What is the recommended antiretroviral therapy (ART) regimen for a patient with heavy resistance to antiretroviral therapy (ART) but sensitivity to cabotegravir (Integrase Strand Transfer Inhibitor) and potential benefit from sunlenca (Lenacapavir), including dosing and treatment duration?

Mechanism of Action: Cabotegravir Plus Lenacapavir (Sunlenca) in Heavily Treatment-Experienced Patients

Direct Answer

For patients with extensive multiclass HIV resistance who retain sensitivity to cabotegravir and can benefit from lenacapavir, this dual-agent regimen provides viral suppression through two distinct, non-overlapping mechanisms: cabotegravir blocks HIV integration into host DNA as an integrase strand transfer inhibitor, while lenacapavir disrupts multiple stages of the viral lifecycle as a capsid inhibitor, creating a potent combination that overcomes existing resistance patterns. 1, 2

Mechanistic Framework

Cabotegravir's Mechanism

• Integrase strand transfer inhibition: Cabotegravir is a second-generation integrase strand transfer inhibitor (InSTI) that prevents HIV-1 integrase from inserting viral DNA into the host cell chromosome 3, 4
• High genetic barrier: As a second-generation InSTI, cabotegravir maintains activity even when first-generation InSTIs (raltegravir, elvitegravir) have failed, provided no InSTI-specific resistance mutations are present 1
• Long-acting formulation: The injectable nanoformulation provides sustained drug levels for extended periods, maintaining therapeutic concentrations that suppress viral replication 4, 5

Lenacapavir's Novel Mechanism

• Capsid inhibition: Lenacapavir (Sunlenca) represents a completely novel mechanism of action by targeting the HIV-1 capsid protein at multiple stages of the viral lifecycle 1, 2
• Multi-stage disruption: This agent interferes with capsid-mediated nuclear entry of HIV DNA, capsid disassembly, and virion assembly—processes that are independent of reverse transcription, integration, or protease activity 2
• Activity against multiclass resistance: Because lenacapavir targets a different viral protein than NRTIs, NNRTIs, protease inhibitors, or InSTIs, it retains full activity against viruses with extensive resistance to these traditional drug classes 1, 2

Why This Combination Works in Heavily Resistant HIV

Complementary Resistance Profiles

• Non-overlapping resistance patterns: Mutations conferring resistance to NRTIs, NNRTIs, and protease inhibitors do not affect cabotegravir or lenacapavir activity 1
• Two fully active agents: The 2025 International Antiviral Society-USA guidelines specifically recommend agents with novel mechanisms of action like lenacapavir in combination to achieve two fully active drugs in patients with extensive multiclass resistance (evidence rating: AIa) 1
• Preserved integrase pathway: If the patient's virus remains sensitive to cabotegravir (no InSTI resistance), this pathway remains fully exploitable for viral suppression 1

Synergistic Viral Suppression

• Dual blockade strategy: Cabotegravir prevents integration of any reverse-transcribed viral DNA, while lenacapavir prevents proper capsid function needed for viral entry and assembly 2, 4
• High barrier to resistance development: Using two fully active agents from different classes simultaneously makes it extremely difficult for the virus to develop escape mutations to both drugs 1
• Long-acting formulations: Both agents can be administered as long-acting injectables (cabotegravir monthly or every 2 months, lenacapavir every 6 months), which improves adherence and maintains consistent drug levels 2, 4, 5

Recommended Dosing Regimen

Lenacapavir (Sunlenca) Initiation - Two Options 2

Option 1:

• Day 1: 927 mg subcutaneous injection (2 × 1.5 mL) + 600 mg oral (2 × 300 mg tablets)
• Day 2: 600 mg oral (2 × 300 mg tablets)
• Maintenance: 927 mg subcutaneous every 6 months (±2 weeks)

Option 2:

• Day 1: 600 mg oral (2 × 300 mg tablets)
• Day 2: 600 mg oral (2 × 300 mg tablets)
• Day 8: 300 mg oral (1 × 300 mg tablet)
• Day 15: 927 mg subcutaneous injection (2 × 1.5 mL)
• Maintenance: 927 mg subcutaneous every 6 months (±2 weeks)

Cabotegravir Dosing

• If using long-acting injectable: Initiate with oral lead-in (30 mg daily for 4 weeks) to assess tolerability, then 600 mg intramuscular injection monthly or 600 mg every 2 months 4, 5
• Coordination with lenacapavir: The lenacapavir every-6-month schedule can be coordinated with cabotegravir monthly or bimonthly injections 4, 5

Treatment Duration

• Indefinite therapy: This is lifelong suppressive therapy, not curative treatment 2, 6
• Maintenance phase: Continue every 6 months for lenacapavir and monthly/bimonthly for cabotegravir as long as viral suppression is maintained 2, 4

Critical Monitoring Parameters

Baseline Assessment

• Comprehensive resistance testing: Confirm sensitivity to cabotegravir (no major InSTI mutations) and document multiclass resistance to justify lenacapavir use 1, 2
• Viral load and CD4 count: Establish baseline values before initiating therapy 1
• Hepatitis B status: Important for overall treatment planning, though not a contraindication to this specific combination 1

Follow-Up Monitoring

• Viral load at 1 month: Check viral response shortly after regimen switch 7
• Viral load every 3 months: Continue frequent monitoring during the first year 7
• Injection site reactions: Monitor for serious injection site reactions with lenacapavir subcutaneous administration 2
• Adherence assessment: Counsel patients extensively about the importance of maintaining the injection schedule to prevent resistance development 2

Important Caveats and Pitfalls

Patient Selection Criteria

• Lenacapavir is specifically indicated: Only for heavily treatment-experienced adults with multidrug resistant HIV-1 whose current regimen is failing due to resistance, intolerance, or safety considerations 2
• Not for treatment-naive patients: This combination should not be used as initial therapy 2
• Documented sensitivity required: Resistance testing must confirm cabotegravir sensitivity before using this combination 1

Adherence Considerations

• Strict injection schedule: The FDA label emphasizes careful patient selection for those who agree to the required every-6-month injection schedule for lenacapavir 2
• Missed dose consequences: If more than 28 weeks elapse since the last lenacapavir injection without oral supplementation, reinitiation with loading doses is required 2
• Resistance risk with non-adherence: Missing scheduled doses increases the risk of viral rebound and resistance development 2

Resistance Testing Before Initiation

• Clinical reassessment: Patients should be clinically reassessed, including consideration of lenacapavir resistance testing, before resuming therapy after prolonged interruptions 2
• InSTI resistance exclusion: Confirm no documented or suspected InSTI resistance before using cabotegravir 1

Contraindications to Alternative Regimens

• Cabotegravir/rilpivirine is NOT appropriate: This patient has heavy resistance to antiretrovirals, and cabotegravir/rilpivirine is only approved for virologically suppressed patients without resistance to either agent 1, 7, 3
• Novel mechanisms required: The extensive resistance profile necessitates agents with novel mechanisms like lenacapavir rather than traditional drug classes 1