What is the current status of lenacapavir (HIV capsid inhibitor) for Pre-Exposure Prophylaxis (PrEP) purposes?

Lenacapavir for HIV Pre-Exposure Prophylaxis: Clinical Trials and Current Status

Lenacapavir has demonstrated exceptional efficacy in two landmark Phase 3 trials (PURPOSE-1 and PURPOSE-2) and is now FDA-approved for HIV PrEP, administered as a 927 mg subcutaneous injection every 6 months for adults and adolescents weighing at least 35 kg. 1

Clinical Trial Evidence

PURPOSE-1 Trial (Cisgender Women)

• Demonstrated 100% efficacy in preventing HIV infections among cisgender women in Southern and Eastern Africa, with zero detected HIV infections against a background incidence of 2.41 per 100 person-years 2, 3
• This unprecedented efficacy represents a major breakthrough for HIV prevention in populations where adherence to daily oral PrEP has been particularly challenging 4

PURPOSE-2 Trial (Cisgender Men, Transgender, and Nonbinary Individuals)

• Achieved 96% reduction in HIV incidence with only 2 infections (HIV incidence 0.10 per 100 person-years) compared to estimated background incidence of 2.37 per 100 person-years 2, 3
• The incidence with lenacapavir was significantly lower than both background incidence (incidence rate ratio 0.04, P<0.001) and daily F/TDF (incidence rate ratio 0.11, P=0.002) 5
• Among 3,265 participants in the modified intention-to-treat analysis, HIV infections occurred in only 2 participants receiving lenacapavir versus 9 receiving daily F/TDF 5

Regulatory Status and Recommendations

• FDA approved lenacapavir in June 2025 for PrEP to reduce the risk of sexually acquired HIV-1 in adults and adolescents weighing at least 35 kg 1, 6
• CDC strongly recommends subcutaneous lenacapavir every 6 months as a PrEP option based on high certainty of evidence for efficacy and safety 6
• The International Antiviral Society-USA Panel recognizes lenacapavir as a crucial advancement, noting that with effective injectables like lenacapavir, global commitment to universal access is essential for equitable implementation 4

Pre-Initiation Requirements

Mandatory Testing Before First Injection

• Fourth- or fifth-generation laboratory-based HIV antigen-antibody assay plus HIV RNA testing with lower limit of quantification ≤50 copies/mL 4, 3
• Serum creatinine and estimated creatinine clearance 4, 3
• Hepatitis B surface antigen 4, 3
• Hepatitis C IgG antibody 4, 3
• Syphilis testing 4, 3
• Pregnancy testing for individuals of childbearing potential 4, 3

Critical Administration Protocol

• The first subcutaneous injection must be overlapped with 2 daily oral doses of lenacapavir 600 mg to achieve adequate drug levels 4
• This oral lead-in is mandatory and cannot be skipped 4

Ongoing Monitoring Schedule

HIV Testing Protocol

• Rapid point-of-care HIV testing on the day of each injection (do not delay injection for results), with combined antibody and antigen test sent to laboratory 4, 3
• Combined HIV antibody and antigen testing at 1 month after initiating lenacapavir 4, 3
• Continue HIV testing every 6 months thereafter 4

Additional Monitoring

• STI testing (gonorrhea, chlamydia, syphilis) every 4 months (at every second injection) 4, 3
• Liver enzyme tests every 6 months 4, 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 4, 3

Safety Profile

• Injection site reactions are the most common adverse effect, occurring in 63% of participants but typically mild to moderate 2
• Only 1.2% of lenacapavir recipients (26 of 2,183) discontinued due to injection-site reactions compared to 0.3% in the F/TDF group 5
• Gastrointestinal symptoms and headache also reported but generally well-tolerated 2
• No significant safety concerns identified in clinical trials 6, 5

Drug Interactions and Contraindications

Absolute Contraindications

• Rifampin, carbamazepine, and other strong CYP3A inducers are absolutely contraindicated 4
• Rifampin reduces lenacapavir exposure by 84% (AUC ratio 0.16) 1

Requires Dose Adjustment

• Rifabutin requires dose adjustment if coadministered 4

Notable Interactions

• Strong CYP3A inhibitors significantly increase lenacapavir exposure: atazanavir/cobicistat increases AUC 4.21-fold 1
• Lenacapavir increases midazolam exposure 3.59-4.08-fold, indicating strong CYP3A inhibition 1
• Lenacapavir increases rosuvastatin exposure 1.31-fold and tenofovir exposure 1.47-fold 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 4, 3
• This timing is critical because residual lenacapavir concentrations may remain in systemic circulation for up to 12 months or longer after discontinuation 3
• Initiating HIV infection during the pharmacokinetic tail poses risk for resistance development 7

Resistance Considerations

Breakthrough Infections

• Among the 2 incident infections in PURPOSE-1, one occurred after lenacapavir levels fell below target concentration following discontinuation (no resistance detected), and the second had viral loads too low for genotyping 1
• In PURPOSE-2, lenacapavir resistance-associated substitutions (N74D in 2 cases, Q67H/K70R in 1 case) were detected in all 3 incident infections 1

Resistance Profile

• Lenacapavir-resistant HIV will not compromise WHO-recommended therapies because there is no cross-resistance between lenacapavir and other licensed antiretroviral drugs 7
• Lenacapavir PrEP is unlikely to drive population-level resistance given the rarity of breakthrough infections and reduced replication capacity of resistant variants 7
• Key resistance mutations include L56I, M66I, Q67H, K70N, N74D/S, and T107N, conferring 4- to >3,226-fold reduced susceptibility 1

Special Populations

Adolescents

• Approved for adolescents weighing at least 35 kg with same dosing and monitoring requirements 4, 1

Pregnancy

• Pregnancy testing required before initiation for individuals of childbearing potential 4, 3
• Counseling about known and unknown risks should be provided to pregnant individuals considering lenacapavir 4

Clinical Advantages

• 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 4
• Lenacapavir has potential to improve PrEP adherence and thus enhance HIV prevention in the United States 6
• With approximately 39,000 persons receiving HIV diagnoses in the United States in 2023, lenacapavir represents a critical new tool despite existing highly effective PrEP options that have had suboptimal acceptance, adherence, and persistence 6