What are the prescribing instructions, side effects, and contraindications for lenacapavir (HIV Pre-Exposure Prophylaxis (PrEP))?

Lenacapavir for HIV 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 (77 lbs) who are at risk for HIV acquisition. 1, 2, 3

Prescribing and Administration Instructions

Initial Dosing Regimen

• Day 1: Administer 927 mg subcutaneously (two 1.5 mL injections) PLUS 600 mg orally (two 300 mg tablets) 2
• Day 2: Administer 600 mg orally (two 300 mg tablets) 2
• Continuation: 927 mg subcutaneously (two 1.5 mL injections) every 6 months (26 weeks ±2 weeks) from the date of the last injection 2

Administration Technique

• Inject subcutaneously into the abdomen (thigh is an alternative site if preferred) 2
• Do NOT inject intradermally due to risk of serious injection site reactions 2
• Two separate 1.5 mL injections are required for each complete dose 2
• Must be administered by a healthcare provider using aseptic technique 2
• Oral tablets may be taken with or without food 2

Delayed or Missed Injections

• If injection is anticipated to be delayed by more than 2 weeks, use oral tablets (300 mg once every 7 days) on an interim basis until injections resume 2
• If more than 28 weeks have elapsed since the last injection and tablets have not been taken, restart the entire initiation regimen from Day 1 2

Mandatory Laboratory Testing

Before Initiating Lenacapavir

• HIV testing: Use a fourth- or fifth-generation laboratory-based antigen-antibody assay 1
• HIV RNA (viral load): Ideally include testing with lower limit of quantification ≤50 copies/mL 1
• Serum creatinine and estimated creatinine clearance 1
• Hepatitis B surface antigen 1
• Hepatitis C IgG antibody (if not previously positive) 1
• Hepatitis A IgG antibody for men who have sex with men and people who inject drugs 1
• STI screening: Genital and nongenital gonorrhea and chlamydia testing by nucleic acid amplification test (NAAT) 1
• Syphilis testing 1
• Pregnancy testing for individuals of childbearing potential 1

Ongoing Monitoring Schedule

• Before each injection: Rapid point-of-care HIV testing on the day of injection; combined antibody and antigen test should be sent to laboratory but do not delay injection 1, 2
• At 1 month: Combined HIV antibody and antigen test 1
• Every 4 months (every second injection): STI testing including gonorrhea, chlamydia, and syphilis 1
• Every 6 months: Liver enzyme tests 1
• Annually: Hepatitis C antibody test (every 3-6 months for people who inject drugs and men who have sex with men who use recreational drugs) 1
• If restarting after ≥7 days off PrEP: Combined HIV antibody and antigen test prior to restarting 1

Contraindications

Lenacapavir is absolutely contraindicated in individuals with unknown or positive HIV-1 status. 2

• Do not initiate lenacapavir unless negative HIV infection status is confirmed 2
• Evaluate for current or recent signs/symptoms consistent with acute HIV-1 infection (fever, fatigue, myalgia, skin rash) before each dose 2

Side Effects and Adverse Reactions

Most Common (≥5% incidence)

• Injection site reactions (most common; often mild to moderate grade 1-2) 1, 2, 3
• Headache 2
• Nausea 2

Important Safety Considerations

• Injection site reactions often diminish in severity over time 1
• Improper intradermal administration has been associated with serious injection site reactions 2
• Lenacapavir was generally safe and well tolerated in clinical trials 4, 5

Drug Resistance Risk

There is a critical risk of developing drug-resistant HIV-1 variants if lenacapavir is used in individuals with undiagnosed HIV-1 infection. 2

• Drug-resistant HIV-1 variants have been identified with use of lenacapavir by individuals with undiagnosed HIV-1 infection 2
• Resistance can develop if HIV-1 is acquired before, during, or following discontinuation of lenacapavir 2
• If HIV-1 is acquired while receiving lenacapavir, immediately transition to a complete HIV-1 treatment regimen (dolutegravir-, bictegravir-, or ritonavir-boosted darunavir-based regimen initially) 1

Drug Interactions

Contraindicated or Requiring Dose Adjustments

• Strong CYP3A inducers: Supplemental dosing required if initiated after lenacapavir is started 2

  • On day strong inducer is initiated: Give 927 mg subcutaneously (two 1.5 mL injections) AND 600 mg orally (two 300 mg tablets) 2
  • On day after strong inducer is initiated: Give 600 mg orally (two 300 mg tablets) 2
  • Repeat supplemental doses every 6 months if strong inducer continues 2

• Moderate CYP3A inducers: Supplemental dosing required 2

  • On day moderate inducer is initiated: Give 463.5 mg subcutaneously (one 1.5 mL injection) 2
  • Repeat supplemental dose every 6 months if moderate inducer continues 2

• Lenacapavir is metabolized by CYP3A and UGT1A1, is a substrate of P-glycoprotein, and is a moderate inhibitor of CYP3A 6

Special Populations

Renal Impairment

• No dose adjustment needed for mild (creatinine clearance 60-89 mL/min), moderate (30-59 mL/min), or severe (15-29 mL/min) renal impairment 4
• Lenacapavir exposures were approximately 1.84-fold higher in severe renal impairment but not considered clinically meaningful 4

Hepatic Impairment

• No dose adjustment needed for mild (Child-Pugh-Turcotte Class A) or moderate (Class B) hepatic impairment 4
• Lenacapavir exposures were approximately 1.47-fold higher in moderate hepatic impairment but not considered clinically meaningful 4

Adolescents

• Approved for adolescents weighing at least 35 kg 2, 3
• May benefit from additional counseling and appointment reminders to support adherence 2

Transgender Individuals

• Use of exogenous estrogens or androgen blockers by transfeminine persons may result in approximately 30% reduction in tenofovir metabolite concentrations 1
• Additional measures to support maximal adherence to daily dosing recommended if using oral PrEP alternatives 1

Comprehensive Prevention Strategy

Lenacapavir must be used as part of a comprehensive HIV prevention strategy, not as monotherapy. 2

• Counsel on consistent and correct condom use to reduce STI risk 2
• Provide knowledge of partner(s)' HIV-1 status, including viral suppression status 2
• Regular testing for STIs that can facilitate HIV-1 transmission 2
• Support efforts in reducing sexual behaviors associated with HIV-1 acquisition risk 2
• Lenacapavir is not always effective in preventing HIV-1 acquisition 2

Pharmacokinetic Considerations

• Residual concentrations of lenacapavir may remain in systemic circulation for up to 12 months or longer after discontinuation 2
• Half-life after subcutaneous administration: 8-12 weeks 6
• If discontinuing lenacapavir but ongoing HIV risk continues, transition to another recommended PrEP regimen (such as tenofovir-based oral PrEP) 1
• Continue alternative PrEP or best available nonpharmacologic HIV prevention strategies as long as exposures continue 1

Clinical Efficacy

• PURPOSE-1 trial (cisgender women): 100% efficacy with no detected HIV infections (background incidence 2.41 per 100 person-years) 1, 3
• PURPOSE-2 trial (cisgender men, transgender people, nonbinary individuals): 96% reduction in HIV incidence with only 2 infections (HIV incidence 0.10/100 person-years vs estimated 2.37/100 person-years) 1, 3