A precautionary tale of lenacapavir drug-drug interactions: A case series of two persons living with HIV receiving long-acting injections

With the recent Federal Food and Drug Administration approval of lenacapavir for pre-exposure prophylaxis (PrEP) and highly treatment experienced persons living with HIV (PLWH), real-world drug-drug interaction data are necessary for this long acting injectable (LA-I) antiretroviral (ARV).^1–4 Lenacapavir is a substrate and moderate cytochrome P450 (CYP) 3A4 and P-glycoprotein inhibitor with additional metabolism via uridine diphosphate glucuronosyl transferase, 1A1.^1–4 Lenacapavir oral lead in for 2 days and every 6-months subcutaneous injections for highly treatment experienced PLWH is expanding with published data demonstrating successful use with concurrent intramuscular cabotegravir/rilpivirine (CAB/RPV) injections for a complete parenteral regimen.^5–7 Vigilance is necessary to avoid concurrent use of medications with possible drug-drug interaction potential. We report two possible drug-drug interaction cases (with patient consent) with lenacapavir necessitating a closer evaluation of our institutional processes for LA-I medication review.^8,9

Case 1: A 72-year-old highly treatment experienced female PLWH with multidrug resistance (Table 1) with inability to maintain viral load control with a daily oral ARV regimen secondary to gastrointestinal intolerance, transitioned to biannual lenacapavir LA-I with biweekly ibalizumab infusions. The patient and her family agreed to a complete parenteral antiretroviral regimen including biweekly ibalizumab infusions with historical non-nucleoside reverse transcriptase and integrase inhibitor resistance not allowing CAB/RPV use. Viral load suppression and immune reconstitution resulted 2 months after initiation with weight gain and improved health symptoms. At month 2, the patient presented with a new cerebrovascular event with historical encounters noting elevated blood pressure values with poor oral adherence to her antihypertensive regimen. During the acute hospitalization, clopidogrel alone was initiated by the Neurology service secondary to a prior documented acetylsalicyclic (ASA) intolerance (nausea). Clopidogrel is a pro-drug and is metabolized by CYP 2C19, 3A4 and 2B6 to the active medication. Based on this necessary conversion to the active moiety, clopidogrel is contraindicated with strong inhibitors (e.g., ritonavir) resulting in reduced antiplatelet activity.^8,10,11 A similar contraindication with lenacapavir and clopidogrel is recommended. ⁸ The ambulatory ID clinic team reviewed this drug-drug interaction after hospital discharge and in coordination with the neurologist, the patient with her daughter agreed to begin enteric coated ASA only with no subsequent intolerances reported. No automated drug-drug interaction in the electronic medical record alerted the inpatient team. No untoward effects resulted with this possible drug-drug interaction. ⁹

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Table 1.

Patient case characteristics.

Patient case	Age, gender	Anti-retroviral regimen pre-LA-I	Compiled genotype	VL (copies/mL), CD4 (normal range 377-1602 cells/mm3): Pre/post LA-I	LA-I regimen	Concurrent non-HIV pharmacotherapy; pre-LA-I
1	72, female	QD: Darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg	RT: K65R, V75A, K103N, V179I, Y181C PR: E35D IN: L74I, G140S, Q148R	Pre: VL 434,000, CD4 = 199 (14%) Post: Month 1: VL 140, CD4 = 157 (18%) Month 2: VL <50, CD4 = 235 (24%) Month 5: VL <50; CD4 = 255(25%) Month 6: VL, <50, CD4 = 278 (24%) Month 9: <50; CD4 = 299 (23%)	Day 1: Lenacapavir oral, 2-300 mg tablets, SQ, 2-463.5 mg (bilateral abdominal wall) IV ibalizumab infusion 2000 mg LD, 800 mg biweekly	Amlodipine 10 mg QD Carvedilol 25 mg BID Diclofenac 1% topical gel, prn left knee Famotidine 20 mg QD Hydrocortisone 1% cream, topically to rash Loperamide 10 mg QID PRN Loratadine 10 mg QD Losartan 50 mg QD
2	65, male	QD: Bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg with doravirine 100 mg	RT: M41L, A98S, M184V, L210W, L214F, T215S/V/Y PR: L10F/I, D30N, L33I/V, M36I, M46L, I54V, D60E, I62V, L63P, A71T, N83D, I85V, N88D IN: No significant mutations	Pre: VL <50, CD4 = 1117 (49%) Post: Month 1: VL <50 Month 2: VL 60 Month 3: VL 55 Month 4: VL <50 Month 6: VL <50, CD4 = 829 (55%)	Day 1: Lenacapavir oral, 2-300 mg tablets, SQ, 2-463.5 mg (bilateral abdominal wall) Monthly IM cabotegravir 400 mg/rilpivirine 600 mg (after 600 mg/900 mg loading dose)	Acyclovir 400 mg BID Albuterol inhaler PRN Amlodipine 10 mg QD Brimonidine 0.2% ophthalmic solution, 1 drop right eye, TID Bupropion XL 150 mg QD Cetirizine 10 mg QD Cholecalciferol 1000 units QD Diclofenac 1% topical gel QID as needed Dorzolamide 2% ophthalmic solution, 1 drop, right eye TID Hydrochlorothiazide 25 mg QD Ipratropium nasal spray, 0.06%, 2 sprays bilateral nares TID Mirtazapine 45 mg QD Nicotine polacrilex 2 mg, 1 lozenge prn Tamsulosin 0.4 mg QD Triamcinolone 0.1% cream; topically prn for rash

Case 2: A 65-year-old highly treatment experienced male PLWH requested transition to intramuscular CAB/RPV with lenacapavir (Table 1). Inhaled/nasal corticosteroids at lenacapavir initiation were not noted. At the second monthly CAB/RPV injection, prescription refills for nasal/inhaled fluticasone were reviewed with patient report of daily use. The patient noted dizziness, fatigue and two recent falls. A random afternoon cortisol concentration was 4.0 µg/dL [reference range before 10 AM (3.7−19.4 µg/dL) and after 5 PM (2.9−17.3 µg/dL)] with immediate fluticasone discontinuation. Three days later a morning cortisol stimulation test demonstrated a baseline value of 6.0 µg/dL and 60-min result of 14.7 µg/dL after intramuscular adrenocorticotropic hormone 250 mcg, denoting a partial response. Based on the patient’s hemodynamic stability, the fluticasone prescriptions were transitioned to inhaled beclomethasone inhaler with continuation of ipratropium nasal spray with no oral hydrocortisone initiated. ¹² At the 3rd CAB/RPV injection, the patient noted no further dizziness or falls with a repeat morning cortisol = 7.2 µg/dL. A repeat random afternoon cortisol 1 month later = 5.8 µg/dL. Patient education and a clinic medication drug-drug interaction card (Figure 1) with continued beclomethasone and ipratropium use was emphasized with this possible adverse event. ⁹ OPEN IN VIEWER

Lenacapavir is a substrate and moderate CYP 3A4 inhibitor with additional metabolism via uridine diphosphate glucuronosyl transferase 1A1. Minimal data to evaluate potential drug-drug interactions are published in real-world studies. In the CAPELLA lenacapavir study for highly treatment experienced PLWH, only 72 persons were followed with no description on drug-drug interactions but exclusion criteria included persons on concurrent corticosteroids, strong CYP 3A4 inducers or uridine diphosphate glucuronosyl transferase inhibitors or inducers. ⁵ A recent study evaluated the potential for drug-drug interactions in HIV negative persons receiving non-lenacapavir PrEP prescriptions between January 1-December 31, 2024 utilizing the IQVIA LRx Dx database. ¹³ The primary outcome included a description of concurrent CYP 3A4 and P-glycoprotein medications concomitantly prescribed to PrEP persons and to determine if significant drug-drug interactions would exist with a new lenacapavir prescription. ¹³ The results demonstrated a primarily male (90.9%) young adult (mean age = 38 years) population. Only 0.5% of PrEP users would necessitate a lenacapavir dose adjustment with concurrent strong CYP 3A4/P-glycoprotein inducers (rifampin, carbamazepine, oxcarbazepine). In 12.6% of persons, a concomitant medication would necessitate a dose adjustment or monitoring before lenacapavir for PrEP is prescribed with the erectile dysfunction medication class [tadalafil (7.45%), sildenafil (4.07%) and vardenafil (0.07%)] representing the most common interacting agents.

In contrast, PLWH prescribed lenacapavir for highly treatment experienced multidrug resistance are usually older (similar to our cases) and are receiving more concomitant medications. Recent data from the Swiss HIV Cohort study highlights increasing polypharmacy trajectories as PLWH age >50 years. ¹⁴

No case reports or drug-drug interaction studies are published with lenacapavir and clopidogrel or inhaled/nasal corticosteroids as reported in this case series. Ritonavir is a strong CYP 3A4 inhibitor with numerous contraindicated concurrent medications including both clopidogrel and corticosteroids.^8,11 Lenacapavir is a moderate CYP 3A4 inhibitor and guidance recommends consideration for using the lowest corticosteroid dose with adrenal suppression monitoring and avoiding concurrent clopidogrel administration.^8,11 Moderate CYP 3A4 inhibitors have less significant drug-drug interactions and may allow concurrent dosing with narrow therapeutic window agents. As an example, diltiazem is a moderate CYP 3A4 inhibitor and published studies may provide guidance with potential lenacapavir drug-drug interactions. ¹⁵ In a small analysis of 17 heart transplant patients receiving a median tacrolimus dose of 5.8 mg twice daily, diltiazem [60 mg (N = 5); 90 mg (N = 12)] was prescribed for concurrent hypertension. After diltiazem initiation, a 54% reduction in tacrolimus elimination necessitated dose reduction to 2.8 mg twice daily. Thus, evaluating the literature for drug-drug interactions with moderate CYP 3A4 inhibitors may provide real-world lenacapavir guidance. Of note, a recent case report describes lenacapavir use in a person with a massive hemorrhage during a liver transplantation. ¹⁶ The authors noted no observed tacrolimus drug-drug interactions, but details on the specific doses or trough concentrations are not included in the report to determine if any decreased clearance resulted.

These two cases resulted in a review of our lenacapavir drug-drug interaction alerts to allow proper monitoring with recommendations for customizing the electronic medical record. Additional considerations will need to include the lenacapavir long elimination (9 months) half-life as PLWH may continue to be at risk for drug-drug interactions even after discontinuation. ¹ Case 2 did not have any adverse events or adrenal insufficiency with concurrent lenacapavir use and inhaled/nasal corticosteroids, but additional data are needed to determine the true clinical significance of this drug-drug interaction. As a safety precaution, we updated our drug-drug interaction card for protease inhibitors used in our clinic with the addition of lenacapavir to assist patient education at treatment initiation (Figure 1). Currently, the FDA label provides the most comprehensive data for lenacapavir DDIs.^1,2 These cases serve as precautionary tale for health systems to ensure proper drug-drug interaction monitoring with LA-I lenacapavir as this agent expands use in highly treatment experienced PLWH and PrEP.