Cabenuva: A Novel Long-Acting Injectable HIV Treatment

BY SARAH M. MICHIENZI, PHARMD, BCPS, AAHIVP, AND RACHEL KAUTZ, PHARMD CANDIDATE 2022

Cabenuva is the first FDA-approved long-acting (LA) injectable regimen for patients with HIV infection.1 Cabenuva (ViiV Healthcare) consists of cabotegravir (CAB), an integrase strand transfer inhibitor (INSTI), and rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI) approved to replace antiretroviral therapy (ART) in patients with HIV-RNA less than 50 copies/mL who have been on a stable ART with no history of treatment failure or suspected resistance to CAB or RPV. The approval of CAB/RPV was an important milestone in the treatment of HIV. This article provides an overview of CAB/RPV and 2 key studies leading to its approval.

About CAB/RPV1

CAB/RPV consists of an oral leadin, followed by the initial injection, which are continued monthly. The oral lead-in includes a Vocabria (CAB, ViiV Healthcare) 30-mg tablet once daily and an Edurant (RPV, Janssen) 25-mg tablet once daily for at least 28 days. Both medications should be taken with food. The purpose of the oral lead-in is to assess the patients’ tolerability to the regimen before the LA form is injected. If tolerated after 1 month, on the last day of oral lead-in therapy, the patient can receive the initial 600-mg CAB and 900-mg RPV injections. These are 2 separate 3-mL intramuscular (IM) injections that should be administered on opposite gluteal sites or at least 2 cm apart on the same gluteal site. The continuation injections are administered the same way but consist of a 400-mg (2-mL) CAB injection and a 600-mg (2-mL) RPV injection.

Before administering the injections, the vials should be removed from the refrigerator and left for 15 minutes to allow the medication to come to room temperature. CAB/RPV can remain in the carton at room temperature for up to 6 hours. After 6 hours at room temperature, the medication should be discarded. Both medications are suspensions that need to be shaken vigorously before being drawn into a syringe. Once drawn into the syringe, the medication should be administered immediately but can remain in the syringes for up to 2 hours. CAB/ RPV should only be administered by a health care professional.

The continuation injections are to be administered monthly. For the monthly visits, the patient may receive their injections up to 7 days before or after their scheduled monthly target date. If this window is missed, and the time since the last injection was less than 2 months prior, the patient should resume the 400-mg CAB injection and 600-mg RPV injection as soon as possible. If it has been more than 2 months since their last injections, they need to reinitiate the regimen with the 600mg CAB injection and 900-mg RPV

injection. If the patient has planned to miss their injection appointment for whatever reason, they can take daily oral therapy to replace up to 2 consecutive monthly injection visits. They should start the oral therapy approximately 1 month after their last injection and continue the oral therapy until the day injection therapy is restarted.

The most common side effects occurring in 2% or greater of patients receiving CAB/RPV include injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. Contraindications to receiving CAB/ RPV include taking carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, systemic dexamethasone (>1 dose), and St John’s wort. These medications can decrease the concentrations of CAB and RPV and coadministration with CAB/RPV could cause potential loss of virologic response and development of resistance. FLAIR and ATLAS are 2 major phase 3 studies that evaluated the safety and efficacy of CAB/ RPV in treatment-naive and -experienced patients, respectively.

Clinical Trials

FLAIR2

FLAIR was a phase 3, randomized, multicenter, open-label, noninferiority trial that compared monthly IM CAB/RPV vs oral daily dolutegravir/ abacavir/lamivudine (DTG/ABC/3TC) in treatment-naive patients. Eligible participants were older than 18 years of age, antiretroviral (ARV) naive, and had HIV-RNA levels of more than 1,000 copies/mL at baseline. All patients were assigned to take 50 mg DTG, 600 mg ABC, and 300 mg 3TC as a daily oral regimen for the initial 16 weeks. At week 16, participants whose HIV-RNA level was less than 50 copies/ mL were randomly placed into 2 treatment groups. Treatment assignments were stratified by baseline HIV-RNA levels and sex at birth. One group continued the DTG/ABC/3TC daily oral regimen for the next 100 weeks. The other group switched to CAB/RPV with the initial 4-week oral lead-in (30 mg CAB and 25 mg RPV daily). This was followed by the one-time initiation injections (600-mg CAB injection and 900-mg RPV injection). Patients then received maintenance injections every 4 weeks, which was the 400-mg CAB injection and 600-mg RPV injection for a total of 100 weeks. Patients with confirmed virologic failure, which was indicated by 2 consecutive HIV-RNA levels of 200 copies/mL or greater, discontinued their assigned treatment.

The primary end point measure was the percentage of patients with an HIV-RNA level of more than 50 copies/mL at week 48, determined with the use of the FDA snapshot algorithm. The percentage of patients with an HIV-RNA level of more than 50 copies/ mL at week 48 was also evaluated as a secondary end point. The primary efficacy analysis included all participants who received at least 1 dose of the assigned trial drugs during the maintenance phase. For the primary end point, a noninferiority margin of 6 percentage points was set based on clinical considerations of the 2 regimens. There were 629 participants who initiated oral induction therapy, with 63 of those participants withdrawing before randomization because of lack of efficacy. The remaining 566 participants were randomly assigned to their maintenance phase treatment.

After 48 weeks, 2.1% of patients on the LA monthly injectable regimen and 2.5% of patients on the daily oral regimen had HIV-RNA levels more than 50 copies/mL (95% CI, -2.8 to 2.1). These results met the criteria for noninferiority. Additionally, 93.6% of patients in the LA injectable group and 93.3% of patients in the daily oral therapy group had HIV-RNA levels of less than 50 copies/mL at week 48 (95% CI, -3.7 to 4.5). Of note, 3 of 54 patients in the LA therapy group who had the L74I integrase polymorphism at baseline had confirmed virologic failure.

Eighty-six percent of the patients who received LA injectable therapy reported injection site reactions (mild or moderate severity for 99% of cases and decreased throughout the study). At week 48, 98% of patients who had been assigned to the LA injectable group were satisfied with the regimen and preferred it over the oral daily regimen. Results of the FLAIR study show therapy with LA CAB/RPV was noninferior to oral therapy with DTG/ ABC/3TC at maintaining HIV suppression and was well tolerated with high satisfaction.

In both the FLAIR and ATLAS trials, most people preferred the injectable regimen.

ATLAS3

The ATLAS study was a phase 3, randomized, multicenter, parallelgroup, open-label, noninferiority trial that compared switching to monthly IM CAB/RPV injections versus staying on a 3-drug ARV regimen in treatment experienced patients. Participants enrolled were older than 18 years of age, taking 2 nucleotide reverse transcriptase inhibitors (NRTIs) plus an INSTI, NNRTI or protease inhibitor (PI), on a stable ARV regimen for more than 6 months prior, and had HIV-RNA levels of less than 50 copies/mL for more than 6 months prior. Patients were excluded if they had a history of virologic failure, NNRTI or INSTI resistance, or chronic hepatitis B. Also, patients taking DTG/ABC/3TC were excluded to maximize generalizability, as this prior regimen was evaluated in the FLAIR trial.

Participants were randomly assigned in a 1:1 ratio to either continue their 3-drug oral ARV for 52 weeks or to

switch to the oral CAB and RPV leadin for the first 4 weeks, followed by initiation and continuation IM CAB and RPV injections every 4 weeks for the remaining 48 weeks. Randomization was stratified according to class of the third ARV agent of their baseline regimen and sex at birth.

There were 308 participants in each group and there were no significant differences in baseline characteristics between the 2 groups. The average patient was 42 years old, white, male, and had been on ART for 52 months. NNRTIs were the most common class of the third ARV agent, followed by INSTIs and PIs.

The primary end point was the percentage of participants with an HIVRNA level of more than 50 copies/mL at week 48, determined with the use of the FDA snapshot algorithm. The percentage of participants with a HIVRNA level of less than 50 copies/mL at week 48 was also evaluated. The primary efficacy analysis included all participants who received at least 1 dose of their assigned treatment. For the primary end point, a noninferiority margin of 6 percentage points was set based on the potential clinical advantages of LA therapy.

The primary end point of HIV-RNA more than 50 copies/mL occurred in 1.6% of participants in the LA injectable group compared with 1.0% in the oral therapy group (95% CI, -1.2 to 2.5). These results met the criteria for noninferiority for the primary end point. Additionally, 92.5% of participants in the LA injectable group achieved an HIV-RNA level of less than 50 copies/mL compared with 95.5% in the oral therapy group (95% CI, -6.7 to 0.7), which also met the noninferiority margin.

Adverse events were more common in the LA injectable group with 83% of participants reporting injection site pain. This side effect was mild to moderate in most cases and only 1% withdrew for the study because of injection site pain. The frequency of injection site reactions declined progressively, reaching 11% at week 48. 86% of participants who received the LA therapy preferred the regimen over previous oral therapy. The ATLAS study showed that monthly LA injections of CAB/ RPV were noninferior to standard triple oral therapy for HIV treatment and provided a high rate of treatment satisfaction despite injection related side effects.

Place in Therapy

CAB/RPV is a revolutionary option for HIV treatment that has the power to improve adherence and quality of life. Current first-line regimens for HIV treatment require lifelong daily oral therapy that can be burdensome and challenging for patients. CAB/RPV reduces the treatment dosing days from 365 to 12 days per year after the oral lead-in. Additionally, while clinic visits are required for injections, CAB/RPV could give patients more privacy for their HIV treatment by not having to store medications at home. While CAB/RPV injection site reactions were common in clinical trials, these reactions significantly decreased after the first injection. Moreover, patients in clinical trials preferred injectable over oral therapy.2,3 The LATITUDE Study (Long-Acting Therapy to Improve Treatment SUccess in Daily LifE) will provide much needed information on the use of CAB/RPV in patients with a history of suboptimal adherence.4

Looking beyond the current FDA approval, an extension of the ATLAS trial, ATLAS-2M, compared CAB/ RPV injections every 4 weeks to every 8 weeks in treatment experienced patients. The results showed that the efficacy and safety profiles of dosing every 4 weeks and every 8 weeks were very similar. Although dosed every 2 months is not FDA approved, the results from ATLAS-2M support this as a therapeutic option. Also, injectable CAB demonstrated excellent results for HIV pre-exposure prophylaxis in men who have sex with men and transgender women.5

For patients interested in injectable therapy, CAB/RPV could help simplify HIV treatment in the presence of resistance (as long as susceptibility to CAB and RPV is maintained) as well as help overcome a variety challenges with daily pill taking. This could result in improve ability to maintain virologic suppression and immunologic function, thus potentially preventing complications of HIV, development of resistance, and viral transmission.

References

1. Cabenuva [package insert]. ViiV Healthcare; 2021.

2. Orkin C, Arasteh K, Górgolas Hernández-Mora

M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection.

N Engl J Med. 2020;382(12):1124-1135.

3. 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.

4. Clinicaltrails.gov. The LATITUDE Study (Long-

Acting Therapy to Improve Treatment SUccess in Daily LifE). Accessed June 5, 2021. http://bit. ly/3gfieL3-IDSE

5. Marzinke MA, et al. Characterization of HIV infection in cisgender men and transgender women who have sex with men receiving injectable cabotegravir for HIV prevention: HPTN 083. J Infect Dis. Published online March 19, 2021. doi:10.1093/infdis/jiab152.

6. HIV Prevention Trials Network. HPTN 084

Study Demonstrates Superiority of CAB LA to Oral FTC/TDF for the Prevention of HIV.

November 20, 2020. Accessed June 5, 2021. https://bit.ly/2OEK6hu-IDSE

The authors reported no relevant financial disclosures.

About the authors:

Sarah Michienzi, PharmD,

BCPS, AAHIVP, is a clinical assistant professor and clinical infectious disease pharmacist in the Pharmacotherapy Section, Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, in Chicago, Illinois.

Rachel Kautz, is a PharmD candidate at the College of Pharmacy, University of Illinois at Chicago, in Chicago, Illinois.