What are the treatment options for an adult patient living with HIV-1 (Human Immunodeficiency Virus type 1) infection, specifically regarding injectable antiretroviral therapy (ART) medications, such as cabotegravir and rilpivirine?

Injectable HIV Medications for Adults with HIV-1

Long-acting cabotegravir plus rilpivirine administered as intramuscular injections every 4 weeks (or every 8 weeks once approved) is the recommended injectable antiretroviral therapy for virologically suppressed adults with HIV-1 who have no history of treatment failure and no known resistance to either drug. 1

Patient Eligibility Criteria

Before initiating long-acting injectable therapy, patients must meet specific requirements:

• Viral suppression: HIV-1 RNA <50 copies/mL for at least 6 months on current stable antiretroviral regimen 2, 3
• No treatment failure history: No prior virological failure on any antiretroviral regimen 1
• No resistance mutations: No known or suspected resistance to cabotegravir or rilpivirine based on historical genotypic testing 1, 3
• No hepatitis B co-infection: This injectable regimen does not treat or protect against HBV 2
• Adequate adherence capacity: Patients must be able to attend scheduled injection appointments, as missed doses create prolonged subtherapeutic drug levels 1

Mandatory Oral Lead-In Phase

An oral lead-in period of approximately 4-5 weeks with daily cabotegravir 30mg plus rilpivirine 25mg tablets is required before starting injections to assess tolerability. 2, 3

This critical safety assessment period serves to:

• Identify potential tolerability issues before committing to long-acting injections 2
• Confirm viral suppression is maintained (check HIV RNA at 4-6 weeks) 2
• Screen for gastrointestinal side effects that could affect rilpivirine absorption 2

The last oral dose should be taken on the same day injections are initiated, and both oral medications must be taken with food. 3

Dosing Regimens

Every 4-Week Dosing (FDA Approved)

• Cabotegravir 400mg plus rilpivirine 600mg intramuscular injections monthly 1
• Evidence rating: AIa 1
• Viral suppression rates approach 95% through 96 weeks 1, 4

Every 8-Week Dosing (Conditional Recommendation)

• Cabotegravir 600mg plus rilpivirine 900mg intramuscular injections every 8 weeks 1
• Evidence rating: BIb (pending full regulatory approval) 1
• Non-inferior to 4-week dosing at 48 weeks 5

Critical caveat for 8-week dosing: Among the 1.5% who experienced virological failure with every 8-week dosing, 75% developed rilpivirine resistance and 60% developed integrase inhibitor resistance—a concerning pattern not observed with oral therapy or 4-week dosing. 1, 2 This underscores the absolute necessity of strict adherence to the injection schedule. 1

Clinical Efficacy and Quality of Life Benefits

The ATLAS and FLAIR phase 3 trials demonstrated:

• Non-inferiority to daily oral ART through 96 weeks 1, 4
• Viral suppression maintained in approximately 94-95% of participants 1
• Protocol-defined virological failure occurred in only 1% of patients 5
• Most participants preferred long-acting injections over their previous daily oral regimen 1

Quality of life advantages include:

• Elimination of daily pill burden (reduced to 12 injections per year with monthly dosing or 6 injections per year with every 8-week dosing) 2
• Reduction in NRTI-related bone, kidney, and cardiovascular complications 2
• Decreased HIV-related stigma associated with daily oral medications 6, 7

Adverse Effects and Tolerability

Injection site reactions are the most common adverse effect, occurring in approximately 88% of patients, but are typically mild to moderate and rarely lead to discontinuation. 1, 4

Specific injection site reaction characteristics:

• 84% are mild intensity, 15% moderate intensity 5
• Median duration is 3 days (range 2-4 days) 4
• Only 1-2% of patients discontinue due to injection site reactions 1, 2
• Frequency decreases over time with continued treatment 4

Other adverse effects include pyrexia, fatigue, and headache, but serious adverse events are uncommon (approximately 10% of patients, with none drug-related in major trials). 5, 8

Monitoring Requirements

Check HIV-1 RNA at 1 month after switching to injectable therapy, then every 3 months for the first year. 1, 2

Additional monitoring considerations:

• Assess for injection site reactions at each visit 4
• Screen for HBV before switching (with immunization if indicated, as this regimen does not treat HBV) 2
• Monitor for adherence to injection schedule, as missed appointments require intervention 2

Managing Missed Injections

If a patient plans to miss a scheduled injection by more than 7 days:

For monthly dosing schedule:

• Resume daily oral cabotegravir 30mg plus rilpivirine 25mg (with food) for up to 2 months 3
• Start oral therapy 1 month (±7 days) after the last injection 3
• For oral therapy durations exceeding 2 months, switch to an alternative oral regimen 3

For every 8-week dosing schedule:

• Resume daily oral cabotegravir 30mg plus rilpivirine 25mg (with food) for up to 2 months 3
• Start oral therapy approximately 2 months after the last injection 3
• For longer durations, use an alternative oral regimen 3

Contraindications and When NOT to Use Injectable Therapy

Do not use cabotegravir/rilpivirine in patients with:

• Known or suspected resistance to either cabotegravir or rilpivirine 9, 3
• History of virological failure on any prior regimen 1, 3
• Hepatitis B co-infection (requires tenofovir-containing regimen) 1, 2
• Poor adherence to care or inability to attend scheduled injections 1, 2
• Archived M184V/I mutations or NNRTI resistance 1

For patients with documented rilpivirine resistance, alternative injectable options such as lenacapavir (administered every 6 months) should be considered instead. 9

Risk of Treatment Failure

Long-acting cabotegravir plus rilpivirine carries a 1-2% risk of virological failure with emergence of 2-class resistance even with perfect adherence—a risk not observed with oral ART. 2

Risk factors for virological failure include:

• Rilpivirine-associated resistance at baseline 2
• Viral subtype A6 2
• BMI >30 2
• Poor adherence to injection schedule 1, 2

Clinicians must discuss the possibility of treatment failure and potential for viral transmission if virologic rebound occurs before initiating therapy. 2

Implementation Algorithm

1. Screen patient eligibility: Confirm viral suppression ≥6 months, no treatment failure history, no resistance mutations, no HBV co-infection 2, 3
2. Initiate oral lead-in: Cabotegravir 30mg + rilpivirine 25mg daily with food for 4-5 weeks 2, 3
3. Assess tolerability: Check HIV RNA at 4-6 weeks to confirm continued suppression 2
4. Start injections: If oral lead-in successful, begin monthly injections (cabotegravir 400mg + rilpivirine 600mg) on same day as last oral dose 3
5. Monitor closely: HIV RNA at 1 month, then every 3 months for first year 1, 2
6. Consider every 8-week dosing: Only after establishing tolerability and adherence with monthly dosing, and only if patient can reliably attend appointments 1, 2