By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved the first once-a-month, complete regimen for the treatment of HIV-1 infected adults. This regimen combines oral and injectable cabotegravir and rilpivirine. Cabotegravir is a HIV-1 integrase strand transfer inhibitor (INSTI) similar to dolutegravir. Rilpivirine is a second-generation HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI). Both the injectable combination and cabotegravir tablets received breakthrough therapy designations and accelerated priority review.1 Oral rilpivirine was approved in 2011. Oral cabotegravir and the injectable combination are manufactured by GlaxoSmithKline and distributed by ViiV Healthcare as Cabenuva and Vocabria, respectively.
Cabotegravir/rilpivirine (CAB/RPV) should be prescribed to treat HIV-1-infected adults. This combination should replace the current antiretroviral (ARV) regimen in those who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable regimen with no history of treatment failure and no known or suspected resistance to ether CAB or RPV.2
Treatment is initiated with a one-month (at least 28 days) oral lead-in period (CAB 30 mg and RPV 25 mg daily with a meal).2 At month 2, administer a one-time 600 mg dose of CAB and 900 mg dose of RPV intramuscularly on the last day of the oral regimen to the ventrogluteal area (preferred) or dorsogluteal area. This is followed by 400 mg of CAB and 600 mg RPV once-monthly intramuscularly. CAB/RPV is available as a kit containing a single dose of CAB 400 mg/2 mL and RPV 600 mg/2 mL and 600 mg/2 mL and 900 mg/2 mL. CAB is available as 30 mg oral tablets. Oral rilpivirine is available as Edurant.
The extended-release formulation of CAB/RPV provides slow absorption from the injection site, resulting in prolonged elimination of the drugs. This allows for once-monthly administration. It provides another treatment option for stable, virologically suppressed HIV-1-infected adults.
The most common adverse reaction is injection site reactions (83%), with 37% considered at least grade 2.2 Rarely (< 1%), serious, post-injection reactions have been reported minutes after injection (e.g., dyspnea, agitation, flushing, or sweating). Eight percent of subjects reported pyrexia, and 5% reported fatigue.2 Residue concentrations of CAB and RPV may remain in the systemic circulation up to 12 months.2 Hypersensitivity reactions have been reported with RPV-containing regimens as well as other INSTIs.2 Nonadherence or missed doses could result in loss of response and development of viral resistance.2 Hepatotoxicity and depressive disorders have been reported. Monitoring of liver enzymes and depressive symptoms are recommended. Cross resistance has been observed among INSTIs and NNRTIs.2 Drugs that are inducers of enzymes that metabolize CAB (UGT1A1 or 1A9) or those that metabolize RPV (CYP3A) are contraindicated. The injection should be administered by a healthcare professional, not by the patient.
The efficacy of CAB/RPV was evaluated in two Phase III randomized, active-controlled, parallel-arm, open-label, non-inferiority trials.2-4 Trial 1 included treatment-naïve subjects, and trial 2 included subjects with HIV-1 RNA < 50 copies/mL for at least six months on an uninterrupted standard oral ARV regimen. Acceptable ARV regimens include two nucleoside or nucleotide reverse-transcriptase inhibitors plus one INSTI, an NNRTI, a boosted protease inhibitor, or unboosted atazanavir.4 Those taking dolutegravir/abacavir/lamivudine were excluded. In trial 1 (n = 566), subjects received a dolutegravir-containing regimen (dolutegravir/abacavir/lamivudine) for 20 weeks. Those who were virologically suppressed were randomized to CAB/RPV regimen or remained on their current oral regimen for an additional 44 weeks. In trial 2 (n = 616), subjects were randomized to the CAB/RPV regimen or remained on their current ARV regimen for an additional 44 weeks. The primary efficacy endpoint was the percentage of subjects with HIV-1 RNA level ≥ 50 HIV-1 RNA copies/mL at week 48.
Results were 2.1% for CAB/RPV and 2.5% for standard therapy for trial 1. Trial 2 results were 1.6% and 1%, respectively. In both cases, results met the criteria for noninferiority at -10% margin.3,4 In trial 2, three subjects experienced confirmed virologic failure in the CAB/RPV arm vs. four subjects in the standard oral therapy group.4
CAB/RPV provides the first once-monthly administration, complete HIV-1 treatment regimen. In the two trials, overall, 88.5% of subjects preferred CAB/RPV over daily oral therapy.3,4 Once-a-month dosing may improve compliance, although injections require a visit to a healthcare professional. Doses of the combination injection cost $3,960 per month, plus $5,940 for the initial dose, plus any additional healthcare professional fees.
- U.S. Food & Drug Administration. FDA approves first extended-release, injectable drug regimen for adults living with HIV. Jan. 21, 2021.
- ViiV Healthcare. Cabenuva prescribing information. January 2021.
- 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;382:1124-1135.
- 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;382:1112-1123.