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

Abstract Background Lenacapavir is a highly potent first-in-class inhibitor of HIV-1 capsid approved for the treatment of heavily treatment-experienced (HTE) people with HIV-1 (PWH) harboring multidrug resistant (MDR) virus, 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 enrolled viremic HTE PWH with resistance to 2 or more drugs per class in at least 3 of the 4 main drug classes. Post-baseline resistance was evaluated in participants experiencing virologic failure using resistance assays (HIV-1 capsid, protease, reverse transcriptase, and integrase genotypic/phenotypic tests). Adherence to OBR was assessed by plasma drug measurement using tandem liquid chromatography/mass spectrometry. Results After 2 years, lenacapavir plus 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 remaining on lenacapavir. 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.