Interest Grows in Long-Acting Injectables for HIV Treatment

With recent innovations in the development of antiretroviral therapy (ART), there is growing interest in the use of long-acting injectable (LAI) therapy. Patients may benefit from the use of an injectable regimen to avoid pill fatigue and reduce confidentiality concerns, and it may also promote therapy adherence.

Cabotegravir and rilpivirine (Cabenuva; ViiV Healthcare) is the first FDA-approved LAI ART regimen for HIV, composed of an integrase strand transfer inhibitor; cabotegravir (CAB); and a non-nucleoside reverse transcriptase inhibitor, rilpivirine (RPV).¹ The US Department of Health & Human Services (HHS) currently recommends CAB/RPV as a replacement for a stable regimen in virologically suppressed patients (HIV RNA, < 50 copies/mL for 3-6 months) with no history of treatment failure or suspected resistance to either CAB or RPV as either a monthly or every-8-week regimen.² Although the original approval was based on results from the FLAIR (NCT02938520) and ATLAS (NCT02951052) trials evaluating the monthly injections, the results of ATLAS-2M (NCT03299049) allowed for the approval of every-2-month injections.^3-5

New Horizons for Long-Acting Injectables

The oral lead-in for CAB/RPV is now optional based on the results from the FLAIR Extension trial.⁶ At week 124, there were no differences in virologic suppression, adverse events, or tolerability in the direct-to-inject and oral lead-in arms. Additionally, HHS and the product package insert now recommend use of a longer 2-inch needle for patients with a body mass index greater than 30 kg/m². In the original trials, patients with a body mass index greater than 30 kg/m² were more likely to have an HIV RNA level greater than 50 copies/mL, leading to efficacy concerns in obese patients; however, longer needles ensure intramuscular administration.^1,5

Although providers have begun implementing LAI therapy as a component of their clinical practice, several challenges remain. Patients who may benefit most from LAI therapy were not included in the original clinical trials, including patients with poor adherence to oral therapy or with virologic failure. Researchers have begun exploring utilization of this therapy in these populations. In a recent demonstration project, 15 patients with detectable viremia (mean log10 viral load, 4.67; SD, 1.16) were able to achieve either viral suppression (12 patients) or a 2-fold viral load decline by a median of 22 days (3 patients).⁷ The ongoing LATITUDE trial (NCT03635788) is also enrolling patients with suboptimal adherence and control regarding their HIV infection to compare oral standard-of-care regimens with once-monthly CAB/RPV injections.⁸

Data from the ViiV compassionate use program were recently published that included patients who were ineligible for the phase 3 clinical trials.⁹ This included patients with a need for parenteral therapy due to malabsorption syndrome, dysphagia, or psychological conditions, and those with prolonged nonadherence to oral therapy leading to progressive HIV disease. Of the 35 patients included, 28 had detectable viremia (median viral load, 60,300 copies/ mL) and 7 were virologically suppressed at enrollment. At the end of the program, 16 of the 28 patients with detectable viremia and 6 of the 7 virologically suppressed patients had achieved or maintained virological suppression.⁹

In addition to evaluating expanded patient populations, ongoing research is evaluating new and innovative ways to administer CAB/RPV to potentially allow for self-administration at home or by pharmacists in an outpatient setting. Pharmacokinetic studies looking at administration of CAB/RPV into the lateral thigh muscle and a novel formulation of CAB 400 mg/mL for subcutaneous injection have revealed promising results, with similar plasma profiles and no difference in tolerability to the current ventrogluteal injections.^10,11

In addition to ongoing innovations with current FDA-approved products, there is a growing pipeline of long-acting agents in various stages of clinical trials. One entering the US market is lenacapavir (Sunlenca; Gilead Sciences), a first-in-class, multistage selective inhibitor of the HIV capsid protein.¹² The Phase 2/3 CAPELLA study (NCT04150068), whose results were recently published, evaluated lenacapavir administered every 6 months as a subcutaneous injection in heavily treatment-experienced patients with multidrug resistant HIV-1 infection.¹³ In cohort 1, 36 participants were randomly allocated to receive oral lenacapavir or placebo in a 2:1 ratio for 14 days, in addition to continuing their failing regimen (functional monotherapy). An additional 36 participants were enrolled in a separate cohort 2 that received open-label oral lenacapavir with an optimized background therapy for 14 days. At day 15, both cohorts received subcutaneous lenacapavir administered every 6 months in combination with an optimized background regimen. In cohort 1, 88% of patients in the lenacapavir group and 17% in the placebo group (absolute difference, 71%; 95% CI, 35%-90%) achieved a decrease of at least 0.5 log10 copies/mL by day 15. At week 26, a viral load of less than 50 copies/mL was reported in 81% of patients in cohort 1 and 83% in cohort 2. The FDA approved this novel LAI agent in December 2022 and provides another treatment option for vulnerable subpopulations of HIV patients.¹⁴

The HIV treatment landscape continues to evolve as we turn to novel mechanisms of action and medication delivery methods to increase treatment options.

About the Authors

Emily Kirkpatrick, PharmD, BCIDP, AAHIVP, is a clinical pharmacy specialist in infectious diseases at University Health in San Antonio, Texas.

Rose Denzer, PharmD, AAHIVP, is a PGY-2 infectious diseases pharmacy resident at University Health in San Antonio, Texas.

References

1. Cabenuva. Prescribing information. ViiV Healthcare; 2022. Accessed December 11, 2022. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Cabenuva/pdf/CABENUVA-PI-PIL-IFU2-IFU3.pdf

2. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. HIV.gov. Updated September 21, 2022. Accessed December 11, 2022. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv

3. Orkin C, Arasteh K, Hernandez-Mora MG, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382(12):1124-1135. doi:10.1056/NEHMoa1909512

4. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 2020;382(12):1112-1123. doi:10.1056/NEJMoa1904398

5. Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomized, multicentre, open-label, phase 3b, non-inferiority study. Lancet. 2021;396(10267):1994-2005. doi:10.1016/S0140-6736(20)32666-0

6. Orkin C, Morell EB, Tan DHS, et al. 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. Lancet HIV. 2021;8(11):e668-e678. doi:10.1016/S2352-3018(21)00184-3

7. Christopoulos KA, Grochowski J, Mayorga-Munoz F, et al. First demonstration project of long-acting injectable antiretroviral therapy for persons with and without detectable human immunodeficiency virus (HIV) viremia in an urban HIV clinic. Clin Infect Dis. 2021;76(3):e645-e651. doi:10.1093/cid/ciac631

8. The LATITUDE study: long-acting therapy to improve treatment success in daily life. ClinicalTrials.gov. Updated December 14, 2022. Accessed December 11, 2022. https://clinicaltrials.gov/ct2/show/NCT03635788

9. D’Amico R, Cenoz Gomis S, Moodley R, et al. Compassionate use of long-acting cabotegravir plus rilpivirine for people living with HIV-1 in need of parenteral antiretroviral therapy. HIV Med. Published online August 9, 2022. doi:10.1111/hiv.13370

10. Han K, Shaik JS, Crauwels H, et al. Pharmacokinetics and tolerability of cabotegravir and rilpivirine long-acting intramuscular injections to the vastus lateralis (lateral thigh) muscles of health adult participants. Poster presented at: 24th International AIDS Conference; July 29-August 2, 2022; Montreal, Canada and Virtual.

11. Benn P, Han K, Sievers J, et al. A study evaluating the safety, tolerability, and pharmacokinetics of a high-concentration (CAB 400 mg/mL) cabotegravir long-acting injectable formulation following subcutaneous and intramuscular administration in healthy adult participants. Poster presented at: 24th International AIDS Conference; July 29-August 2, 2022; Montreal, Canada and Virtual.

12. Dvory-Sobol H, Shaik N, Callebaut C, Rhee MS. Lenacapavir: a first-in-class HIV-1 capsid inhibitor. Curr Opin HIV AIDS. 2022;17(1):15-21. doi:10.1097/COH.0000000000000713

13. Segal-Maurer S, DeJesus E, Stellbrink HJ, et al; CAPELLA Study Investigators. Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection. N Engl J Med. 2022;386(19):1793-1803. doi:10.1056/NEJMoa2115542

14. FDA approves new HIV drug for adults with limited treatment options. News release. FDA. December 22, 2022. Accessed January 10, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-new-hiv-drug-adults-limited-treatment-options