HIV: Cabotegravir plus rilpivirine every 2 months on average works similar to monthly injection

The effect of intramuscular administration of long-acting cabotegravir and rilpivirine is not inferior to monthly injections in maintenance therapy for patients with HIV infection, as found by the ATLAS-2M study.

Longer-dosing intervals should be investigated

The effect of intramuscular administration of long-acting cabotegravir and rilpivirine is not inferior to monthly injections in maintenance therapy for patients with HIV infection. This was the result of the randomized, open-label ATLAS-2M study, presented by Edgar Turner Overton, University of Alabama, Birmingham (USA) at the virtual CROI in March 2020.

There is still a strong need to simplify the oral treatment of patients with HIV infection, for example, to reduce the pill burden, reduce food interactions and improve compliance to treatments.

ViiV is currently developing a depot injection of the integrase inhibitor cabotegravir and the non-nucleoside reverse transcriptase inhibitors (NNRTI) rilpivirine. In the two randomized Phase-3 trials ATLAS and FLAIR, viral suppression with intramuscular administration of cabotegravir plus rilpivirine every 4 weeks was not inferior to the effect of oral triple therapy.

These results, as well as the compounds’ pharmacokinetic parameters, hinted at the need to look further into an even longer dosing interval. Therefore, the open-label Phase-3b study ATLAS-2M compared the effect of a four-week and an eight-week injection of cabotegravir plus rilpivirine.

Injection every 4 versus every 8 weeks

The study included 391 patients from the ATLAS study who were still treated with the monthly injection. In addition, 654 participants were included who had not yet received parenteral therapy. Most of the test subjects were also from the ATLAS study.

The study participants received maintenance treatment with cabotegravir + rilpivirine on average every 8 weeks (n = 522) or every 4 weeks (n = 523) on a 1:1 randomized basis. The dosage was higher in the 8-week group with 600mg cabotegravir and 900mg rilpivirine than in the 4-week group with 400mg cabotegravir and 600mg rilpivirine.

The primary endpoint of the study was the proportion of patients with plasma HIV-RNA ≥ 50 copies (c)/ml after 48 weeks. The study was designed for non-inferiority. An important secondary endpoint was the proportion of patients with plasma HIV-RNA below 50 c/ml at week 48.

The demographic parameters of the two groups were well comparable. The median age of the patients was 42 years, 27% were women, 27% were not Caucasians. The median body mass index was 26 kg/m², the CD4 cell count was 661.

Non-inferiority was proven

The non-inferiority of the two treatment regimes was demonstrated in the primary and secondary endpoints after 48 weeks. The viral suppression rate was comparably good at 94.3% (8 weeks) and 93.5%. In comparison, the viral suppression rate in the ATLAS study was 93% in the injection group and 95% in the oral therapy group.

Confirmed treatment failure occurred in 10 patients in total, 8 in the 8-week group and 2 in the 4-week group. Markers of rilpivirine resistance were found in 6 patients in the 8-week group and resistance to integrase inhibitors in 5 patients. All cases were still sensitive to dolutegravir

Less than 1% of the injections in each group experienced severe injection-related reactions.

The intramuscular injection of cabotegravir and rilpivirine every 8 weeks thus offers an alternative in maintenance therapy for test persons with HIV infection. However, the resistance rate in the 8-week arm was viewed critically. Further data should be presented here.

However, in December 2019, the FDA had rejected approval of the monthly depot formulation due to manufacturing and control problems. An application for approval has been submitted to the EMA.

Overton ET, et al. Cabotegravir + Rilpivirine every 2 months is non-inferior to monthly: ATLAS-2M study. Virtual CROI 2020, Abstract 34.