Lenacapavir: Difference between revisions

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*Dosage Forms: 300 mg oral tablets; 463.5 mg/1.5 mL (309 mg/mL) subcutaneous injection solution (single-dose vials)<ref name="SunlencaPI">Sunlenca (lenacapavir) [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; 2024.</ref>
*Dosage Forms: 300 mg oral tablets; 463.5 mg/1.5 mL (309 mg/mL) subcutaneous injection solution (single-dose vials)<ref name="SunlencaPI">Sunlenca (lenacapavir) [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; 2024.</ref>
*Routes of Administration: Oral (tablets); Subcutaneous injection (abdomen preferred; thigh as alternate site)
*Routes of Administration: Oral (tablets); Subcutaneous injection (abdomen preferred; thigh as alternate site)
**Do '''NOT''' administer intradermally — intradermal injection has been associated with serious injection site reactions including necrosis and ulcer<ref name="SunlencaPI"/>
**Do NOT administer intradermally — intradermal injection has been associated with serious injection site reactions including necrosis and ulcer<ref name="SunlencaPI"/>
*Common Trade Names: Sunlenca (HIV treatment), Yeztugo (HIV PrEP)
*Common Trade Names: Sunlenca (HIV treatment), Yeztugo (HIV PrEP)


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===HIV-1 Treatment (Sunlenca) — used with other antiretroviral(s)===
===HIV-1 Treatment (Sunlenca) — used with other antiretroviral(s)===
'''Initiation Option 1:'''<ref name="SunlencaPI"/>
Initiation Option 1:<ref name="SunlencaPI"/>
*Day 1: 927 mg SC injection + 600 mg PO (2 × 300 mg tablets)
*Day 1: 927 mg SC injection + 600 mg PO (2 × 300 mg tablets)
*Day 2: 600 mg PO (2 × 300 mg tablets)
*Day 2: 600 mg PO (2 × 300 mg tablets)


'''Initiation Option 2:'''
Initiation Option 2:
*Day 1: 600 mg PO (2 × 300 mg tablets)
*Day 1: 600 mg PO (2 × 300 mg tablets)
*Day 2: 600 mg PO (2 × 300 mg tablets)
*Day 2: 600 mg PO (2 × 300 mg tablets)
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*Day 15: 927 mg SC injection
*Day 15: 927 mg SC injection


'''Maintenance:''' 927 mg SC injection every 26 weeks (±2 weeks) from the date of last injection<ref name="SunlencaPI"/>
Maintenance: 927 mg SC injection every 26 weeks (±2 weeks) from the date of last injection<ref name="SunlencaPI"/>


===HIV PrEP (Yeztugo)===
===HIV PrEP (Yeztugo)===
'''Initiation:'''<ref name="YeztugoPI">Yeztugo (lenacapavir) [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; 2025.</ref>
Initiation:<ref name="YeztugoPI">Yeztugo (lenacapavir) [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; 2025.</ref>
*Day 1: 927 mg SC injection + 600 mg PO (2 × 300 mg tablets)
*Day 1: 927 mg SC injection + 600 mg PO (2 × 300 mg tablets)
*Day 2: 600 mg PO (2 × 300 mg tablets)
*Day 2: 600 mg PO (2 × 300 mg tablets)


'''Continuation:''' 927 mg SC injection every 26 weeks (±2 weeks)
Continuation: 927 mg SC injection every 26 weeks (±2 weeks)
*Individuals '''must''' be confirmed HIV-1 negative before each injection<ref name="CDC2025">CDC. Clinical Recommendation for the Use of Injectable Lenacapavir as HIV Preexposure Prophylaxis — United States, 2025. ''MMWR''. 2025;74(35).</ref>
*Individuals must be confirmed HIV-1 negative before each injection<ref name="CDC2025">CDC. Clinical Recommendation for the Use of Injectable Lenacapavir as HIV Preexposure Prophylaxis — United States, 2025. ''MMWR''. 2025;74(35).</ref>


===Missed Doses===
===Missed Doses===
*'''Treatment (Sunlenca):''' If >28 weeks since last injection, restart the full initiation regimen if clinically appropriate<ref name="SunlencaPI"/>
*Treatment (Sunlenca): If >28 weeks since last injection, restart the full initiation regimen if clinically appropriate<ref name="SunlencaPI"/>
*If discontinuing, begin an alternative suppressive ARV regimen no later than 28 weeks after last injection to avoid resistance development<ref name="SunlencaPI"/>
*If discontinuing, begin an alternative suppressive ARV regimen no later than 28 weeks after last injection to avoid resistance development<ref name="SunlencaPI"/>
*'''PrEP (Yeztugo):''' If >28 weeks since last injection and oral tablets not taken, restart with initiation dosing<ref name="YeztugoPI"/>
*PrEP (Yeztugo): If >28 weeks since last injection and oral tablets not taken, restart with initiation dosing<ref name="YeztugoPI"/>


==Pediatric Dosing==
==Pediatric Dosing==
*'''PrEP:''' Approved for adolescents ≥35 kg; same dosing as adults<ref name="YeztugoPI"/>
*PrEP: Approved for adolescents ≥35 kg; same dosing as adults<ref name="YeztugoPI"/>
*'''Treatment:''' Not established in pediatric patients
*Treatment: Not established in pediatric patients


==Special Populations==
==Special Populations==
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*Animal studies showed no adverse developmental effects at exposures ≥16 times the human dose (AUC)
*Animal studies showed no adverse developmental effects at exposures ≥16 times the human dose (AUC)
*Antiretroviral Pregnancy Registry (APR) has been established — report exposures at 1-800-258-4263
*Antiretroviral Pregnancy Registry (APR) has been established — report exposures at 1-800-258-4263
*'''PrEP use:''' May be used in pregnancy after shared decision-making, considering HIV risk without PrEP<ref name="CDC2025"/>
*PrEP use: May be used in pregnancy after shared decision-making, considering HIV risk without PrEP<ref name="CDC2025"/>


===Lactation risk===
===Lactation risk===
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===Key interactions for the ED physician===
===Key interactions for the ED physician===
*'''Strong CYP3A inducers''' — Contraindicated (treatment) or require supplemental dosing (PrEP). Remember the mnemonic '''COPPER''': '''C'''arbamazepine, '''O'''xcarbazepine, '''P'''henobarbital (and primidone), '''P'''henytoin, '''E'''nzalutamide, '''R'''ifampin (also rifabutin, rifapentine)<ref name="NYSDOH"/>
*'''Strong CYP3A inducers''' — Contraindicated (treatment) or require supplemental dosing (PrEP). Remember the mnemonic '''COPPER''': '''C'''arbamazepine, '''O'''xcarbazepine, '''P'''henobarbital (and primidone), '''P'''henytoin, '''E'''nzalutamide, '''R'''ifampin (also rifabutin, rifapentine)<ref name="NYSDOH"/>
*'''St. John's wort''' — Avoid; significantly decreases lenacapavir levels<ref name="SunlencaPI"/>
*St. John's wort — Avoid; significantly decreases lenacapavir levels<ref name="SunlencaPI"/>
*Lenacapavir is a '''moderate CYP3A inhibitor''' and '''P-gp inhibitor''' — may increase levels of CYP3A substrates for up to 9 months after last SC dose<ref name="SunlencaPI"/>
*Lenacapavir is a moderate CYP3A inhibitor and P-gp inhibitor — may increase levels of CYP3A substrates for up to 9 months after last SC dose<ref name="SunlencaPI"/>
**Be aware of interactions with common ED medications metabolized by CYP3A (e.g., midazolam, fentanyl, certain statins)
**Be aware of interactions with common ED medications metabolized by CYP3A (e.g., midazolam, fentanyl, certain statins)
*Lenacapavir is a substrate of CYP3A, P-gp, and UGT1A1<ref name="SunlencaPI"/>
*Lenacapavir is a substrate of CYP3A, P-gp, and UGT1A1<ref name="SunlencaPI"/>
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==Mechanism of Action==
==Mechanism of Action==
Lenacapavir binds directly to the interface between HIV-1 capsid protein (p24) subunits within capsid hexamers.<ref name="DvorySobol2022">Dvory-Sobol H, et al. Lenacapavir: a first-in-class HIV-1 capsid inhibitor. ''Curr Opin HIV AIDS''. 2022;17(1):15-21. doi:10.1097/COH.0000000000000713</ref> This binding interferes with multiple stages of the HIV lifecycle:<ref name="Paik2022"/>
Lenacapavir binds directly to the interface between HIV-1 capsid protein (p24) subunits within capsid hexamers.<ref name="DvorySobol2022">Dvory-Sobol H, et al. Lenacapavir: a first-in-class HIV-1 capsid inhibitor. ''Curr Opin HIV AIDS''. 2022;17(1):15-21. doi:10.1097/COH.0000000000000713</ref> This binding interferes with multiple stages of the HIV lifecycle:<ref name="Paik2022"/>
*'''Early stages:''' Over-stabilizes the capsid, causing premature brittle fracture before the virus reaches the nucleus — the exposed genetic material is degraded in the cytoplasm<ref name="eLife">Walsh J, et al. Lenacapavir molecular mechanisms. ''eLife''. 2024.</ref>
*Early stages: Over-stabilizes the capsid, causing premature brittle fracture before the virus reaches the nucleus — the exposed genetic material is degraded in the cytoplasm<ref name="eLife">Walsh J, et al. Lenacapavir molecular mechanisms. ''eLife''. 2024.</ref>
*'''Late stages:''' Disrupts Gag/Gag-Pol polyprotein function, reduces capsid subunit production, and accelerates capsid assembly leading to malformed, non-functional virions<ref name="DvorySobol2022"/>
*Late stages: Disrupts Gag/Gag-Pol polyprotein function, reduces capsid subunit production, and accelerates capsid assembly leading to malformed, non-functional virions<ref name="DvorySobol2022"/>


Because it targets a structural protein rather than an enzyme, mutations conferring resistance to other antiretroviral classes do not affect lenacapavir activity.<ref name="Paik2022"/>
Because it targets a structural protein rather than an enzyme, mutations conferring resistance to other antiretroviral classes do not affect lenacapavir activity.<ref name="Paik2022"/>
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**Send HIV Ag/Ab and HIV-1 RNA viral load testing
**Send HIV Ag/Ab and HIV-1 RNA viral load testing
**Patients who acquire HIV while on lenacapavir must be transitioned to a complete HIV treatment regimen<ref name="CDC2025"/>
**Patients who acquire HIV while on lenacapavir must be transitioned to a complete HIV treatment regimen<ref name="CDC2025"/>
*Lenacapavir does '''not''' protect against other sexually transmitted infections
*Lenacapavir does not protect against other sexually transmitted infections
*When prescribing medications in the ED for patients on lenacapavir, be mindful of CYP3A interactions — the inhibitory effect may persist up to 9 months after the last SC dose<ref name="SunlencaPI"/>
*When prescribing medications in the ED for patients on lenacapavir, be mindful of CYP3A interactions — the inhibitory effect may persist up to 9 months after the last SC dose<ref name="SunlencaPI"/>
*There is no known antidote for overdose; management is supportive. Hemodialysis is unlikely to be effective due to high protein binding<ref name="SunlencaPI"/>
*There is no known antidote for overdose; management is supportive. Hemodialysis is unlikely to be effective due to high protein binding<ref name="SunlencaPI"/>

Latest revision as of 09:12, 22 March 2026

Lenacapavir is a first-in-class HIV capsid inhibitor. It is the first antiretroviral that targets the HIV-1 capsid protein (p24), interfering with multiple stages of viral replication rather than a single enzyme.[1] It is available as an oral tablet and subcutaneous injection, with the injectable formulation designed for twice-yearly (every 6 months) administration.

Background

  • Approved by the FDA in December 2022 (as Sunlenca) for HIV-1 treatment in heavily treatment-experienced adults with multidrug-resistant (MDR) HIV-1[2]
  • Approved by the FDA in June 2025 (as Yeztugo) for HIV pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults and adolescents ≥35 kg[3]
  • Named "2024 Breakthrough of the Year" for its efficacy in HIV prevention trials[4]

Administration

  • Type: First-in-class HIV-1 capsid inhibitor (antiretroviral)
  • Dosage Forms: 300 mg oral tablets; 463.5 mg/1.5 mL (309 mg/mL) subcutaneous injection solution (single-dose vials)[5]
  • Routes of Administration: Oral (tablets); Subcutaneous injection (abdomen preferred; thigh as alternate site)
    • Do NOT administer intradermally — intradermal injection has been associated with serious injection site reactions including necrosis and ulcer[5]
  • Common Trade Names: Sunlenca (HIV treatment), Yeztugo (HIV PrEP)

Adult Dosing

HIV-1 Treatment (Sunlenca) — used with other antiretroviral(s)

Initiation Option 1:[5]

  • Day 1: 927 mg SC injection + 600 mg PO (2 × 300 mg tablets)
  • Day 2: 600 mg PO (2 × 300 mg tablets)

Initiation Option 2:

  • Day 1: 600 mg PO (2 × 300 mg tablets)
  • Day 2: 600 mg PO (2 × 300 mg tablets)
  • Day 8: 300 mg PO (1 tablet)
  • Day 15: 927 mg SC injection

Maintenance: 927 mg SC injection every 26 weeks (±2 weeks) from the date of last injection[5]

HIV PrEP (Yeztugo)

Initiation:[6]

  • Day 1: 927 mg SC injection + 600 mg PO (2 × 300 mg tablets)
  • Day 2: 600 mg PO (2 × 300 mg tablets)

Continuation: 927 mg SC injection every 26 weeks (±2 weeks)

  • Individuals must be confirmed HIV-1 negative before each injection[7]

Missed Doses

  • Treatment (Sunlenca): If >28 weeks since last injection, restart the full initiation regimen if clinically appropriate[5]
  • If discontinuing, begin an alternative suppressive ARV regimen no later than 28 weeks after last injection to avoid resistance development[5]
  • PrEP (Yeztugo): If >28 weeks since last injection and oral tablets not taken, restart with initiation dosing[6]

Pediatric Dosing

  • PrEP: Approved for adolescents ≥35 kg; same dosing as adults[6]
  • Treatment: Not established in pediatric patients

Special Populations

Pregnancy Rating

  • No adequate, well-controlled studies in pregnant women[5]
  • Animal studies showed no adverse developmental effects at exposures ≥16 times the human dose (AUC)
  • Antiretroviral Pregnancy Registry (APR) has been established — report exposures at 1-800-258-4263
  • PrEP use: May be used in pregnancy after shared decision-making, considering HIV risk without PrEP[7]

Lactation risk

  • Lenacapavir is present in human milk[6]
  • Individuals with HIV-1 infection should be counseled regarding the risks of breastfeeding (risk of HIV transmission)
  • For PrEP: consider risks and benefits; limited data suggest no increased drug-associated risks for infant outcomes[7]

Renal Dosing

  • Adult: No dose adjustment required for mild, moderate, or severe renal impairment (CrCl ≥15 mL/min)[8]
    • Not studied in ESRD (CrCl <15 mL/min); use with caution
    • Highly protein bound (≥99.8%); hemodialysis not expected to significantly affect levels[8]
  • Pediatric: Not established

Hepatic Dosing

  • Adult: No dose adjustment for mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment[8]
    • Not studied in severe hepatic impairment (Child-Pugh C)
  • Pediatric: Not established

Contraindications

  • Allergy to lenacapavir or any component of the formulation
  • Treatment (Sunlenca): Coadministration with strong CYP3A inducers is contraindicated (may reduce lenacapavir concentrations, risking treatment failure and resistance)[5]
  • PrEP (Yeztugo): Use in individuals with HIV-1 infection or unknown HIV status is contraindicated[6]

Adverse Reactions

Serious

  • Immune reconstitution inflammatory syndrome (IRIS) (when used for HIV treatment)[5]
  • Serious injection site reactions (necrosis, ulcer — associated with improper intradermal administration)[5]
  • Risk of drug-resistant HIV if used for PrEP in undiagnosed HIV infection (Boxed Warning on Yeztugo)[6]
  • Hepatitis B reactivation flares may occur in patients with pre-existing chronic hepatitis B

Common

  • Injection site reactions (65% in treatment trials): swelling, pain, erythema, subcutaneous nodules, induration, pruritus[9]
    • Nodules may persist for months (median ~183 days in PrEP trials)[10]
    • Most ISRs are mild (Grade 1) or moderate (Grade 2); median time to resolution (excluding nodules/indurations) is ~5 days[9]
  • Nausea (4% in treatment; common in PrEP trials)[5]
  • Headache (common in PrEP trials)[6]

Drug Interactions

Key interactions for the ED physician

  • Strong CYP3A inducers — Contraindicated (treatment) or require supplemental dosing (PrEP). Remember the mnemonic COPPER: Carbamazepine, Oxcarbazepine, Phenobarbital (and primidone), Phenytoin, Enzalutamide, Rifampin (also rifabutin, rifapentine)[10]
  • St. John's wort — Avoid; significantly decreases lenacapavir levels[5]
  • Lenacapavir is a moderate CYP3A inhibitor and P-gp inhibitor — may increase levels of CYP3A substrates for up to 9 months after last SC dose[5]
    • Be aware of interactions with common ED medications metabolized by CYP3A (e.g., midazolam, fentanyl, certain statins)
  • Lenacapavir is a substrate of CYP3A, P-gp, and UGT1A1[5]

Pharmacology

  • Half-life: 10–12 days (oral); 8–12 weeks (subcutaneous — due to slow depot release/flip-flop kinetics)[1]
  • Protein Binding: ≥99.8%[8]
  • Metabolism: Minor metabolism via CYP3A and UGT1A1; unchanged drug is the predominant species in plasma (~69% of total radioactivity after IV dose)[5]
  • Excretion: 76% in feces (33% as unchanged drug); <1% in urine[1]

Mechanism of Action

Lenacapavir binds directly to the interface between HIV-1 capsid protein (p24) subunits within capsid hexamers.[11] This binding interferes with multiple stages of the HIV lifecycle:[1]

  • Early stages: Over-stabilizes the capsid, causing premature brittle fracture before the virus reaches the nucleus — the exposed genetic material is degraded in the cytoplasm[12]
  • Late stages: Disrupts Gag/Gag-Pol polyprotein function, reduces capsid subunit production, and accelerates capsid assembly leading to malformed, non-functional virions[11]

Because it targets a structural protein rather than an enzyme, mutations conferring resistance to other antiretroviral classes do not affect lenacapavir activity.[1]

ED Relevance

  • Emergency physicians may encounter patients on lenacapavir in two contexts: as part of MDR-HIV treatment or as twice-yearly PrEP
  • If a patient on lenacapavir PrEP presents to the ED with concern for acute HIV exposure or seroconversion symptoms:
    • Confirm whether they are up-to-date on their injection schedule
    • Send HIV Ag/Ab and HIV-1 RNA viral load testing
    • Patients who acquire HIV while on lenacapavir must be transitioned to a complete HIV treatment regimen[7]
  • Lenacapavir does not protect against other sexually transmitted infections
  • When prescribing medications in the ED for patients on lenacapavir, be mindful of CYP3A interactions — the inhibitory effect may persist up to 9 months after the last SC dose[5]
  • There is no known antidote for overdose; management is supportive. Hemodialysis is unlikely to be effective due to high protein binding[5]
  • If a patient receiving lenacapavir for treatment is admitted or has their ARV regimen disrupted, consult HIV/ID service promptly — nonadherence risks virologic failure and resistance development[5]

Clinical Pearls

  • PURPOSE 1 trial: 100% efficacy in preventing HIV in cisgender women; PURPOSE 2: ~96% efficacy in men and gender-diverse individuals[13][14]
  • Resistance mutations (e.g., M66I, Q67H, N74D) alter capsid binding sites; no cross-resistance to other ARV classes[15]
  • Lenacapavir has not been associated with significant nephrotoxicity or hepatotoxicity; no routine liver or kidney function monitoring is required for PrEP use[16]

See Also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Paik J. Lenacapavir: first approval. Drugs. 2022;82(14):1499-1504. doi:10.1007/s40265-022-01786-0
  2. ↑ U.S. Food and Drug Administration. FDA approves new HIV drug for adults with limited treatment options. December 2022.
  3. ↑ Gilead Sciences. Yeztugo (lenacapavir) is now the first and only FDA-approved HIV prevention option offering 6 months of protection. June 2025.
  4. ↑ Lenacapavir. Wikipedia. Accessed 2025.
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 5.15 5.16 5.17 Sunlenca (lenacapavir) [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; 2024.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 Yeztugo (lenacapavir) [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; 2025.
  7. ↑ 7.0 7.1 7.2 7.3 CDC. Clinical Recommendation for the Use of Injectable Lenacapavir as HIV Preexposure Prophylaxis — United States, 2025. MMWR. 2025;74(35).
  8. ↑ 8.0 8.1 8.2 8.3 Shaik N, et al. Pharmacokinetics of long-acting lenacapavir in participants with hepatic or renal impairment. Antimicrob Agents Chemother. 2024;68(4):e01344-23. doi:10.1128/aac.01344-23
  9. ↑ 9.0 9.1 Sunlenca HCP. Safety and Tolerability. Gilead Sciences, 2024.
  10. ↑ 10.0 10.1 NYSDOH AI. Interim Guideline on the Use of Twice-Yearly Lenacapavir for HIV Prevention. 2025.
  11. ↑ 11.0 11.1 Dvory-Sobol H, et al. Lenacapavir: a first-in-class HIV-1 capsid inhibitor. Curr Opin HIV AIDS. 2022;17(1):15-21. doi:10.1097/COH.0000000000000713
  12. ↑ Walsh J, et al. Lenacapavir molecular mechanisms. eLife. 2024.
  13. ↑ Bekker LG, et al. Twice-yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women. N Engl J Med. 2024;391(13):1179-1192. doi:10.1056/NEJMoa2407001
  14. ↑ Kelley CF, et al. Twice-yearly lenacapavir for HIV prevention in men and gender-diverse persons. N Engl J Med. 2025;392(14):1261-1276. doi:10.1056/NEJMoa2411858
  15. ↑ Segal-Maurer S, et al. Lenacapavir: a novel injectable HIV-1 capsid inhibitor. Int J Antimicrob Agents. 2023;62(6):107003. doi:10.1016/j.ijantimicag.2023.107003
  16. ↑ World Health Organization. Guidelines on lenacapavir for HIV prevention. Geneva: WHO; 2025.
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