Introduction
HIV continues to be a major global health concern, with an estimated 39 million people living with the virus worldwide and 29 million people accessing antiretroviral therapy (ART) in 2022. The burden of HIV is particularly high in sub-Saharan Africa, which accounted for approximately two-thirds of all new HIV infections in 2022 . Treatment fatigue and poor adherence to ART causes treatment failure and favours the emergence of drug-resistant viral strains, and thus constitutes an important impediment to reaching the UNAIDS goal of ending the HIV/AIDS epidemic worldwide by 2030 .
Suboptimal adherence to HIV prevention and treatment has motivated the search for alternatives to daily oral medicines, and among the most promising novel approaches is long-acting injectable (LAI) therapy which has leveraged nanotechnology to modify the pharmacokinetics of the existing compounds. The frontrunner LAI regimen for HIV treatment consists of a combination of the integrase strand transfer inhibitor (INSTI) cabotegravir (CAB) together with the non-nucleotide reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV), given monthly or every two months by intramuscular (IM) injection, and demonstrated comparable efficacy to standard oral therapy in maintaining viral suppression in a number of clinical trials. Roll out of this injectable regimen is now underway in Europe, USA and Australia and licensing applications are in process in several African countries. In Europe, CAB and RPV are marketed as two separate injectable medicines under the brand names VOCABRIA® and REKAMBYS®respectively, while in Canada and the United States the regimen is marketed as a combined pack called CABENUVA®.
LAI cabotegravir has also been examined for prevention of HIV infection and is superior to standard oral pre-exposure prophylaxis (PrEP). A global coalition is currently accelerating the roll out of LAI cabotegravir PrEP in many high HIV burden countries.
The use of LAI ART in sub-Saharan settings presents a promising advancement in HIV prevention and treatment as it is discreet and convenient. However, this novel LAI preventive and therapeutic option brings new clinical pharmacology challenges. Firstly, it is critical to ensure that the drug is deposited into muscle not adipose tissue, which is less vascular and can result in poor absorption and distribution of the drug. As a result, body mass index (BMI) >30kg/m2 is known to be an independent risk factor for virological failure and longer needles (2-inch) are required in people with high BMI . Secondly, due to the nature of the LAI formulation, the drug is slowly cleared from the body after administration. This means, that should a dose be missed, or treatment discontinued, there is a resultant long pharmacokinetic (PK) ‘tail’. During this prolonged period of terminal decay ART plasma concentrations steadily decline eventually reaching non-suppressive concentrations), leading to a risk of viral replication together with selection of drug-resistant variants . Thirdly, in addition to LAI ART, individuals in sub-Saharan countries may require treatment with other medications, including antitubercular, antimalarial, or psychotropic agents, to manage comorbidities, some of which come with clinically significant drug-drug interactions (DDIs). Healthcare professionals may be unfamiliar with the numerous potential DDIs between LAI cabotegravir and rilpivirine and frequently prescribed concomitant medicines. In addition, many drugs are available over the counter in lower-income settings, meaning DDIs may go unchecked, so patient counselling is important.
DDIs with cabotegravir or rilpivirine have the potential to lead to catastrophic HIV treatment failure, through the lowering of the drugs’ plasma concentration with ensuing viral rebound . The evolution and spread of INSTI resistance has significant consequences for the individual and societies, as it requires management with protease-inhibitor-based ART, which is toxic, costly and also plagued with further DDI risk . Therefore, avoiding DDIs that add to the risk of viral rebound and drug resistance is of key importance during use of LAI ART.
Due to the long terminal half-life of LAI CAB and RPV, the associated long dosing interval and the high consequence of low drug exposures causing virological failure, it is challenging to perform DDI studies in people on LAI ART. For this reason, to date, DDI studies have been performed in silico with a virtual clinical population (with physiological parameters that are important for the prediction of drug disposition) using an approach called physiologically based pharmacokinetic (PBPK) modelling. PBPK uses known mechanistic and physiologic properties such as organ-specific blood flow, tissue partition coefficients, specificity and capacity of metabolic enzymes to create whole-body profiles of drug disposition. It then combinesin vitro data and clinically observed data to simulate pharmacokinetics and DDIs in the virtual population, an approach that is essential in understanding LAI CAB/RPV pharmacokinetics in the context of DDIs or complex and difficult to study populations.
This literature review aims to raise awareness amongst healthcare professionals of the pharmacokinetics of LAI CAB and RPV, dosing schedules, and the risk of DDIs with commonly used medications in sub-Saharan Africa. This will enable clinicians to adequately counsel patients and to make informed decisions regarding the use of concomitant medications in people receiving LAI ART for HIV prevention or treatment, ultimately improving patient care, and reducing the risk of virological failure.