What is the recommended dosing regimen for lenacapavir (Sunlenca) as long‑acting pre‑exposure prophylaxis (PrEP) in individuals weighing at least 35 kg?

Lenacapavir Dosing for PrEP

For individuals weighing ≥35 kg (≥77 lbs) at risk for HIV acquisition, initiate lenacapavir with 927 mg subcutaneous injection (two 1.5-mL injections at least 4 inches apart) plus 600 mg oral (two 300-mg tablets) on Day 1, followed by 600 mg oral on Day 2, then maintain with 927 mg subcutaneous injection every 6 months (26 weeks ±2 weeks). 1

Loading Regimen

The CDC 2025 PrEP Guidelines strongly recommend the following initiation sequence 1:

• Day 1: 927 mg subcutaneous injection (administered as two separate 1.5-mL injections at least 4 inches apart in the abdomen or anterior thigh) PLUS 600 mg orally (two 300-mg tablets)
• Day 2: 600 mg orally (two 300-mg tablets)

Time to protection: Protective drug levels are achieved approximately 2 hours after the Day 2 oral dose if both loading days are completed. If both oral loading doses are missed, protection is delayed to 21-28 days. 1

Maintenance Dosing

• 927 mg subcutaneous injection every 6 months (26 weeks) ±2 weeks from the date of the last injection 1
• Administered as two 1.5-mL injections at least 4 inches apart
• Injection sites: abdomen or anterior thigh at 90° angle (not ≤45°, which causes intradermal injection and increases reaction risk) 1

Eligibility Requirements Before First Dose

Critical pre-treatment screening 1:

• Negative blood-based HIV antigen/antibody test within 7 days before first dose
• Negative confirmatory HIV RNA test if available (though results should not delay initial injection—obtain contact information to relay any positive results)
• No signs or symptoms of acute HIV infection (if suspected, perform HIV RNA testing before initiating)
• No significant drug interactions or contraindications (check for CYP3A inducers)

When switching from tenofovir-based or cabotegravir PrEP without interruption: Only a laboratory-based HIV antigen/antibody test is needed (no confirmatory RNA test required) 1

Managing Missed Injections

Planned Missed Injection (≥14 days late)

If a maintenance injection will be ≥14 days late 1:

• Prescribe 300 mg oral lenacapavir once every 7 days for up to 6 months
• First oral dose taken 6 months after last injection
• Resume maintenance injection within 7 days after the last oral dose

Unplanned Missed Injection (>28 weeks since last injection)

If more than 28 weeks have elapsed without oral bridging 1:

• Clinically reassess the patient, including consideration of lenacapavir resistance testing
• Reinitiate with full loading regimen (Day 1 and Day 2 as above)
• Then continue with maintenance injection dosing

Follow-Up Schedule

Every 6 months (or more frequently as needed) 1:

• HIV testing: Blood-based antigen/antibody test before each injection. If using rapid HIV test for follow-up injections, obtain confirmatory laboratory-based test as well (oral HIV antibody tests should NOT be used due to low sensitivity for recent infection)
• STI screening: Vaginal, oral, rectal, urine, or blood as indicated—may need more frequent screening than lenacapavir visits based on risk
• Hepatitis B considerations when switching from tenofovir-based PrEP: Ensure patient does not have HBV infection or is HBV immune. If HBV-infected, initiate alternative HBV treatment before discontinuing tenofovir. Provide HBV vaccination if not immune 1

Critical Safety Considerations

Injection Site Reactions

Most common adverse event with lenacapavir 1:

• Subcutaneous nodules (can be several centimeters, lasting months to >1 year)
• Pain and induration
• Mostly mild (grade 1) to moderate (grade 2)
• Prevention: Use 90° injection angle (NOT ≤45°, which causes intradermal injection)
• Management: Ice packs and topical/oral analgesics before and after injection
• Discontinuation due to injection site reactions is rare (≤1.2%) 2

Drug-Drug Interactions

1:

• Strong and moderate CYP3A inducers require supplemental lenacapavir dosing (consult FDA prescribing information)
• Lenacapavir increases concentrations of certain medications for up to 9 months after last injection—requires dose adjustments and monitoring

Evidence Base

This recommendation is based on high-certainty evidence from two phase III randomized controlled trials (PURPOSE 1 and PURPOSE 2) demonstrating 1:

• 100% efficacy in preventing HIV infection among cisgender women (PURPOSE 1)
• 96% efficacy among cisgender men, transgender women, transgender men, and gender-nonbinary persons (PURPOSE 2)
• HIV incidence: 0.00-0.10 per 100 person-years with lenacapavir versus 2.37-2.41 per 100 person-years background incidence 1, 3
• Number needed to treat: 70 (14 fewer HIV infections per 1000 people treated) 3

The CDC PrEP Guidelines Work Group used GRADE methodology and strongly recommends lenacapavir as a PrEP option for persons weighing ≥35 kg who would benefit from PrEP. 1

Common Pitfalls to Avoid

1. Do NOT use oral HIV antibody tests for follow-up—low sensitivity for recent infection 1
2. Do NOT inject at ≤45° angle—causes intradermal injection and severe reactions 1
3. Do NOT forget hepatitis B screening when switching from tenofovir-based PrEP 1
4. Do NOT delay initial injection for HIV RNA results—obtain contact information to relay results later 1
5. Do NOT restart without clinical reassessment if >28 weeks elapsed—consider resistance testing 1