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.

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Dolutegravir Population Pharmacokinetics in a Real-Life Cohort of People Living With HIV Infection

Therapeutic Drug Monitoring ◽

10.1097/ftd.0000000000000618 ◽

2019 ◽

Vol 41 (4) ◽

pp. 444-451 ◽

Cited By ~ 3

Author(s):

François Parant ◽

Patrick Miailhes ◽

Florence Brunel ◽

Marie-Claude Gagnieu

Keyword(s):

Hiv Infection ◽

Population Pharmacokinetics ◽

Real Life ◽

People Living With Hiv ◽

Living With Hiv

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Long-acting injectable cabotegravir for the prevention of HIV infection

Current Opinion in HIV and AIDS ◽

10.1097/coh.0000000000000597 ◽

2020 ◽

Vol 15 (1) ◽

pp. 19-26 ◽

Cited By ~ 12

Author(s):

Meredith E. Clement ◽

Ryan Kofron ◽

Raphael J. Landovitz

Keyword(s):

Hiv Infection ◽

Long Acting ◽

Prevention Of Hiv

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Regulatory challenges in developing long-acting antiretrovirals for treatment and prevention of HIV infection

Current Opinion in HIV and AIDS ◽

10.1097/coh.0000000000000163 ◽

2015 ◽

Vol 10 (4) ◽

pp. 278-281 ◽

Cited By ~ 2

Author(s):

Vikram Arya ◽

Stanley Au ◽

Yodit Belew ◽

Peter Miele ◽

Kimberly Struble

Keyword(s):

Hiv Infection ◽

Treatment And Prevention ◽

Long Acting ◽

Prevention Of Hiv ◽

Regulatory Challenges

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Modeling the Time Course of the Tissue Responses to Intramuscular Long-acting Paliperidone Palmitate Nano-/Microcrystals and Polystyrene Microspheres in the Rat

Toxicologic Pathology ◽

10.1177/0192623315618291 ◽

2015 ◽

Vol 44 (2) ◽

pp. 189-210 ◽

Cited By ~ 11

Author(s):

Nicolas Darville ◽

Marjolein van Heerden ◽

Tim Erkens ◽

Sandra De Jonghe ◽

An Vynckier ◽

...

Keyword(s):

Drug Absorption ◽

Time Course ◽

Drug Exposure ◽

Critical Time ◽

Granulomatous Inflammation ◽

Mechanistic Modeling ◽

Paliperidone Palmitate ◽

Therapeutic Drug ◽

Monocyte Chemoattractant Protein 1 ◽

Long Acting

Long-acting injectable (LAI) drug suspensions consist of drug nano-/microcrystals suspended in an aqueous vehicle and enable prolonged therapeutic drug exposure up to several months. The examination of injection site reactions (ISRs) to the intramuscular (IM) injection of LAI suspensions is relevant not only from a safety perspective but also for the understanding of the pharmacokinetics. The aim of this study was to perform a multilevel temporal characterization of the local and lymphatic histopathological/immunological alterations triggered by the IM injection of an LAI paliperidone palmitate suspension and an analog polystyrene suspension in rats and identify critical time points and parameters with regard to the host response. The ISRs showed a moderate to marked chronic granulomatous inflammation, which was mediated by multiple cyto-/chemokines, including interleukin-1β, monocyte Chemoattractant Protein-1, and vascular endothelial growth factor. Lymphatic uptake and lymph node retention of nano-/microparticles were observed, but the contribution to the drug absorption was negligible. A simple image analysis procedure and empirical model were proposed for the accurate evaluation of the depot geometry, cell infiltration, and vascularization. This study was designed as a reference for the evaluation and comparison of future LAIs and to support the mechanistic modeling of the formulation–physiology interplay regulating the drug absorption from LAIs.

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Principles of Applied Clinical Pharmacokinetics and Pharmacodynamics in Antiretroviral Therapy

10.1093/med/9780190493097.003.0018 ◽

2017 ◽

Author(s):

Neha Sheth Pandit ◽

Emily L. Heil

Keyword(s):

Antiretroviral Therapy ◽

Drug Exposure ◽

Virologic Failure ◽

Treatment Success ◽

Antiretroviral Drugs ◽

Therapeutic Drug ◽

Virologic Suppression ◽

Hiv Replication ◽

Clinical Pharmacokinetics ◽

Suboptimal Adherence

Systemic concentrations of antiretroviral drugs (ARVs) are influenced by the pharmacokinetic properties of absorption, distribution, metabolism, and excretion. Pharmacokinetics and local drug exposure can differ significantly within anatomical sanctuary sites compared with the systemic compartment. High variability in interpatient ARV concentrations is common, which makes population pharmacokinetics for ARVs very difficult to interpret. HIV replication is dynamic and requires combination antiretroviral therapy with multiple active agents in order to achieve durable virologic suppression. Direct and indirect relationships between drug exposure, efficacy, and/or toxicity are common for most ARVs, which can be used to improve overall treatment success. Suboptimal adherence can result in inadequate concentrations, drug resistance, and virologic failure. Therapeutic drug monitoring can be considered in certain scenarios that should be evaluated on a case-by-case basis.

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Antiretroviral adherence for adolescents growing up with HIV: understanding real life, drug delivery and forgiveness

Therapeutic Advances in Infectious Disease ◽

10.1177/2049936120920177 ◽

2020 ◽

Vol 7 ◽

pp. 204993612092017 ◽

Cited By ~ 1

Author(s):

Caroline Foster ◽

Sara Ayers ◽

Sarah Fidler

Keyword(s):

Drug Delivery ◽

Young People ◽

Real Life ◽

Adult Life ◽

Poor Adherence ◽

People Living With Hiv ◽

Genetic Barrier ◽

Antiretroviral Adherence ◽

Adherence To Medication ◽

Long Acting

Poorer adherence to medication is normal in adolescence and is one of a range of risk-taking behaviours common during a developmental stage that encompasses enormous cognitive, physical, sexual, social and emotional change. For adolescents living with human immunodeficiency virus (HIV) infection, poor adherence to antiretroviral therapy (ART) confers two significant challenges: poor health, but also the specific additional burden of onward transmission to partners. Late adolescence (15–19 years) is the only age group where HIV-associated mortality is rising, driven by poor adherence to ART and lack of access to second-line therapy, particularly amongst surviving perinatally infected young people. A previous lack of well-powered randomised multimodal behavioural ART adherence interventions specifically targeting adolescents is now being addressed and ongoing studies registered to ClinicalTrials.gov are described in the context of previous data. Accepting that despite enhanced support, some adolescents will continue to struggle with adherence, we must address how best to use existing ART agents to reduce mortality and allow adolescents the time to mature into adult life. Single-tablet regimens with a high genetic barrier to resistance based on integrase inhibitors and boosted protease inhibitors exist, but global access, in resource limited settings of young people living with HIV reside, is limited. Pragmatically, such regimens tolerate the intermittent adherence so characteristic of adolescence, preserving immune function, without the rapid evolution of resistance. The potential role of long-acting injectable ART, specifically cabotegravir and rilpivirine, is discussed and future strategies including ultra-long-acting drug-delivery systems and broadly neutralising monoclonal antibodies explored.

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Validation and Clinical Application of a New Liquid Chromatography Coupled to Mass Spectrometry (HPLC-MS) Method for Dalbavancin Quantification in Human Plasma

Separations ◽

10.3390/separations8100189 ◽

2021 ◽

Vol 8 (10) ◽

pp. 189

Author(s):

Valeria Avataneo ◽

Miriam Antonucci ◽

Elisa Delia De De Vivo ◽

Antonio Briozzo ◽

Jessica Cusato ◽

...

Keyword(s):

Renal Function ◽

Human Plasma ◽

Normal Renal Function ◽

Extraction Procedure ◽

Real Life ◽

Therapeutic Drug ◽

Continuous Hemodiafiltration ◽

Positive Skin ◽

High Doses ◽

Long Acting

Dalbavancin (DBV) is an intravenous long-acting second-generation glycolipopeptide antibiotic with high efficacy and excellent tolerability, approved for use in the treatment of Gram-positive skin and skin structure infections (ABSSSI). Nevertheless, little is known about its pharmacokinetic/pharmacodynamic (PK/PD) properties in real life, which is also due to technical challenges in its quantification in human plasma, preventing an effective application of therapeutic drug monitoring (TDM). In fact, DBV has a high affinity to plasma proteins, possibly resulting in poor recovery after extraction procedure. The aim of this study was to validate a simple, cheap and reliable HPLC-MS method for use in TDM, in accordance with FDA and EMA guidelines. The optimized protein precipitation protocol required 50 μL of plasma, while chromatographic analysis could be performed in 12 min/sample. This method fulfilled the guidelines requirements and then, it was applied for routine DBV TDM in patients receiving off-label high doses (two 1500 + 1500 mg weekly infusions instead of 1000 + 500 mg), with normal renal function or undergoing hemodialysis: continuous hemodiafiltration caused a relevant reduction in DBV exposure, while intermittent dialysis showed comparable DBV concentrations with those of patients with normal renal function. This confirmed the eligibility of the presented method for use in TDM and its usefulness in clinical practice.

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