Background
ARTISTRY-1 is a Phase 2/3 study evaluating the safety and efficacy of the complete regimen of the capsid inhibitor lenacapavir (LEN) given with the integrase strand-transfer inhibitor (INSTI) bictegravir (BIC) compared to remaining on a complex multi-tablet regimen. Virologically suppressed participants with no known INSTI resistance mutations were enrolled in the Phase 2 portion. At Week 48, BIC+LEN showed high efficacy in maintaining viral suppression. Here we describe the resistance profile of participants at baseline and Week 48.
Methods
The presence of HIV-1 resistance-associated mutations (RAMs) was assessed using historical genotypic reports (HGR) and retrospective proviral DNA analysis of Day 1 samples (GenoSure Archive, Monogram). The impact of baseline RAMs on response at Week 48 was evaluated. Post-baseline resistance was assessed in participants with rebound (confirmed HIV-1 RNA ≥ 50 c/mL or last visit ≥ 50 c/mL; analyzed if ≥ 200 c/mL) using assays from Monogram or Seq-IT. Phenotypic assays were also conducted.
Results
Baseline HIV-1 genotypic resistance from HGR and/or proviral DNA analyses were obtained from 98% of participants (125/128). Resistance to NRTI, NNRTI, and PI was present in 81%, 65%, and 46% of participants, respectively; 11% of participants had primary INSTI RAMs (proviral DNA analysis only). The presence of baseline RAMs did not affect efficacy at Week 48. A single participant met the criteria for resistance testing; no INSTI mutation was observed, and sequencing of CA identified a novel substitution at CA N74 (N74T) as treatment-emergent, with 2.1-fold decrease in LEN susceptibility. This participant had known NRTI, NNRTI, and PI resistance. Though he had viral load (VL) <50 c/mL at screening, VL was detectable at baseline. He had been on a complex regimen of DRV/r bid+DTG bid+MVC prior to switching to BIC+LEN. Data on prior INSTI use or VL/genotype while on INSTI were not available. On study, he experienced viral load blips and confirmed virologic rebound (VL 305 c/mL at Week 48). This participant resuppressed on a regimen of LEN SC+DTG bid+MVC.
Conclusions
The frequency of baseline drug resistance in ARTISTRY-1 was high, but did not affect the efficacy of BIC+LEN in virologically suppressed participants. On-treatment low-level LEN resistance was observed in 1 participant who resuppressed on a LEN-containing regimen. These data underscore the potential of the use of once-daily BIC and LEN to optimize therapy in people receiving a complex ART regimen.
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