Evaluation of integrase resistance in individuals who failed a regimen containing dolutegravir in French and Italian clinical settings

Abstract

Background This work aims to evaluate integrase resistance and its predictors in HIV-1 infected combined antiretroviral therapy (cART) experienced individuals failing a dolutegravir-based regimen. Methods Major resistance mutations (MRM) and genotypic susceptibility score (GSS) of dolutegravir companion drugs were evaluated on plasma genotypic resistance test (GRT) performed at dolutegravir failure. Logistic regression was used to evaluate factors associated to the risk of integrase strand-transfer inhibitors (INSTI)-resistance at dolutegravir failure. Results We retrospectively analysed 467 individuals. At failure GRT, individuals had been under dolutegravir for a median (IQR) time of 11 (5–20) months; around half of them had never been exposed to INSTI (52%) and 10.7% were at first-line regimen. Fifty-eight (12.4%) individuals showed ≥1 INSTI MRM. Among them, people INSTI-exposed showed significantly higher prevalence of INSTI resistance compared to those who were INSTI naïve [46 (21.2%) versus 9 (3.9%), P < 0.001]. N155H was the most prevalent MRM (5.4%), followed by G140S (4.5%) and Q148H (4.3%). These MRM were more probably present in INSTI-experienced individuals compared to those INSTI naïve. Despite failure, 89.5% of individuals harboured viral strains fully susceptible to dolutegravir and bictegravir and 85.0% to all INSTI. No INSTI exposure before receiving dolutegravir [OR: 0.35 (0.16–0.78), P < 0.010] and a GSS for companion drugs ≥2 (OR: 0.09 [0.04–0.23], P < 0.001) were negatively associated with INSTI resistance at failure. Conclusions In a large set of individuals failing dolutegravir in real-life, INSTI resistance was low and mainly related to previous first-generation INSTI exposure. Surveillance of integrase resistance remains crucial to preserve efficacy of INSTI class in the future.

Treatment Emergent Dolutegravir Resistance Mutations in Individuals Naïve to HIV-1 Integrase Inhibitors: A Rapid Scoping Review

“…Following the review of their titles and abstracts, 232 publications were submitted for full-text review. Following full-text review, 36 publications were found to have reports of INSTI-naïve PLWH who developed one or more INSTI-associated DRMs while receiving DTG [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ], and 21 publications contained in vitro susceptibility results performed using the PhenoSense assay [ 32 , 33 , 35 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , ...…”

A Comprehensive Literature Review of Treatment-Emergent Integrase Resistance with Dolutegravir-Based Regimens in Real-World Settings

“…In general, INSTI mutations were infrequently detected at VF across studies identified in this review, even in cohorts where individuals had previous VF and/or historical mutations. VF rates ranged from 1% to 60% among the 16 lead studies reporting VF outcomes [33,[36][37][38][39][40][41][42][43]45,46,49,50,53,58,59] for individuals on DTG-based regimens (excluding 8 lead studies with 100% VF rates due to study design [31,32,35,44,48,52,60,62], i.e., resistance analyses in populations failing treatment); of note, the highest rates (50% and 60%) were observed in cohorts with N ≤ 5 [53,58]. These results are consistent with other real-world studies [69][70][71] reporting low VF rates and/or infrequent INSTI RAM development in people receiving DTG-based treatment and reinforce the high barrier to resistance observed in interventional studies in ART-naive and ART-experienced individuals [14][15][16][17][18][19][20][21][22][23][24][25]27,…”

“…The proportions of people living with HIV who experienced VF on DTG-based therapy and developed treatment-emergent integrase mutations by study and regimen are shown in Table 1. While the definition of VF varied, many included 1 or 2 consecutive measurements of "detectable" HIV-1 RNA [31,32], or 1 or 2 consecutive measurements of HIV-1 RNA > or ≥50 copies/mL [33][34][35][36][37][38][39][40][41], >200 copies/mL [40,42,43], >400 copies/mL [37,44], ≥500 copies/mL [41], and/or >1000 copies/mL [45,46] as part of study-defined VF criteria. Many did not explicitly define VF criteria [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62].…”

“…First-generation INSTIs (RAL and EVG) have a relatively low barrier to resistance, and people living with HIV with prior exposure to these drugs can develop RAMs that also confer resistance to DTG [12]. In a retrospective multicenter cohort study of 467 individuals who experienced VF while on a DTG-based regimen in France and Italy, 58 (12.4%) had at least 1 major INSTI RAM [35]. INSTI RAMs were more frequent in individuals with first-generation INSTI experience (21.2%; n = 46) compared with INSTI-naive individuals (3.9%; n = 9).…”