IAS 2023: LA-CAB/RPV as first-line ART and implementation studies
1 October 2023. Related: Conference reports, Antiretrovirals, IAS 2023 Brisbane.
Kirk Taylor, HIV i-Base
IAS 2023 included an oral abstract, four posters and seven e-posters on the injectable combination of cabotegravir/rilpivirine (LA-CAB/RPV). [1]
- Most notably, Monica Gandhi from the University of California San Francisco presented a pilot study using LA-CAB/RPV off-label as first-line ART. [1]
The current indication for LA-CAB/RPV is as a switch combination in people who have maintained undetectable viral load of six months on oral ART, despite the potential for long-acting formulations to have specific advantages for people who have difficulty adhering to oral meds.. - Week 48 data from the JABS implementation study shows high levels of virologic suppression for Australian participants who received LA-CAB/RPV. [2]
- Data from other implementation studies high levels of participant satisfaction and discussed barriers to implementation. [3, 4, 5]
LA-CAB/RPV as first-line ART to enable easier adherence
Monica Gandhi presented an oral symposium presentation on the implementation of long-acting ART for people in hard-to-reach populations. [1]
The original registrational trials of LA-CAB/RPV (FLAIR, ATLAS and ATLAS-2M) evaluated efficacy and safety in treatment-naive and -experienced participants. These studies all reported high levels of virologic suppression (>80%), but inclusion criteria required baseline virologic suppression on oral ART. Virologic failure rates across these trials was low (1.4%) and linked to INSTI and/or NNRTI resistance associated mutations (RAMs). This has widespread implications for alternative therapy options for these participants.
However, LA-CAB/RPV has specific advantages over daily oral meds for populations where adherence is low.
This demonstration study was run at Ward 86 at San Francisco General Hospital. The majority of participants were on public health insurance (96%), had high rates of mental ill-health complication (45%), recreational drug ise (35%) and/or had an insecure housing (34%). Inclusion criteria did not require an undetectable viral load, but participants needed to be willing to attend monthly clinics.
Results were available for the first 133/194 participants enrolled into the study. Baseline demographics included women (12%), Black (16%), Latinx (38%), median age 45 years (range: 38 to 45) and 43% of participants had detectable viral load. Participants with virologic suppression at baseline (n=76) maintained undetectable viral load through a median period of 26 weeks (range 2 to 42 weeks).
LA-CAB/RPV injections were given on time for 74% of participants.
Mean baseline viral load was 4.21 log copies/mL (SD ± 1.3) for 57 participants. Viral load decreased after a median of 33 days, with virologic suppression anticipated within 26 weeks. Early virologic failure (n=2) included drug resistance to INSTI and NNRTIs.
An interim analysis reported virologic failure in 1.5% of participants, comparable to the Phase 3 switch studies.
The protocol has since been updated to exclude people with baseline RAMs.
Other implementation studies
Other studies (OPERA, CARLOS and CARISEL) had low numbers of participants with baseline viraemia.
In OPERA 21/183 participants had baseline viremia with 91% (n=19) achieving virologic suppression. Both CARLOS and CARISEL reported virologic suppression for >87% participants at months 6 and 12, respectively. Across both studies there were four confirmed virologic failures.
Practical and clinical considerations for implementation of LA-CAB/RPV include a small number of participants who develop virological failure despite perfect adherence to the injection schedule. The risk factors for viral failure in these cases include having two or more of the following:
- Baseline resistance to RPV.
- Low trough levels of rilpivirine.
- HIV-1 subtype A6/A1.
- BMI ≥25 kg/m2.
People with high BMI are recommended to use longer 2-inch needles for the injections, based on pharmacokinetic data showing higher CAB Cmin and drug penetration to target tissues. A study at IAS 2022 last year reported on injecting LA-CAB/RPV into the thigh rather than buttocks, providing alternative injection sites and reducing the chance of injection fatigue. [2]
HPTN 077 trial data show that LA-CAB has a longer tail in women (median: 66.3 weeks, range: 17.7 to 182 weeks) than men (median: 42.7 weeks, range: 20.4 to 134 weeks), suggesting there may be more forgiveness for delayed doses in women.
An open-label single centre implementation study of LA-CAB/RPV conducted in Perth called JABS, included 48-week results in an e-poster. [3]
Baseline characteristics of the 60 participants included: women (15%), mean age 41 years (range: 18 to 63) and mean BMI 26.2kg/m2 (range: 18.8 to 39.9).
The majority of injections were administered within the target window period (97%) and there were no confirmed virologic failures. Week 48 data included 98% viral suppression with no adverse events relating to the drug formulation. Low-grade injection site reactions were common (30%), and participants reported high levels of treatment satisfaction.
The ILANA (implementing long-acting novel antiretrovirals) implementation study explored the feasibility and acceptability of LA-CAB/RPV in the UK. [4]
Participants received their first dose in clinic and opted to receive future doses in clinic or at a community-based settings (at home or at community-based HIV support NGO). Healthcare professionals (HCP) were interviewed on barriers and facilitators to LA-CAB/RPV implementation at sites in London (n=8), Brighton (n=3) and Liverpool (n=2).
HCP reported concerns relating to clinic attendance, potential for drug resistance and effective dosing. Meanwhile, people living with HIV were concerned that they may be forced to switch to injectables, potential for RAMs and side-effects. Other barriers included increased visit frequency, longer appointments and more complex prescribing and medication stock levels.
LA-CAB/RPV was preferred compared to oral ART because it increased treatment privacy and reduced pill fatigue. Ongoing communication between people living with HIV and HCPs built confidence and trust in treatment. HCP capacity is a major implementation challenge and additional funding is required to support service provision.
Updates from the phase 3b SOLAR study
A poster included data on Inflammatory markers in the phase 3b SOLAR study. [5]
Participants were randomised (2:1) to either LA-CAB/RPV (n=454, Q2M) or daily oral BIC/FTC/TAF (n=227, QD).
Baseline characteristics were matched between groups and participants were women (17%), white (69%), Black (21%) or Asian (5%) and median age was 37 years (range: 18 to 74). Median BMI was 26.0 kg/m2 (IQR: 23.2 to 29.6) and 22% of participants had BMI ≥30 kg/m2 at baseline.
This study measured inflammatory markers (IL-6, CRP, D-dimer, CD4/8 ratio, sCD14 and sCD143) at baseline and a year later, with no changes or differences between groups, likely reflecting high levels of virologic suppression.
Another poster presented participant reported outcomes in SOLAR. [5]
Overall, 402/447 participants who switched to LA-CAB/RPV reported a preference for injectable (Q2M) vs oral (QD) therapy. The primary reason for LA therapy preference was not needing to remember to take their ART (85%). Flexibility, convenience and overall treatment satisfaction increased from baseline. Injection tolerance increased across one year and participants reported improved wellbeing benefits, including removal of disclosure fear and adherence anxiety.
comment
Much of the Q&A discussion related to practical considerations for implementation of injectable ART. Some of these included the limited options to giving injections out of the clinic due to cold chain needed for rilpivirine-LA. This will not be the case if cabotegravir-LA is used with alternative long-acting drugs, such as bNAbs ir lenacapavir.
We also heard that cabotegravir had been used off-label with lenacapavir in some individuals but that this combination could only be formally studied outside the US.
Although the discussion included concerns in people broadly defined hard-to-reach, phone calls and messages to remind people about visits achieved very high levels of adherence. For many participants. this was the first time that they had experienced an undetectable viral load, and this also motivated them to return for subsequent visits.
There might also be a potential for therapeutic drug monitoring to reduce the chance of vrial rebound. There is high interpatient variability of RPV levels and CAB point of care tests are in development. The PK CAB tail is longer for women compared to men and early data (from PrEP studies) might support quarterly injections.
Using longer (2-inch) needles was reported to be effective in people with higher BMI, but so far this is limited to up to 40 kg/m2.
References
Unless stated otherwise, all references are to the Programme and Abstracts of the 12th IAS conference (IAS 2023), 23–26 July 2023, Brisbane, Australia.
- Gandhi M. Implementation in hard-to-reach populations. IAS 2023, 23–26 July 2023, Brisbane, Australia. Symposium presentation SY08.
https://programme.ias2023.org/Programme/Session/4424 - Taylor K. Early data on injecting CAB/RPV-LA into thigh muscle. HTB 3 August 2022.
https://i-base.info/htb/43560 - John M et al. Implementation of long-acting cabotegravir and rilpivirine in vulnerable populations with complex needs: primary 48-week results of JABS. IAS 2023, 23–26 July 2023, Brisbane, Australia. e-Poster abstract EPB0212
https://programme.ias2023.org/Abstract/Abstract/?abstractid=2593 - Hayes R et al. Barriers and facilitators to implementation of cabotegravir + rilpivirine long-acting injectable HIV treatment among healthcare providers: baseline qualitative interview findings from the ILANA study. IAS 2023, 23–26 July 2023, Brisbane, Australia. Poster Abstract MOPEE25.
https://programme.ias2023.org/Abstract/Abstract/?abstractid=1681 - Elliot E et al. Similar inflammatory markers after switching to cabotegravir + rilpivirine long-acting compared with bictegravir/emtricitabine/tenofovir alafenamide in the phase 3b SOLAR study. IAS 2023, 23–26 July 2023, Brisbane, Australia. Poster abstract TUPEB04.
https://programme.ias2023.org/Abstract/Abstract/?abstractid=4213 - Chounta V et al. Patient reported outcomes after 12 months maintenance therapy with cabotegravir + rilpivirine long-acting compared with bictegravir/emtricitabine/tenofovir alafenamide in the phase 3b SOLAR study. IAS 2023, 23–26 July 2023, Brisbane, Australia. Poster abstract TUPEB06.
https://programme.ias2023.org/Abstract/Abstract/?abstractid=4379