CROI 2022: Injectable CAB/RPV-LA results after three years follow-up
Long-acting injections of cabotegravir (CAB) plus rilpivirine (RPV) are now a recommended combination in US and EU treatment guidelines based on two-monthly IM dosing.
CAB/RPV-LA is already available in Scotland and will soon be available in the rest of the UK. Long-acting therapies have many potential benefits, but drug resistance has been highlighted by BHIVA and others despite full adherence. [1, 2]
CROI 2022 included a poster of year three results from the ATLAS-2M phase 3b non-inferiority ITT-E study . Participants were randomised to receive injections every four (Q4W, n=523) or eight weeks (Q8W, n=522). Participants on this multicentre study (Argentina, Australia, Canada, Europe, Korea, Mexico, Russia, South Africa and USA) were women (27%, n=280), median age 42 years (range: 19 to 83), white (73%), BMI >30 kg/m2 (20%); 37% had previous exposure to CAB/RPV.
Non-inferiority of Q4W vs Q8W was reported based on the primary endpoint detectable viral load (>50 copies/mL at week 48) and efficacy remains high at week 152 (86-87%).
Non-inferiority was confirmed between Q4W and Q8W regimens within 4% and 10% margins for detectable and undetectable viral load, respectively. This was 3% (n=14, Q8W) vs 1% (n=5, Q4W) in the ITT-E analysis. Withdrawal rates were higher in Q4W (18%) vs Q4W (14%) with participants citing frequency of visits and intolerability of injections.
Total confirmed virologic failure (CVF) occurred in 11 and 2 for Q8W and Q4W, respectively, with two new CVF between weeks 96 to 152 on Q8W.
Both participants developed resistance associated mutations to both CAB and RPV, despite perfect protocol adherence. Of concern, viral load at failure was approximately 24,000 and 59,000, sufficiently high to risk HIV transmission to partners who are relying on U=U for prevention.
Viral suppression with alternative ART was achieved.
Adverse events were similar to week 96 results.
Two new low-grade drug-related (non-ISR) adverse events were reported (lipoatrophy and pyrexia).
Treatment satisfaction scores were higher for Q8W than Q4W regimens (p=0.004).
This study confirms previous safety and efficacy data supporting a Q8W strategy, which is also much preferred by people using this option.
However, the mechanism to explain drug resistance in some participants, despite perfect adherence, has not been explained.
In a predictive model, viral failure has been associated with having two or more of the following four factors: (i) BMI >30; (ii) low RPV levels at week 8; (iii) baseline mutations to RPV; and (iv) the A1 or A6 HIV subtype (common in Russia). Of these, low RPV levels and baseline mutations are easiest to monitor and explain, as they would results in periods of effective cabotegravir monotherapy. 
But the unpredictability of rebound, and the related implications for HIV transmission for people relying on U=U will involve new discussion on acceptability of risk.
Potential differences in interpatient PK related to injection technique might also be related. 
Other posters at CROI 2022 include early results from a phase 1/2 PK study in 23 adolescents adding either cabotegravir or rilpivirine to current active ART. Both involved oral formulations before the IM injections and reported comparable drug levels to adults. 
There were 2/23 discontinuations, both in the rilpivirine group. One was due to a hypersensitivity reaction to the first oral dose and one due to pain from the needle, before the full injection.
Another poster used physiologically-based pharmacokinetic (PBPK) modelling to predict that dose adjustment should not be needed during pregnancy. 
- Long-acting cabotegravir and rilpivirine injections support two-monthly dosing. (HTB 12 March 2020).
- BHIVA interim guidance on long-acting cabotegravir and rilpivirine injections. HTB (February 2022).
- Overton et al. Long-acting cabotegravir+rilpivirine every 2 months: ATLAS-2M week 152 results. CROI 2022. 12-16 February 2022, virtual. Poster abstract 479.
- Cutrell AD et al. Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis. AIDS, 2021 Jul 15; 35(9): 1333–1342, doi: 10.1097/QAD.0000000000002883..
- Khoo S. Long-acting ARVs: Research into the pharmacology of treatment and prevention. hanc HIV AIDS Network. (30 April 2021).
- Bolton Moore C et a. Safety and pk of long-acting cabotegravir and rilpivirine in adolescents. CROI 2022. 12-16 February 2022, virtual. Poster abstract 738.
- Atoyebi SA et al. PBPK modeling of long-acting injectable cabotegravir in pregnancy. CROI 2022. 12-16 February 2022, virtual. Poster abstract 686.
This report was first posted on 14 February 2022.