Can lenacapavir be used for Pre-Exposure Prophylaxis (PrEP)?

Lenacapavir for Pre-Exposure Prophylaxis (PrEP)

Lenacapavir administered as a 927 mg subcutaneous injection every 6 months is strongly recommended for HIV PrEP in adults and adolescents weighing at least 35 kg who are at risk for HIV acquisition. 1, 2

Clinical Efficacy and Evidence Base

The recommendation for lenacapavir is supported by exceptionally strong clinical trial data demonstrating superior efficacy compared to existing PrEP options:

• The PURPOSE-1 trial demonstrated 100% efficacy in preventing HIV infections among cisgender women in Southern and Eastern Africa (background incidence 2.41 per 100 person-years), with zero detected HIV infections in the lenacapavir arm. 1, 2, 3

• The PURPOSE-2 trial showed 96% reduction in HIV incidence among cisgender men, transgender women, transgender men, and gender-nonbinary persons, with only 2 infections occurring (HIV incidence 0.10 per 100 person-years versus estimated background incidence of 2.37 per 100 person-years). 1, 2, 4

• Lenacapavir demonstrated superiority over daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF) in head-to-head comparison, with an incidence rate ratio of 0.11 (95% CI, 0.02 to 0.51; P = 0.002). 4

• CDC's GRADE analysis concluded there is high certainty of evidence for both efficacy and safety, leading to a strong recommendation for lenacapavir as a PrEP option. 5

Pre-Initiation Requirements

Before starting lenacapavir, the following comprehensive testing panel is mandatory:

HIV Testing

• Fourth- or fifth-generation laboratory-based HIV antigen-antibody assay is required to exclude acute and established HIV infection. 1, 2
• HIV RNA (viral load) testing with lower limit of quantification ≤50 copies/mL must be performed to detect acute HIV infection that may be missed by antibody testing. 1, 2

Additional Laboratory Testing

• Serum creatinine and estimated creatinine clearance to assess baseline renal function. 1, 2
• Hepatitis B surface antigen testing to identify chronic hepatitis B infection. 1, 2
• Hepatitis C IgG antibody testing for baseline hepatitis C screening. 1, 2
• Syphilis testing as part of comprehensive STI screening. 1, 2
• Pregnancy testing for individuals of childbearing potential, with counseling about known and unknown risks if pregnancy is present or planned. 1, 2

Administration Protocol

Initial Dosing

The first subcutaneous injection (927 mg) must be overlapped with 2 daily oral doses of lenacapavir 600 mg to achieve adequate protective drug levels immediately. 1 This loading strategy is critical and should not be omitted.

Ongoing Injections

• Administer 927 mg subcutaneously every 6 months (every 26 weeks) after the initial dose. 2, 4

Monitoring Requirements During PrEP

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 for laboratory results). 1, 2
• Combined HIV antibody and antigen testing at 1 month after initiating lenacapavir to detect any breakthrough infections during the early period. 1, 2
• Continue HIV testing every 6 months (at each injection visit). 1

STI and Other Monitoring

• STI testing (gonorrhea, chlamydia, and syphilis) every 4 months (every second injection). 1, 2
• Liver enzyme tests every 6 months to monitor for hepatotoxicity. 1, 2
• 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. 1, 2

Safety Profile and Adverse Effects

Lenacapavir has an excellent safety profile with no significant safety concerns identified in clinical trials. 5, 4

• Injection site reactions are the most common adverse effect, occurring in 63% of participants, but are typically mild (grade 1) to moderate (grade 2). 3, 4
• Only 1.2% of participants discontinued lenacapavir due to injection-site reactions in the PURPOSE-2 trial (26 of 2183 participants). 4
• Gastrointestinal symptoms and headache are other common but generally mild adverse effects. 3, 6

Critical Drug Interactions

Absolute Contraindications

Rifampin, carbamazepine, and other strong CYP3A inducers are absolute contraindications as they significantly reduce lenacapavir concentrations and may compromise efficacy. 1

Dose Adjustments Required

Rifabutin requires dose adjustment if coadministered with lenacapavir. 1

Discontinuation Protocol

If lenacapavir is discontinued but ongoing HIV risk continues, transition to another recommended PrEP regimen no later than 28 weeks after the final injection. 1, 2 This timing is critical because:

• Residual concentrations of lenacapavir may remain in systemic circulation for up to 12 months or longer after discontinuation, but protective levels decline before complete elimination. 2
• The 28-week window ensures continuous HIV protection without gaps in coverage. 1

Special Populations

Adolescents

Lenacapavir is approved for adolescents weighing at least 35 kg (77 lbs), with the same dosing and monitoring requirements as adults. 1, 5

Pregnancy

Pregnancy testing is required before initiation for individuals of childbearing potential. 1, 2 Counseling about known and unknown risks should be provided to pregnant individuals considering lenacapavir, as data in pregnancy are limited. 1

Advantages Over Existing PrEP Options

The twice-yearly dosing schedule addresses the major adherence challenges that have limited the effectiveness of daily oral PrEP, particularly in populations where adherence to daily tablets has been problematic. 7 This represents a transformative advance in HIV prevention, especially for adolescent girls and young women in sub-Saharan Africa who have struggled with daily oral PrEP adherence. 7

The International Antiviral Society-USA Panel (2024) recognizes lenacapavir as a future option for PrEP, noting that with the advent of effective injectables like lenacapavir, a global commitment to universal access is crucial for equitable implementation. 8