key: cord-0025034-100w2xey
authors: Mills, Anthony; Richmond, Gary J.; Newman, Cheryl; Osiyemi, Olayemi; Cade, Jerry; Brinson, Cynthia; De Vente, Jerome; Margolis, David A.; Sutton, Kenneth C.; Wilches, Viviana; Hatch, Sarah; Roberts, Jeremy; McCoig, Cynthia; Garris, Cindy; Vandermeulen, Kati; Spreen, William R.
title: Long-acting cabotegravir and rilpivirine for HIV-1 suppression: switch to 2-monthly dosing after 5 years of daily oral therapy
date: 2022-02-01
journal: AIDS
DOI: 10.1097/qad.0000000000003085
sha: ba2e89542d9169c896b29bab212cfa50b9c883cb
doc_id: 25034
cord_uid: 100w2xey

Long-acting formulations of cabotegravir (CAB) and rilpivirine (RPV) have demonstrated efficacy in Phase 3 studies. POLAR (NCT03639311) assessed antiviral activity and safety of CAB+RPV long-acting administered every 2 months (Q2M) in adults living with HIV-1 who previously received daily oral CAB+RPV in LATTE (NCT01641809). DESIGN: A Phase 2b, multicenter, open-label, rollover study. METHODS: LATTE participants with plasma HIV-1 RNA less than 50 copies/ml who completed at least 300 weeks on study were eligible. Participants elected to switch to either CAB+RPV long-acting Q2M or daily oral dolutegravir/RPV for maintenance of virologic suppression. The primary endpoint was the proportion of participants with HIV-1 RNA greater than or equal to 50 copies/ml at Month 12 (M12) per the Food and Drug Administration Snapshot algorithm. The incidence of confirmed virologic failure (CVF, two consecutive HIV-1 RNA measurements greater than or equal to 200 copies/ml), as well as safety, laboratory, and patient-reported outcomes (HIV Treatment Satisfaction and preference questionnaires) were also assessed. RESULTS: Of 97 participants enrolled, 90 chose to receive CAB+RPV long-acting and seven chose dolutegravir/RPV. At M12, no participant had HIV-1 RNA greater than or equal to 50 copies/ml or met the CVF criterion in either treatment group. No new safety signals were identified. Total treatment satisfaction was high at Baseline and remained stable through M12 across both treatment groups. Overall, 88% (n = 77/88) of long-acting arm participants preferred CAB+RPV long-acting to oral CAB+RPV. CONCLUSION: CAB+RPV long-acting maintained virologic suppression in participants who had previously received daily oral CAB+RPV for at least 5 years in LATTE, with a favorable safety profile. Most participants preferred CAB+RPV long-acting to their prior oral CAB+RPV regimen at M12.

Advances in the development of new antiretroviral therapies (ARTs) have substantially improved treatments for people with HIV (PWH) [1] . However, several patient-related challenges have been linked to the current treatment paradigm of lifelong adherence to daily oral pill taking. These include the maintenance of such adherence, taking personal day-to-day responsibility for care, stigmatization concerns, and the daily reminder of HIV status, as well as intrinsic medical issues, such as difficulty swallowing and drug-food and drug-drug interactions [2] [3] [4] [5] [6] . These challenges can impact the likelihood of treatment failure, as even small digressions in adherence to daily oral ART are believed to increase the risk of treatment-emergent resistance, contributing to virologic rebound [7] [8] [9] [10] [11] [12] . Treatment adherence is critical to achieve the Joint United Nations Programme on HIV/ AIDS (UNAIDS) 95-95-95 2030 target, an ambitious goal set to ensure that 95% of all individuals receiving ART will achieve and sustain viral suppression [13] . Consequently, there is a need to develop new ARTs that offer more convenient dosing while retaining high rates of virologic suppression, an acceptable safety profile, and a high barrier to resistance. Injectable long-acting ARTs have the potential to mitigate some of the challenges associated with daily oral regimens, offering reduced dosing frequencies and bypassing the gastrointestinal tract to avoid many common drug-food and drug-drug interactions. In addition, long-acting regimens have the potential to improve adherence by minimizing the impacts of forgetfulness and high pill burdens [4] .

Cabotegravir (CAB), an integrase strand transfer inhibitor, and rilpivirine (RPV), a nonnucleoside reverse transcriptase inhibitor, are two agents for which an approved complete monthly (Australia, USA, Canada, and EU) and every 2 month (Q2M; Australia, Canada, and EU) long-acting injectable dosing regimen has been developed [14] [15] [16] . CABþRPV long-acting is indicated for the treatment of HIV-1 infection in virologically suppressed adults (HIV-1 RNA < 50 copies/ml) [14] [15] [16] . Regulatory approval was based on several large clinical studies, including two pivotal randomized Phase 3 studies, ATLAS (NCT02951052) and FLAIR (NCT02938520), which demonstrated the noninferiority of intramuscular (i.m.) injections of CABþRPV long-acting dosed every 4 weeks as a maintenance therapy compared with daily oral comparator regimens [17, 18] . A reduced dosing frequency for CABþRPV long-acting of every 8 weeks was shown to be noninferior to every 4 week dosing in the Phase 3b ATLAS-2 M study (NCT03299049) [19] . The Phase 2b LATTE study (NCT01641809) preceded the ATLAS, FLAIR, and ATLAS-2 M long-acting clinical evaluations, investigating daily oral formulations of CABþRPV compared with three-drug efavirenzbased ART for the maintenance of viral suppression [20] . LATTE demonstrated the antiviral activity of the twodrug oral maintenance therapy CABþRPV was comparable to efavirenz plus dual nucleoside reverse transcriptase inhibitors at Week 96. POLAR (NCT03639311) is a Phase 2b rollover study assessing the antiviral activity and safety of CABþRPV long-acting Q2M in ARTexperienced participants who received once-daily oral CABþRPV treatment for at least 5 years in the Phase 2b LATTE study. The Month 12 results from POLAR are presented here.

Study design and participants POLAR is a Phase 2b, open-label, multicenter (Canada and the USA), nonrandomized rollover study assessing the efficacy and safety of i.m. CABþRPV long-acting Q2M in ART-experienced adults living with HIV-1 who received once-daily oral CABþRPV treatment in the Phase 2b LATTE study (Fig. 1a) . The full study protocol is available at ClinicalTrials.gov: NCT03639311. In brief, eligible participants were at least 18 years of age, virologically suppressed, and had completed at least 300 weeks of the LATTE study with plasma HIV-1 RNA less than 50 copies/ml at Week 300. If participants had plasma HIV-1 RNA greater than or equal to 50 copies/ml at Week 300, a single repeat test to determine eligibility was allowed after consultation with the medical monitor. Participants from LATTE were excluded if they had two or more sequential plasma HIV-1 RNA greater than or equal to 50 copies/ml or any plasma HIV-1 RNA greater than or equal to 200 copies/ml in the last 6 months.

The study included a Maintenance Phase (Day 1 until CABþRPV long-acting is commercially available locally) and a Long-Term Follow-Up Phase (LTFU, 52 weeks) for participants who discontinued for any reason after receiving at least one dose of CAB long-acting and/or RPV long-acting. Participants entered the study on Day 1 and elected to transition from daily oral CABþRPV to either i.m. CABþRPV long-acting Q2M (long-acting arm; CAB long-acting 600 mg and RPV long-acting To be accessed commercially once CABþRPV LA Q2M is approved. Any participant who received at least one dose of CAB LA and/or RPV LA and discontinued the CABþRPV LA regimen for any reason entered a 52-week Long-Term Follow-Up Phase and transitioned to an alternative ART regimen. d To be accessed longer term via a commercial route. Participants will continue to receive DTG/RPV if located in a region where not commercially available. Figure 1a was presented previously at IDWeek; October 21-25, 2020; Virtual; Oral. ART, antiretroviral therapy; CAB, cabotegravir; DTG, dolutegravir; IM, intramuscular; LA, long-acting; Q2M, every 2 months; RPV, rilpivirine. 900 mg) or daily oral single-tablet dolutegravir (DTG) 50 mg/RPV 25 mg (DTG/RPV arm) for 12 months. To cover preplanned, short-term interruptions of longacting dosing, investigators could provide daily oral CAB 30 mg and RPV 25 mg as an oral therapy following consultation with the medical monitor. Participants in the long-acting arm will continue to receive CABþRPV long-acting Q2M until the regimen is approved and commercially available within the local sector (including through local public/government health sectors), the participant no longer derives clinical benefit, or the participant meets a protocol-defined reason for discontinuation. DTG/RPV tablets were provided via commercial routes. Any participant who received at least one dose of CAB long-acting and/or RPV long-acting and discontinued CABþRPV long-acting for any reason entered a 52-week LTFU Phase and remained on an alternative suppressive ART regimen for at least 52 weeks after the last dose. The cut-off date for this analysis predates the COVID-19 2020 pandemic. POLAR was conducted in accordance with the principles founded in the Declaration of Helsinki and with Good Clinical Practice [21, 22] . All participants provided written informed consent, and the protocol was approved by an institutional review board or ethics committee.

The primary objective of the study was to demonstrate the antiviral activity of CABþRPV long-acting Q2M in suppressed HIV-1-infected ART-experienced participants. The primary endpoint was the proportion of participants with HIV-1 RNA greater than or equal to 50 copies/ml at Month 12 as per the Food and Drug Administration (FDA) Snapshot algorithm. Secondary endpoints assessed at Month 12 included the proportion of participants with plasma HIV-1 RNA less than 50 copies/ ml at Month 12 as per the FDA Snapshot algorithm; the incidence of protocol-defined confirmed virologic failure (CVF; two consecutive plasma HIV-1 RNA measurements of 200 copies/ml); incidence of treatmentemergent genotypic and phenotypic resistance; absolute values and changes in CD4 þ cell count over time; incidence and severity of adverse events and laboratory abnormalities; proportion of participants who discontinue treatment due to adverse events; change from Baseline in laboratory parameters over time; and treatment satisfaction, as measured by the 12-item HIV Treatment Satisfaction Questionnaire status (HIVTSQs) and change (HIVTSQc) versions at Baseline, Month 6, and Month 12. HIVTSQ responses are rated on 6-point Likert scales, with the HIVTSQs total score ranging from 0 (very dissatisfied) to 66 (very satisfied), and the HIVTSQc total score ranging from -33 (much less satisfied now) to 33 (much more satisfied now). An exploratory endpoint evaluating participant preference for CABþRPV long-acting compared with their prior daily oral CABþRPV regimen was also included (single-item questionnaire) at Month 12. The pharmacokinetic profiles of CAB and RPV were not investigated in the study as they have been extensively characterized in previous Phase 2 and Phase 3 studies of the daily oral regimen and the i.m. therapy given every 4 or 8 weeks [17] [18] [19] 23] .

No statistical hypotheses of treatment comparisons were tested within this study due to the nonrandomized nature of the study and the unbalanced number of participants between comparator arms. Consequently, all presented data are descriptive.

Of the 98 participants from the LATTE study who were screened for eligibility, 97 entered the Maintenance Phase of POLAR [intention-to-treat exposed (ITT-E) population]. One participant failed screening due to abnormal electrocardiogram results (prolonged QTc interval). Participant disposition is shown in Fig. 1b . Of those enrolled, 90 of 97 participants (93%) elected to receive CABþRPV long-acting therapy, while the remaining seven of 97 (7%) chose to receive daily oral DTG/RPV. Baseline participant characteristics are summarized in Table 1 .

AIDS 2022, Vol 36 No 2 

In the ITT-E population, no participant in either treatment arm had HIV-1 RNA greater than or equal to 50 copies/ml at Month 12, as per the FDA Snapshot algorithm ( Fig. 2 and Supplemental Digital Content, Table S1 , http://links.lww.com/QAD/C328, Efficacy outcomes at Month 12). Overall, 88 of 90 (98%) and seven of seven (100%) participants in the CABþRPV long-acting and DTG/RPV arms, respectively, maintained virologic suppression at Month 12. The remaining two (2%) participants in the CABþRPV long-acting arm had no virologic data at Month 12; one discontinued treatment due to an adverse event and the other was lost to follow-up. Through Month 12, no participants met the CVF criterion in either treatment arm. Consequently, no resistance data were generated. At Month 12, following at least 6 years of CABþRPV therapy (including 300 weeks of oral CABþRPV in LATTE), the median [interquartile range (IQR)] CD4 þ cell count change from Baseline in POLAR was -12.5 (-138.0, 71.0) cells/ml in the CABþRPV long-acting arm and -68.0 (-152.0, 152.0) cells/ml in the DTG/RPVarm. CD4 þ cell counts prior to initiating oral CABþRPV are detailed in the primary publication of the LATTE study [20] .

Through Month 12, 86 of 90 (96%) participants in the CABþRPV long-acting arm and three of seven (43%) in the DTG/RPVarm reported adverse events ( Table 2 ). All reported drug-related adverse events were of mild (Grade 1) or moderate (Grade 2) severity, most of which were injection site reactions (ISRs) in the CABþRPV longacting arm. The most frequently reported non-ISR drugrelated adverse events in the CABþRPV long-acting arm were pyrexia (8%, n ¼ 7/90) and fatigue (4%, n ¼ 4/90). One participant experienced a drug-related adverse event in the DTG/RPV arm (headache). There was one withdrawal due to an adverse event (CABþRPV longacting arm; drug-related adverse event of depression) and one drug-related serious adverse event (CABþRPV long-acting arm; injection site extravasation) that resolved by drainage on the same day and did not lead to study discontinuation. No clinically relevant patterns of adverse events over the 12-month period were observed.

In total, 70 of 90 (78%) participants in the CABþRPV long-acting arm reported at least one ISR, for a total of 463 ISR events (Supplemental Digital Content, Table S2 , http://links.lww.com/QAD/C328, ISR overview). All ISR events were either mild (Grade 1; 84%, n ¼ 389/463) or moderate (Grade 2; 16%, n ¼ 74/463) in severity, and most (92%, n ¼ 424/463) resolved within 7 days, with a median (IQR) duration of 3 (2, 4) days. The incidence of ISRs decreased over the study period (Supplemental Digital Content, Figure S1 , http://links.lww.com/ QAD/C328, ISR incidence over time through Month 12), with 67% (n ¼ 60/90) of participants reporting ISRs on Day 1 compared with 26% (n ¼ 23/88) at the Month 12 visit. The most commonly reported ISRs in the CABþRPV long-acting arm (5% of participants) were injection site pain (74%, n ¼ 67), injection site discomfort (11%, n ¼ 10), injection site swelling (6%, n ¼ 5), and injection site nodule (6%, n ¼ 5). No participants withdrew from the study due to an ISR or injection intolerability. SAEs included cholecystitis acute (n ¼ 1), cholelithiasis (n ¼ 1), anal abscess (n ¼ 1), orchitis (n ¼ 1), urinary tract infection bacterial (n ¼ 1), proctitis (n ¼ 1), and injection site extravasation (n ¼ 1). Participants could have experienced >1 SAE. c Drug-related SAE of injection site extravasation. Table 2 was presented previously at IDWeek; October 21-25, 2020; Virtual; Oral. AE, adverse event; CAB, cabotegravir; DTG, dolutegravir; IM, intramuscular; ISR, injection site reaction; LA, long-acting; QD, once daily; Q2M, every 2 months; RPV, rilpivirine; SAE, serious adverse event. across both treatment groups. At Month 12, mean (SD) total HIVTSQc scores, representing changes in satisfaction from prior therapy, were high in both treatment groups [CABþRPV long-acting arm, 28.0 (6.78); DTG/ RPV arm, 27.7 (6.97)], with positive mean change scores observed for all individual items for both arms (Supplemental Digital Content, Figure S2 , http:// links.lww.com/QAD/C328, Mean HIVTSQc individual item scores at Month 12) . An exploratory analysis of therapy preference at Month 12 indicated that, of the 88 participants in the CABþRPV long-acting arm with a recorded response to the preference questionnaire, 88% (n ¼ 77/88) preferred CABþRPV long-acting Q2M over daily oral CABþRPV, the regimen received in the LATTE study for at least 5 years (Fig. 3) . The most commonly cited reasons for preference among the 83 participants who provided responses included increased convenience (69%, n ¼ 57/83) and the frequency of administration (57%, n ¼ 47/83).

The results from the POLAR study complement those collected from larger Phase 3 studies and together support the therapeutic potential of i.m. CABþRPV long-acting administered monthly or Q2M for the maintenance of virologic suppression in PWH [17] [18] [19] . Notably, the POLAR study is the first clinical study to investigate the CABþRPV long-acting regimen dosed Q2M, as indicated, instead of every 8 weeks.

The high level of virologic suppression and low rate of CVF reflect the results obtained from the larger Phase 3 studies of CABþRPV long-acting, and contribute to a growing library of clinical evidence supporting its efficacy as a maintenance regimen [17] [18] [19] . Furthermore, the safety and tolerability profile was consistent with previous studies and no new safety signals were identified [17] [18] [19] . As previously observed, ISRs were of mild-to-moderate intensity, of short duration, and decreased in incidence over time [17] [18] [19] . Notably, ISRs did not lead to treatment discontinuation.

Participants transitioning from the Phase 2b LATTE study were treatment experienced, having received daily oral CABþRPV for at least 5 years. At the beginning of the Maintenance Phase, 93% (n ¼ 90/97) of study participants elected to receive CABþRPV long-acting over daily oral tablets. This may reflect the substantial interest in long-acting therapies observed in the population of PWH and serves as an encouraging sign for the clinical uptake of the injectable regimen [24] [25] [26] [27] [28] . Notably, participants were more satisfied with the regimens that they chose to receive in POLAR (both CABþRPV long-acting and oral DTG/RPV) than with the daily oral CABþRPV regimen they had previously received for at least 5 years, as measured by the HIVTSQc. In addition, 88% (n ¼ 77/88) of CABþRPV long-acting respondents stated a preference for CABþRPV longacting over their prior oral regimen, consistent with findings from the other Phase 3 studies (ATLAS, FLAIR, and ATLAS-2 M) evaluating CABþRPV long-acting [17] [18] [19] [29] [30] [31] . Taken together, these results demonstrate high levels of preference for, and satisfaction with, the injectable regimen.

Owing to the small number of participants enrolled, the study was not adequately powered to draw statistical inferences from the results. Further, as participants could choose which maintenance regimen they received, POLAR was nonrandomized and, therefore, the numbers of participants differed greatly between comparator arms. As a result, comparisons between CABþRPV long-acting and DTG/RPV cannot be drawn and any differences in results must be interpreted within this context. In addition, all participants had completed more than 300 weeks of oral CABþRPV therapy prior to study entry and are therefore a highly selected population comprising participants with established efficacy with, and tolerability to, CABþRPV. This caveat limits the generalizability of the findings to a wider population initiating CABþRPV long-acting as a novel regimen. The small number of females (sex at birth) in the study should also be considered in the interpretation of the findings. The design of the study prevented blinding, which could influence the reporting of adverse events and patient-reported outcomes; however, this would not affect the efficacy findings, which were based on objective measurements of viral load.

Injectable CABþRPV long-acting, administered Q2M, maintained high levels of virologic suppression in participants previously treated with oral CABþRPV, with no participants having virologic nonresponse or meeting the CVF criterion through Month 12 of the POLAR study. The injectable CABþRPV long-acting regimen was well tolerated and preferred over oral therapy by this treatment-experienced cohort, who had previously received daily oral CABþRPV for at least 5 years in the LATTE study. Taken together, these results complement the results observed in larger Phase 3 studies evaluating the injectable regimen and support CABþRPV long-acting as an efficacious and welltolerated Q2M maintenance therapy for PWH. families, and the clinical investigators and their staff. Professional medical writing and editorial assistance was provided by Euan Paul at SciMentum (Nucleus Global) and funded by ViiV Healthcare.

The POLAR study (NCT03639311) was funded by ViiV Healthcare and Janssen Pharmaceuticals.

A.M., G.J.R., C.N., O.O., J.C., C.B., and J.D.V. participated in the collection and interpretation of the data. D.A.M., K.C.S., V.W., S.H., J.R., C.M., C.G., K.V., and W.R.S. were responsible for the development, conception, and data analysis of the study. All authors contributed to the review and development of the manuscript.

Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com

A.M. has received research funding and consulting fees from ViiV Healthcare, Gilead, Janssen Pharmaceuticals, and Merck, and consulting fees from Shionogi & Co., Ltd. G.J.R. reports grants from Gilead, ViiV Healthcare, and TaiMed. C.N. reports consulting fees from Glaxo-SmithKline and ViiV Healthcare, and research support from GlaxoSmithKline and Gilead. O.O. received consulting fees from Gilead, ViiV Healthcare, and Merck. J.C. reports grants, consulting fees, and speaker fees from Gilead, ViiV Healthcare, and Merck. C.B. has received speaker fees from ViiV Healthcare and Gilead and other from GlaxoSmithKline, Janssen Pharmaceuticals, and Sangamo, outside the submitted work.

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The authors thank everyone who has contributed to the success of the study: all study participants and their