Yeztugo - Drug Monograph

Introduction

Yeztugo (lenacapavir) is a first-in-class HIV-1 capsid inhibitor approved by the U.S. Food and Drug Administration in 2025 for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in adults and adolescents weighing at least 35 kg. It represents a paradigm shift in HIV prevention by offering a twice-yearly subcutaneous dosing schedule after a brief oral lead-in phase. Its clinical relevance lies in addressing long-standing adherence challenges associated with daily oral PrEP and providing a highly effective option for individuals at risk of sexually acquired HIV.

Drug Class and Overview

• Class: HIV-1 capsid inhibitor (first-in-class)
• Related agents: None; lenacapavir is the only approved agent in this class
• Distinguishing features:
• Novel mechanism targeting the viral capsid protein
• Long-acting subcutaneous depot formulation enabling twice-yearly dosing
• Activity against HIV-1 strains resistant to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs)
• The same active ingredient is also marketed as Sunlenca for treatment of multidrug-resistant HIV-1 infection

Mechanism of Action

Lenacapavir binds to a conserved interface between capsid protein (CA) subunits in the mature HIV-1 capsid. This binding disrupts multiple stages of the viral replication cycle:

• Inhibition of capsid disassembly (uncoating) after viral entry into host cells
• Disruption of nuclear import of the viral pre-integration complex by interfering with capsid-host factor interactions (e.g., with nucleoporins and CPSF6)
• Inhibition of capsid assembly during virion maturation and budding

By targeting the capsid at multiple points, lenacapavir prevents both early and late stages of HIV-1 replication and retains activity against strains with resistance to other antiretroviral classes.

Indications

• Pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in adults and adolescents weighing at least 35 kg (FDA-approved 2025)
• Note: The same active ingredient (lenacapavir) is approved under the brand name Sunlenca for the treatment of multidrug-resistant HIV-1 infection in heavily treatment-experienced adults, in combination with other antiretrovirals

Dosage and Administration

PrEP (Yeztugo) — Initiation and Maintenance:

• Oral lead-in: 600 mg (two 300 mg tablets) orally once daily on Days 1 and 2
• Subcutaneous maintenance: 927 mg (1.5 mL of 309 mg/mL solution) administered subcutaneously every 6 months (26 weeks), beginning approximately on Day 3 or as soon as feasible after the oral lead-in
• Injection sites: Abdomen (avoid the 2-inch area around the umbilicus); do not inject into scarred, inflamed, or abnormal skin

Renal/hepatic adjustments:

• No dose adjustment required for mild-to-moderate renal or hepatic impairment
• Not studied in severe renal or hepatic impairment; use with caution

Special populations:

• Pediatric: Approved for adolescents weighing ≥35 kg (same dosing as adults)
• Pregnancy: Limited human data; use during pregnancy should be individualized and discussed with an HIV specialist
• Geriatric: Limited data in patients ≥65 years; no dose adjustment expected based on age alone

Pharmacokinetics

• Absorption: Oral bioavailability is low (approximately 6–10%) due to extensive first-pass metabolism; subcutaneous absorption is slow, providing sustained release from the depot
• Distribution: Highly protein-bound (>99%); distributes extensively into tissues
• Metabolism: Primarily metabolized by CYP3A4; also a substrate of UGT1A1 and P-glycoprotein (P-gp)
• Elimination: Predominantly fecal (~76%); minor renal excretion
• Half-life: Terminal half-life after subcutaneous administration is approximately 8–12 weeks, supporting twice-yearly dosing

Contraindications

• Concomitant use with strong CYP3A inducers (e.g., rifampin, carbamazepine, phenytoin, rifabutin, St. John's wort) — significantly reduces lenacapavir exposure and may compromise efficacy
• Known hypersensitivity to lenacapavir or any component of the formulation
• HIV-1 positive status — must confirm HIV-negative status before initiation and at regular intervals thereafter

Warnings and Precautions

• HIV testing required before initiation and every 3 months during use; undiagnosed HIV infection during PrEP use may lead to development of drug resistance
• Injection site reactions (nodules, induration, pain, erythema) are common; usually mild-to-moderate and self-limited, but severe reactions can occur
• Hepatotoxicity: Monitor liver function in patients with underlying hepatic disease or concurrent hepatotoxic medications
• Drug interactions: Concomitant medications must be carefully reviewed due to CYP3A4 metabolism
• Adherence to injection schedule: Missed or delayed injections may lead to subtherapeutic concentrations and increased risk of HIV acquisition or resistance if infection occurs

Drug Interactions

• Strong CYP3A inducers (rifampin, carbamazepine, phenytoin, rifabutin, St. John's wort): Contraindicated — markedly reduce lenacapavir plasma concentrations
• Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir): May increase lenacapavir exposure; use with caution and clinical monitoring
• P-glycoprotein substrates: Lenacapavir may alter disposition of P-gp substrates; monitor accordingly
• Antacids containing aluminum or magnesium: May affect absorption of oral lenacapavir doses; separate administration

Adverse Effects

Common:

• Injection site reactions (pain, nodule, induration, erythema, swelling) — very common with subcutaneous administration
• Headache
• Nausea
• Diarrhea
• Fatigue
• Abdominal pain

Serious/rare:

• Hepatotoxicity
• Severe injection site reactions (e.g., abscess, ulceration)
• Development of drug resistance if used in undiagnosed HIV infection

Monitoring Parameters

• HIV testing (HIV-1 RNA or antigen/antibody combination assay) before initiation and every 3 months during use
• Renal function (serum creatinine, eGFR) at baseline and periodically
• Liver function tests (ALT, AST, bilirubin) at baseline and periodically
• Injection site assessment at each visit
• Adherence assessment at each visit
• Sexually transmitted infection (STI) screening per CDC PrEP guidelines (syphilis, gonorrhea, chlamydia)
• Pregnancy testing in individuals of reproductive potential

Patient Education

• Take the oral lead-in doses exactly as prescribed (Days 1 and 2)
• Return for subcutaneous injections every 6 months — do not miss scheduled appointments
• Report any injection site reactions that worsen, persist, or show signs of infection
• Continue safer sex practices (e.g., condom use) — PrEP does not protect against other STIs
• Inform all healthcare providers about Yeztugo use due to potential drug interactions
• Get tested for HIV every 3 months while on PrEP
• Do not take with strong CYP3A inducers (certain seizure medications, rifampin, St. John's wort)
• Report any flu-like symptoms or possible HIV exposure promptly

Clinical Pearls

1. Yeztugo is the first twice-yearly PrEP option, representing a major advance for individuals with adherence challenges to daily oral PrEP.
2. The HIV capsid is a novel therapeutic target — lenacapavir retains activity against HIV-1 strains resistant to NRTIs, NNRTIs, PIs, and INSTIs.
3. Confirm HIV-negative status before every injection — missed HIV infection during PrEP use can lead to resistance and limit future treatment options.
4. Strong CYP3A inducers can render lenacapavir ineffective — always perform a thorough medication reconciliation, including over-the-counter and herbal products.
5. The very long terminal half-life means missed doses have prolonged consequences; subtherapeutic concentrations can persist for weeks, increasing resistance risk if HIV acquisition occurs.
6. Injection site reactions are common but typically self-limited — counsel patients that nodules and induration may persist for weeks but usually resolve without intervention.

References

1. Gilead Sciences. Yeztugo (lenacapavir) Prescribing Information. U.S. Food and Drug Administration; 2025.
2. Gilead Sciences. Sunlenca (lenacapavir) Prescribing Information. U.S. Food and Drug Administration; 2022 (revised 2025).
3. Bekker LG, et al. Twice-yearly lenacapavir or daily emtricitabine/tenofovir alafenamide for HIV prevention in cisgender women (PURPOSE 1). N Engl J Med. 2025.
4. Kelley CF, et al. Twice-yearly lenacapavir for HIV prevention in cisgender men, transgender women, transgender men, and gender-nonbinary persons (PURPOSE 2). N Engl J Med. 2025.
5. Centers for Disease Control and Prevention. Preexposure Prophylaxis for the Prevention of HIV Infection in the United States - 2024 Clinical Practice Guideline.
6. U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV.
7. Link JO, et al. Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature. 2020.
8. Segal-Maurer S, et al. Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection (CAPELLA). N Engl J Med. 2022.