Contemporary Drug–Drug Interactions in HIV Treatment

Abstract

Despite development of modern antiretrovirals with lower drug interaction potential than their predecessors, drug interaction challenges remain. Standard treatment regimens still require multiple antiretrovirals that may cause, or may be the target of, drug interactions. Additionally, people living with HIV are living longer and often present with comorbid conditions that require concomitant long-term drug therapy. Also, treatment of infectious diseases in resource-limited settings can result in significant interactions. In this review, we describe absorption, distribution, metabolism, and excretion pathways as they relate to relevant drug interactions with antiretrovirals along with the potential clinical consequences of these interactions. We highlight clinical data that illustrate pertinent interactions and provide tools to assist in predicting drug interactions in the absence of clinical data. Given these tools and thoughtful consideration of drug combinations, drug therapy in people living with HIV can be safely and effectively managed throughout their lifetime.Understanding, predicting, and managing antiretroviral drugdrug interactions (DDIs) has traditionally been a challenge for both drug developers and clinicians treating people living with HIV (PLWH). Of more than 20 antiretrovirals developed to date, most are lipophilic in nature. Lipophilic compounds generally have higher cellular permeability and greater affinity for cytochrome P450 (CYP) drug-metabolizing enzymes and efflux drug transporters. Since these enzymes and transporters concentrate in the gastrointestinal tract and liver, most drug interactions occur at these sites. New antiretroviral (ARV) therapies bypassing CYP metabolism and drug transport have alleviated some drug interaction concerns but challenges remain. In particular, because PLWH are living longer due to effective ARV therapy, they are developing age-related comorbidities, with increasing DDI potential of polypharmacy for cardiovascular, endocrine, and oncologic disorders. In addition to bone marrow transplants for leukemia and lymphomas, the availability of solid organ transplant in PLWH can pose a DDI challenge with medications used to prevent rejection and prophylax against opportunistic infections. Finally, the introduction of new and novel ARV therapies may lag in resource-limited settings, where most of the burden of HIV exists and where other infections such as malaria and tuberculosis need to be treated or prophylaxed. This review highlights interactions between ARVs themselves and interactions between ARVs and common classes of concomitant medications. We review the relevant absorption, distribution, metabolism, and excretion pathways for these medications, the clinical consequences of administering concomitant medications with ARVs, key clinical examples of interactions where ARVs are affected by other drugs (otherwise known as the "victim" drug) or are the agent affecting concomitant drugs (otherwise known as the "perpetrator" drug), and investigate how ARV interactions...

Toxicity of chloroquine and hydroxychloroquine following therapeutic use or overdose

“…Significant inhibitors of the CYP enzymes responsible for chloroquine or hydroxychloroquine metabolism (CYP 2C8, 3A4, 2D6), including azole antifungals (e.g., fluconazole, itraconazole) [127,128] and antiretroviral agents (e.g., ritonavir, tenofovir) [130,131], may increase the toxicity of chloroquine or hydroxychloroquine by increasing their concentrations. Chloroquine has been shown to be both a substrate for and inhibitor of drug transporters, including P-glycoprotein [123] and organic anion transporting polypeptide [143].…”

The management of treatment-experienced HIV patients (including virologic failure and switches)

“…The interactions may occur during absorption, distribution, metabolism, or elimination, and should be considered carefully when readjusting ARV regimens. 57 The following are examples of drug-drug interactions between ARVs and non-ARVs that should be considered:…”

“…The interactions may occur during absorption, distribution, metabolism, or elimination, and should be considered carefully when readjusting ARV regimens. 57…”

New Frontiers in Measuring and Characterizing the HIV Reservoir

“…While antiretroviral therapy (ART) can control viremia and improve health outcomes, durably ART-suppressed HIV seropositive individuals are still at higher risk for diseases related to immune dysfunction and inflammation compared to uninfected individuals (Hunt et al, 2016). Moreover, lifelong adherence to ART is required for optimal health outcomes and is associated with financial burden, drug interactions, and unknown long-term effects of treatment (Deeks et al, 2017;Devanathan et al, 2019). Further, the stigma associated with HIV disease contributes to negative health outcomes (Rueda et al, 2016).…”