Introduction
Cabotegravir is an integrase strand transfer inhibitor (INSTI) antiretroviral medication used for the treatment and prevention of HIV-1 infection. It represents a significant advancement in HIV management as the first long-acting injectable antiretroviral regimen when combined with rilpivirine. Cabotegravir offers an alternative to daily oral therapy, potentially improving adherence and quality of life for appropriate patients.
Mechanism of Action
Cabotegravir inhibits HIV-1 integrase, an enzyme essential for viral replication. By blocking the strand transfer step of HIV-1 DNA integration into host chromosomal DNA, cabotegravir prevents the formation of the HIV-1 provirus. This action effectively halts the viral replication cycle, reducing viral load and preventing further infection of new cells.
Indications
Cabotegravir is approved for:
- Treatment of HIV-1 infection in adults as part of a complete regimen with rilpivirine, in patients who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and no known or suspected resistance to either cabotegravir or rilpivirine
- Pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in at-risk adults and adolescents weighing at least 35 kg
Dosage and Administration
For HIV Treatment (with rilpivirine):- Initiation: Oral lead-in with cabotegravir 30 mg plus rilpivirine 25 mg once daily for approximately one month to assess tolerability
- Maintenance: Cabotegravir 600 mg (3 mL) plus rilpivirine 900 mg (3 mL) intramuscular injections monthly or cabotegravir 400 mg (2 mL) plus rilpivirine 600 mg (2 mL) every 2 months
- Initiation: Oral lead-in with cabotegravir 30 mg daily for approximately one month
- Maintenance: Cabotegravir 600 mg (3 mL) intramuscular injection every 2 months
- Administer by deep intramuscular injection into the gluteal muscle
- Use separate injection sites for each medication when administered with rilpivirine
- Rotate injection sites between left and right gluteal muscles
- Hepatic impairment: No dosage adjustment recommended for mild to moderate impairment; not studied in severe impairment
- Renal impairment: No dosage adjustment recommended
- Elderly: No specific dosage adjustment recommended
- Pediatrics: Approved for PrEP in adolescents weighing ≥35 kg
Pharmacokinetics
Absorption: Following IM administration, peak plasma concentrations are achieved approximately 7 days post-injection. Absolute bioavailability of IM formulation is approximately 90%. Distribution: Apparent volume of distribution is approximately 198 L. Protein binding is >99%, primarily to albumin. Cerebrospinal fluid penetration is limited. Metabolism: Primarily metabolized by UGT1A1 with some contribution from UGT1A9. Cabotegravir does not inhibit or induce major CYP450 enzymes. Elimination: Terminal half-life is approximately 41.5 days following IM administration. Excretion is primarily fecal (47%) and urinary (27%) as metabolites.Contraindications
- Hypersensitivity to cabotegravir or any component of the formulation
- Concomitant use with drugs that strongly induce UGT1A1 (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) due to significantly decreased cabotegravir concentrations
- For PrEP: Use in individuals with unknown or positive HIV-1 status (must confirm HIV-negative status before initiation and periodically during therapy)
Warnings and Precautions
Hypersensitivity Reactions: Although rare, hypersensitivity reactions including rash, constitutional symptoms, and sometimes organ dysfunction have been reported. Discontinue immediately if hypersensitivity reaction is suspected. Hepatotoxicity: Hepatic adverse events have been reported. Monitor patients with underlying hepatic disease or co-infection with hepatitis viruses. Depressive Disorders: Mood disorders, including depression, have been reported with cabotegravir/rilpivirine combination therapy. Monitor patients for depression symptoms. Long-acting Properties: Consider the prolonged presence of cabotegravir after discontinuation (may persist for 12 months or longer). During this period, viral resistance may develop if adequate alternative antiretroviral therapy is not initiated. Injection Site Reactions: Very common (≥10%), including pain, tenderness, nodules, induration, swelling, erythema, pruritus, and ecchymosis. Typically mild to moderate and self-limiting. Risk of Drug Resistance with Undiagnosed HIV-1: For PrEP, must confirm HIV-negative status before initiation and at least every 4 months during therapy.Drug Interactions
Strong UGT1A1 Inducers: Concomitant use significantly decreases cabotegravir concentrations. Contraindicated with drugs such as:- Rifampin
- Rifapentine
- Carbamazepine
- Oxcarbazepine
- Phenytoin
- Phenobarbital
- St. John's wort (Hypericum perforatum)
- Etravirine
- Efavirenne
- Nevirapine
Adverse Effects
Common (≥10%):- Injection site reactions (pain, tenderness, nodules, induration)
- Pyrexia
- Fatigue
- Headache
- Musculoskeletal pain
- Nausea
- Sleep disorders
- Dizziness
- Rash
- Hypersensitivity reactions
- Hepatotoxicity
- Depressive disorders
- Post-injection reactions (systemic symptoms following injection)
Monitoring Parameters
Before initiation:- HIV-1 RNA viral load (must be <50 copies/mL for treatment)
- HIV-1 resistance testing (if available)
- Hepatitis B and C serology
- Liver function tests
- Renal function
- Pregnancy testing if appropriate
- Assessment of depression and mood disorders
- HIV-1 RNA viral load (monthly for first 6 months, then every 2-3 months)
- Clinical assessment for injection site reactions
- Monitoring for signs/symptoms of hypersensitivity
- Liver function tests (baseline and clinically indicated)
- Regular assessment of mood and depressive symptoms
- For PrEP: HIV testing every 4 months
Patient Education
- Understand that cabotegravir is part of a complete HIV treatment regimen and must be taken as prescribed
- For injectable formulation: Expect injection site reactions that typically resolve within a few days
- Report any signs of hypersensitivity (rash, fever, fatigue, muscle/joint pain, blisters, oral lesions, conjunctivitis, facial edema, difficulty breathing)
- Report any symptoms of depression or mood changes
- Understand the importance of adherence to the injection schedule
- For PrEP: Continue using other HIV prevention methods (condoms) until after first two injections; regular HIV testing is essential
- Inform healthcare providers about all medications being taken, including over-the-counter drugs and herbal supplements
- Understand that drug remains in the body for many months after last injection
References
1. FDA prescribing information: Vocabria (cabotegravir) and Cabenuva (cabotegravir/rilpivirine) 2. FDA prescribing information: Apretude (cabotegravir for PrEP) 3. Spreen WR, Margolis DA, Pottage JC Jr. Long-acting injectable antiretrovirals for HIV treatment and prevention. Curr Opin HIV AIDS. 2013;8(6):565-571. 4. Orkin C, Arasteh K, Hernández-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. 5. 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. 6. Clinical guidelines for the use of cabotegravir for treatment and prevention. US Department of Health and Human Services. 7. European AIDS Clinical Society Guidelines, version 11.0, October 2022.