Courtney Moc, PharmD, MS

The FDA recently approved Cabenuva, the first long-acting injectable for the treatment of HIV. Cabenuva is a 2-drug copackaged product containing cabotegravir (CAB) and rilpivirine (RPV) and requires 2 intramuscular (IM) gluteal injections once monthly. It is indicated as maintenance therapy for individuals who are virologically suppressed, defined as HIV-1 RNA with less than 50 copies/ mL, on a stable regimen with no history of treatment failure and no known or suspected resistance to either drug.

The FDA approved the regimen on the basis on results from 2 phase 3, multi-center, randomized, noninferiority trials: FLAIR (NCT02938520) and ATLAS (NCT02951052). Both met noninferiority for the primary end point of the proportion of participants with plasma HIV-1 RNA greater than or equal to 50 copies/mL at week 48. FLAIR compared monthly IM CAB/RPV with daily oral dolutegravir/abacavir/lamivudine therapy (primary end point, 2.1% vs 2.5%, respectively; adjusted difference, –0.4 percentage points; 95% CI, –2.8 to 2.1), whereas ATLAS compared monthly IM CAB/RPV with patients’ current daily antiretroviral regimen (primary end point, 1.6% vs 1.0%, respectively; adjusted difference, 0.6 percentage points; 95% CI, –1.2 to 2.5).

To ensure tolerability prior to transitioning to the long-acting injectable formulation, an oral lead-in with one 30-mg tablet of CAB (Vocabria) and two 25-mg tablets of RPV (Edurant) once daily with food for at least 1 month is recommended.

 The long-acting injectables are then initiated on the last day of oral lead-in therapy and dosed once monthly. Interestingly, both CAB/RPV are slowly absorbed following IM administration, in which the absorption rate half-lives are about 40 days and 90 to 200 days, respectively. Thus, a less frequent IM administration may be needed.

 The phase 3, multicenter, randomized, noninferiority ATLAS-2M study (NCT03299049) compared CAB 400 mg/RPV 600 mg every 4 weeks with CAB 600 mg/RPV 900 mg every 8 weeks. The primary outcome was the same as in the FLAIR and ATLAS trials, which was the proportion of participants with plasma HIV-1 RNA greater than or equal to 50 copies/mL at week 48. Findings from this study established that administration every 8 weeks was noninferior to dosing every 4 weeks (2% vs 1%, respectively; adjusted difference, 0.8; 95% CI –0.6 to 2.2). Although the study met its primary end point, an extension phase is under way and will follow patients through week 100. Pending FDA review, dosing every 8 weeks may be recommended.

 Regardless of the dosing regimen, patients who are unable to obtain their injectables in clinic on the exact targeted administration day have a buffer period of 7 days to receive the next dose.

Given that the product is administered as an IM injection, a notable advantage is its ability to overcome drug-drug interactions present with the oral formulation of RPV. Proton pump inhibitors (PPIs) increase gastric pH, resulting in the reduction of RPV plasma concentration when given orally. When RPV is given in combination with omeprazole, RPV area under the curve, maximum plasma concentration, and minimum plasma concentration decrease by 40%, 40%, and 33%, respectively.

 As a result, PPIs are contraindicated in patients who take oral RPV.

However, given the IM formulation, this is no longer an issue. This also holds true for histamine-2 receptor antagonists and antacids.

Practitioners should note certain prescribing considerations for the use of Cabenuva. For the oral lead-in phase, only a single specialty pharmacy, TheraCom, is contracted to provide a 30-day supply, which can be shipped directly to a patient’s home or a prescriber’s office. Once patients demonstrate tolerability of oral therapy, they can switch to the long-acting, once-monthly IM injections, which must be administered in a health care setting, such as a prescriber’s office. The first IM kit contains CAB 600 mg and RPV 900 mg, whereas subsequent monthly dosing consists of CAB 400 mg and RPV 600 mg. If a patient misses 1 to 2 months of Cabenuva, resume with CAB 400-mg and RPV 600-mg IM monthly injections as soon as possible.7 But if a patient misses more than 2 months of Cabenuva, reinitiate with CAB 600-mg and RPV 900-mg IM injections, then continue to follow the CAB 400-mg and RPV 600-mg IM monthly injection dosing schedule. If patients are unable to access or continue Cabenuva, switching to an oral antiretroviral regimen is permissible under the supervision of a health care provider.

Although practitioners must consider many factors when prescribing Cabenuva, the agent has the potential to revolutionize the treatment landscape for HIV and, with hope, will play a fundamental role in ending the HIV epidemic.

 is an infectious diseases resident at The University of Texas MD Anderson Cancer Center in Houston.

Melissa Badowski, PharmD, MPH, FCCP, BCIDP, BCPS, AAHIVP, 

is a clinical associate professor at the University of Illinois Chicago College of Pharmacy.

FDA approves Cabenuva and Vocabria for the treatment of HIV-1 infection. News release. FDA. January 27, 2021. Accessed April 12, 2021. https://www.fda.gov/drugs/human-immunodeficiency-virus-hiv/fda-approves-cabenuva-and-vocabria-treatment-hiv-1-infection 

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/ NEJMoa1909512

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

Vocabria. Prescribing information. ViiV Healthcare; 2021. Accessed April 12, 2021. https:// gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Vocabria/pdf/ VOCABRIA-PI-PIL.PDF

Letendre SL, Mills A, Hagins D, et al. Pharmacokinetics and antiviral activity of cabotegravir and rilpivirine in cerebrospinal fluid following long-acting injectable administration in HIV -infected adults. J Antimicrob Chemother. 2020;75(3):648-655. doi:10.1093/jac/dkz504

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, multirecentre, open-label, phase 3b, non-inferiority study. Lancet. 2020;396(10267):1994-2005. doi:10.1016/S0140-6736(20)32666-0

Cabenuva. Prescribing information. ViiV Healthcare; 2021. Accessed April 12, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212888s000lbl.pdf

Edurant. Prescribing information. Tibotec Therapeutics; 2011. Accessed April 12, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf

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FDA approval of 2-drug injectable Cabenuva is a game changer in maintaining viral suppression in patients.