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).