The treatment and prevention of HIV has continued to evolve with innovative long-acting injectable medications that improve medication adherence. In January of 2021, the first long-acting injectable HIV treatment, cabotegravir/rilpivirine (Cabenuva), was approved by the FDA.

In December 2021, the FDA approved cabotegravir (Apretude), a long-acting injectable for HIV pre-exposure prophylaxis (PrEP). This is only the third medication to be approved for PrEP, following emtricitabine/tenofovir disoproxil fumarate (Truvada) and emtricitabine/tenofovir alafenamide (Descovy), which is only indicated for men and transgender women.

Apretude FDA Indication

• Pre-exposure prophylaxis for all at-risk adults/adolescents >35 kg in weight
• Must have negative HIV-1 test prior to initiation

Dosage & Administration

With oral lead-in: Recommended to assess tolerability, but not required to reach adequate plasma concentrations.

• Month 1: cabotegravir oral tablets 30 mg by mouth for 28 days.
  • First intramuscular (IM) injection should be given on last day or within 3 days after last dose.
• Months 2, 3, 5, then every 2 months thereafter: Apretude IM injection 600 mg (3 mL).

Without oral lead-in:

• Months 1, 2, 4, then every 2 months thereafter: Apretude IM injection 600 mg (3 mL).

Apretude is an integrase strand-transfer inhibitor (INSTI) that is given as an IM gluteal injection by a health care provider every 2 months after the lead-in period. The injection can be given up to 7 days before or after the scheduled injection.

If a patient plans to miss a dose, they can take cabotegravir oral tablets 30 mg daily in the interim between injections. If an unplanned injection occurs, if it is within 3 months of the previous injection, then an every 2-month schedule can continue. If it has been greater than 3 months, the patient must re-complete the lead-in with 2 injections one month apart before resuming an every 2-month schedule.

Contraindications

• Unknown or positive HIV status.
• Hypersensitivity to cabotegravir.
• Coadministration with medications that are substrates of UGT1A1.
  • Anticonvulsants (carbamazepine, oxcarbamazepine, phenobarbital, phenytoin) and antimycobacterials (rifampin, rifapentine).

Warnings & Precautions

Patients should be counseled on adherence to dosing and HIV testing schedules. Patients who develop HIV while on Apretude should be transitioned to an HIV treatment regimen to avoid resistance.

When discontinuing Apretude, patients with a continued risk of HIV should be initiated on an alternative agent for PrEP within 2 months of the final injection.

Cabotegravir Adverse Events (AEs)

• Rare, but serious: hypersensitivity reactions, hepatotoxicity, depressive disorders.
• Common: injection site reactions, headache, diarrhea/GI upset, dizziness, fatigue.

Clinical Trials of Cabotegravir

Cabotegravir was approved based on the results of the HPTN 083 and HPTN 084 clinical trials.

HPTN 083: Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women

Study design:

• Randomized, double-blind, double dummy, non-inferiority trial in 4566 patients.
• Cabotegravir 600 mg IM every 8 weeks vs tenofovir disoproxil fumarate/emtricitabine (TDF-FTC) 300/200 mg PO once daily.
  • Patients in the cabotegravir group were given an oral lead-in.

Primary efficacy endpoint:

• Incidence of HIV infection: 13 patients in the cabotegravir group vs 39 in the TDF-FTC group.
  • Hazard ratio: 0.34 (95% CI, 0.18 to 0.62, P<0.001).
  • Cabotegravir was non-inferior to TDF-FTC.

Primary safety endpoint:

• Occurrence of a grade 2 or higher AE: 92.4% in the cabotegravir group vs 92.7% in the TDF-FTC group
  • There was no significant difference in the primary safety endpoint.

HPTN 084: Cabotegravir for the Prevention of HIV-1 in Women

Study design:

• Randomized, double-blind, double dummy, active-controlled, superiority trial in 3224 patients.
• Cabotegravir 600 mg IM every 8 weeks vs tenofovir disoproxil fumarate/emtricitabine (TDF-FTC) 300/200 mg PO once daily.
  • Patients in the cabotegravir group were given an oral lead-in for 5 weeks.

Primary efficacy endpoint:

• Incidence of HIV infection: 4 patients in the cabotegravir group vs 36 in the TDF-FTC group
  • Hazard ratio: 0.12 (95% CI, 0.05 to 0.31], p<0·0001)
  • Cabotegravir was superior to TDF-FTC

Primary safety endpoint:

• Occurrence of a grade 2 or higher AE: 92.1% in the cabotegravir group vs 92.3% in the TDF-FTC group.
  • There was no significant difference in the primary safety endpoint.

Conclusion

Overall, cabotegravir showed promising results in preventing HIV transmission in men, women, and transgender women with similar rates of AEs to oral PrEP options. The convenient long-acting injectable formulation may decrease HIV transmission rates further than oral medications in a real-world setting due to improved adherence.

About the Author

Chelsea Morken, PharmD, PGY2, is an ambulatory care pharmacy resident, Mayo Clinic Health System.

References

Apretude® [package insert]. Triangle Park, NC: GlaxoSmithKline. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215499s000lbl.pdf. December, 2021.

Landovitz RJ, Donnell D, Clement ME, et al. Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women. N Engl J Med. 2021;385(7):595-608. doi:10.1056/NEJMoa2101016

Delany-Moretlwe S, Hughes JP, Bock P, et al. Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial [published correction appears in Lancet. 2022 May 7;399(10337):1778]. Lancet. 2022;399(10337):1779-1789. doi:10.1016/S0140-6736(22)00538-4