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Clinical Trial
. 2025 Jun 2;231(5):1239-1245.
doi: 10.1093/infdis/jiaf050.

Resistance Analyses in Heavily Treatment-Experienced People With HIV Treated With the Novel HIV Capsid Inhibitor Lenacapavir After 2 Years

Nicolas A Margot  1 , Vamshi Jogiraju  1 , Nina Pennetzdorfer  1 , Vidula Naik  1 , Laurie A VanderVeen  1 , John Ling  1 , Renu Singh  1 , Hadas Dvory-Sobol  1 , Onyema Ogbuagu  2 , Sorana Segal-Maurer  3 , Jean-Michel Molina  4 , Martin S Rhee  1 , Christian Callebaut  1
Affiliations
Clinical Trial

Resistance Analyses in Heavily Treatment-Experienced People With HIV Treated With the Novel HIV Capsid Inhibitor Lenacapavir After 2 Years

Nicolas A Margot et al. J Infect Dis. .

Abstract

Background: Lenacapavir is a highly potent first-in-class inhibitor of HIV-1 capsid that was approved for the treatment of heavily treatment-experienced people with HIV-1 harboring multidrug-resistant virus, and it is used in combination with an optimized background regimen (OBR). Resistance analyses conducted after 2 years of lenacapavir treatment in the phase 2/3 CAPELLA study are described.

Methods: CAPELLA enrollment consisted of viremic cases of heavily treatment-experienced people with HIV-1 and resistance to ≥2 drugs per class in at least 3 of the 4 main drug classes. Postbaseline resistance in participants experiencing virologic failure was evaluated by resistance assays (HIV-1 capsid, protease, reverse transcriptase, and integrase genotypic/phenotypic tests). Adherence to OBR was assessed by plasma drug measurement via liquid chromatography-tandem mass spectrometry.

Results: After 2 years, lenacapavir + OBR treatment led to HIV-1 RNA suppression in 82% of participants (missing = excluded). Treatment-emergent capsid resistance occurred in 19% (14/72) of participants, including capsid mutations M66I, Q67H/K/N, K70H/N/R/S, and/or N74D/H/K, which were all associated with functional lenacapavir monotherapy. Seven participants with lenacapavir resistance reattained HIV-1 RNA <50 copies/mL upon OBR resumption or change while maintaining lenacapavir treatment.

Conclusions: Emergence of lenacapavir resistance after 2 years in CAPELLA was a consequence of functional lenacapavir monotherapy. In half of participants with lenacapavir resistance, continued treatment with lenacapavir + active OBR led to HIV-1 RNA resuppression.

Keywords: HIV; capsid; lenacapavir; monotherapy; multidrug resistance.

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Conflict of interest statement

Potential conflicts of interest. N. A. M., V. J., N. P., V. N., L. A. V., J. L., R. S., H. D.-S., M. S. R., and C. C. are employees and stockholders of Gilead Sciences, Inc, which funded the study. O. O. has served as an advisor/consultant to Gilead Sciences, Inc, ViiV, and Janssen and has received honoraria from Gilead Sciences, Inc. J.-M. M. has served as an advisor/consultant to Gilead Sciences, Inc, ViiV, and Merck and has received research support from Gilead Sciences, Inc. At the time of study conduct, data analysis, and manuscript preparation, S. S.-M. had served as an advisor/consultant to Gilead Sciences, Inc, Janssen, ViiV, and Theratechnologies and received research support and honoraria from Gilead Sciences, Inc. S. S.-M. is now an employee and shareholder of Gilead Sciences, Inc. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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