Initiation of long-acting cabotegravir plus rilpivirine as direct-to-injection or with an oral lead-in in adults with HIV-1 infection: week 124 results of the open-label phase 3 FLAIR study
Previous work established non-inferiority of switching participants who were virologically suppressed from daily oral standard of care to monthly long-acting intramuscular injections of cabotegravir plus rilpivirine over 96 weeks following a cabotegravir plus rilpivirine oral lead-in. Here, we report an evaluation of switching participants from standard of care oral regimens to long-acting cabotegravir plus rilpivirine via direct-to-injection or oral lead-in pathways.
Methods
This study reports the week 124 results of the FLAIR study, an ongoing phase 3, randomised, open-label, multicentre (11 countries) trial. Antiretroviral therapy (ART)-naive participants who were virologically suppressed (HIV-1 RNA <50 copies per mL) during the 20-week induction phase with standard of care were randomly assigned (1:1) to continue the standard of care oral regimen or switch to long-acting cabotegravir plus rilpivirine (283 per group) in the 100-week maintenance phase. Randomisation was stratified by sex at birth and baseline (pre-induction) HIV-1 RNA (<100 000 or ≥100 000 copies per mL). Participants randomly assigned to long-acting therapy at baseline received a cabotegravir (30 mg) plus rilpivirine (25 mg) once daily oral lead-in for at least 4 weeks before first injection and could choose to continue long-acting cabotegravir (400 mg) plus rilpivirine (600 mg) every 4 weeks from week 100 or withdraw. At week 100, participants in the oral comparator ART group, in discussion with the investigator, could elect to switch to long-acting therapy (extension switch population), either direct-to-injection or with a 4 week oral lead-in (oral lead-in group), or withdraw. Week 124 endpoints included plasma HIV-1 RNA 50 or more copies per mL and less than 50 copies per mL (US Food and Drug Administration [FDA] Snapshot), confirmed virological failure (two consecutive HIV-1 RNA ≥200 copies per mL), and safety and tolerability. The study is registered at ClinicalTrials.gov, NCT02938520.
Findings
Screening occurred between Oct 27, 2016, and March 24, 2017. At week 100, 232 (92%) of 253 participants transitioned to long-acting cabotegravir plus rilpivirine in the extension phase (111 [48%] in the direct-to-injection group and 121 [52%] in the oral lead-in group; extension switch population). 243 (86%) of the 283 who were randomly assigned to the long-acting therapy group continued the long-acting regimen into the extension phase. One (<1%) participant in each extension switch group had 50 or more HIV-1 RNA copies per mL; 110 (99%) participants in the direct-to-injection group and 113 (93%) participants in the oral lead-in group remained suppressed (HIV-1 RNA <50 copies per mL) at the week 124 Snapshot. The lower suppression rates in the oral lead-in group were driven by non-virological reasons. For participants in the randomly assigned long-acting group, 227 (80%) of 283 participants remained suppressed; at the week 124 Snapshot, 14 (5%) participants had HIV-1 RNA 50 or more copies per mL, including five additional participants since the week 96 analysis. The remaining 42 (15%) participants in the randomly assigned long-acting group had no virological data. Adverse events leading to withdrawal were infrequent, occurring in three (1%) participants in the extension switch population (one in the direct-to-injection group and two in the oral lead-in group) after 24 weeks of cabotegravir plus rilpivirine therapy, and 15 (5%) participants in the randomly assigned long-acting group up to 124 weeks of therapy. No deaths occurred in the extension phase. Overall, cabotegravir plus rilpivirine adverse event type, severity, and frequency were similar across all groups. Injection site reactions were the most common adverse event, occurring after 914 (21%) of 4442 injections in the extension switch population and 3732 (21%) of 17 392 injections in the randomly assigned long-acting group. Injection site reactions were mostly classified as mild-to-moderate in severity and decreased in incidence over time. Four (2%) of 232 participants in the extension switch population and seven (2%) of 283 in the randomly assigned long-acting group withdrew due to injection-related reasons.
Interpretation
After 24 weeks of follow-up, switching to long-acting treatment with or without an oral lead-in phase had similar safety, tolerability, and efficacy, supporting future evaluation of the simpler direct-to-injection approach. The week 124 results for participants randomly assigned originally to the long-acting therapy show long-acting cabotegravir plus rilpivirine remains a durable maintenance therapy with a favourable safety profile.
Funding
ViiV Healthcare and Janssen Research & Development.
Introduction
Contemporary antiretroviral therapy (ART) has revolutionised HIV treatment, with sustained virological suppression an achievable target for nearly all people with HIV with access to ART. Guideline-recommended regimens generally consist of one or two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a boosted protease inhibitor.1, 2
Current regimens require strict adherence to daily oral therapy for sustained virological suppression. Poor adherence, which results in insufficient drug concentrations, is associated with virological failure, emergent resistance, and worse outcomes.3, 4, 5 Because modern regimens are highly effective, the emphasis of HIV care has shifted from solely efficacy to quality of life improvements through treatment simplification, better tolerability, and patient satisfaction, which can positively influence adherence. These drivers have led to the development of two-drug oral regimens, with the aim of reducing cumulative drug exposure compared with standard three-drug therapy.6, 7
People with HIV have expressed increasing interest in long-acting ART to afford greater convenience with daily routines and travel,8, 9, 10, 11 which together with a reduced dosing frequency might support improved treatment adherence.12, 13 Furthermore, long-acting therapy might alleviate the psychological burden of daily oral therapy, including fear of inadvertent disclosure of HIV status and possible stigmatisation.14, 15 Additionally, some people with HIV have reported that daily ART restricts their daily life.16 This patient-first approach to HIV treatment aims to improve quality of life and health outcomes for people with HIV.17
Research in context
Evidence before this study
We searched PubMed for publications on antiretroviral therapy (ART), long-acting HIV therapies, and treatment adherence using the search terms “antiretroviral therapy”, “cabotegravir”, “rilpivirine”, “HIV injectable therapy”, “long-acting treatment”, and “HIV treatment adherence” from the inception of the database until April 12, 2021. Since 2012, there has been increasing interest in long-acting HIV therapies, with several studies evaluating their use in people with HIV. The need for long-acting ART focuses on improving adherence to regimens, with the acknowledgment that, despite the high efficacy of daily oral ART regimens, current treatment regimens have intrinsic challenges associated with the need for daily pill taking that might negatively affect long-term adherence. These challenges include pill burden, drug–drug or drug–food interactions that occur in the gastrointestinal tract, worries related to fear of stigma resulting from inadvertent disclosure, and the daily reminder of their HIV status. In addition, for some, daily oral pill taking is physically problematic (eg, due to swallowing problems or cognitive impairment). Long-acting injectable ARTs have the potential to address these challenges. The two-drug regimen of cabotegravir and rilpivirine is the only approved long-acting antiretroviral regimen indicated for the maintenance of HIV-1 suppression, administered monthly or every 2 months. Approval was made primarily on the basis of the phase 3 ATLAS (NCT02951052) and FLAIR (NCT02938520) studies and the phase 3b ATLAS-2M (NCT03299049) study. The phase 3 programme evaluating long-acting cabotegravir plus rilpivirine employed an oral lead-in with daily cabotegravir (30 mg) plus rilpivirine (25 mg) to assess individual tolerability before starting the long-acting intramuscular therapy.
Added value of this study
Because oral therapy can be burdensome for some people, and as a result of not observing significant safety concerns with cabotegravir plus rilpivirine that would be mitigated by oral lead-in, across clinical studies of more than 1000 participants, we investigated long-acting intramuscular cabotegravir plus rilpivirine as a direct-to-injection regimen, without an oral lead-in, for the first time during the extension phase (ie, as of week 100) of the FLAIR study. Such a strategy would remove the need for an initial introduction of oral cabotegravir plus rilpivirine followed by a switch to long-acting formulations of cabotegravir plus rilpivirine. The results showed that initiating long-acting cabotegravir plus rilpivirine direct-to-injection has a similar safety and pharmacokinetic profile to initiation following an oral lead-in, with no diminution of efficacy. These data, taken with the previous clinical results, support the use of long-acting cabotegravir plus rilpivirine every 4 weeks in virologically suppressed adults living with HIV-1, with this analysis supporting direct initiation of a long-acting cabotegravir plus rilpivirine regimen.
Implications of all the available evidence
Current oral ART requires continuous high levels of adherence and daily good decision making, which can be difficult to sustain long term. Initiation of cabotegravir plus rilpivirine direct-to-injection is a practical treatment simplification strategy that has similar initial tolerability, safety, efficacy, and pharmacokinetics to commencing the regimen with an oral lead-in. The longer-term data suggest that long-acting cabotegravir plus rilpivirine is a durable therapeutic alternative to daily oral therapy and might help overcome some of the challenges associated with life-long daily oral therapy.
The only currently approved long-acting ART regimen is an NRTI-sparing two-drug combination comprising the INSTI cabotegravir and the NNRTI rilpivirine.18, 19, 20 Long-acting cabotegravir plus rilpivirine is an intramuscular injectable regimen administered monthly or every 2 months indicated for the maintenance of virological suppression in adults with HIV-1 and is recommended in treatment guidelines.2, 21 In two large phase 3 studies, ATLAS (NCT02951052)18 and FLAIR (NCT02938520),19 long-acting cabotegravir plus rilpivirine dosed every 4 weeks had non-inferiority for the maintenance of virological suppression compared with continuing daily comparator ART over 48 weeks, both individually and in a pooled analysis.22 The safety profiles of long-acting cabotegravir plus rilpivirine and oral comparator ART, excluding injection site reactions, were similar. Injection site reactions were mostly mild, short-lived, and decreased in incidence over time. In the large phase 3b ATLAS-2M study (NCT03299049),20 long-acting cabotegravir plus rilpivirine dosed every 8 weeks had non-inferior efficacy compared with dosing of the same drugs every 4 weeks, with a similar safety profile.20 In all three studies, cabotegravir plus rilpivirine was taken once a day as an oral lead-in to assess individual tolerability for 4 weeks or more before initiating the long-acting regimen, and was also used to manage interruptions in scheduled long-acting dosing.18, 19, 20 No significant safety concerns with cabotegravir plus rilpivirine that would be mitigated by an oral lead-in were identified across the phase 2 and 3 programme,18, 19, 20, 23 providing the rationale to investigate long-acting cabotegravir plus rilpivirine administered directly without an oral lead-in (direct-to-injection), which would simplify the regimen.
We report efficacy and safety findings from the extension phase of the FLAIR study for participants who switched to long-acting therapy either with or without an oral lead-in, after having previously been randomly assigned to receive oral standard of care for 100 weeks. In addition, longer-term week 124 data for those randomly assigned originally to receive long-acting therapy are also presented.
Section snippets
Study design and participants
FLAIR is a phase 3, randomised, open-label, multicentre study evaluating the efficacy, safety, and tolerability of long-acting cabotegravir plus rilpivirine compared with continuing the daily oral combination of dolutegravir, abacavir, and lamivudine. For participants who were HLA-B*5701 positive, dolutegravir was taken with a non-abacavir NRTI backbone chosen by the investigator. The study was done in 108 centres in 11 countries (Canada [six centres], France [eight], Germany [11], Italy
Results
Between Oct 27, 2016, and March 24, 2017, 809 participants were screened for inclusion in FLAIR, 631 (78%) of whom entered the induction phase. 566 (90%) of the 629 participants who then initiated study drug (intention-to-treat population) entered the maintenance phase and were randomly assigned to the long-acting group (283 [50%] participants) or the standard of care group (283 [50%] participants). The analysis cut-off was Feb 21, 2020, at which time the COVID-19 pandemic had not significantly
Discussion
This is the first study to investigate direct initiation of long-acting cabotegravir plus rilpivirine injectable therapy without an oral lead-in in a subgroup of stably suppressed participants on oral comparator ART electing for this option. This phase 3 study also shows longer-term durability and safety over 124 weeks. Direct-to-injection long-acting cabotegravir plus rilpivirine administered every 4 weeks is an effective initiation strategy for the maintenance of virological suppression in
Data sharing
Data sharing requests will be considered by the management group upon written request to the corresponding author. Deidentified participant data or other prespecified data will be available subject to a written proposal and a signed data sharing agreement.
Declaration of interests
CO reports grants, personal fees, non-financial support, and travel sponsorship during the study from ViiV Healthcare; and grants, personal fees, non-financial support, speaker's bureau, and travel sponsorship from GlaxoSmithKline, Gilead Sciences, Merck Sharp & Dohme, Janssen, and ViiV Healthcare, outside the submitted work. EBM reports grants from ViiV Healthcare, during the study; and grants, personal fees, and non-financial support from Gilead Sciences, Janssen, ViiV Healthcare, and Merck
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Combined intramuscular long-acting cabotegravir and long-acting rilpivirine constitute the first long-acting combination antiretroviral therapy (ART) regimen approved for adults with HIV. The goal of the IMPAACT 2017 study (MOCHA [More Options for Children and Adolescents]) was to assess the safety and pharmacokinetics of these drugs in adolescents.
In this phase 1/2, multicentre, open-label, non-comparative, dose-finding study, virologically suppressed adolescents (aged 12–17 years; weight ≥35 kg; BMI ≤31·5 kg/m2) with HIV-1 on daily oral ART were enrolled at 15 centres in four countries (Botswana, South Africa, Thailand, and the USA). After 4–6 weeks of oral cabotegravir (cohort 1C) or rilpivirine (cohort 1R), participants received intramuscular long-acting cabotegravir or long-acting rilpivirine every 4 weeks or 8 weeks per the adult dosing regimens, while continuing pre-study ART. The primary outcomes were assessments of safety measures, including all adverse events, until week 4 for oral cabotegravir and until week 16 for long-acting cabotegravir and long-acting rilpivirine, and pharmacokinetic measures, including the area under the plasma concentration versus time curve during the dosing interval (AUC0–tau) and drug concentrations, at week 2 for oral dosing of cabotegravir and at week 16 for intramuscular dosing of cabotegravir and rilpivirine. Enrolment into cohort 1C or cohort 1R was based on the participant's pre-study ART, meaning that masking was not done. For pharmacokinetic analyses, blood samples were drawn at weeks 2–4 after oral dosing and weeks 4–16 after intramuscular dosing. Safety outcome measures were summarised using frequencies, percentages, and exact 95% CIs; pharmacokinetic parameters were summarised using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03497676, and is closed to enrolment.
Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled: 30 in cohort 1C and 25 in cohort 1R. At week 16, 28 (97%, 95% CI 82–100) of the 29 dose-evaluable participants in cohort 1C and 21 (91%; 72–99) of the 23 dose-evaluable participants in cohort 1R had reported at least one adverse event, with the most common being injection-site pain (nine [31%] in cohort 1C; nine [39%] in cohort 1R; none were severe). One (4%, 95% CI 0–22) participant in cohort 1R had an adverse event of grade 3 or higher, leading to treatment discontinuation, which was defined as acute rilpivirine-related allergic reaction (self-limiting generalised urticaria) after the first oral dose. No deaths or life-threatening events occurred. In cohort 1C, the week 2 median cabotegravir AUC0–tau was 148·5 (range 37·2–433·1) μg·h/mL. The week 16 median concentrations for the every-4-weeks and every-8-weeks dosing was 3·11 μg/mL (range 1·22–6·19) and 1·15 μg/mL (<0·025–5·29) for cabotegravir and 52·9 ng/mL (31·9–148·0) and 39·1 ng/mL (27·2–81·3) for rilpivirine, respectively. These concentrations were similar to those in adults.
Study data support using long-acting cabotegravir or long-acting rilpivirine, given every 4 weeks or 8 weeks, per the adult dosing regimens, in virologically suppressed adolescents aged 12 years and older and weighing at least 35 kg.
The National Institutes of Health and ViiV Healthcare.
The global HIV response has made tremendous progress but is entering a new phase with additional challenges. Scientific innovations have led to multiple safe, effective, and durable options for treatment and prevention, and long-acting formulations for 2-monthly and 6-monthly dosing are becoming available with even longer dosing intervals possible on the horizon. The scientific agenda for HIV cure and remission strategies is moving forward but faces uncertain thresholds for success and acceptability. Nonetheless, innovations in prevention and treatment have often failed to reach large segments of the global population (eg, key and marginalised populations), and these major disparities in access and uptake at multiple levels have caused progress to fall short of their potential to affect public health. Moving forward, sharper epidemiologic tools based on longitudinal, person-centred data are needed to more accurately characterise remaining gaps and guide continued progress against the HIV epidemic. We should also increase prioritisation of strategies that address socio-behavioural challenges and can lead to effective and equitable implementation of existing interventions with high levels of quality that better match individual needs. We review HIV epidemiologic trends; advances in HIV prevention, treatment, and care delivery; and discuss emerging challenges for ending the HIV epidemic over the next decade that are relevant for general practitioners and others involved in HIV care.
The efficacy and tolerability of long-acting cabotegravir and rilpivirine were demonstrated in Phase III trials. However, low concentrations combined with other risk factors have been associated with an increased risk of virologic failure. This study aims to verify whether drug concentrations measured in a real-world setting are consistent with those previously reported.
SHCS-879 is a nationwide observational study within the Swiss HIV Cohort Study for the monitoring of people with HIV (PWH) on long-acting cabotegravir plus rilpivirine. Samples were collected from March 2022 to March 2023.
Overall, 725 samples were obtained from 186 PWH. Our data show a large inter-individual variability in cabotegravir and rilpivirine concentrations, with some individuals exhibiting repeatedly low concentrations. Rilpivirine trough concentrations were consistent with those from Phase III trials, while cabotegravir concentrations were lower. The first concentrations quartile was only slightly above the target of 664 ng/mL. Exploratory statistical analyses found 35% (p < 0·01) lower cabotegravir trough in males compared to females. Overall, 172 PWH (92%) remained suppressed and three experienced virologic failures (1·6%), of those, two had sub-optimal drug exposure. No association was found between low trough levels and detectable viral load.
Real-world cabotegravir concentrations are substantially lower than previously reported. However, these concentrations appear sufficient to ensure sustained virological suppression in almost every PWH. These reassuring data challenge the rather conservative thresholds adopted to date, which may raise unnecessary concerns. Yet, our study reveals that some PWH have repeatedly very low drug levels, for reasons that remain to be elucidated.
This work was funded by the Swiss National Science Foundation, grant number N◦ 324730_192449. This study received no support from pharmaceutical industries. This study was performed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant #201369), by SHCS project #879, and by the SHCS research foundation. The SHCS data were gathered by the Five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians (listed in http://www.shcs.ch/180-health-care-providers).
The massive scale-up of HIV treatment and prevention over the past two decades has resulted in important reductions in new infections and mortality globally. Reduction in HIV incidence, however, has been unequal, with worsening epidemics in regions where the reach and scale of HIV control programmes have been insufficient, especially in eastern Europe, central Asia, the Middle East, north Africa, and Latin America where HIV epidemics are concentrated among key populations, including people who inject drugs, men who have sex with men, transgender people, and some minority racial and ethnic groups. The global state of the HIV pandemic highlights disparities in HIV control efforts and provides a roadmap for what should be done, including investment to better implement the effective HIV prevention and treatment tools that are available, but whose adoption and scale-up are not yet sufficient to get us close to an AIDS-free generation. To achieve the full potential of global HIV control, we call for urgent, evidence-informed implementation at scale of our existing and novel HIV prevention and treatment strategies in ways that are better, faster, more efficient, and cost-effective, especially in key populations and regions where the HIV pandemic continues to expand.
Cabotegravir plus rilpivirine is the only approved complete long-acting regimen for the maintenance of HIV-1 virological suppression dosed every 2 months. The SOLAR study aimed to compare long-acting cabotegravir plus rilpivirine every 2 months with continued once-daily bictegravir, emtricitabine, and tenofovir alafenamide for the maintenance of HIV-1 virological suppression in adults living with HIV.
SOLAR is a randomised, open-label, multicentre, phase 3b, non-inferiority study. The study was done in 118 centres across 14 countries. Participants with HIV-1 RNA less than 50 copies per mL were randomly assigned (2:1), stratified by sex at birth and BMI, to either long-acting cabotegravir (600 mg) plus rilpivirine (900 mg) dosed intramuscularly every 2 months or to continue daily oral bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg). Participants randomly assigned to long-acting therapy had a choice to receive cabotegravir (30 mg) plus rilpivirine (25 mg) once daily as an optional oral lead-in for approximately 1 month. The primary efficacy endpoint was the proportion of participants with virological non-response (HIV-1 RNA ≥50 copies per mL; the US Food and Drug Administration snapshot algorithm, 4% non-inferiority margin; modified intention-to-treat exposed population) at month 11 (long-acting start with injections group) and month 12 (long-acting with oral lead-in group and bictegravir, emtricitabine, and tenofovir alafenamide group). The study is registered with ClinicalTrials.gov, NCT04542070, and is ongoing.
837 participants were screened between Nov 9, 2020, and May 31, 2021, and 687 were randomly assigned to switch treatment or continue existing treatment. Of 670 participants (modified intention-to-treat exposed population), 447 (67%) switched to long-acting therapy (274 [61%] of 447 start with injections; 173 [39%] of 447 with oral lead-in) and 223 (33%) continued bictegravir, emtricitabine, and tenofovir alafenamide. Baseline characteristics were similar; median age was 37 years (range 18–74), 118 (18%) of 670 were female sex at birth, 207 (31%) of 670 were non-White, and median BMI was 25·9 kg/m2 (IQR 23·3–29·5). At month 11–12, long-acting cabotegravir plus rilpivirine showed non-inferior efficacy versus bictegravir, emtricitabine, and tenofovir alafenamide (HIV-1 RNA ≥50 copies per mL, five [1%] of 447 vs one [<1%] of 223), with an adjusted treatment difference of 0·7 (95% CI –0·7 to 2·0). Excluding injection site reactions, adverse events and serious adverse events were similar between groups. No treatment-related deaths occurred. More long-acting group participants had adverse events leading to withdrawal (25 [6%] of 454 vs two [1%] of 227). Injection site reactions were reported by 316 (70%) of 454 long-acting participants; most (98%) were grade 1 or 2.
These data support the use of long-acting cabotegravir plus rilpivirine dosed every 2 months as a complete antiretroviral regimen that has similar efficacy to a commonly used integrase strand transfer inhibitor-based first-line regimen, while addressing unmet psychosocial issues associated with daily oral treatment.
