A long-acting therapy may be noninferior to the current daily oral antiretroviral therapy (ART) in maintaining viral suppression in the treatment of HIV-1 infection, according to a poster presented at the virtual 2020 Conference on Retroviruses and Opportunistic Infections held from March 8 to 11, 2020.
Although daily oral ART has shown success, there remain several challenges to its use for some patients including stigma, pill burden, drug/food interactions, and adherence. These challenges have resulted in considerable interest in the development of long-acting therapeutics for the treatment of HIV-1. Currently, the daily oral 3-drug ART therapy consists of dolutegravir, abacavir, and lamivudine (DTG/ABC/3TC). However, cabotegravir (CAB) and rilpivirine (RPV) are under development as a long-acting, 2-drug intramuscular injectable regimen for the maintenance of virologic suppression in HIV-1 infection.
A previous study demonstrated that when administered every 4 to 8 weeks, CAB + RPV treatment maintained <50 copies/mL HIV-1 RNA for >3 years. Therefore, the phase 3, randomized, multicenter, parallel-group, noninferiority, open-label trial (FLAIR) aimed to establish noninferiority of the antiretroviral activity of monthly long-acting intramuscular CAB + RPV compared with the 3-drug ART in previously treatment-naïve participants (ClinicalTrials.gov identifier: NCT02938520).
A total of 629 ART-naïve participants were included in the induction phase of the study, in which they received DTG/ABC/3TC therapy. After 16 weeks, participants who had <50 copies/mL of HIV-1 RNA were eligible to enter the maintenance phase and were randomly assigned (1:1) to either switch to long-acting therapy or continue DTG/ABC/3TC. Participants who were randomly assigned to receive long-acting therapy received an oral lead-in dosage of 30 mg of CAB and 25 mg of RPV once daily for 4 weeks as a tolerability check; after this, dosing was adjusted to the long-acting intramuscular formulation of 400 mg CAB + 600 mg RPV. The primary endpoint was the percentage of participants with plasma HIV-1 RNA ³50 copies/mL at week 48 using the United States Food and Drug Administration Snapshot algorithm (6% noninferiority margin on difference between groups).
Data from week 96 endpoints included percentage of HIV-1 RNA ³50 copies/mL compared with participants who demonstrated <50 copies/mL at week 96 (Snapshot, intention-to-treat exposed; incidence of confirmed virologic failure, defined as 2 consecutive measurements of HIV-1 RNA ³200 copies/mL; treatment-emergent genotypic resistance, incidence and severity of adverse events and the number of discontinuations for adverse events; and participant satisfaction and quality of life.
Results from week 96 suggested noninferior antiviral activity among patients in the long-acting treatment group compared with those in the DTG/ABC/3TC group. Each group had 3.2% participants with HIV-1 RNA ³50 copies/mL at week 96, which confirmed the noninferiority established at week 48. From week 48 to week 96, no virologic failures were reported in the long-acting group, whereas 1 virologic failure was reported in the DTG/ABC/3TC group.
Among participants in the long-acting ART group, 96% of drug-related adverse events (excluding injection-site reactions) were grade £2 and 1 drug‑related serious adverse event of right knee monoarthritis occurred. No serious adverse events occurred in the DTG/ABC/3TC group. In the long-acting group, the most common drug-related adverse event (6%) (excluding injection-site reactions) was pyrexia. Between week 48 and week 96, a total of 4 participants in the long-acting ART group discontinued treatment due to the following adverse events (excluding injection-site reactions): drug-related depression (n=2), hepatitis A (n=1), and hepatitis C (n=1). Overall, 99% of injection-site reactions were grade £2.
Participants who received long-acting treatment reported treatment satisfaction that was a statistically significant improvement from baseline (P <.001) and was higher than oral DTG/ABC/3TC satisfaction as measured by HIV Treatment Satisfaction Questionnaire.
Overall, the study authorsconcluded that, “These results build on the positive data collected at Week 48 and support the therapeutic potential of monthly [long-acting] CAB + RPV.”
Orkin C, Oka S, Philibert P, et al. Long-acting cabotegravir + rilpivirine for HIV treatment: FLAIR week 96 results. Poster presented at: CROI 2020; March 8-11, 2020; Boston, MA. http://www.croiconference.org/sites/default/files/uploads/croi2020-boston-abstract-ebook.pdf. Accessed March 26, 2020.