Background: Evaluating long-term efficacy, safety and pharmacokinetics of long-acting cabotegravir + rilpivirine (CAB+RPV LA) in sub-Saharan African populations is important because of the region’s unique demographics and antiretroviral therapy resistance patterns. Objectives: To describe the 96-week efficacy, safety and pharmacokinetics of CAB+RPV LA in South African participants from the pooled FLAIR and ATLAS-2M Phase 3/3b randomised studies. Method: Primary endpoint: proportion of participants with plasma HIV-1 RNA levels ≥ 50 copies/mL at Week 96. Secondary endpoints: proportion of participants with plasma HIV-1 RNA levels 50 copies/mL, confirmed virological failure (CVF; two consecutive plasma HIV-1 RNA ≥ 200 copies/mL), adverse events and pharmacokinetics. Results: Sixty-six participants were included, (CAB+RPV LA, n = 49; current oral antiretroviral regimen [CAR], n = 17). Forty-five (92%) on CAB+RPV LA and 15 (88%) on CAR maintained HIV-1 RNA levels 50 copies/mL. At Week 96, two participants, one in each arm, had CVF. Ninety per cent on CAB+RPV LA and 76% on CAR of participants experienced an adverse event; six (12%) of which were drug-related (CAB+RPV LA: n = 6). Injection-site reactions were common (78% [Grade 1: 80%; Grade 2: 20%]). CAB and RPV trough plasma concentrations remained above respective in vitro protein-adjusted 90% inhibitory concentrations following all doses. Conclusion: This subgroup analysis of South African participants demonstrated durable efficacy, acceptable safety profile and pharmacokinetics of injectable CAB+RPV LA up to 96 weeks, consistent with long-term data from other regions and studies.

Background: Cabotegravir + rilpivirine long-acting (LA) is a novel antiretroviral therapy (ART) administered intramuscularly monthly or every 2 months by a health care provider. The COVID-19 pandemic presents a potential challenge to patients' ability to attend scheduled clinic visits for dosing administration. Setting: This analysis evaluated implementation fidelity across 6 phase IIb/III/IIIb cabotegravir + rilpivirine LA clinical trials in 16 countries during the COVID-19 pandemic. Methods: COVID-19-impacted visits were defined as modified dosing visits for which oral therapy was provided to participants unable to attend the clinic or injection visits that were rescheduled. Data from December 1, 2019, to March 1, 2021, were aggregated and analyzed using descriptive statistics. Results: Of 2127 participants in cabotegravir + rilpivirine LA trials, 1997 (94%) had LA dosing visits proceed as planned during the COVID-19 pandemic. Of 130 (6%) participants with injection visits affected by COVID-19, most were from North America (57%) and Europe (26%). Most participants with COVID-19-impacted visits used oral therapy with cabotegravir + rilpivirine (75%) or alternative oral standard-of-care ART (21%) to maintain continuous ART. The most common reasons for missed visits were clinic closure/staffing constraints (48%) and COVID-19-related travel restrictions (23%). Most (98%) participants who used oral ART maintained virologic suppression; 2 participants had viral load between 50 and 100 copies/mL. Conclusion: During the COVID-19 pandemic, most trial participants maintained their LA dosing schedules. Flexibility of the LA dosing regimen, with the ability to switch to oral therapy, facilitated continuous ART provision and implementation fidelity.

The FLAIR study demonstrated noninferiority of monthly long-acting cabotegravir + rilpivirine versus daily oral dolutegravir/abacavir/lamivudine for maintaining virologic suppression. Three participants who received long-acting therapy had confirmed virologic failure (CVF) at Week 48, and all had HIV-1 that was originally classified as subtype A1 and contained the baseline integrase polymorphism L74I; updated classification algorithms reclassified all 3 as HIV-1 subtype A6. Retrospectively, the impact of L74I on in vitro sensitivity and durability of response to cabotegravir in HIV-1 subtype B and A6 backgrounds was studied. Site-directed L74I and mutations observed in participants with CVF were generated in HIV-1 subtype B and a consensus integrase derived from 3 subtype A6 CVF baseline sequences. Rilpivirine susceptibility was assessed in HIV-1 subtype B and A1 containing reverse transcriptase mutations observed in participants with CVF. HIV-1 subtype B L74I and L74I/G140R mutants and HIV-1 subtype A6 I74L and I74/G140R mutants remained susceptible to cabotegravir; L74I/Q148R double mutants exhibited reduced susceptibility in HIV-1 subtypes B and A6 (half maximal effective capacity fold change, 4.4 and 4.1, respectively). Reduced rilpivirine susceptibility was observed across HIV-1 subtypes B and A1 with resistance-associated mutations K101E or E138K (half maximal effective capacity fold change, 2.21 to 3.09). In cabotegravir breakthrough experiments, time to breakthrough was similar between L74 and I74 viruses across HIV-1 subtypes B and A6; Q148R was selected at low cabotegravir concentrations. Therefore, the L74I integrase polymorphism did not differentially impact in vitro sensitivity to cabotegravir across HIV-1 subtype B and A6 integrase genes (ClinicalTrials.gov identifier: NCT02938520).

BACKGROUND: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.

Background There is a need for more convenient, less frequent treatment to help address challenges associated with daily oral HIV treatment in people living with HIV, including stigma, pill burden, drug-food interactions, and adherence. The phase 3 ATLAS and FLAIR studies showed non-inferiority of long-acting cabotegravir and rilpivirine dosed every 4 weeks compared with standard oral therapy for the maintenance of virological suppression in adults with HIV-1 over 48 weeks. We present the 96-week findings. Methods FLAIR is a randoinised, phase 3, open-label, multicentre study done in 11 countries investigating whether switching to long-acting cabotegravir and rilpivirine is non-inferior to daily dolutegravir, abacavir, and lamivudine in virologically suppressed adults living with HIV-1. Antiretroviral therapy (ART)-naive participants received induction therapy with daily oral dolutegravir (50 mg), abacavir (600 mg), and lamivudine (300 mg) for 20 weeks. After 16 weeks, participants with less than 50 HIV-1 RNA copies per mL were randomly assigned (1:1) to continue the standard of care regimen (standard care group) or switch to receive daily oral cabotegravir 30 mg and rilpivirine 25 mg for at least 4 weeks followed by long-acting cabotegravir 400 mg and rilpivirine 600 mg, administered as two 2 inL intramuscular injections, every 4 weeks for at least 96 weeks (long-acting group). Randomisation was stratified by baseline (preinduction) HIV-1 RNA (<100000 or >= 100000 copies per mL) and sex at birth and used GlaxoSmithKline-verified randomisation software (RandAll NG, version 1.3.3) for treatment assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per tnL or more assessed as per the US Food and Drug Adininistration (FDA) Snapshot algorithm at week 48, which has been reported previously. Here, we report the proportion of participants with 50 or more HIV-1 RNA copies per mL using the FDA Snapshot algorithm at week 96 (intention-to-treat population; non-inferiority margin 6%). The trial is registered with ClinicalTrials.gov, NCT02938520. Findings Between Oct 27, 2016, and March 24, 2017, 809 participants were screened. 631 (78%) participants entered the induction phase and 566 (70%) were randomly assigned to either the standard care group (283 [50%] participants) or the long-acting group (283 [50%]). Median age was 34 years (IQR 29 to 43), 62 (11%) were 50 years or older, 127 (22%) were women (sex at birth), and 419 (74%) were white. At week 96, nine (3%) participants in each arm had 50 or more HIV-1 RNA copies per mL, with an adjusted difference of 0.0 (9S% CI -2.9 to 2.9), consistent with non-inferiority established at week 48. Across both treatment groups, adverse events leading to withdrawal were infrequent (14[5%] participants in the long-acting group and four [1%] in the standard care group). Injection site reactions were the most common adverse event, reported by 245 (88%) participants in the long-acting group; their frequency decreased over time. Median injection site reaction duration was 3 days (IQR 2 to 4), and 3082 (99%) of 3100 reactions were grade 1 or 2. No deaths occurred during the maintenance phase. Interpretation The 96-week results reaffirm the 48-week results, showing long-acting cabotegravir and rilpivirine continued to be non-inferior compared with continuing a standard care regimen in adults with HIV-1 for the maintenance of viral suppression. These results support the durability of long-acting cabotegravir and rilpivirine, over an almost 2-year-long period, as a therapeutic option for virally suppressed adults with HIV-1. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

Long-acting injectable antiretroviral therapy (LA ART) may be an alternative for people living with HIV (PLHIV) with adherence challenges or who prefer not to take pills. Using in-depth interviews, this study sought to understand the experiences of PLHIV (n = 53) participating in Phase 3 LA ART trials in the United States and Spain. The most salient consideration when contemplating LA ART was its clinical efficacy; many participants reported wanting to ensure that it worked as well as daily oral ART, including with less frequent dosing (every 8 versus 4 weeks). While injection side effects were often reported, most participants felt that regimen benefits outweighed such drawbacks. Participants described the main benefit of LA ART as the “freedom” it afforded both logistically and psychosocially, including through reduced HIV stigma. Findings highlight the importance of patient-provider communication related to weighing potential benefits and side effects and the continued need to address HIV stigma.

Abstract Background Phase III/IIIb studies demonstrated cabotegravir (CAB) + rilpivirine (RPV) long-acting (LA) dosed every 4 weeks (Q4W) was noninferior to current antiviral regimen (CAR) (FLAIR and ATLAS) and CAB + RPV LA dosed every 8 weeks (Q8W) was noninferior to Q4W (ATLAS-2M) through Week 48 (W48). HIV-1 ribonucleic acid (RNA) blips (viral load [VL] ≥50 to < 200 c/mL) are common during antiretroviral therapy (ART) and generally not associated with subsequent virologic failure (2 consecutive HIV-1 RNA ≥200 c/mL). We compared the frequency of HIV-1 RNA blips and low-level qualitative and quantitative HIV-1 RNA replication among participants treated with CAB+RPV LA and oral CAR and assessed impact on virologic outcome. Methods Plasma samples collected at study visits were analyzed for HIV-1 RNA viral load using the Abbott RealTime HIV-1 assay and qualitative target detected (TD) or target not detected (TND) outcomes were provided for HIV-1 RNA < 40 c/mL. The HIV-1 SuperLow assay (bioMONTR Labs) was used to measure HIV-1 RNA < 2 c/mL at Baseline and W48. Results The proportion of participants with HIV-1 RNA blips was similar overall between Q4W CAB + RPV LA and CAR arms in FLAIR (38/283 [13%] vs 39/283 [14%]) and ATLAS (17/308 [6%] vs 23/308 [7%]). Presence of HIV-1 RNA blips in either arm was not associated with virologic non-response at W48 (HIV-1 RNA ≥50 c/mL per US Food and Drug Administration Snapshot). In ATLAS-2M, HIV-1 RNA blips were observed in 32/523 (6%; Q4W) and 18/522 (3%; Q8W) of participants, with W48 virologic nonresponse in 2 Q4W and 0 Q8W participants. TD outcomes at individual study visits were comparable between study arms for the 3 studies. At W48, the proportion of participants with HIV-1 RNA < 2 c/mL was similar to Baseline and similar between treatment groups in all studies. Conclusion The proportions of study participants with HIV-1 RNA blips, TD viral load results, and HIV-1 < 2 c/mL were similar between the Q4W and Q8W CAB+RPV LA and the oral 3-drug CAR arms through W48 in phase III/IIIb studies. HIV-1 RNA blips did not predict virologic nonresponse (Snapshot analysis) at W48. Disclosures Christine L. Talarico, M.S, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Sterling Wu, PhD, GlaxoSmithKline (Employee, Shareholder) Marty St. Clair, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Veerle Van Eygen, MSc, Janssen Pharmaceutica NV (Employee) Krischan J. Hudson, PhD, MPH, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Sandy Griffith, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Conn M. Harrington, BA, ViiV Healthcare (Employee) Jan van Lunzen, MD, PhD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) David Margolis, MD, MPH, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) William Spreen, PharmD, ViiV Healthcare (Employee, Shareholder)

BACKGROUND Long-acting injectable regimens may simplify therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection. METHODS We conducted a phase 3, randomized, open-label trial in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir-abacavir-lamivudine. Participants who had an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were randomly assigned (1:1) to continue the current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly injections of long-acting cabotegravir plus rilpivirine. The primary end point was the percentage of participants who had an HIV-1 RNA level of 50 copies per milliliter or higher at week 48 (Food and Drug Administration snapshot algorithm). RESULTS At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 participants (2.1%) who received long-acting therapy and in 7 of 283 (2.5%) who received oral therapy (adjusted difference, -0.4 percentage points; 95% confidence interval [CI], -2.8 to 2.1), a result that met the criterion for noninferiority for the primary end point (margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% who received long-acting therapy and in 93.3% who received oral therapy (adjusted difference, 0.4 percentage points; 95% CI, -3.7 to 4.5), a result that met the criterion for noninferiority for this end point (margin, -10 percentage points). Of the participants who received long-acting therapy, 86% reported injection-site reactions (median duration, 3 days; mild or moderate severity, 99% of cases); 4 participants withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, who received long-acting therapy and in 4% and 1% who received oral therapy. Treatment satisfaction increased after participants switched to long-acting therapy; 91% preferred long-acting therapy at week 48. CONCLUSIONS Therapy with long-acting cabotegravir plus rilpivirine was noninferior to oral therapy with dolutegravir-abacavir-lamivudine with regard to maintaining HIV-1 suppression. Injection-site reactions were common. (Funded by ViiV Healthcare and Janssen; FLAIR ClinicalTrials.gov number, NCT02938520.).

SARS-CoV-2 (COVID-19) has disrupted healthcare service delivery globally. CAB+RPV LA is a novel, long-acting antiretroviral therapy (ART) currently in development and is administered intramuscularly monthly or every 2 months by a healthcare provider. COVID-19 and the resultant restrictions on access to some clinical trial sites presents challenges to the continuous delivery (‘implementation fidelity’) of CAB+RPV LA during a pandemic. Descriptive analyses were conducted using aggregated data from ongoing CAB+RPV LA clinical trials (LATTE-2, ATLAS, ATLAS-2M, FLAIR, POLAR, and CUSTOMIZE) to evaluate impact of COVID-19 on LA dosing. Data through 15 July 2020 were aggregated, categorized, and summarized to show trends. Data collection is continuously ongoing. As of 15 July 2020, 1831 participants are currently on CAB+RPV LA across these clinical studies. As of 15 July, 113 (6%) participants had injection visits that were impacted by COVID-19. LA dosing was interrupted in 51 (45%) participants due to clinic closure or staffing constraints, 9 (8%) for self-quarantine, 11 (10%) for confirmed or suspected COVID-19, and 42 (37%) for other reasons. Among participants impacted, 64 (58%) were from N. America, 29 (26%) Europe, 14 (13%) S. Africa, and 3 (3%) Latin America. Majority of participants were male (87, 79%), white (74, 65%), with median age 35 years. Mitigation strategies included short-term oral therapy with CAB+RPV (78, 69%), short-term standard of care ART (28, 25%), and rescheduling of LA injections (6, 5%). Although some are still receiving oral therapy, current median duration of oral therapy has been 45 days. To date, 65 (58%) have restarted LA and viral load data collection is ongoing. No suspected or confirmed virologic failure was observed for any participant impacted by COVID-19 to date. In the midst of the global pandemic, no treatment interruptions were seen across the ongoing CAB+RPV LA clinical studies. Missed visits were manageable and successfully mitigated, primarily by temporary transition to oral therapy with no resultant virologic failure or emerging resistance through 15 July 2020. CAB+RPV LA is a new HIV-1 treatment modality that has demonstrated implementation fidelity across clinical studies during the current COVID-19 pandemic. Ronald D'Amico, DO, MSc, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Paul Benn, MB ChB FRCP, ViiV Healthcare (Employee, Shareholder) Cynthia C. McCoig, MD, ViiV Healthcare (Employee) Cynthia C. McCoig, MD, ViiV Healthcare (Individual(s) Involved: Self): Employee Sandy Griffith, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Krischan J. Hudson, PhD, MPH, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Kenneth Sutton, MA, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Kenneth Sutton, MA, GlaxoSmithKline (Individual(s) Involved: Self): Shareholder; ViiV Healthcare (Individual(s) Involved: Self): Employee Conn M. Harrington, BA, ViiV Healthcare (Employee) Sterling Wu, PhD, GlaxoSmithKline (Employee, Shareholder) Kai S. Hove, MRes, GSK (Independent Contractor) E Jane Fricker, BSc. (Hons) Applied Biochemistry, GSK (Employee, Shareholder) Parul Patel, PharmD, ViiV Healthcare (Employee) David Margolis, MD, MPH, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) David Margolis, MD, MPH, GlaxoSmithKline (Individual(s) Involved: Self): Shareholder; ViiV Healthcare (Individual(s) Involved: Self): Employee

The phase 3 ATLAS and FLAIR studies demonstrated that maintenance with Long-Acting (LA) intramuscular cabotegravir and rilpivirine is non-inferior in efficacy to current antiretroviral (CAR) oral therapy. Both studies utilized Patient-Reported Outcome instruments to measure treatment satisfaction (HIVTSQ) and acceptance (ACCEPT general domain), health status (SF-12), injection tolerability/acceptance (PIN), and treatment preference. In pooled analyses, LA-treated patients (n = 591) demonstrated greater mean improvements from baseline than the CAR group (n = 591) in treatment satisfaction (Week 44, + 3.9 vs. +0.5 HIVTSQs-points; p < 0.001) and acceptance (Week 48, +8.8 vs. +2.0 ACCEPT-points; p < 0.001). The acceptability of injection site reactions (PIN) significantly improved from week 5 (2.10 points) to week 48 (1.62 points; p < 0.001). In both studies, ≥ 97% of LA group participants with recorded data preferred LA treatment compared with prior oral therapy. These results further support the potential of a monthly injectable option for people living with HIV seeking an alternative to daily oral treatment.

Background: Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1. Setting: ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, multicenter, multinational phase 3 studies. Methods: Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithm: noninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints. Results: The pooled intention-to-treat exposed population included 591 participants in each arm [28% women (sex at birth), 19% aged ≥50 years]. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm. Conclusion: This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression.

Abstract Background In the phase 3 FLAIR study, switching to monthly injectable long-acting (LA) cabotegravir (CAB) + rilpivirine (RPV) was noninferior to continued daily oral dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) for the maintenance of virologic suppression over 96 weeks in adults with HIV-1. Key patient-reported outcomes (PROs) through Week 96 are presented. Methods In FLAIR, ART-naive adult participants received induction therapy with oral DTG/ABC/3TC for 20 weeks. Those with HIV-1 RNA < 50 c/mL at 16 weeks were randomized (1:1) to continue DTG/ABC/3TC or receive monthly CAB + RPV LA injections after a 4-week lead-in with daily oral CAB + RPV through Week 96. Treatment satisfaction (HIV Treatment Satisfaction Questionnaire status version [HIVTSQs]) and acceptability of injections (Perception of Injection [PIN] Questionnaire) up to Week 96 were secondary endpoints. Results A total of 566 participants were randomized (median age, 34 years; 22% female); baseline characteristics were similar between treatment groups. At Week 96, significantly greater improvement from baseline in total treatment satisfaction score was observed in the CAB + RPV LA vs DTG/ABC/3TC treatment group (adjusted mean difference, 2.3 [95% CI, 1.1-3.5]; P< 0.001), further increasing from Weeks 24 (2.1 [0.9-3.3]) and 44 (0.7 [−0.4, 1.9]). Key drivers for the difference in HIVTSQs between treatment groups were items assessing convenience, flexibility, and satisfaction to continue with LA therapy. In participants receiving CAB + RPV LA, mean score for the “Acceptability of ISRs” dimension of PIN (scale, 1-5) significantly decreased (improved) from Week 5 to Weeks 41, 48, and 96 (2.08 to 1.71, 1.66, and 1.71, respectively; P< 0.001 for all). In addition, 82% and 85% of LA participants, respectively, rated pain and local reactions due to injections as “totally” or “very acceptable” at Week 96. Conclusion At Week 96, FLAIR participants receiving LA therapy reported greater improvement in treatment satisfaction compared with participants continuing on daily oral medication as well as overall good acceptability of injections with improvement over time. Overall, these results support monthly CAB + RPV LA as an alternative to daily oral regimens for adults with HIV-1. Disclosures Vasiliki Chounta, MSc, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Sharon Walmsley, FRCPC, MD, MSC, GSK (Grant/Research Support)ViiV Healthcare (Grant/Research Support) David Dorey, MMATH, GlaxoSmithKline Inc. (Employee, Shareholder) William Spreen, PharmD, ViiV Healthcare (Employee, Shareholder) Sandy Griffith, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) David Margolis, MD, MPH, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

Abstract Background Cabotegravir (CAB) and rilpivirine (RPV) are under development as a novel long-acting (LA) regimen for maintenance of HIV virologic suppression. Pooled data from pivotal phase III trials demonstrated noninferiority of CAB + RPV LA given as gluteal intramuscular injections vs current antiretroviral regimen (CAR) on the primary endpoint of HIV-1 ribonucleic acid (RNA) ≥50c/mL at Week 48, with high levels of adherence. Long-term adherence to dosing visits and outcomes after use of oral CAB+RPV to cover planned missed injections in FLAIR through Week 96 and in LATTE-2 through Week 256 is reported here. Methods Virologically suppressed participants (HIV-1 RNA < 50c/mL) were randomized to switch to CAB+RPV LA or to continue CAR. On-time injections occurred every 4 weeks or every 8 weeks (LATTE-2 only) within a ±7-day dosing window of the projected dosing date. Adherence to LA therapy was calculated as the number of on-time injection visits divided by the number of expected dosing visits through the period of follow up. Injection visits outside the prespecified window and missed injection visits with or without use of oral dosing were characterized. Results Of 6005 expected injection visits through Week 96 in FLAIR, 97% of injections were given within the allowed ±7-day dosing window, with 43% on the projected dosing date. 45 (< 1%) injection visits were early and 107 (2%) were late. Adherence to 9803 expected injection visits in LATTE-2, through Week 256, was similarly high, with 96% of injections given within the allowed ±7-day dosing window and 39% on the projected dosing date. For 31 missed injection visits in 18 participants across both trials, 30 were covered with oral CAB+RPV, with all participants maintaining HIV-1 RNA < 50c/mL through the last study visit. In those participants who used oral CAB + RPV for planned treatment interruptions, 3 had repeat use on ≥2 separate occasions. Conclusion Participants maintained high levels of long-term adherence to CAB+RPV LA, through 2-5 years of follow up, with 97% of injections given within the ±7-day dosing window in the FLAIR and LATTE-2 clinical trials. Oral CAB+RPV to cover planned missed visits provides an effective strategy to maintain virologic suppression during short periods of LA treatment interruption. Disclosures Paula Teichner, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Sterling Wu, PhD, GlaxoSmithKline (Employee, Shareholder) David Dorey, MMATH, GlaxoSmithKline Inc. (Employee, Shareholder) Ronald D’Amico, DO, MSc, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Sandy Griffith, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Kenneth Sutton, MA, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Cynthia C. McCoig, MD, ViiV Healthcare (Employee) Joseph Polli, PhD, FAAPS, ViiV Healthcare (Employee) David Margolis, MD, MPH, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Rodica Van Solingen-Ristea, MD, Janssen R&D (Employee) Kati Vandermeulen, M.SC., Janssen Pharmaceutica (Employee, Shareholder) William Spreen, PharmD, ViiV Healthcare (Employee, Shareholder) Parul Patel, PharmD, ViiV Healthcare (Employee)