Lenacapavir drug resistance: rapid switching and the need for resistance testing

Drugs resistance data from a phase 1b switch study of lenacapavir plus two bNAbs in people who were already suppressed on standard ART included high-level drug resistance in 3/30 participants with low-level viral rebound, with one developing treatment failure at week 26.

Genotypic and phenotypic analyses of proviral gag and envelope DNA were performed at baseline and viral failure and results are published in an open access paper in JID.

Because viral RNA genotyping methods were unsuccessful at viral load levels >50 to 1000 copies/mL, low copy number genotyping methods for both capsid and a 1 kb stretch of gp120 from rebound virus were developed, and assessed phenotypically.

This case included detectable viral load at 155 copies/mL at week 16, which by week 18 (when VL had increased to 534 c/mL) developed the Q67H mutation in capsid associated with 4.7 fold-change phenotypic resistance to lenacapavir.

Drug resistance did not develop against either bNABs, likely due to rapid switching to oral ART (rilpivirine/F/TAF), which led to viral resuppression in this participant.

However, baseline resistance to single bNAbs was identified retrospectively in two participants with low level viral rebound (to 55 and 72 c/mL respectively) that was too low to be defined as viral failure, but who were still switched to oral ART.

Drug resistance mutations with reduced susceptibility to lenacapavir have been reported in 19/258 participants in three other RCTs, including M66I, Q67H/K/N, K70H/N/R/S, N74D/H/K, A105S/T and T107A/C/N/S, usually in high treatment-experienced participants.

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This study is important because drug resistance testing for capsid still isn’t currently commercially available, even though lenacapavir was approved as an MDR treatment several years ago. Rapid switching due to a careful study protocol will not be available outside a research setting.

In the UK, doctors needing to test for lenacapavir resistance should contact the central UKHSA laboratory at Colindale.

Easier access to resistance testing for treatment for MDR HIV, including for ibalizumab, fostemsavir and lenacapavir should arguably be included as part of the drugs approval processes in order to enable more sensitive monitoring for the management of people with multidrug resistance.

Baseline drug sensitivity testing is also important for use of bNAbs before these compounds can be approved as treatment. The current study required participants to be phenotypically sensitive to both bNAbs at baseline.

Selzer L et al. Resistance analysis of low-level virologic rebound during HIV-1 treatment with lenacapavir and broadly neutralizing antibodies teropavimab and zinlirvimab. J Infect Dis. 2025 Nov 5:jiaf559. doi: 10.1093/infdis/jiaf559. Online ahead of print.
https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiaf559/8314390