tients are considered particularly vulnerable to the pharmacokinetic influences of other medications, and any drug that reduces the absorption of an HIV medication or alters its metabolism through the CYP450 system can potentially undermine the efficacy of HIV treatment.…”

“…Indeed, this drug is commonly used at low doses in HIV treatment (100-200 mg/d) not for its antiviral activity but rather to take advantage of its inhibition of CYP3A4, which "boosts" the plasma concentrations of coadministered protease inhibitors and thereby allows for once-daily dosing. 2,10 Ritonavir has a greater potential for drug-drug interactions than other protease inhibitors, because it also inhibits CYP2D6 in the liver and induces CYP2B6, CYP2C19, CYP2C9 and CYP1A2. 10,11 Box 1: Antiretroviral agents Nucleoside/nucleotide reverse transcriptase inhibitors…”

“…2,10 Ritonavir has a greater potential for drug-drug interactions than other protease inhibitors, because it also inhibits CYP2D6 in the liver and induces CYP2B6, CYP2C19, CYP2C9 and CYP1A2. 10,11 Box 1: Antiretroviral agents Nucleoside/nucleotide reverse transcriptase inhibitors…”

In vitro interaction between Zidovudine and some adsorptive antacids

“…Antiretrovirals are prone to drug-drug and drug-food interactions that can result in subtherapeutic or supratherapeutic concentrations. 3 Zidovudine, 1-(3-Azido-2,3-dideoxy-β-D-ribofuranosyl)-5-methylpyrimidine-2,4-(1H,3H)-dione is a nucleoside reverse transcriptase inhibitor structurally related to thymidine with antiviral activity against HIV-1. It is used in the treatment of HIV infection and AIDS.…”