The two-drug regimen of long-acting (LA) cabotegravir (CAB) and rilpivirine (RPV) given IM every 4 weeks was found to be highly effective and non-inferior to daily oral ART in two Phase 3 studies. These results and the known pharmacokinetics of CAB+RPV enabled the evaluation of a longer and more convenient 8-week dosing interval. The ATLAS-2M is a multicenter, open-label, Phase 3b non-inferiority (NI) study of CAB+RPV maintenance therapy given Q 8-weeks or Q 4-weeks to treatment-experienced, HIV-infected adults. The study randomized 1,045 persons who were virologically suppressed on IM CAB+RPV every 4 weeks (rolled over from the ATLAS study) or on oral therapy, to receive CAB+RPV every 8 or every 4 weeks. Sixty-three percent were naive to CAB+RPV LA while 37% transitioned from the Q 4-week arm of the ATLAS trial. The primary endpoint (at week 48) was the proportion of subjects with plasma HIV-1 RNA ≥ 50 c/mL with a NI margin of 4% and the secondary endpoint was the proportion with HIV-1 RNA < 50 c/mL based on a NI margin of 10%. For the primary endpoint CAB +RPV given Q 8 weeks was noninferior to Q 4-week dosing (1.7% vs 1.0%) and for the secondary analysis 94.3% vs 93.5% had viral loads < 50 c/mL. There were eight confirmed virologic failures (2 sequential VLs of > 200 c/mL) in the 8-week arm and two confirmed virologic failures in the Q 4-week arm. Five and 0 of the virologic failures respectively, had archived resistance-associated mutations to RPV either alone (n=4) or with a CAB mutation (n=1) at baseline. On-treatment resistance mutations to RPV, CAB, or both drugs not present at baseline were found in 5/8 of the 8-week virologic failures and both of the four-week virologic failures. The safety profiles were similar for 4-week and 8-week dosing. Injection site reactions were reported in 98% of participants but were mild or moderate and lasted a median of 3 days. Discontinuation for an adverse event occurred in only 2% of patients including 12 in the 8-week and 13 in the 4-week groups. Of those treated every 8 weeks (rolled over from ATLAS Q 4-weeks), 93% expressed a preference for Q 8-week dosing. This study concludes that Q 8-week dosing of LA CAB+RPV is non-inferior to Q 4-Week dosing and generally well tolerated, thus supporting the therapeutic effectiveness of these two antiviral agents given at 2-month intervals.

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