Lenacapavir for HIV-1 Treatment and Prevention
Primary Recommendation
Lenacapavir is recommended as a first-in-class HIV-1 capsid inhibitor with two distinct FDA-approved indications: (1) for treatment of multidrug-resistant HIV-1 infection in heavily treatment-experienced adults when combined with other antiretrovirals, and (2) for pre-exposure prophylaxis (PrEP) to prevent HIV-1 acquisition in at-risk individuals, administered as a subcutaneous injection every 6 months. 1, 2
Treatment Indication: Multidrug-Resistant HIV-1
Patient Selection Criteria
- Use lenacapavir for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection where the current antiretroviral regimen is failing due to resistance, intolerance, or safety considerations. 2, 3
- Specifically indicated for patients with resistance to ≥2 drugs per class in at least 3 of the 4 main antiretroviral drug classes. 4
- Lenacapavir demonstrates no cross-resistance to existing antiretroviral classes (INSTIs, NNRTIs, NRTIs, PIs), making it valuable when other options are exhausted. 2, 5
Dosing Regimen for Treatment
- Initiate with oral loading: 600 mg twice daily on days 1 and 2, followed by 600 mg once daily on day 8. 2
- Maintenance: 927 mg subcutaneous injection every 6 months (26 weeks) starting on day 15. 2
- Must be used in combination with an optimized background regimen (OBR) of other active antiretrovirals—never as monotherapy. 3, 4
Efficacy in Treatment-Experienced Patients
- In the CAPELLA study of heavily treatment-experienced patients, 82% achieved HIV-1 RNA suppression (<50 copies/mL) at 2 years when lenacapavir was combined with an active OBR. 4
- Treatment-emergent capsid resistance occurred in 19% of participants, but this was exclusively associated with functional lenacapavir monotherapy (inadequate OBR activity). 4
- Notably, 7 participants who developed lenacapavir resistance reattained viral suppression by resuming or changing their OBR while continuing lenacapavir. 4
Prevention Indication: Pre-Exposure Prophylaxis (PrEP)
Recommendation for PrEP Use
After regulatory approval and availability, lenacapavir is recommended for prevention of HIV-1 infection for all routes of sexual exposure in at-risk individuals, including cisgender men, cisgender women, transgender people, and nonbinary individuals. 1
Dosing Regimen for PrEP
- Initiate with oral loading: Two daily oral doses of 600 mg lenacapavir overlapping with the first subcutaneous injection. 1
- Maintenance: Subcutaneous injection every 6 months. 1
Efficacy for PrEP
- PURPOSE-1 trial (cisgender women in Southern and Eastern Africa): Zero detected HIV infections among lenacapavir recipients in a population with background HIV incidence of 2.41 per 100 person-years. 1
- PURPOSE-2 trial (cisgender men, transgender people, nonbinary individuals): Only 2 incident HIV infections (HIV incidence 0.10/100 person-years) versus estimated background incidence of 2.37 per 100 person-years—representing a 96% reduction in HIV incidence. 1
HIV Screening Before PrEP Initiation
- At initiation or resumption after ≥6 months hiatus, perform both HIV RNA testing (viral load with lower limit of quantification ≤50 copies/mL) and a laboratory-based fourth- or fifth-generation antigen-antibody test. 1
- If HIV RNA testing is unavailable, begin lenacapavir after a negative rapid point-of-care HIV antibody test while awaiting laboratory-based antigen/antibody results. 1
- Do not routinely use HIV RNA testing for follow-up monitoring of PrEP breakthrough infections due to low positive predictive value and significant negative consequences of false-positive results. 1
Mechanism of Action
Lenacapavir is a multistage capsid inhibitor that directly binds to the interface between HIV-1 capsid protein (p24) subunits in hexamers, interfering with multiple essential viral lifecycle steps: 2
- Blocks capsid-mediated nuclear uptake of HIV-1 proviral DNA by preventing nuclear import protein binding to capsid. 2
- Interferes with virus assembly and release by disrupting Gag/Gag-Pol functioning. 2
- Disrupts capsid core formation by altering the rate of capsid subunit association, leading to malformed capsids. 2
Resistance Profile and Management
Resistance Mutations
- Capsid mutations associated with lenacapavir resistance include: L56I, M66I, Q67H/K/N, K70H/N/R/S, and N74D/H/K/S, T107N. 2, 4
- M66I confers >3,226-fold decreased susceptibility; L56I confers 239-fold; K70N and N74D confer 22-32-fold; Q67H and T107N confer 4-6.3-fold decreased susceptibility. 2
Clinical Resistance Patterns
- In PURPOSE trials for PrEP, lenacapavir resistance-associated substitutions (primarily N74D, also Q67H/K70R, T107A) were detected in participants with incident or prevalent infections. 2
- Critical caveat: Resistance emergence in treatment trials occurred exclusively in the context of functional lenacapavir monotherapy—when the OBR lacked sufficient activity. 4
- Half of participants who developed resistance achieved viral resuppression by continuing lenacapavir with an improved active OBR. 4
Drug Interactions
Strong CYP3A and P-gp Inhibitors
- Atazanavir/cobicistat increases lenacapavir AUC by 4.21-fold and Cmax by 6.60-fold. 2
- Darunavir/cobicistat increases lenacapavir AUC by 1.94-fold and Cmax by 2.30-fold. 2
- Dose adjustment may be necessary with strong CYP3A inhibitors. 2
Strong CYP3A Inducers
- Rifampin decreases lenacapavir AUC by 84% and Cmax by 55%—avoid coadministration. 2
- Efavirenz decreases lenacapavir AUC by 56% and Cmax by 36%. 2
- Do not use lenacapavir with potent inducers of UGT1A1 or CYP3A. 1
Effect on Other Drugs
- Lenacapavir increases midazolam (CYP3A substrate) AUC by 3.59-4.08-fold—avoid drugs highly dependent on CYP3A clearance with narrow therapeutic index. 2
- Lenacapavir increases tenofovir alafenamide AUC by 1.32-fold and tenofovir AUC by 1.47-fold. 2
- Lenacapavir increases rosuvastatin (BCRP/OATP substrate) AUC by 1.31-fold and Cmax by 1.57-fold. 2
Special Populations
Hepatic Impairment
- No dose adjustment needed for mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. 6
- Lenacapavir AUC increased 1.47-fold and Cmax 2.61-fold in moderate hepatic impairment, but this was not considered clinically meaningful. 6
Renal Impairment
- No dose adjustment needed for mild, moderate, or severe renal impairment (creatinine clearance ≥15 mL/min). 6
- Lenacapavir AUC increased 1.84-fold and Cmax 2.62-fold in severe renal impairment, but this was not considered clinically meaningful. 6
Pregnancy
- Lenacapavir is not included in current pregnancy treatment guidelines. 1
- No specific data available for use during pregnancy; risk-benefit discussion required if considering use in pregnant individuals.
Safety and Tolerability
Common Adverse Events
- Injection site reactions occur in 63% of participants, often diminishing in severity over time. 1, 3
- Lenacapavir was generally safe and well tolerated in clinical trials across treatment and prevention indications. 3, 5, 6
Administration Considerations
- Use caution in individuals with gluteal implants or fillers. 1
- Subcutaneous injections must be administered in the abdomen; anterior thigh injections did not reach pharmacokinetic targets and had poor tolerability. 1
Critical Clinical Pitfalls
Avoiding Functional Monotherapy
- Never use lenacapavir as monotherapy or with an inadequate OBR—all resistance emergence in CAPELLA occurred with functional monotherapy. 4
- Ensure at least one (preferably two) fully active agents in the OBR based on resistance testing. 4
Reloading After Missed Doses
- If subcutaneous injections are ≥8 weeks late for injection 2, or ≥16 weeks late for injection 3 and beyond, perform "reloading" with two injections 4 weeks apart before returning to every-6-month dosing. 1
- This guidance differs from current FDA package insert recommendations. 1
Transition from PrEP
- When stopping injectable lenacapavir PrEP, transition to another form of HIV prevention (e.g., tenofovir-based oral PrEP) appropriate for the individual's exposures and continue as long as exposures persist. 1