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.