Integrase resistance variants among integrase inhibitor treatment‐na?ve and treated patients from Northwestern Poland

摘要

Purpose of the study HIV integrase inhibitor use is limited by low genetic barrier to resistance and possible cross‐resistance among representatives of the class. The aim of this study was to analyse the sequence variability in the integrase region in treatment‐na?ve and experienced patients with no prior integrase inhibitor (InI) exposure and to investigate the development of the InI drug resistance mutations following the virologic failure of the raltegravir (RAL)‐containing regimen. Methods Sequencing of HIV‐1 integrase region (866 base pair, HXB2 genome location: positions 4230–5096) from plasma samples of 80 integrase treatment‐na?ve patients and treatment failing subjects from a group of the 46 RAL‐treated patients were analysed. Drug resistance mutations were called with Stanford DB database and grouped into major and minor mutations. For subtyping, bootstrapped phylogenetic analysis (1000 replicates) with under the GTR + I+gamma model with reference sequences. Results Majority of the integrase region sequences were classified as subtype B; the remaining ones being subtype D, C, G, and CRF01_AE, CRF02_AG and CRF13_cpx recombinants. No major integrase drug resistance mutations have been observed in InI‐treatment na?ve patients. In 30 (38.5%) cases polymorphic variation, with predominance of the E157Q mutation was observed. This mutation was more common among subtype B (26 cases, 54.2%) than non‐B sequences (5 cases, 16.7%), p = 0.00099, OR: 5.91 (95% CI: 1.77–22.63)] (Figure 1a, 1b). Other variants included L68V, L74IL, T97A, E138D, V151I, R263. Of the RAL‐treated patients in 12 cases (26.1%) treatment failure was observed. In 4 cases major the following InI drug resistance mutations were found: N155H, V151I, E92EQ, V151I, G163R (3 cases) and Q148H, G140S mutant (one case). Time to the development of drug resistance ranged from 2.6 to 16.3 months with mean increase of HIV viral load of 4.34 (95% CI: 1.86–6.84) log HIV‐RNA copies/ml at the time of emergence of the major mutations. Baseline polymorphisms, including E157Q were not associated with the virologic failure on RAL (p = 0.5). Conclusions In InI treatment‐na?ve patients polymorphic integrase sequence variation was common, with no major resistance mutants observed. In the failing patients selection of drug resistance occur rapidly, and follows the typical drug resistance pathways accumulation of mutations. Pre‐existing integrase polymorphisms were not associated with the treatment failure.