The FLAIR study evaluated the efficacy and safety of the long-acting injectable regimen of cabotegravir (CAB) + rilpivirine (RPV) in previously ART-naïve individuals who switched to CAB+RPV after viral suppression on a standard 3-drug oral regimen (dolutegravir [DTG]/ABC/3TC). At both 48 weeks (the primary endpoint) and 96 weeks, CAB+RPV given once monthly as an intramuscular injection was found to be non-inferior to DTG/ABC/3TC. At the International AIDS Society 2021 meeting, investigators presented week 124 efficacy and safety data on the CAB+RPV arm of the study. Key findings included:
- 80.2% of persons had viral suppression to <50 copies/mL at week 124 in ITT-E analysis.
- 4.9% had HIV RNA ≥50 copies/mL, and 14.8 % had no virologic data.
- 1 person developed confirmed virologic failure between week 96 and week 124
- Resistance testing showed 4 NNRTI and 2 INSTI resistance mutations (RT: V106V/A, V108V/I, E138G, M230L; IN: N155H, R263K)
- The patient’s HIV subtype was A6 (which has been associated with earlier cases of virologic failure on CAB+RPV in the FLAIR and ATLAS studies)
- CAB and RPV levels at week 108 were in target range
- No significant new adverse events were reported; injection site reactions (ISRs), while common, were generally mild and tolerable – over the course of 124 weeks, only 7 of 283 participants (2%) withdrew from the study because of ISRs.
- Minimal information was given about the other study participants who had nonsuppressed HIV RNA at week 124, or who had no available data at that time point.
Clinical bottom line
These extended data from FLAIR confirm the long-term durability of monthly long-acting injectable CAB+RPV in appropriate patients and also demonstrated (as in previous reports from FLAIR and ATLAS) that while virologic failure appears to be rare, it can be consequential, and result in extensive resistance to both NNRTIs and INSTIs.
Long-acting CAB+RPV is approved by the FDA for once-monthly dosing in appropriate persons (e.g., those with stable HIV suppression on ART, no NNRTI or INSTI resistance, and no hepatitis B). Based on data from the ATLAS 2M study (references below), which show comparable (non-inferior) virologic outcomes with either once-monthly or every-two-month dosing of long-acting CAB+RPV, the FDA is currently considering approval of every-two-monthly dosing of CAB+RPV.
Many U.S. clinics currently are starting CAB+RPV programs, so we soon will learn the elements needed to successfully implement long-acting injectable ART in clinics and to support patients in treatment (e.g., monitoring adherence to injection visits, tracking patients who miss appointments, having oral ART options readily available for those who interrupt or stop injectable CAB+RPV, etc.). A separate presentation at IAS evaluated the implementation of long-acting injectable CAB+RPV in a variety of U.S. care settings; for more information, see Czarnogorski, below.
It is important to remember that long-acting CAB+RPV has only been studied in the context of switching from oral ART regimens in persons with sustained virologic suppression; we need data on directly starting CAB+RPV in persons whose HIV RNA is not suppressed – many of whom are persons who have struggled to take oral ARVs and maintain regular clinical care and for whom long-acting injectable regimens may be an attractive (but perhaps challenging) treatment option.
- Orkin C, Morell EB, Tan DHS, et al. Week 124 results of the randomized, open-label, phase 3 FLAIR study evaluating long-acting cabotegravir + rilpivirine for treatment in adults with HIV-1 infection (ITT-E population). 11th IAS Conference on HIV Science, July 18-21, 2021. Abstract OAB0302.
- Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al. Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection. N Engl J Med. 2020 Mar 19;382(12):1124-1135. doi: 10.1056/NEJMoa1909512. Epub 2020 Mar 4.
- Orkin C, Oka S, Philibert P, et al. Long-acting cabotegravir plus rilpivirine for treatment in adults with HIV-1 infection: 96-week results of the randomised, open-label, phase 3 FLAIR study. Lancet HIV. 2021 Apr;8(4):e185-e196.
- Overton ET, Richmond G, Rizzardine G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. The Lancet, 396, 10267, 1994-2005, December 19, 2020.
- Jaeger H, Overton ET, Richmond G, et al. Week 96 Efficacy and Safety of Cabotegravir + Rilpivirine every 2 Months: ATLAS-2M. 28th Conference on Retroviruses and Opportunistic Infections (CROI), March 6-10, 2021. Abstract 401.
- Czarnogorski M, Garris C, D'Amico R, et al. CUSTOMIZE: Overall Results From A Hybrid III Implementation-Effectiveness Study Examining Implementation Of Cabotegravir And Rilpivirine Long-Acting Injectable For HIV Treatment In US Healthcare Settings; Final Patient And Provider Data. 11th IAS Conference on HIV Science, July 18-21, 2021. Abstract PED463.