Integrase Strand Transfer Inhibitor (INSTI) Genotypic Resistance Analysis in Treatment-Naive, INSTI Free Antiretroviral-Experienced and INSTI-Experienced Turkish Patients Infected with HIV-1.

Integrase strand transfer inhibitors (INSTIs) are currently the standard of practice for first-line HIV therapy for most patients. We evaluated the mutations associated with INSTI resistance in naive HIV-1 infected patients and treated them with antiretrovirals (ART). The study, conducted in the 2018 - 2020 period, included 50 ART-naïve patients, 69 INSTI free ART-experienced patients, and 82 INSTI-experienced patients. INSTI resistance mutations were interpreted using the Stanford University HIVdb Program algorithm. INSTI resistance was not detected in ART naïve patients. At least one INSTI resistance mutation was detected in 10% of the INSTI-free patients and 29% of the INSTI-treated patients. Major INSTI-mutations E138K, Y143R, S147G, Q148R, N155H, and E157Q were found in raltegravir. Additional mutations, E92Q, E138K, G140A, S147G, and Q148R were found in elvitegravir; E192Q, E138K/T, G140A/S, S147G, Q148H/R, N155H, E157Q were found in dolutegravir (DTG) experienced patients. According to all drug classes, drug resistance mutation prevalences were determined at the rate of 60%, 46%, and 46% in the RAL, EVG, and DTG groups, respectively. Our findings provide data for treatment and resistance management of INSTIs and may provide feedback for INSTIs resistance surveillance consensus-building efforts. In viral rebound under INSTI treatment, INSTI-resistant mutations follow typical INSTI resistance pathways and high resistance rates. INSTI resistance genotypic analysis should be considered before any DTG-based regimes can be initiated in the future, and reduced DTG susceptibility should be carefully monitored and investigated.

Sayan M ，Yildirim FS ，Akhan S ，Karaoglan I ，Akalin H ... -  《-》

Prevalence and determinants of resistance mutations in HIV-1-infected patients exposed to integrase inhibitors in a large Italian cohort.

The aim of the study was to analyse the prevalence of integrase resistance mutations in integrase strand transfer inhibitor (INSTI)-experienced HIV-1-infected patients and its predictors. We selected HIV-1 integrase sequences from the Antiviral Response Cohort Analysis (ARCA) database, derived from INSTI-experienced patients between 2008 and 2017. Differences in the prevalence of resistance to raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) were assessed by χ2 test and predictors of resistance were analysed by logistic regression. We included 462 genotypes from INSTI-exposed individuals: 356 'INSTI-failing' patients and 106 'previously INSTI-exposed' patients (obtained a median of 42 weeks after INSTI discontinuation [interquartile range (IQR) 17-110 weeks]). Overall, at least low-level resistance (LLR) to any INSTI (Stanford 8.5 algorithm) was detected in 198 (42.9%) cases. The most frequent INSTI resistance mutation was N155H, followed by Q148H/K/R, G140A/C/S, E138A/K/T and Y143C/H/R. Y143R and E138A were more prevalent in viral subtype B versus non-B [5.2 versus 1.5%, respectively (P = 0.04), and 3.1 versus 0%, respectively (P = 0.02)]. Overall, the Q148H/K/R plus G140A/C/S and/or E138A/K/T pattern, defining an intermediate level of resistance to DTG, was detected in 70 (15%) cases. Independent predictors of at least LLR to any INSTI were current use versus past use of INSTIs, a lower genotypic sensitivity score (GSS) for contemporary antiretroviral drugs used, and having an integrase sequence obtained in calendar year 2016 as compared to 2008-2009. The results support integrase resistance testing in INSTI-experienced patients. Emergence of INSTI resistance is facilitated by the reduced genetic barrier of the regimen as a consequence of resistance to companion drugs. However, INSTI resistance may become undetectable by standard population sequencing upon INSTI discontinuation.

Modica S ，Rossetti B ，Lombardi F ，Lagi F ，Maffeo M ，D'Autilia R ，Pecorari M ，Vicenti I ，Bruzzone B ，Magnani G ，Paolucci S ，Francisci D ，Penco G ，Sacchini D ，Zazzi M ，De Luca A ，Di Biagio A ... -  《-》

Accumulation of integrase strand transfer inhibitor resistance mutations confers high-level resistance to dolutegravir in non-B subtype HIV-1 strains from patients failing raltegravir in Uganda.

Increasing first-line treatment failures in low- and middle-income countries (LMICs) have led to increased use of integrase strand transfer inhibitors (INSTIs) such as dolutegravir. However, HIV-1 susceptibility to INSTIs in LMICs, especially with previous raltegravir exposure, is poorly understood due to infrequent reporting of INSTI failures and testing for INSTI drug resistance mutations (DRMs). A total of 51 non-subtype B HIV-1 infected patients failing third-line (raltegravir-based) therapy in Uganda were initially selected for the study. DRMs were detected using Sanger and deep sequencing. HIV integrase genes of 13 patients were cloned and replication capacities (RCs) and phenotypic susceptibilities to dolutegravir, raltegravir and elvitegravir were determined with TZM-bl cells. Spearman's correlation coefficient was used to determine cross-resistance between INSTIs. INSTI DRMs were detected in 47% of patients. HIV integrase-recombinant virus carrying one primary INSTI DRM (N155H or Y143R/S) was susceptible to dolutegravir but highly resistant to raltegravir and elvitegravir (>50-fold change). Two patients, one with E138A/G140A/Q148R/G163R and one with E138K/G140A/S147G/Q148K, displayed the highest reported resistance to raltegravir, elvitegravir and even dolutegravir. The former multi-DRM virus had WT RC whereas the latter had lower RCs than WT. In HIV-1 subtype A- and D-infected patients failing raltegravir and harbouring INSTI DRMs, there is high-level resistance to elvitegravir and raltegravir. More routine monitoring of INSTI treatment may be advised in LMICs, considering that multiple INSTI DRMs may have accumulated during prolonged exposure to raltegravir during virological failure, leading to high-level INSTI resistance, including dolutegravir resistance.

Ndashimye E ，Avino M ，Olabode AS ，Poon AFY ，Gibson RM ，Li Y ，Meadows A ，Tan C ，Reyes PS ，Kityo CM ，Kyeyune F ，Nankya I ，Quiñones-Mateu ME ，Arts EJ ... -  《-》

Susceptibility to HIV-1 integrase strand transfer inhibitors (INSTIs) in highly treatment-experienced patients who failed an INSTI-based regimen.

The aim of this study was to characterize the genotypic and phenotypic resistance profile to the integrase strand transfer inhibitor (INSTI) bictegravir (BIC) and other INSTIs in patients who previously failed twice-daily raltegravir (RAL)-based or twice-daily dolutegravir (DTG)-based regimens. Twenty-two samples were collected after failure on an INSTI-based regimen in 17 highly treatment-experienced patients with HIV-1 with multi-drug-resistant virus, recorded in the Italian PRESTIGIO registry. Genotypic resistance mutations and phenotypic susceptibility to INSTIs were detected by GeneSeqIN and PhenoSenseIN assays, respectively (Monogram Biosciences, San Francisco, CA, USA). The primary INSTI resistance substitutions E138A/K, G140S, Y143C/H/R, Q148H and N155H were detected in 14 of 22 samples and were associated with resistance to one or more INSTIs, with G140S+Q148H present in 11 of 22 samples. Of these 14 samples, all showed high levels of resistance to elvitegravir (EVG) and RAL. Two isolates contained L74M, E138K, G140S and Q148H, or L74M, T97A, S119T, E138K, G140S, Y143R and Q148H, and had high-level resistance to all INSTIs, including BIC and DTG. Intermediate resistance was reported for eight of 14 isolates for BIC and nine of 14 isolates for DTG. Overall, for the 14 INSTI-resistant isolates, the median fold-change values in phenotypic susceptibility were: BIC 3.2 [interquartile range (IQR) 0.6-66], DTG 6.3 (IQR 0.8->186), EVG >164 (IQR 2.6->164) and RAL >188 (IQR 2.7->197). In conclusion, the study findings supported the in-vitro activity of BIC and DTG against most isolates derived from highly treatment-experienced patients who failed INSTI regimens.

Santoro MM ，Fornabaio C ，Malena M ，Galli L ，Poli A ，Menozzi M ，Zazzi M ，White KL ，Castagna A ，PRESTIGIO Study Group ... -  《-》

Selective resistance profiles emerging in patient-derived clinical isolates with cabotegravir, bictegravir, dolutegravir, and elvitegravir.

Oliveira M ，Ibanescu RI ，Anstett K ，Mésplède T ，Routy JP ，Robbins MA ，Brenner BG ，Montreal Primary HIV (PHI) Cohort Study Group ... -  《Retrovirology》