Long-acting antiretrovirals: a new era for the management and prevention of HIV infection

Abstract

The long-acting antiretroviral cabotegravir and rilpivirine combination has just received FDA, EMA and Health Canada approval. This novel drug delivery approach is about to revolutionize the therapy of people living with HIV, decreasing the 365 daily pill burden to only six intramuscular injections per year. In addition, islatravir, a first-in-class nucleoside reverse transcriptase translocation inhibitor, is intended to be formulated as an implant with a dosing interval of 1 year or more. At present, long-acting antiretroviral therapies (LA-ARTs) are given at fixed standard doses, irrespectively of the patient’s weight and BMI, and without consideration for host genetic and non-genetic factors likely influencing their systemic disposition. Despite a few remaining challenges related to administration (e.g. pain, dedicated medical procedure), the development and implementation of LA-ARTs can overcome long-term adherence issues by improving patients’ privacy and reducing social stigma associated with the daily oral intake of anti-HIV treatments. Yet, the current ‘one-size-fits-all’ approach does not account for the recognized significant inter-individual variability in LA-ART pharmacokinetics. Therapeutic drug monitoring (TDM), an important tool for precision medicine, may provide physicians with valuable information on actual drug exposure in patients, contributing to improve their management in real life. The present review aims to update the current state of knowledge on these novel promising LA-ARTs and discusses their implications, particularly from a clinical pharmacokinetics perspective, for the future management and prevention of HIV infection, issues of ongoing importance in the absence of curative treatment or an effective vaccine.

Could Long-Acting Cabotegravir-Rilpivirine Be the Future for All People Living with HIV? Response Based on Genotype Resistance Test from a Multicenter Italian Cohort

“…In this regard, therapeutic drug monitoring (TDM), which is current practice for some antibiotics, antiepileptics, immunosuppressants, antifungals, and anti-HIV drugs, may play a role for a particular subgroup of patients, such as people with BMI > 30 kg/m 2 , people with drug interaction problems, or elderly people with sarcopenia [28]. Indeed, if these patients show a substantially lower or higher minimum blood plasma concentration, in order to improve efficacy, a personalized dosing schedule could be designed,with a consequent decrease of the costs [29]. Cutrell et al demonstrated how virological failure in people treated with long-acting CAB/RPV had a multifactorial cause, but people with increased BMI, subtype A6/A1, and having at least two proviral RPV RAMs had an increased risk of failure [26].…”

Long‐acting injectable Cabotegravir: How drug concentrations could help guide patient management

“…In their manuscript, Yu et al discussed assessing plasma concentrations (i.e., therapeutic drug monitoring) to guide patient management in the era of long-acting antiretrovirals, a sentiment that is echoed by others. 9 As the Food and Drug Administration approval for CAB-LA (and RPV-LA) currently stands, front-line clinicians are required to implement 1-size-fits-all dosing in patients who often do not conform to the controlled clinical trial settings in which the drugs were originally studied. The availability of drug concentrations for these clinicians would empower them to make informed decisions to manage these patients.…”

Implementation of long-acting antiretroviral therapy in low-income and middle-income countries

“…Secondary deposits are also formed within the lymphatic system, macrophages and T lymphocytes. As a result, the half-life of the nanocrystal preparations of CAB and RPV are 35-fold and 76-fold greater than their oral formulations respectively (Table 1)[6 ▪▪ ]. Novel prodrugs of CAB/RPV that could provide year-long exposure after a single injection are in the early stages of development.…”