At CROI 2019, investigators presented 48-week results from the Phase 3 international multisite ATLAS and FLAIR studies of long-acting 2-drug injectable therapy. The study regimen consisted of the integrase inhibitor cabotegravir (CAB) plus the NNRTI rilpivirine (RPV), both given every 4 weeks as intramuscular (IM) injections.
In the ATLAS study, 616 patients (30% women, 68% white) on stable suppressive ART regimens were randomized to switch to CAB + RPV or continue their baseline ART. The CAB + RPV subjects initially took oral CAB and RPV for 4 weeks (to ensure they tolerated the new ARVs), then switched to monthly injections. At week 48, by snapshot algorithm, 92.5% of the CAB + RPV group and 95.5% of the comparator group maintained HIV RNA levels of <50 copies/mL; this result met criteria for noninferiority.(1)
In the FLAIR study, 629 previously untreated persons (22% women, 74% white) were initially treated with dolutegravir (DTG)/ABC/3TC; at baseline, their HIV had no identified resistance to rilpivirine (RPV). After 20 weeks, patients whose HIV RNA was <50 copies/mL (n = 566) were randomized to switch to CAB + RPV, with a 4-week oral medication lead-in followed by once-monthly injections, or to continue DTG/ABC/3TC. At 48 weeks of randomized treatment, by snapshot analysis, viral suppression was seen in 93.6% of the injectable CAB + RPV group and 93.3% of the DTG/ABC/3TC group, this result also met criteria for noninferiority.(2)
In ATLAS and FLAIR, virologic failure with ARV drug resistance occurred in a total of 6 subjects treated with CAB + RPV, 3 in each study. Five of the 6 had both NNRTI and INSTI resistance mutations and 1 had only NNRTI mutations. DNA genotyping of HIV from blood collected at study entry showed that some of these mutations were present at baseline (particularly the RT mutation E138A or E138K and the IN mutation L74I). All 6 of the patients with virologic failure and ARV resistance were from Russia and had HIV-1 subtype A (5 of them had A1). In both studies, plasma concentrations of CAB and RPV in those with virologic failure were reported to below the means of the CAB + RPV cohorts, but were not frankly low.
Adverse effects to CAB + RPV in both studies mostly consisted of painful injection site reactions (ISRs)--these almost always were grade 1 or 2 in severity, and lasted a median of 3 days; roughly 3% of subjects in both ATLAS and FLAIR quit the study because of ISRs. The frequency of ISRs decreased after the first several injections, but continued to occur in about 15-25% of study subjects throughout the 48 weeks. Despite this, a high proportion of CAB + RPV participants reported satisfaction with the injectable therapy.
Clinical Bottom Line
In these studies, once-monthly IM CAB + RPV was effective as maintenance therapy in persons with HIV viral suppression. As with all investigational regimens, some concerns remain unanswered by these preapproval studies and may have to be answered in clinical practice. Among these are:
- The forgiveness of this regimen for missed or delayed doses: Because both CAB and RPV, in the IM formulation, have very long half-lives (40 days for CAB, 90 days for RPV), missed or late doses or discontinuation (without switching to an oral ART regimen) may result in virologic failure and resistance to the ARVs. In ATLAS and FLAIR, subjects were given oral CAB and RPV to take during any periods during which their injections were delayed (and of course were given incentives to receive their monthly injections on schedule). How will clinics support their CAB + RPV patients in adhering closely to the injection schedule? This will be a crucial question for each practice as we start to use this regimen.
- The effect of preexisting resistance mutations on CAB + RPV, and the resistance consequences of virologic failure: In ATLAS and FLAIR, few study subjects experienced virologic failure, but virologic failure was accompanied by a concerning degree of resistance. At this time, the significance of the pretreatment HIV mutations seen on DNA genotyping is not clear, nor is the fact that all who experienced virologic failure and resistance to CAB and RPV had subtype A HIV-1.
- Patient willingness to tolerate ISRs over time: Patient satisfaction in ATLAS and FLAIR was reported to be high, but it is not clear that this will be true in a more general patient population.
- Finally, it is important to note that these studies do not provide any data on whether CAB + RPV can be used as initial ART--in both studies, only subjects with suppressed HIV were eligible to switch to CAB + RPV.
While injectable long-acting CAB + RPV will free certain persons from the need to take pills on a daily basis (eg, those with stable HIV suppression on ART, no NNRTI or INSTI resistance, no hepatitis B, and a willingness to go to the clinic monthly for IM injections), it will bring particular challenges. This regimen of long-acting CAB + RPV is likely to gain FDA approval this year. As it comes into the clinics, it will be important to learn from our early clinical experience with it and to apply those lessons to optimizing its potential.
1. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir + rilpivirine for maintenance therapy: ATLAS week 48 results. In: Program and abstracts of the 2019 Conference on Retroviruses and Opportunistic Infections; March 4-7, 2109; Seattle. Abstract 139.
2. Orkin C, Arastéh K, Hernández-Mora MG, et al. Long-acting cabotegravir + rilpivirine for HIV maintenance: FLAIR week 48 results. In: Program and abstracts of the 2019 Conference on Retroviruses and Opportunistic Infections; March 4-7, 2109; Seattle. Abstract 140LB.