Pre-Existing HIV Resistance Mutations Do Not Compromise Dolutegravir Efficacy in NGS Study
A multicentre retrospective cohort of 326 treatment-naive individuals starting dolutegravir-based therapy found transmitted drug resistance mutations in 24% by NGS, yet virological failure occurred in only 3.4%, with no emergent high-abundance mutations with phenotypic impact. The findings support dolutegravir's high resistance barrier and suggest baseline integrase resistance testing may not be necessary in routine practice.
The original study
Baseline resistance mutations and virological response to dolutegravir in treatment-naïve patients: a multicentre NGS study.
- Authors
- Inciarte A, Berrocal L, Santos JR, Aleman MR, Curran A, Medina Gonzalez R, et al.
- Journal
- The Journal of antimicrobial chemotherapy
- PMID
- 41873440
Original abstract
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.