Baseline resistance mutations and virological response to dolutegravir in treatment-naïve patients: a multicentre NGS study

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OBJECTIVES: To assess the prevalence of transmitted drug resistance mutations (TDRMs) and the impact of pre-existing resistance mutations, including minority variants, on virological response in ART-naïve individuals initiating dolutegravir-based triple therapy using next-generation sequencing (GRT-NGS). METHODS: A multicentre, retrospective cohort study was conducted including ART-naïve individuals who started a dolutegravir-3DR between 2015 and 2019. Baseline GRT-NGS Illumina®, covering RT, PR and IN genes identified primary (P-DRM) and secondary/polymorphic (S/p-DRM) mutations in high-abundance drug resistance variants (HA-DRVs; ≥20%) and low-abundance drug resistance variants (LA-DRVs; 1%-19%). Virological failure (VF) was defined as two consecutive HIV-1 RNA ≥ 50 copies/mL. Virological response was assessed at Weeks 48 and 96. RESULTS: Of 326 participants, 86% were male and 72% were MSM; 78% received DTG/ABC/3TC and 22% TDF/FTC + DTG. At least one TDRM was detected in 24% and any DRM in 48% of subjects. Virological suppression was achieved in 76% by intention-to-treat (ITT), 97% on-treatment (OT) and 56% (ITT), 94% (ITT) at Weeks 48 and 96, respectively. VF occurred in 11 subjects (3.4%), mostly within 48 weeks, all with low-level viraemia (<1000 copies/mL; 8 < 200 copies/mL) and no emergent of new DRM in HA-DRVs with phenotypic impact. Among those with pre-existing DRM, including 36 P-HA-DRVs, 79 S/p-HA-DRVs, 57 P-LA-DRVs and 45 S/P-LA-DRVs, no significant association with VF was observed. CONCLUSIONS: Our findings indicate that pre-existing IN and RT DRM, including low-abundance and secondary/polymorphic variants, did not compromise the virological efficacy of dolutegravir-based triple therapy in ART-naïve individuals, supporting the high resistance barrier of dolutegravir and the lack of need for baseline resistance testing.

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