Clinical Overview: Cabotegravir (Apretude) for HIV Pre-Exposure Prophylaxis

Cabotegravir (Apretude) is an injectable FDA-approved HIV-1 integrase strand transfer inhibitor (INSTI) used for pre-exposure prophylaxis (PrEP) in undiagnosed HIV-1 infection.¹ Approved in December 2021, it is the first injectable medication available for HIV-1 PrEP. Cabotegravir is the only current HIV-1 PrEP medication that does need to be taken daily.²

Previously approved as a treatment for HIV-1 infection,³ the FDA approved cabotegravir for HIV-1 PrEP based on the results of 2 international trials: HPTN 083 and HPTN 084. Both studies were randomized, double-blind trials comparing the risk of acquiring HIV-1 infection when using either injectable cabotegravir or once daily oral tenofovir disoproxil fumarate/emtricitabine.

Study participants administered cabotegravir were given oral cabotegravir and placebo to take daily for 5 weeks, followed by cabotegravir injections and daily oral placebo tablets. Study participants receiving tenofovir disoproxil fumarate/emtricitabine were given a placebo and tenofovir disoproxil fumarate/emtricitabine to take daily for 5 weeks, followed by daily tenofovir disoproxil fumarate/emtricitabine tablets and placebo injections.

HPTN 083 was a non-inferiority study comparing cabotegravir to tenofovir disoproxil fumarate/emtricitabine. The researchers randomized 4566 cisgender men and transgender women who have sex with men 1:1 to receive either cabotegravir injections every 2 weeks or tenofovir disoproxil fumarate/emtricitabine oral tablets daily for up to 153 weeks.

Study participants in the cabotegravir arm had a 69% reduction in risk of HIV-1 infection incidence when compared to the tenofovir disoproxil fumarate/emtricitabine arm.

HPTN 084 was a superiority study comparing cabotegravir to tenofovir disoproxil fumarate/emtricitabine that enrolled 3224 cisgender women. The researchers randomized participants 1:1 to receive either cabotegravir injections every 2 weeks or tenofovir disoproxil fumarate/emtricitabine oral tablets daily for up to week 153. This study revealed a 90% reduced risk of HIV-1 infection incidence in the cabotegravir group compared to the tenofovir disoproxil fumarate/emtricitabine group.^1,2

Mechanism of Action

Cabotegravir is the newest member of the INSTI antiretroviral medication class. HIV uses the enzyme integrase to incorporate its deoxyribonucleic acid (DNA) into the host CD4 cell.¹ All medications in the INSTI class bind to the integrase active site, thereby blocking viral DNA integration and subsequent HIV replication.⁴ Compared with other INSTIs, cabotegravir is one of the more potent agents with a mean 50% inhibitory concentration (IC50) of 3 nM.

Dosage and Administration

The FDA approved 2 dosing schedules for cabotegravir: 1 with and 1 without an optional 28-day oral lead-in. The oral lead-in is not required based on clinical safety and efficacy data from HIV-1 treatment trials.

Regardless of the chosen schedule, cabotegravir is dosed at 600 mg for adults and adolescents weighing at least 35 kilograms. If a dose is missed, prescribers should evaluate patients before continuing therapy to ensure cabotegravir remains the best HIV-1 PrEP choice (see Table 1 for manufacturer suggested make-up schedule).

If using optional lead-in, patients should receive 30 mg oral cabotegravir once daily for 28 days, followed by cabotegravir injection at months 2 and 3. Cabotegravir is given again at month 5 then repeated every 2 months.

When using the direct to injection regimen, oral cabotegravir is avoided. Cabotegravir injection is given at months 1 and 2. Patients will receive another dose at month 4 then repeat every 2 months.

Supplied as an extended-release cabotegravir 600 mg/3 mL suspension, cabotegravir is given as a gluteal intramuscular injection. Cabotegravir can be stored at 2o to 25o C and is packaged with administration supplies.

If a patient has a BMI exceeding 30 kg/m², health care providers should consider using a longer needle than provided in the kit. Before administration, they should visually inspect the suspension and discard it if the product is discolored or contains particulate matter.

They should shake the vial vigorously then draw the product aseptically into the provided syringe using the vial adaptor. If the injection is not given immediately, it may be stored in the syringe for up to 2 hours at room temperature.

Adverse Events (AEs)

Prescribers must monitor patients receiving cabotegravir for the development of hepatoxicity and depressive disorders. In clinical trials, injection site reaction was the most commonly reported AE. GI symptoms (diarrhea, nausea, flatulence, and abdominal pain) and neurologic symptoms (headache, pyrexia, fatigue, dizziness, and sleep disorders) were experienced in at least 1% of study participants.

When counseling patients, pharmacists need to remember this medication’s long-acting properties. Cabotegravir remains in the systemic circulation for at least 12 months.

Warnings/Precautions

Pharmacists need to counsel patients, focusing on adherence to testing and dosing schedule, before and during treatment with cabotegravir. Adherence is key to preventing HIV-1 infection and the formation of drug-resistant HIV-1 infection.

Accordingly, cabotegravir is contraindicated in individuals with unknown or positive HIV-1 status. An individual testing positive for HIV-1 must transition from cabotegravir to a complete HIV-1 treatment regimen.

Patients with a previous hypersensitivity reaction to cabotegravir must avoid further use. Medications that may significantly decrease cabotegravir plasma concentrations need to also be avoided.

These medications affect uridine diphosphate glucuronosyltransferase (UGT1A1) and include carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, and rifapentine.

Pregnancy/Lactation

Pregnant women should only use cabotegravir if the expected benefits outweigh potential fetal risks. It is not known whether the use of cabotegravir during pregnancy causes adverse outcomes.

Although data on cabotegravir use in pregnant women has not been evaluated, another INSTI, dolutegravir, is associated with neural tube defects. Providers can enroll pregnant women using cabotegravir with the Antiretroviral Pregnancy Registry to monitor outcomes.

Cabotegravir was present in the milk of lactating animals, but human data are lacking. Women who breastfeed should only take cabotegravir if the expected benefits outweigh the potential risks.

Pharmacists should counsel pregnant women, women of childbearing age, and women breastfeeding children of potential risks. As previously mentioned, practitioners should remember cabotegravir is present in the body for at least 12 months after discontinuation.¹

About the Author

Edmond M Nunes, PharmD, RPh, BCSCP is the pharmacy clinical coordinator at Sturdy Memorial Hospital in Attleboro, MA.

References

1. Apretude prescribing information. December 2021. Accessed March 6, 2022. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Apretude/pdf/APRETUDE-PI-PIL-IFU.PDF
2. US food & drug administration. FDA approves first injectable treatment for HIV pre-exposure prevention. Accessed March 6, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-first-injectable-treatment-hiv-pre-exposure-prevention
3. Cabenuva prescribing information. February 2022. Accessed March 6, 2022. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Cabenuva/pdf/CABENUVA-PI-PIL-IFU2-IFU3.PDF
4. HIV.gov. Integrase strand transfer inhibitors (INSTI). Accessed March 6, 2022. https://clinicalinfo.hiv.gov/en/glossary/integrase-strand-transfer-inhibitor-insti#:~:text=Integrase%20strand%20transfer%20inhibitors%20(INSTIs,integrase%20prevents%20HIV%20from%20replicating.