Injectable Long-Acting ART: Optimizing Evidence-Based Candidate Selection

When I evaluate a patient with HIV as a candidate for switching from a suppressive oral antiretroviral therapy (ART) regimen to long-acting (LA) IM cabotegravir (CAB) plus rilpivirine (RPV), I consider several factors, including:

• The patient’s HIV treatment history, including any evidence of previous virologic failure or RPV resistance mutations
• Other potential risk factors for virologic failure, including high BMI and HIV-1 subtype A6/A1

Indications for Use of LA IM CAB Plus RPV and Risk Factors for Virologic Failure
The combination of LA IM CAB plus RPV is indicated as a switch regimen for patients who are virologically suppressed on a stable ART regimen with no history of treatment failure and with no known or suspected resistance to either CAB or RPV. In the European Union, the prescribing label is slightly more stringent in requiring that the patient does not have known or suspected resistance to any agents of the non-nucleoside reverse transcriptase inhibitor or integrase strand transfer inhibitor drug classes. Therefore, treatment history and confirmed or potential RPV resistance are important factors. In addition, a post hoc multivariate analysis of data from the phase III trials of LA IM CAB plus RPV identified the following 4 risk factors for virologic failure: proviral RPV resistance mutations, HIV-1 subtype A6/A1, higher BMI (per unit increase), and lower Week 8 RPV trough concentrations (per halving of log₂ value).

As testing for plasma RPV concentration is not widely available, that leaves 3 factors that can be assessed for at baseline. However, the analysis also demonstrated that the presence of only 1 of these 3 baseline factors alone was not associated with increased risk of confirmed virologic failure (CVF), with a 0.37% CVF rate among patients with 1 of the 3 factors vs 0.41% among patients with none of those 3 factors. The BMI cutoff was set at ≥30 kg/m² for this analysis. Strikingly, the CVF rate increased to 25.7% among the 35 patients with ≥2 of these 3 baseline factors. The single patient in the analysis with all 3 baseline factors also experienced CVF. 

Putting the Data Into Practice
I really appreciate that even at this early stage of implementing long-acting ART in the clinic, we have available data to inform the risk of virologic failure and help optimize the selection of patient candidates for this regimen. In my practice, I do not use LA IM CAB plus RPV in any patient with known or suspected RPV or CAB resistance, adhering to the approved indications for the regimen. We do not routinely perform proviral DNA sequencing, so the presence of RPV resistance only detectable by this method also is generally not considered. 

If a person has the A6/A1 HIV-1 subtype or BMI ≥30 kg/m² alone as the only risk factor, I feel comfortable treating them with LA IM CAB plus RPV. By contrast, if a patient has both risk factors, then I likely would not consider them a candidate for this regimen. I would note, however, that although it is important to carefully consider risk for virologic failure with any regimen, it also is critical that we provide patients with the best regimen to meet their individual needs. For example, if a patient is physically unable to swallow pills, an injectable regimen could make the difference between that patient being treated or not. In such cases, I would do a careful risk–benefit analysis with the patient and include additional viral monitoring if proceeding with the injectable option in the setting of multiple risk factors for virologic failure.

Regarding BMI considerations, longer needles (2-inch) are recommended for LA CAB plus RPV injections in patients with BMI ≥30 kg/m² to ensure administration into gluteal muscle. Use of 2-inch needles in this patient group was shown to be associated with higher CAB trough concentrations vs use of shorter needles, particularly during the first few months after switching. 

Women of Childbearing Age Not Using Contraception
Women generally have been underrepresented in HIV clinical trials during the past several decades. Corrective measures are underway to address this issue, and the FLAIR, ATLAS, and ATLAS-2M trials evaluating LA IM CAB plus RPV were approximately 22% to 33% women. However, pregnant women were excluded, as is nearly always the case in clinical trials of new drugs. Although we have extensive data supporting the safety and general efficacy (some concerns related to pharmacokinetic changes) of oral RPV in pregnancy, we do not yet have sufficient data for CAB use during pregnancy, nor do we have sufficient data for 2-drug oral or 2-drug injectable regimens.

Some women became pregnant while receiving LA IM CAB plus RPV in the clinical trials, and additional data are emerging from the HPTN 084 phase III and open-label extension studies of LA IM CAB for use as pre-exposure prophylaxis (PrEP) in women. In general, the major concerns related to ART use during pregnancy are the risk of teratogenicity with first trimester use and the risk of loss of virologic suppression during the second and third trimesters as a result of the physiologic changes during pregnancy altering the drug pharmacokinetics. Although CAB is a structural analogue of dolutegravir and is anticipated to have highly similar clinical features, it still is necessary to confirm this regarding its safety in pregnancy. Therefore, until there are more data on the safety and efficacy during pregnancy, I will avoid the use of LA IM CAB plus RPV in women of childbearing potential who are not using contraception. Indeed, 2-drug oral regimens such as dolutegravir/lamivudine are likewise not recommended during pregnancy because of a lack of available data at this time. However, the same caveats noted above also apply here regarding the risk factors for virologic failure; it must always be a balance between what the patient can/will take and the available data. For all patients with HIV, including women of childbearing age who are not using contraception, the most important goal of their HIV care is to maintain virologic suppression.

Final Thoughts
There is an understandable wave of enthusiasm on the part of patients and providers for this new LA injectable regimen. Although I share this excitement, I remain concerned that expanding use outside of the indications and evidence base could lead to the wrong patients being started on the regimen, with the potential for unnecessary virologic failures. This outcome could in turn cause healthcare professionals to lose confidence in the regimen and subsequently refrain from offering it to appropriate patients who could greatly benefit. Therefore, I prefer to offer LA IM CAB plus RPV to patients with the greatest possibility of success based on our current knowledge base. Our decision-making will most certainly evolve as more data emerge and as we gain more experience with the use of this new treatment paradigm.

Your Thoughts?
In your clinical practice, how do you evaluate patients when considering a switch to LA IM CAB plus RPV? Join the discussion by posting a comment.