Introduction
Cabenuva is a revolutionary long-acting injectable antiretroviral therapy for the treatment of HIV-1 infection in adults. It represents a significant advancement in HIV management by combining two antiretroviral medications—cabotegravir (an integrase strand transfer inhibitor) and rilpivirine (a non-nucleoside reverse transcriptase inhibitor)—into a monthly or every-two-month injection regimen. This formulation offers an alternative to daily oral therapy, potentially improving adherence and quality of life for appropriately selected patients.
Mechanism of Action
Cabenuva contains two active components with complementary mechanisms of action:
Cabotegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration, which is essential for the HIV replication cycle. Rilpivirine inhibits HIV-1 replication by non-competitively inhibiting HIV-1 reverse transcriptase (RT). It does not inhibit human cellular DNA polymerases α, β, or mitochondrial DNA polymerase γ.Together, these agents provide potent suppression of HIV replication through two distinct mechanisms, reducing the likelihood of resistance development.
Indications
Cabenuva is indicated for the treatment of HIV-1 infection in adults who:
- Are virologically suppressed (HIV-1 RNA <50 copies/mL)
- Are on a stable antiretroviral regimen with no history of treatment failure
- Have no known or suspected resistance to either cabotegravir or rilpivirine
This regimen is approved for both monthly (every 4 weeks) and every-two-month (every 8 weeks) dosing schedules after an initial oral lead-in period.
Dosage and Administration
Initiation Protocol:1. Oral lead-in with cabotegravir 30mg and rilpivirine 25mg once daily for approximately one month to assess tolerability 2. First injection: Cabenuva (cabotegravir 600mg/rilpivirine 900mg) administered intramuscularly in two separate gluteal injections 3. Maintenance dosing: Either monthly (cabotegravir 400mg/rilpivirine 600mg) or every two months (cabotegravir 600mg/rilpivirine 900mg)
Administration:- Administer by healthcare professional via intramuscular injection
- Use separate gluteal sites (preferably ventrogluteal or dorsogluteal)
- Rotate injection sites between appointments
- If a dose is missed by >7 days for monthly regimen or >14 days for every-two-month regimen, re-initiate with oral lead-in
- Hepatic impairment: No dosage adjustment needed for mild to moderate impairment; not studied in severe impairment
- Renal impairment: No dosage adjustment needed for mild to moderate impairment; not studied in severe impairment or ESRD
- Elderly: No specific dosage adjustment recommended
- Pregnancy: Limited data available; use only if potential benefit justifies potential risk
Pharmacokinetics
Absorption: Following IM administration, cabotegravir reaches peak concentration in approximately 7 days; rilpivirine reaches peak concentration in approximately 4 days. Bioavailability is nearly 100% for both components via IM route. Distribution: Both components are highly protein-bound (>99%). Cabotegravir has a volume of distribution of 1.5 L/kg; rilpivirine has a volume of distribution of 1.7 L/kg. Metabolism: Cabotegravir is primarily metabolized by UGT1A1 and UGT1A9. Rilpivirine is primarily metabolized by CYP3A4. Elimination: Cabotegravir has a half-life of approximately 5.5-11 weeks; rilpivirine has a half-life of approximately 13-28 weeks. Both are eliminated primarily via hepatic metabolism.Contraindications
- Previous hypersensitivity reaction to cabotegravir or rilpivirine
- Concomitant use with the following medications due to potential for decreased rilpivirine concentrations:
- Carbamazepine, oxcarbazepine, phenobarbital, phenytoin - Rifampin, rifapentine - Dexamethasone (more than a single dose) - St. John's wort (Hypericum perforatum)
Warnings and Precautions
Hypersensitivity Reactions: May include rash, constitutional symptoms, and sometimes organ dysfunction. Discontinue immediately if hypersensitivity suspected. Post-Injection Reactions: Approximately 1% of patients experience post-injection reaction syndrome within minutes after injection, including symptoms such as anxiety, flushing, sweating, nausea, and abdominal pain. These typically resolve within several hours. Hepatotoxicity: Hepatic adverse events have been reported. Monitor liver function before and during treatment. Depressive Disorders: Depression, depressed mood, anxiety, and sleep disturbances have been reported. Monitor patients with pre-existing psychiatric illness. Long-acting Properties: Consider the prolonged half-life and potential prolonged adverse reactions when discontinuing therapy.Drug Interactions
Strong CYP3A Inducers: Concomitant use may significantly decrease rilpivirine concentrations, leading to loss of virologic response and possible resistance. Contraindicated. CYP3A Inhibitors: May increase rilpivirine concentrations. Monitor for increased adverse effects. Drugs Affecting Gastric pH: H2-receptor antagonists and proton pump inhibitors may decrease rilpivirine absorption. Avoid concomitant use. Other Antiretrovirals: Not studied with other antiretroviral medications. Use only as complete regimen.Adverse Effects
Common Adverse Reactions (≥2%):- Injection site reactions (pain, induration, nodules, swelling, erythema)
- Pyrexia
- Fatigue
- Headache
- Musculoskeletal pain
- Nausea
- Sleep disorders
- Dizziness
- Rash
- Hypersensitivity reactions
- Hepatotoxicity
- Depressive disorders
- Post-injection reactions
Monitoring Parameters
Prior to Initiation:- HIV-1 RNA viral load (must be <50 copies/mL)
- Resistance testing (ensure no resistance to cabotegravir or rilpivirine)
- Liver function tests
- Assessment of psychiatric history
- HIV-1 RNA viral load at regular intervals (monthly for first 6 months, then every 3-6 months)
- Liver function tests periodically
- Monitoring for injection site reactions
- Assessment of mood and psychiatric symptoms
- Pregnancy testing if applicable
Patient Education
- Cabenuva requires regular healthcare visits for administration
- Complete the oral lead-in period as prescribed
- Report any injection site reactions that are severe or persistent
- Immediately report symptoms of hypersensitivity (rash, fever, fatigue)
- Inform healthcare providers about all medications being taken
- Do not stop treatment without consulting healthcare provider due to long-acting nature
- Use alternative contraception methods if appropriate, as drug interactions may affect hormonal contraception
- Continue treatment until healthcare provider advises discontinuation
- Understand that missed doses may require re-initiation with oral therapy
References
1. U.S. Food and Drug Administration. (2021). Cabenuva prescribing information. 2. Orkin C, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382(12):1124-1135. 3. Swindells S, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 2020;382(12):1112-1123. 4. ClinicalInfo.HIV.gov. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. 5. Jaeger H, et al. Long-acting injectable cabotegravir + rilpivirine for HIV maintenance therapy: Week 48 pooled analysis of phase 3 ATLAS and FLAIR trials. J Int AIDS Soc. 2020;23(Suppl 5):e25587. 6. Overton ET, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M): 96-week results. Lancet HIV. 2021;8(11):e679-e689.