Long-Acting Cabotegravir and Rilpivirine for HIV-1 Suppression

Switch to 2-Monthly Dosing After 5 Years of Daily Oral Therapy

Anthony Mills; Gary J. Richmond; Cheryl Newman; Olayemi Osiyemi; Jerry Cade; Cynthia Brinson; Jerome De Vente; David A. Margolis; Kenneth C. Sutton; Viviana Wilches; Sarah Hatch; Jeremy Roberts; Cynthia McCoig; Cindy Garris; Kati Vandermeulen; William R. Spreen

Disclosures

AIDS. 2022;36(2):195-203. 

In This Article

Abstract and Introduction

Abstract

Objectives: 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.

Introduction

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.[2–6] 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.[7–12] 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.[14–16] CAB+RPV long-acting is indicated for the treatment of HIV-1 infection in virologically suppressed adults (HIV-1 RNA < 50 copies/ml).[14–16] 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 CAB+RPV long-acting dosed every 4 weeks as a maintenance therapy compared with daily oral comparator regimens.[17,18] A reduced dosing frequency for CAB+RPV 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 CAB+RPV compared with three-drug efavirenz-based ART for the maintenance of viral suppression.[20] LATTE demonstrated the antiviral activity of the two-drug oral maintenance therapy CAB+RPV 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 CAB+RPV long-acting Q2M in ART-experienced participants who received once-daily oral CAB+RPV treatment for at least 5 years in the Phase 2b LATTE study. The Month 12 results from POLAR are presented here.

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