Clinical Overview: Apretude for HIV Pre-Exposure Prophylaxis

On December 21, 2021, the FDA approved cabotegravir extended-release injectable suspension (Apretude) for adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of acquiring HIV through sexual activity.^1,2

Patients can take oral cabotegravir (Vocabria) prior to beginning Apretude to assess drug tolerance or they can initiate injections immediately with 2 loading injections administered 1 month apart followed by maintenance injections every 2 months thereafter.

“[The approval of Apretude] adds an important tool in the effort to end the HIV epidemic by providing the first option to prevent HIV that does not involve taking a daily pill. This injection, given every two months, will be critical to addressing the HIV epidemic in the US, including helping high-risk individuals and certain groups where adherence to daily medication has been a major challenge or not a realistic option,” said Dr. Debra Birnkrant, director of the Division of Antivirals in the FDA’s Center for Drug Evaluation and Research.²

Mechanisms of Action

Apretude is an antiretroviral drug that inhibits HIV replication by binding to the active site of integrase and blocking the strand transfer step of retroviral DNA integration. In other words, cabotegravir prevents the HIV DNA from being integrated into human DNA, which stops replication of the virus.^2,3

Dosage and Administration

Apretude contains an extended-release injectable suspension that is administered by a health care provider via gluteal intramuscular (IM) injection. Oral cabotegravir can be initiated prior to Apretude injection, or the patient may initiate PrEP with an Apretude injection without starting with oral cabotegravir.⁴

Oral lead-in dosing of Apretude is used to determine tolerability of the medication and will be decided between the health care provider and patient upon initiation of cabotegravir. Oral lead-in dosing is not necessary to ensure effective plasma concentration upon initiation of cabotegravir injections. Individuals taking oral lead-in dosing will take 30 mg of cabotegravir by mouth once daily for 28 days.⁴

Apretude is initiated with a single 600 mg, 3 mL IM injection given 1 month apart for 2 consecutive months. Individuals using oral lead-in dosing should administer Apretude within 3 days of taking their last oral lead-in dose of cabotegravir. After the 2 initial injections are administered, maintenance injections of Apretude consist of a single 600 mg, 3 mL IM injection taken every 2 months.⁴

Individuals may be given Apretude up to 7 days before or after the date the individual is scheduled to receive the injection. Individuals must weigh at least 35 kg to receive Apretude for PrEP.

Clinical Studies

In the HPTN 083 clinical trial, 4566 cisgender men and transgender women who have sex with men and have evidence of high-risk behavior for HIV-1 infection were randomized to receive either Apretude or Truvada for up to 153 weeks.^4,5

Apretude demonstrated superiority compared with Truvada with a 69% reduction in acquiring HIV-1 infection relative to Truvada. Only 12 HIV-1 infections per 100 person-years were noted with Apretude patients versus 39 HIV-1 infections reported for Truvada patients.

In the HPTN 084 clinical trial, 3224 cisgender women were randomized to receive either Apretude or Truvada for up to 153 weeks. As with the HPTN 083 clinical trial, Apretude exhibited superiority in meeting the primary endpoint of HIV-1 infection incidence compared with Truvada.

Apretude demonstrated a 90% reduction in the risk of acquiring HIV-1 infection compared with Truvada. Truvada patients experienced 36 HIV-1 incident infections per 100 person-years compared with 3 incident infections experienced by the Apretude patients.^4,5

Warnings and Precautions

Apretude carries a warning concerning the development of drug resistance with use for HIV-1 PrEP in patients with an undiagnosed HIV-1 infection. Prior to initiation of Apretude or oral cabotegravir therapy and with each injection of Apretude, individuals must test for HIV-1 infection using a test approved by the FDA for the diagnosis of HIV-1 infection.⁴

Apretude cannot be used for PrEP unless negative infection status is confirmed. If an individual becomes infected with HIV-1 while receiving Apretude for PrEP, they must transition to a complete HIV-1 treatment regimen.

Apretude is not always effective in preventing HIV-1 acquisition and should be used as part of a prevention strategy that includes adherence to the administration schedule and use of condoms to reduce the risk of sexually-transmitted infections (STIs). The time from initiation of Apretude to maximal protection against HIV-1 infection is unknown. The risk of HIV-1 acquisition becomes greater from condomless sex, past or current STIs, having sexual partners of unknown HIV-1 status, or sexual activity in high prevalence areas.

Serious hypersensitivity reactions have been reported with integrase inhibitors and could occur with Apretude. Initiation of oral cabotegravir dosing prior to Apretude injections can help identify patients who could be at risk of developing a hypersensitivity reaction. Discontinue Apretude if a hypersensitivity reaction occurs.

Hepatotoxicity has been reported in patients taking cabotegravir with or without known pre-existing hepatic disease or risk factors. Depressive disorders such as depression and depressed mood have been reported with Apretude. Assess individuals with depressive symptoms to determine whether the symptoms are related to Apretude use and to determine whether the risks of continued therapy outweigh the benefits.

Adverse Reactions

Injection site reactions are the most common adverse effect (AE) of Apretude and were the only AE to occur in greater than 5% of HPTN 083 trial participants. Researchers found that 82% of HPTN 083 trial participants experienced injection site reactions, with 3% discontinuing therapy as a result.⁴

In HPTN 083, the most prominent injection site reaction experienced by patients reporting at least 1 ISR was pain and tenderness (98%). Swelling (12%), nodules (15%), and induration (15%) were also somewhat commonly experienced. Patients taking Apretude can also experience diarrhea (4%), headache (12%), fatigue (3%), nausea (4%), and dizziness (4%), according to HPTN 084 clinical trial results.⁴

Use of Apretude can also lead to certain laboratory abnormalities, the most common being an increase in creatine phosphokinase (15%, HPTN 083). Serum lipids can also increase from baseline. Triglycerides increased a median of 2.7 mg/dL in HPTN 083 patients and low-density lipoprotein and total cholesterol increased a median +1.0 mg/dL.

For a comprehensive list of AEs, refer the patient to the FDA package insert.

Contraindications

Use of Apretude is contraindicated in patients with unknown or positive HIV-1 status. Apretude can lead to the development of drug resistance with use for HIV-1 PrEP in patients with an undiagnosed HIV-1 infection. Do not use Apretude in patients who previously had a hypersensitivity reaction to cabotegravir.⁴

Drug Interaction Studies

Based upon drug interaction trials following oral administration of cabotegravir or predicted interactions, coadministration with the following agents and Apretude is contraindicated due to the potential for significant decreases in Apretude plasma concentrations: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, and rifapentine. An altered dosing schedule of Apretude is recommended when coadministered with rifabutin.⁴

UGT1A1 and UGT1A9 are primarily responsible for the metabolism of cabotegravir. Drugs that are strong induces of UGT1A1 or 1A9 are contraindicated with Apretude due to the potential for significant decreases in cabotegravir plasma concentrations that such agents can cause.

No clinically significant changes in concentrations of Apretude were observed for the following agents when coadministered with Apretude: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, and rilpivirine.⁴

Use in Specific Populations

Pregnancy

Insufficient human data are available to establish whether Apretude poses a risk to pregnancy outcomes. There is a pregnancy exposure registry that monitors outcomes in women exposed to Apretude during pregnancy. Health care providers are encouraged to register their patients by calling the Antiretroviral Pregnancy Registry.⁴

Lactation

It is unknown whether or not cabotegravir is present in human breast milk, affects human milk production, or has effects on breastfed infants. Cabotegravir was present in the milk of lactating rats.⁴

Cabotegravir can persist in humans for up to 12 months. It is recommended that women breastfeed only if the expected benefit justifies the potential risk to the infant.

Pediatric Use

The safety and efficacy of Apretude have not been established in pediatric patients less than 12 years of age. Two open-label multicenter clinical trials are being conducted to determine the safety and efficacy of Apretude in adolescent populations. In adolescents receiving Apretude of HIV-1 PrEP, the safety data were comparable to the safety data reported in adults receiving Apretude for HIV-1 PrEP.

Geriatric Use

No dose adjustments are required in elderly individuals, but there are limited data available on the use of Apretude in individuals 65 years of age and older. Caution should be used when administering Apretude in elderly individuals because of the increased frequency of hepatic, renal, or cardiac issues, as well as concomitant diseases and other drug therapies experienced or utilized in this population.

Renal Impairment

No Apretude dose adjustment is required for individuals with mild or moderate renal impairment. For individuals with severe or end stage renal impairment, monitoring for AEs is recommended. Effects of dialysis on Apretude pharmacokinetics are unknown, but cabotegravir is >99% protein bound so dialysis is not expected to alter plasma.

Hepatic Impairment

No dosage adjustment of Apretude is required in patients with mild or moderate (Child-Pugh Class A or B) hepatic impairment. Apretude has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

Storage and Handling

Store Apretude at 2^oC to 25^oC (36^oF to 77^oF) in the original carton. Exposure up to 30^oC (86^oF) are permitted. Do not mix with any other product or diluent and do not freeze.

About the Author

Daniel Paul earned his Bachelor of Science in Biology from Allegheny College and his Doctor of Pharmacy degree from Duquesne University in Pittsburgh. He is currently earning a Master of Pharmacy Business Administration (MPBA) at the University of Pittsburgh, a 12-month, executive-style graduate education program designed for working professionals striving to be tomorrow’s leaders in the business of medicines. Paul has spent the last 2.5 years working in Specialty Pharmacy, initially as a clinical pharmacist and most recently as the manager of Pharmacy Operations.

References

1. FDA Approves First Injectable Treatment for HIV Pre-Exposure Prevention. FDA News Release.https://www.fda.gov/news-events/press-announcements/fda-approves-first-injectable-treatment-hiv-pre-exposure-prevention.Published December 20, 2021. Accessed March 10, 2022.

2. ViiV Healthcare announces US FDA approval of Apretude (cabotegravir extended-release injectable suspension), the first and only long-acting injectable option for HIV prevention. ViiV Healthcare. News release. March 10, 2022.

3. Saro Arakelians. Daily Medication Pearl: Cabotegravir (Apretude) for HIV. Pharmacy Times. https://www.pharmacytimes.com/view/daily-medication-pearl-cabotegravir-apretude-for-hiv.Published January 14, 2022. Accessed March 10, 2022.

4. Apretude – HIGHLIGHTS OF PRESCRIBING INFORMATION. APRETUDE (cabotegravir) Label (fda.gov). Accessed March 10, 2022.

5. Alana Hippensteele. FDA Approves Apretude, the First, Only Long-acting Injectable Option for HIV Prevention. Pharmacy Times. https://www.pharmacytimes.com/view/fda-approves-apretude-the-first-only-long-acting-injectable-option-for-hiv-prevention.Published December 22, 2021. Accessed March 10, 2022.