Discussion
Our review aimed to discuss potential DDIs between LAI cabotegravir and
rilpivirine and common concomitant medications in sub-Saharan African
healthcare settings. Although the potential for DDIs caused by
cabotegravir or rilpivirine is low, a certain number of CYP3A4- and/or
UGT1A1-inducing medications can reduce the exposure of cabotegravir
and/or rilpivirine and create a risk of treatment failure. Notable
concomitant medications that are contraindicated include rifamycins,
carbamazepine, phenytoin, griseofulvin, and flucloxacillin. Rilpivirine
is associated with a risk of QT prolongation at supratherapeutic dosing
. Patients receiving co-medications with QT prolongation risk may
require ECG monitoring with rilpivirine.
With the current roll-out of LAI cabotegravir and LAI rilpivirine for
HIV treatment and prevention, it is crucial to raise awareness on
potential DDIs. As discussed above, the long pharmacokinetic tail linked
to the slow clearance of the drug, as well as its irreversibility,
create a risk of resistance development in the case of treatment
discontinuation (Figure 2) . Awareness of the risks must be present at
multiple levels. Healthcare professionals and HIV clinicians in
particular must take the risk of DDIs into account when initiating LAI
ART and ask about new prescribed, herbal or over the counter medicines
being used at every appointment. Likewise, patients, as well as
community pharmacies and drug vendors, must also be aware of potential
DDIs and their implications. This is particularly essential in settings
where medications can be bought without requiring prescriptions.
The optional CAB/RPV oral lead-in may give rise to interactions that are
specific to the oral formulation as they affect drug absorption rather
than drug metabolism. For example, proton pump inhibitors that decrease
absorption of oral rilpivirine or antacids that decrease absorption of
oral cabotegravir. In such cases omitting the oral lead-in by opting for
the direct to injection approach may be preferable to discontinuing or
altering the dosing schedule of their co-medications.
In addition to DDIs, appropriate administration of the drug itself is
critical. Healthcare professionals may want to consider injecting LAI
CAB/RPV with longer (2 inch) needles in patients with BMI
>30 kg/m2, to avoid administering the
drug in adipose tissue. Injection into adipose tissue alters the
pharmacokinetics and can lead to nodule formation. Virological failure
has been associated with BMI >30 kg/m2(adjusted incidence rate ratio 1.09, 95% confidence interval 1.00-1.19,
P=0.044) highlighting the importance of injection placement .
Few studies have been conducted on specific drug classes and their
possible interactions with LAI ART. Notably, the evidence on
antimalarials and antifungals, including PBPK studies, is scarce, and
some of the recommendations outlined in this review, along with part of
the Liverpool HIV Interaction Database guidance, have been based on
theoretical predictions, derived from established induction or
inhibition effects with other drugs. Furthermore, the need for
well-established therapeutic targets that accurately correlate to
clinical endpoints such as viral suppression in the absence of
resistance are needed to accurately interpret the clinical significance
of DDI studies, either measured or predicted. Additional research is
required to provide comprehensive guidance to healthcare providers and
patients.
The limited number of DDI studies and their complexity is partly due to
the magnitude of the extended half-life, and irreversibility, of
long-acting agents. Therefore, the field is increasingly relying on
alternative predictive modelling and simulation to estimate impact of
co-administration. PBPK studies are one tool that has been applied and
has allowed to model drug-drug interactions with increasing precision .
LAI ART is a promising treatment option for people living with HIV and
other regimens in the development pipeline could prove invaluable for
patients for whom the use of cabotegravir/rilpivirine may be
contraindicated (e.g. those with underlying NNRTI resistance).