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...

A treatment gap exists for pediatric patients with renal impairment. Alterations in renal clearance and metabolism of drugs render standard dosage regimens inappropriate and may lead to drug toxicity, but these studies are not routinely conducted during drug development. The objective of this study was to examine the clinical evidence behind current renal impairment dosage recommendations for pediatric patients in a standard pediatric dosing handbook. The sources of recommendations and comparisons included the pediatric dosing handbook (Lexicomp), the U.S. Food and Drug Administration-approved manufacturer's labels, and published studies in the literature. One hundred twenty-six drugs in Lexicomp had pediatric renal dosing recommendations. Only 14% (18 of 126) of Lexicomp pediatric renal dosing recommendations referenced a pediatric clinical study, and 15% of manufacturer's labels (19 of 126) described specific dosing regimens for renally impaired pediatric patients. Forty-two products had published information on pediatric renal dosing, but 19 (45%) were case studies. When pediatric clinical studies were not referenced in Lexicomp, the renal dosing recommendations followed the adult and pediatric dosing recommendations on the manufacturer's label. Clinical evidence in pediatric patients does not exist for most renal dosing recommendations in a widely used pediatric dosing handbook, and the adult renal dosing recommendations from the manufacturer's label are currently the primary source of pediatric renal dosing information.

Tenofovir diphosphate (TFVdp; an active metabolite of oral HIV pre‐exposure prophylaxis (PrEP)) is measured in dried blood spots (DBS) to estimate adherence. However, TFVdp's long half‐life in whole blood may lead to misclassification following a recent change in adherence. PrEP's other metabolite, emtricitabine triphosphate (FTCtp), has a shorter half‐life in whole blood but adherence thresholds are undefined. We characterized DBS TFVdp and FTCtp concentrations across many dosing scenarios. Population pharmacokinetic models were fit to TFVdp and FTCtp DBS concentrations from a directly observed therapy study (NCT03218592). Concentrations were simulated for 90 days of daily dosing followed by 90 days of 1 to 7 doses/week and for event‐driven PrEP (edPrEP) scenarios. Thresholds of 1,000 and 200 fmol/punch, for TFVdp and FTCtp, respectively, were reflective of taking 4 doses/week (a minimum target for effective PrEP in men). TFVdp was < 1,000 fmol/punch for 17 days after initiating daily PrEP and > 1,000 fmol/punch for 62 days after decreasing to 3 doses/week. Respectively, FTCtp was < 200 fmol/punch for 4 days and > 200 fmol/punch for 6 days. Accuracy of edPrEP adherence classification depended on duration between last sex act and DBS sampling for both measures with misclassification ranging from 9–100%. These data demonstrate adherence misclassification by DBS TFVdp for 2 months following a decline in adherence, elucidating the need for FTCtp to estimate recent adherence. We provide proof of principle that individualized interpretation is needed to support edPrEP adherence monitoring. Our collective approach facilitates clinicians' ability to interpret DBS results and administer patient‐centric interventions.