HTB

Long-acting cabotegravir and rilpivirine injections support two-monthly dosing

Simon Collins, HIV i-Base

In one of the first oral presentations, 48-week results from the ATLAS-2M study provided first data reporting that two-monthly injections of long-acting cabotegravir and rilpivirine are non-inferior to monthly dosing. [1]

Although phase 3 ATLAS and FLAIR studies used monthly dosing, the pharmacokinetics of both long acting injections supported looking at extended dosing. If effective, this would halve the number of annual clinic visits that are currently needed, and also reduce administration costs.

ATLAS-2M is a phase 3, open-label, non-inferiority study that randomised 1045 treatment-experienced participants (including approximately 33% from the original ATLAS study) to injections either every 8 weeks (Q8W, n=522) or every 4 weeks (Q4M, n=523) dosing schedules.

The primary endpoint is detectable viral load (>50 copies/mL) at week-48 by ITT-E snapshot analysis, based on non-inferiority margin of 4%, with the option for all participants to continue with either dosing schedule after week-100.

Baseline characteristics included median age 42 years (range: 19 to 83); 28% women; 73% white, 18% black/African American, 9% other; median BMI 26 kg/m2 (IQR: 23–29) and median CD4 count 661 cells/mm3 (IQR: 508 to 849).

At week-48, viral load was detectable in 1.7% vs 1% of the Q8M vs Q4M groups respectively (adj diff: 0.8% [95%CI: –0.6 to +2.2]) showing non-inferiority on the primary endpoint.

Non-inferiority was also achieved based on secondary endpoint of viral suppression to < 50 copies/mL (adj diff: 0.8% [95%CI: –2.1 to +3.7]). This included 6 (1.1%) vs 2 (0.4%) participants in the Q8W vs Q4W arms who discontinued for lack of efficacy. This was balanced by slight fewer discontinuations in the Q8W group due to side effects (n = 9 vs 13) or for other reasons (n=12 vs 16).

Overall, there were 10 confirmed virologic failures: 8 vs 2 in the Q8M vs Q4M arms; with RPV resistance in 6/8 vs 1/2 and INSTI resistance in 5/8 vs 2/2, respectively.

A post-hoc analysis of baseline resistance of HIV DNA in PBMCs in the Q8W arm showed: 5/8 had pre-existing major RPV RAMs (E138A, Y188L, Y181Y/C, H221H/Y, E138E/A, Y188Y/F/H/L); 1/8 had pre-existing major INI RAM (G140G/R) and 5/8 had L74I polymorphism (3 subtype A or A1, 1 subtype C, 1 complex subtype). Resistance data were not presented for the Q4W arm and further analyses are underway.

Side effects were similar in both groups and overall, 96% of drug-related events were grade 1–2

Drug-related side effects led to withdrawal in 5 vs 8 participants in the Q8W arm vs Q4W arms.

Injection site reactions were also similar in both groups, despite the fewer number of injections in the Q8W group (8,470 vs 15,711 injections respectively overall).

Approximately 94% of participants with experience of both dosing regimens, preferred Q8W dosing.

comment

Although the higher reports of drug resistance were at least partially explained by baseline resistance, this aspect of the study requires greater analysis.

Otherwise, the option to halve the number of injections would clearly benefit both participants and health systems. It should also cut the proposed price for CAB/RPV LA which anecdotally has been discussed as being considerably more expensive than oral ART. This study certainly justifies a more affordable price.

Cabotegravir LA and rilpivirine LA are currently still being evaluated by the FDA and EMA based on results of the phase 3 ATLAS and FLAIR studies that used monthly dosing.

Although an FDA decision was expected by the end of December 2019, a manufacturing problem relating to scale-up led to an FDA complete response letter. The letter has not raised safety or efficacy concerns, but will delay approval until these issues are resolved. [2]

References

  1. Overton ET et al. cabotegravir + rilpivirine every 2 months is noninferior to monthly: ATLAS-2M study. CROI 2020. Oral abstract 34.
    http://www.croiconference.org/sessions/cabotegravir-rilpivirine-every-2-months-noninferior-monthly-atlas-2m-study (abstract)
  2. Collins S. FDA decision on long-acting cabotegravir/rilpivirine (Cabenuva) injections delayed due to scale-up manufacturing problems. HTB (January 2020).
    http://i-base.info/htb/37064

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