What are the administration guidelines, potential drug-drug interactions (DDI), common side effects, and protocols for managing immune reconstitution syndrome (ISR) and missed doses for a patient taking Lenacapavir (Lenacapavir) for HIV treatment?

Lenacapavir Administration, Drug Interactions, Side Effects, and Missed Dose Management

Administration Protocol

Lenacapavir requires a specific two-phase administration: an initial oral loading phase followed by subcutaneous injections every 26 weeks (6 months). 1, 2

Initial Oral Loading Phase

• Day 1 and 2: 600 mg orally 1, 3
• Day 8: 300 mg orally (some protocols use 600 mg on days 1-2 then 50 mg daily) 1, 3
• This oral coverage is essential because lenacapavir is slowly released from injection sites and requires adequate pharmacokinetic exposure during the first days of treatment 2

Subcutaneous Injection Phase

• 927 mg subcutaneously every 26 weeks starting after the oral loading phase 1, 3, 4
• The twice-yearly dosing may be particularly advantageous for patients with substance use disorders who struggle with daily oral medication adherence 5
• Lenacapavir must be combined with other antiretrovirals as part of a complete regimen; it is not used as monotherapy 1, 6

Preparation and Administration

• Refer to FDA prescribing information section 2.4 for detailed preparation and subcutaneous injection technique 1
• Healthcare providers should be trained in proper subcutaneous administration technique 1

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Drug-Drug Interactions (DDI)

Lenacapavir has a moderate CYP3A inhibitory effect and is metabolized by CYP3A and UGT1A1, making it susceptible to strong inducers but causing relatively few clinically significant interactions as a perpetrator. 2

Contraindicated Combinations

• Strong CYP3A inducers are contraindicated with lenacapavir 2
• Co-administration with strong inducers can significantly reduce lenacapavir levels, compromising efficacy 2

Lenacapavir as a Substrate

• Lenacapavir is metabolized by CYP3A and UGT1A1 2
• It is a substrate of P-glycoprotein (Pgp) 2
• Weaker inducers of these enzymatic pathways are not recommended but may be less problematic than strong inducers 2

Lenacapavir as a Perpetrator

• Moderate inhibitor of CYP3A 2
• Weak inhibitor of Pgp 2
• In most cases, no preventive dosage adjustments are recommended for co-administered drugs; clinical monitoring only is advised 2
• The low metabolic interactive potential makes lenacapavir favorable compared to older antiretrovirals like protease inhibitors 2

Special Considerations

• Unlike protease inhibitors and NNRTIs, lenacapavir does not have the extensive drug interaction profile that requires multiple dose modifications 7, 2
• No specific interactions with cocaine have been identified, though standard cardiovascular monitoring remains important 5

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Common Side Effects

Injection site reactions are the most common adverse effect, occurring in 63% of participants, but are typically mild to moderate and rarely lead to discontinuation. 8, 3

Injection Site Reactions (Most Common)

• Erythema: 27% of participants 3
• Swelling: 23% of participants 3
• Pain: 19% of participants 3
• Induration: Less common but can lead to discontinuation 3
• Generally mild (grade 1) to moderate (grade 2) 9
• Only 1-3% of participants discontinued due to injection site reactions 3, 4

Systemic Side Effects

• Headache: 13% of participants 3
• Nausea: 13% of participants 3
• Gastrointestinal symptoms: Common but generally manageable 8

Serious Adverse Events

• No Grade 4 or serious treatment-related adverse events were reported in clinical trials 6
• No serious adverse events related to study treatment occurred in phase 2 trials 3
• Excellent safety profile compared to older antiretrovirals 6, 3

Long-Term Considerations

• Liver enzyme monitoring every 6 months is recommended, particularly important in patients with hepatotoxicity risk factors 5
• No significant metabolic toxicities (bone, kidney, cardiovascular) associated with lenacapavir itself 2

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Immune Reconstitution Syndrome (IRS/IRIS)

Immune reconstitution syndrome can occur when initiating potent antiretroviral therapy, including lenacapavir-containing regimens, particularly in patients with advanced HIV disease and subclinical opportunistic infections. 7, 1

Clinical Presentation

• Patients with advanced HIV disease (CD4 <200 cells/µL) and subclinical opportunistic infections (e.g., Mycobacterium avium complex, CMV) may develop new immunologic responses to pathogens 7
• New symptoms develop in association with heightened immunologic and/or inflammatory response 7
• This occurs as immune function recovers with effective antiretroviral therapy 7

Management Algorithm

1. Do not interpret IRIS as antiretroviral therapy failure 7
2. Maintain the patient on the lenacapavir-containing antiretroviral regimen 7
3. Treat newly presenting opportunistic infections appropriately while continuing antiretrovirals 7
4. Use viral load measurement to clarify whether symptoms represent IRIS versus treatment failure 7
5. Monitor closely for resolution of inflammatory symptoms while treating the underlying opportunistic infection 7

Key Distinction

• IRIS represents immune recovery, not drug failure 7
• Viral load should remain suppressed or continue declining if IRIS is the correct diagnosis 7
• Rising viral load would suggest treatment failure rather than IRIS 7

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Missed Dose Protocol

The long-acting properties of lenacapavir require specific protocols for missed injections to prevent subtherapeutic drug levels and potential resistance development. 1

Timing Considerations

• Lenacapavir has a half-life of 8-12 weeks after subcutaneous administration 2
• The every-26-week dosing schedule provides some buffer for minor delays 1, 3
• However, significant delays require intervention to maintain therapeutic levels 1

Management of Missed Injections

For Short Delays (Days to 1-2 Weeks)

• Administer the missed injection as soon as possible 1
• Resume the regular 26-week schedule from the new injection date 1

For Extended Delays (Weeks to Months)

• Initiate oral bridging therapy with a potent antiretroviral regimen 10
• Start bridging at the time the next injection would have been due 10
• Continue bridging for the entire missed period plus 1-2 weeks beyond when the patient returns for their next scheduled injection 10
• Bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy) is an excellent bridging option due to its high barrier to resistance 10

Critical Adherence Counseling

• Emphasize the critical importance of daily adherence to oral bridging therapy, as missed oral doses create greater risk for resistance than the long-acting formulation 10
• Patients unable to attend scheduled injections require close attention and interventions to return to care 10
• Poor adherence to injection schedule is a risk factor for virological failure 10

Monitoring After Missed Doses

• Check HIV RNA at 4-6 weeks after resuming lenacapavir injections to ensure successful transition back to long-acting therapy 10
• If the bridge period extends beyond 2-3 months or if there are adherence concerns, consider resistance testing before resuming lenacapavir 10

Resistance Considerations

• Among participants with virological failure in clinical trials, 14 developed treatment-emergent lenacapavir resistance 6
• However, 7 of these participants resuppressed (HIV-1 RNA <50 copies/mL) while maintaining lenacapavir use 6
• This suggests that even with emergent resistance, continuing lenacapavir as part of an optimized regimen may still be beneficial 6

Long-Acting Properties Warning

• Lenacapavir remains in the body for extended periods after discontinuation due to its long half-life 1
• This creates potential for subtherapeutic drug levels if other antiretrovirals are stopped, which could lead to resistance 1
• Any decision to discontinue lenacapavir must account for this prolonged washout period 1