Year: 2026 | Month: July | Volume: 13 | Issue: 7 | Pages: 564-575
DOI: https://doi.org/10.52403/ijrr.20260760
Lenacapavir and Long-Acting HIV Therapeutics Pharmacological Mechanisms, Clinical Evidence from the PURPOSE Trials, and Future Directions in Antiretroviral Therapy
Dr. Pasham Uma1, Ch. Sreya Sri2, Dr. R. L. Manisha3, Muvvala Sudhakar4
1Assistant Professor, Department of Pharmacology, Malla Reddy College of Pharmacy, Maisammaguda, Dhullapally, Secunderabad, Telangana, India, 500100.
2,3,4Department of Pharmacology, Malla Reddy College of Pharmacy, Maisammaguda, Dhulapally, Secunderabad–500100, Telangana, India.
Corresponding Author: Dr. Pasham. Uma
ABSTRACT
Lenacapavir (Sunlenca for treatment; Yeztugo for prevention) is a first-in-class HIV-1 capsid inhibitor with an unprecedented pharmacokinetic profile enabling subcutaneous administration only twice yearly, representing a transformative advance in both HIV treatment and prevention.[2,3,23] The HIV capsid — the conical protein shell encasing the viral genome — performs essential functions across multiple stages of the viral life cycle (uncoating, reverse transcription, nuclear import, integration, and assembly), and lenacapavir's multi-stage inhibition of capsid function produces potent, durable antiviral activity with a novel mechanism distinct from all existing antiretroviral classes.[3,5,6] The 2024 PURPOSE 1 and PURPOSE 2 trials demonstrated remarkable efficacy of twice-yearly subcutaneous lenacapavir for HIV pre-exposure prophylaxis (PrEP): PURPOSE 1, conducted in cisgender women and adolescent girls in sub-Saharan Africa, demonstrated 100% efficacy (zero infections among approximately 2,134 participants receiving lenacapavir),[4] while PURPOSE 2, in cisgender men and gender-diverse individuals, demonstrated 96% efficacy versus background incidence.[9] These results — among the most striking in HIV prevention history — led to FDA approval of lenacapavir for PrEP in 2025,[23,56] offering the prospect of transforming HIV prevention through the convenience and adherence advantages of twice-yearly dosing. This review provides a comprehensive pharmacological analysis of lenacapavir and long-acting HIV therapeutics including the HIV capsid biology and the novel capsid inhibition mechanism, lenacapavir pharmacology and the engineering of its extraordinary half-life, the treatment indication for multidrug-resistant HIV (CAPELLA), the PURPOSE PrEP trial program, the comparison with long-acting injectable cabotegravir (and cabotegravir-rilpivirine for treatment), the broader long-acting antiretroviral pipeline, the access and equity considerations including generic licensing for low- and middle-income countries, the Indian HIV epidemiology and prevention context, and future directions including once-yearly formulations, combination long-acting regimens, and the potential impact on the global HIV epidemic.
Keywords: Lenacapavir; Sunlenca; Yeztugo; HIV capsid inhibitor; pre-exposure prophylaxis; PrEP; PURPOSE; long-acting antiretroviral; cabotegravir; HIV prevention; twice-yearly dosing; multidrug-resistant HIV.
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