Injectable Long-Acting CAB + RPV: Choices for Mode of Use

In Canada where I practice, as well as in the United States, the approvals for use of long-acting (LA) injectable cabotegravir (CAB) plus rilpivirine (RPV) as a complete switch regimen for select patients with viral suppression on their current antiretroviral therapy (ART) regimen include several different options for how to use the regimen. The first decision is whether to use an optional 4-week oral lead-in phase during which patients are first switched to daily oral CAB plus RPV, primarily to assess for unexpected toxicity, before switching to the long-acting intramuscular injections. The second decision to be made is whether or not to administer the injections once monthly or once every 2 months. Once-monthly dosing injections are 400-mg (2-mL) CAB and 600-mg (2-mL) RPV, whereas every-2-month dosing is 600-mg (3-mL) CAB and 900-mg (3-mL) RPV. 

More Choices = Improved Care With Shared Decision-Making
Before discussing my approach to these options, it is important to underscore that the overarching theme across HIV treatment and care is expanding the number and type of safe and effective choices for patients, where shared decision-making between healthcare professional and patient is paramount. This strategy follows the clearest path for advancing truly individualized care; the best option for one patient is not necessarily the ideal choice for another patient. Keeping this guiding message in mind is critical for providing the right care for our patients. 

Optional Oral Lead-in Phase
The formal change in the prescribing indications for LA CAB plus RPV to remove the requirement for the oral lead-in phase and instead make it optional was based on findings from the extension phase of the open-label phase III FLAIR trial, which initially randomized ART-naive patients to switch to LA CAB plus RPV using the 4-week oral lead-in phase vs continue standard oral ART after achieving viral suppression on a 20-week standard-of-care oral ART regimen. At Week 100, patients initially randomized to the control arm (continued standard-of-care oral ART) were given the option to switch to LA CAB plus RPV either with the 4-week oral lead-in or with a direct-to-injection approach that omitted the oral lead-in phase. Outcomes 24 weeks later demonstrated similar efficacy, tolerability, and safety with or without the oral lead-in. Although this was a nonrandomized comparison, the results provided reassurance that the oral lead-in might not be necessary. 

When considering whether or not to use the optional oral lead-in phase, it is helpful to recall that the reason this phase was included in the original clinical trials was to ensure that if any unexpected acute toxicity or hypersensitivity occurred, particularly with a new drug (ie, CAB), they would be identified using the short-acting oral version of the drug before administering a long-acting injection that would not be systemically eliminated for weeks or months. The fact that several thousand patients have now been treated in both the HIV treatment trials (ATLAS, FLAIR, ATLAS-2M) as well as the HIV prevention trials of injectable CAB (HPTN 083, HPTN 084) provides a substantial body of evidence supporting a lack of such events, at least at a frequency that would be detectable in a population size of approximately 5000-10,000 patients. Of course, the caveat is that the lack of a concerning event among that number of individuals does not absolutely rule out the potential for an event that may be extremely rare. Therefore, the key question for the patient and the healthcare professional when deciding to include or omit the oral lead-in phase is related to risk tolerance: How comfortable are you with the current body of available data? For some, this will be sufficient reassurance to move forward without the oral phase, but for others it may not. Once again, having the conversation in a shared decision-making process is my approach. 

One other potential reason to consider the oral lead-in might be to give patients the opportunity to ensure that they are comfortable with taking the daily oral regimen, which has a food requirement and is contraindicated in combination with proton-pump inhibitors (the RPV component), in anticipation of the potential need for an oral bridging strategy if the patient has any planned missed doses of the injectable regimen.

Monthly vs Every-2-Month Dosing
Results from the randomized, open-label phase IIIb ATLAS-2M trial comparing once monthly vs every-2-month dosing demonstrated that the longer dosing interval was noninferior to once monthly dosing at the primary endpoint of 48 weeks. Noninferiority has now been maintained through 152 weeks of treatment. In addition, in a post hoc multivariable analysis of data from the phase III trials of LA CAB plus RPV aimed at identifying risk factors for virologic failure with this regimen, every-2-month dosing was not associated with increased risk of failure. 

When considering the question of convenience, every-2-month dosing is the obvious choice, both for the patient and the healthcare professional/healthcare system because it requires fewer visits and less burden on the patient and reduced capacity needs for the healthcare professional or system. In addition, the primary adverse event associated with LA CAB plus RPV is injection-site reactions. Although the severity and frequency of injection-site reactions decrease over time with either dosing schedule, an every-2-month strategy will obviously result in a 2-fold lower risk of experiencing these events vs every-month dosing. 

One potential argument for selecting monthly dosing may be to allow for more frequent monitoring, which some the healthcare professionals prefer to conduct when beginning a new treatment regimen or paradigm. However, more frequent monitoring can be done independently of using a monthly dosing schedule by having the patient come in for viral load testing more frequently and including the treatment injections only every 2 months. Another consideration may be a theoretical scenario in which a patient is keenly interested in switching to LA treatment, but the healthcare professional has concerns about whether it will be the best approach for that particular patient. In this theoretical situation, one may prefer to use a monthly dosing approach at first that would allow more rapid pivoting to daily oral therapy if needed. However, healthcare professionals should ideally be limiting use of LA CAB plus RPV to patients for whom they have high confidence it will be successful.

Your Thoughts?
In your clinical practice, how are you considering use of the optional oral lead-in phase and selecting the dosing interval when switching patients to LA CAB plus RPV? Join the discussion by posting a comment.