Glasgow 2022: long-acting cabotegravir/rilpivirine: adverse events, implementation and PROMs
Kirk Taylor, HIV i-Base
HIV Drug Therapy Glasgow included several presentations on long-acting cabotegravir plus rilpivirine formulations (CAB+RPV-LA). Focus was given to adverse events, implementation and participant-reported outcomes (PROMs).
Confirmed virologic failures (CVF) on phase 3 CAB+RPV-LA trials were evaluated and baseline rilpivirine resistance, HIV subtype A6/A1, BMI >30 kg/m2 and reduced CAB levels at week 4 were identified as risk factors.  Frequency of viral blips on CAB+RPV-LA were comparable to those observed on oral therapy and were not predictive of CVF. 
Neuropsychiatric adverse events (NPAEs) were reported for 9% of participants on CAB+RPV-LA trials and the majority were classified as low grade (≤2). 
A survey of healthcare workers reported ‘very’ or ‘extremely positive’ views regarding implementation and delivery of long-acting antiretroviral therapy. 
PROMs from phase 3 and real-world implementation studies consistently highlighted benefits of long-acting formulations for HIV therapy. [5-7]
HPTN 083 reports efficacy of long-acting cabotegravir (CAB-LA) for high-risk gay men and transgender women. A 66% reduction of new HIV diagnoses was reported for those on CAB-LA. 
Confirmed virologic failures (CVF) on CAB+RPV-LA therapy through week 48 of phase 3 trials were reported for 1.4% of participants (n=23).  CVF risk increased for participants with ≥2 baseline factors (RPV resistance mutations, BMI >30 kg/m2 or HIV subtype A6/A1).
Participant data were pooled from FLAIR (124 weeks), ATLAS (96 weeks) and ATLAS-2M (152 weeks) for post-hoc analysis of risk factors. This analysis highlighted reduced week 4 CAB levels as an additional risk factor for CVF.
A second study reported results from an exploratory analysis of viral blips using RNA samples collected during FLAIR and ATLAS-2M.  Blips occurred at similar frequencies for CAB+RPV-LA QM (12%), Q2M (8%) and QD oral therapy (17%). Snapshot analyses at weeks 96 (FLAIR) and 152 (ATLAS-2M) reported undetectable viral load for >90% of participants that had viral blips during the study period. Of the 17 reported CVFs on long-acting therapy, only one participant also experienced a viral blip during the trial. These findings suggest that viral blips are not predictive of CVF.
NPAEs (e.g. headache, dizziness, depression and anxiety) have been reported for people taking CAB+RPV-LA. Post-hoc analysis of NPAEs that occurred on phase 3 studies (ATLAS, ATLAS-2M and FLAIR) was conducted to evaluate trends.  The frequency of drug-related NPAEs was 9% (n=111) for participants that received long-acting formulations. 96% of NPAEs were ≤grade 2 and no drug-related grade 4 or 5 events were recorded. NPAEs occurred infrequently and events were mostly reported between weeks 4 to 12. Headache and dizziness tended to resolve within a week, whilst sleep and psychiatric disorders persisted for significantly longer.
Participants with a history of psychiatric disorders or substance abuse were more likely to experience NPAEs. No serious drug-related NPAEs were reported across the study period. Participants were female (26%), Black (19%) and median age was 40 years (IQR 18 to 83).
Implementation and PROMs
Healthcare workers were surveyed to ascertain perceptions of CAB+RPV-LA formulations and inform optimal implementation strategies.  Respondents were interviewed after a month (n=70) and again at one year (n=62). Most respondents were nurses (41%) and doctors (37%). Identified barriers included perceived risk of resistance (35%) and viral rebound (30%), lack of staff to administer injections (35%).
Attitudes to implementation of CAB+RPV-LA were ‘very’ or ‘extremely’ positive after one year (76%). Side effects and being unable to administer injections at home were perceived as implementation barriers. 68% of healthcare providers wanted more information prior to trial initiation, but were positive about the benefits of long-acting formulations.
Participants on ATLAS-2M were surveyed to evaluate experiences of injections, chronic therapy and treatment satisfaction.  Participants were female (27%), White (73%), median age was 42 years (IQR: 34 to 50) and 37% had previously received CAB+RPV-LA on the ATLAS trial.
At three years, ISRs were rated as ‘totally’ or ‘very acceptable’ for 78% of participants. Treatment acceptance was ranked >80 on a scale of ‘totally unacceptable’ (0) to ‘totally acceptable’ (100). Treatment satisfaction was ranked from 0 to 66 and mean scores were >55 for participants on QM and Q2M regimens. Participants were satisfied with the convenience and flexibility of treatment but side effects, discomfort and pain scored negatively.
Participants that missed at least one dose and received oral therapy during the trial period (n=70) were included in a sub-analysis. 88% of people in this group indicated a preference for long-acting therapies over oral regimens. These data may explain high retention and low discontinuation rates observed in ATLAS-2M.
European participants on the CARISEL study (n=430) were surveyed to gauge their opinions on CAB+RPV-LA therapy.  Responses were scored on a five-point scale of ‘completely disagree’ (1) to ‘completely agree’ (5) at months 1, 4 and 12. Acceptability and feasibility scores were ≥4.5 at month 1 and moderately increased over time. Treatment satisfaction scores dipped at month 1 (-0.73, 95% CI -1.37 to -0.10) but improved to ≥+2.84 at later timepoints. Most participants (91%) were positive about long-acting therapy at one year. Participants spent an average of 1 hour in the clinic and 75% agreed that this was acceptable.
Whilst 31% of participants reported no challenges with LA therapy, negatives included ISRs (56%), missing work (13%) and travel schedules (9%). Not needing to carry medication, convenience and reduced stigma contributed to 99% of participants reporting a preference for LA formulations.
Real-world data on the efficacy and adherence to Q2M CAB+RPV-LA were collected through the German CARLOS cohort study.  Participants (n=236) were male (95%) and median age was 43 years (IQR: 36 to 50). Baseline risk factors for CVF were recorded for 24 people and one person had 2 known risk factors. The primary reason for switch to long-acting therapy was participant request (92%).
At six months, 89.5% of participants had undetectable viral load, 2% had ≥50 copies/mL and there was one instance of CVF. The majority of drug-related AEs were low grade with a single grade 3 event of worsening anxiety. ISRs were common with 218 reports across 866 injections. Injections were delivered within the dosing widow for >97% of participants. Treatment satisfaction scores were 60.6 at six months.
Cabotegravir as long-acting PrEP
HPTN 083 is a Phase 2b/3 randomised controlled trial of PrEP formulations for gay men and transgender women at increased risk of HIV transmission risk. 
Participants were recruited across 43 sites from 7 countries. CAB-LA was evaluated as an alternative to oral TDF/FTC PrEP.
A 66% reduction of new HIV diagnoses were observed for those receiving CAB-LA vs TDF/FTC. There were 52 breakthrough cases of HIV that occurred in the first year after unblinding. Of these, diagnoses were more common on TDF/FTC (n=34) than for CAB-LA (n=18).
PK data indicated that CAB levels were mostly within range but one participant had rapid CAB clearance with unknown cause. For three cases, INSTI-associated resistance mutations were observed. CAB continues to show efficacy as a long-acting alternative to oral PrEP.
- Orkin C et al. Expanded multivariable models to assist patient selection for long-acting cabotegravir + rilpivirine treatment: clinical utility of a combination of patient, drug concentration, and viral factors associated with virological failure over 152 weeks. HIV Drug Therapy Glasgow, October 23-26, 2022. Oral abstract O34.
- Latham C et al. HIV-1 RNA blips, low-level viral replication, and mean CD4+/CD8+ ratio during phase 3/3b cabotegravir + rilpivirine long-acting studies up to 152 weeks of therapy. P083. HIV Drug Therapy Glasgow, October 23-26, 2022. Poster abstract P083.
- Elliot E et al. Drug-related neuropsychiatric adverse events across phase 3/3b studies of long-acting cabotegravir + rilpivirine through week 48. HIV Drug Therapy Glasgow, October 23-26, 2022. Poster abstract P168.
- Slama L et al. Overcoming barriers and achieving optimal implementation of Cabotegravir and rilpivirine long-acting (CAB + RPV LA): staff study participant (SSP) results from the CAB + RPV implementation study in European locations (CARISEL). HIV Drug Therapy Glasgow, October 23-26, 2022. Poster abstract P116.
- Chounta V et al. Patient-reported outcomes after 152 weeks of HIV maintenance therapy with long-acting cabotegravir + rilpivirine in the phase 3b ATLAS-2M study. HIV Drug Therapy Glasgow, October 23-26, 2022. Poster abstract P070.
- Lutz T et al. Perceptions of cabotegravir and rilpivirine long-acting (CAB + RPV LA) from patients in the CAB + RPV implementation study in European locations (CARISEL). HIV Drug Therapy Glasgow, October 23-26, 2022. Poster abstract P123.
- Borch J et al. 6-month outcomes of every 2 months long-acting cabotegravir and rilpivirine in a real-world setting – effectiveness, adherence to injections, and patient-reported outcomes of people living with HIV in the German CARLOS cohort. HIV Drug Therapy Glasgow, October 23-26, 2022. Oral abstract O43.
- Landovitz R. Laboratory analysis of HIV infections in the year 1 unblinded period of HPTN 083: injectable cabotegravir for PrEP in MSM and TGW. HIV Drug Therapy Glasgow, October 23-26, 2022. Oral abstract.