Contraindications and Considerations for Lenacapavir for PrEP
Absolute Contraindication
Lenacapavir is contraindicated with concomitant use of strong CYP3A inducers (such as rifampin, carbamazepine, phenytoin, St. John's wort), as these drugs decrease lenacapavir plasma concentrations and may result in loss of therapeutic effect and development of resistance. 1
Pre-Initiation Requirements
Mandatory Laboratory Testing Before Starting
- Fourth- or fifth-generation laboratory-based HIV antigen-antibody assay 2, 3
- HIV RNA (viral load) testing with lower limit of quantification ≤50 copies/mL 2, 3
- Serum creatinine and estimated creatinine clearance 3
- Hepatitis B surface antigen 3
- Hepatitis C IgG antibody 3
- Syphilis testing 3
- Pregnancy testing for individuals of childbearing potential 3
Critical Pre-Dosing Protocol
The first subcutaneous injection must be overlapped with 2 daily oral doses of lenacapavir 600 mg to achieve adequate drug levels. 2 This oral lead-in is essential for immediate protection.
Administration Considerations
Injection Site Reactions
- Injection site reactions (ISRs) are common and may include swelling, pain, erythema, nodules, induration, pruritus, or mass formation. 1
- Nodules and indurations can persist for prolonged periods—in clinical studies, 30% of nodules and 13% of indurations from first injections had not fully resolved after median follow-up of 553 days. 1
- Must administer subcutaneously into the abdomen only—do NOT administer intradermally due to risk of serious injection site reactions. 1
- Injection site reactions often diminish in severity over time 2
Proper Administration Technique
- Must be administered by a healthcare provider using aseptic technique 1
- Visually inspect solution for particulate matter and discoloration before administration 1
- Two 1.5 mL injections are required for a complete dose 1
- Administer as soon as possible after withdrawal from vials 1
Ongoing Monitoring Requirements
Regular HIV Testing Schedule
- Rapid point-of-care HIV testing on the day of each injection, with combined antibody and antigen test sent to laboratory (do not delay injection) 3
- Combined HIV antibody and antigen testing at 1 month after initiating lenacapavir 3
- Continue HIV testing every 6 months (at each injection visit) 3
Additional Laboratory Monitoring
- STI testing (gonorrhea, chlamydia, syphilis) every 4 months (every second injection) 3
- Liver enzyme tests every 6 months 3
- Annual hepatitis C antibody testing, or every 3-6 months for people who inject drugs and men who have sex with men who use recreational drugs 3
Long-Acting Properties and Associated Risks
Prolonged Drug Persistence
Residual concentrations of lenacapavir may remain in systemic circulation for up to 12 months or longer after the last subcutaneous dose. 1 This creates several critical considerations:
- Maintenance dosing by injection is required every 6 months—missed doses or non-adherence could lead to loss of virologic response and development of resistance 1
- Lenacapavir acts as a moderate CYP3A inhibitor and may increase exposure to drugs primarily metabolized by CYP3A initiated within 9 months after the last subcutaneous dose 1
Discontinuation Protocol
If lenacapavir is discontinued but ongoing HIV risk continues, transition to another recommended PrEP regimen (such as tenofovir-based oral PrEP) no later than 28 weeks after the final injection to minimize risk of developing viral resistance. 2, 3, 1 That alternative regimen should be continued as long as HIV exposures continue 2.
Special Populations
Pregnancy Considerations
- Pregnancy testing is required before initiation for individuals of childbearing potential 3
- The FDA label does not provide specific guidance on use during pregnancy, and clinical trial data are limited
- Counseling about known and unknown risks should be provided to pregnant individuals considering lenacapavir
Adolescents
- Approved for adolescents weighing at least 35 kg 3
- Same dosing and monitoring requirements apply
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, though this is primarily a treatment consideration rather than PrEP-specific. 1 During initial treatment, patients whose immune system responds may develop inflammatory responses to indolent or residual opportunistic infections 1.
Drug Interaction Considerations
Absolute Contraindications (Strong CYP3A Inducers)
- Rifampin
- Carbamazepine
- Phenytoin
- Phenobarbital
- St. John's wort
- Other strong CYP3A inducers 1
Dose Adjustment Required
Rifabutin requires dose adjustment if coadministered, though specific guidance for lenacapavir is not provided in current guidelines (this recommendation is for cabotegravir). 2
Medications to Monitor
- Any drugs primarily metabolized by CYP3A may have increased exposure when initiated within 9 months of last lenacapavir dose 1
- Evaluate all concomitant medications before prescribing
Common Pitfalls to Avoid
- Never skip the 2-day oral lead-in with 600 mg lenacapavir before the first injection 2
- Never delay HIV testing on injection day—use rapid point-of-care test and do not delay injection while awaiting laboratory results 3
- Never administer intradermally—subcutaneous abdominal administration only 1
- Never discontinue lenacapavir without transitioning to alternative PrEP if ongoing HIV risk continues 2, 3
- Never miss the 6-month injection window—adherence to every-6-month dosing is critical to prevent resistance 1
- Never prescribe with strong CYP3A inducers 1
Efficacy Data Supporting Use
- PURPOSE-1 trial demonstrated 100% efficacy in cisgender women (no detected HIV infections vs. background incidence of 2.41 per 100 person-years) 2, 3
- PURPOSE-2 trial demonstrated 96% reduction in HIV incidence in cisgender men, transgender people, and nonbinary individuals (0.10 vs. 2.37 per 100 person-years) 2, 3, 4