Long-Acting Cabotegravir Protects Macaques Against Repeated Penile Simian-Human Immunodeficiency Virus Exposures

Dobard, Charles; Makarova, Natalia; Nishiura, Kenji; Dinh, Chuong; Holder, Angela; Sterling, Mara; Lipscomb, Jonathan; Mitchell, James; Deyounks, Frank; Garber, David; Khalil, George; Spreen, William; Heneine, Walid; Garcı́a-Lerma, J. Gerardo

doi:10.1093/infdis/jiaa095

Cited by 19 publications

(10 citation statements)

References 14 publications

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“…The safety and efficacy of long-acting CAB as part of ART highlighted its potential as a PrEP strategy. After efficacy was demonstrated in a nonhuman primate model [ 33 , 34 ], long-acting CAB safety, tolerability and pharmacokinetics were assessed in two phase 2 studies [ 35 ▪ , 36 ]. Recently, results of two phase 3, double-blind studies evaluating long-acting CAB for PrEP were reported (Table 3 ) [ 37 ▪▪ , 38 ▪▪ ].…”

Section: Cabotegravir For Hiv Preventionmentioning

confidence: 99%

A new paradigm for antiretroviral delivery: long-acting cabotegravir and rilpivirine for the treatment and prevention of HIV

Bares¹,

Scarsi

2021

Current Opinion in HIV and AIDS

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Purpose of review Cabotegravir (CAB) and rilpivirine (RPV) is the first long-acting injectable antiretroviral therapy (ART) option approved for virologically suppressed adults with HIV-1. In addition, long-acting CAB is a promising agent for HIV preexposure prophylaxis (PrEP). This review focuses on phase 3 clinical trial results and implementation considerations for these long-acting ART and PrEP strategies. Recent findings Long-acting CAB and RPV administered every 4 weeks demonstrated noninferiority to oral ART through week 96 in both the ATLAS and FLAIR studies, whereas ATLAS-2M found similar efficacy through 96 weeks when the long-acting injectable ART was administered every 8 weeks instead of every 4 weeks. For prevention, two phase 3 trials were stopped early due to fewer incident HIV infections in participants receiving long-acting CAB every 8 weeks compared with daily oral tenofovir disoproxil fumarate–emtricitabine for PrEP. The long-acting therapies were well tolerated across all clinical trials. Summary Clinical trial results support the use of long-acting CAB for HIV PrEP and long-acting CAB and RPV as a switch strategy for adults with HIV-1 who are first virologically suppressed with oral ART. Implementation challenges persist, and data are urgently needed in populations who may benefit most from long-acting therapy, including adolescents, pregnant individuals, and those with barriers to medication adherence.

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Section: Cabotegravir For Hiv Preventionmentioning

confidence: 99%

A new paradigm for antiretroviral delivery: long-acting cabotegravir and rilpivirine for the treatment and prevention of HIV

Bares¹,

Scarsi

2021

Current Opinion in HIV and AIDS

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“…17 Macaque models of rectal, vaginal, penile, and parenteral exposures have further supported the development of CAB LA as a promising PrEP agent. [18][19][20][21] In a low-dose rectal challenge model, plasma CAB concentrations above 3x PA-IC 90 provided 100% protective efficacy, concentrations 1x-3x PA-IC 90 provided 97% protective efficacy, and concentrations <1x PA-IC 90 provided 45% protective efficacy compared to control untreated macaques (CM). 19 In a vaginal challenge model, plasma levels >4x PA-IC 90 were 87% protective compared to CM, while plasma levels <4x PA-IC 90 were not protective compared to CM.…”

Section: Early Phase Studiesmentioning

confidence: 99%

Long-acting injectable cabotegravir for the prevention of HIV infection

Clement

Kofron²,

Landovitz³

2020

Current Opinion in HIV and AIDS

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Purpose: This review highlights the development of long-acting injectable cabotegravir (CAB LA) for HIV pre-exposure prophylaxis (PrEP), with a focus on Phase 2 studies and later development. Recent findings:Early studies of CAB LA for HIV prevention offered promising PK data and paved the way for Phase 2 studies which have now been completed. Based on Phase 2 data, dosing of CAB LA at 8-week intervals consistently delivers target trough concentrations in both males and females. Recent studies have shown no required dose adjustments for hepatic or renal disease and minimal drug-drug interactions. Additionally, injectable PrEP is desired by potential PrEP candidates. Still, gaps in knowledge remain with respect to implementation and delivery, the clinical significance of the pharmacologic tail, and dosing in key populations. Phase 3 trials are underway that are anticipated to inform some of these questions and provide efficacy and safety data to support regulatory submissions for CAB LA as a potential PrEP agent. Summary:Recent studies have defined an appropriate CAB LA dosing interval and offered insight into its safety profile. Phase 3 studies will provide much-anticipated efficacy data. If efficacious, CAB LA may provide a desirable PrEP option for those who face challenges to daily pill adherence. A more complete understanding of how to best integrate LA PrEP into service delivery models will be critical for success.

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“…Preclinical and phase 2a/b studies in humans have supported the clinical development of CAB LA as PrEP in individuals at high risk of HIV infection. In macaques, CAB LA administered at human therapeutic doses provided significant protection against, rectal, vaginal, penile, and intravenous virus exposures 8–12 . In Phase 2a/b studies, CAB LA was generally safe and well tolerated with injection site reactions that were mild or moderate as the most common adverse events 4,13 .…”

Section: Introductionmentioning

confidence: 99%

Drug resistance emergence in macaques administered cabotegravir long-acting for pre-exposure prophylaxis during acute SHIV infection

et al. 2019

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A long-acting injectable formulation of the HIV integrase inhibitor cabotegravir (CAB-LA) is currently in clinical development for PrEP. Although the long plasma half-life of CAB-LA is an important attribute for PrEP, it also raises concerns about drug resistance emergence if someone becomes infected with HIV, or if PrEP is initiated during undiagnosed acute infection. Here we use a macaque model of SHIV infection to model risks of drug resistance to CAB-LA PrEP. Six macaques infected with SHIV received CAB-LA before seroconversion. We show integrase mutations G118R, E92G/Q, or G140R in plasma from 3/6 macaques as early as day 57, and identify G118R and E92Q in viruses from vaginal and rectal fluids. G118R and G140R confer > 800-fold resistance to CAB and cross-resistance to all licensed integrase inhibitors. Our results emphasize the need for appropriate HIV testing strategies before and possibly shortly after initiating CAB LA PrEP to exclude acute infection.

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Long-Acting Cabotegravir Protects Macaques Against Repeated Penile Simian-Human Immunodeficiency Virus Exposures

Cited by 19 publications

References 14 publications

A new paradigm for antiretroviral delivery: long-acting cabotegravir and rilpivirine for the treatment and prevention of HIV

A new paradigm for antiretroviral delivery: long-acting cabotegravir and rilpivirine for the treatment and prevention of HIV

Long-acting injectable cabotegravir for the prevention of HIV infection

Drug resistance emergence in macaques administered cabotegravir long-acting for pre-exposure prophylaxis during acute SHIV infection

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