HIV-1 integrase resistance among antiretroviral treatment naive and experienced patients from Northwestern Poland

Abstract

BackgroundHIV integrase inhibitor use is limited by low genetic barrier to resistance and possible cross-resistance among representatives of this class of antiretrovirals. The aim of this study was to analyse integrase sequence variability among antiretroviral treatment naive and experienced patients with no prior integrase inhibitor (InI) exposure and investigate development of the InI drug resistance mutations following the virologic failure of the raltegravir containing regimen.MethodsSequencing of HIV-1 integrase region from plasma samples of 80 integrase treatment naive patients and serial samples from 12 patients with observed virologic failure on raltegravir containing treatment whenever plasma vireamia exceeded >50 copies/ml was performed. Drug resistance mutations were called with Stanford DB database and grouped into major and minor variants. For subtyping bootstrapped phylogenetic analysis was used; Bayesian Monte Carlo Marcov Chain (MCMC) model was implemented to infer on the phylogenetic relationships between the serial sequences from patients failing on raltegravir.ResultsMajority of the integrase region sequences were classified as subtype B; the remaining ones being subtype D, C, G, as well as CRF01_AE , CRF02_AG and CRF13_cpx recombinants. No major integrase drug resistance mutations have been observed in InI-treatment naive 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)]. Other variants included L68V, L74IL, T97A, E138D, V151I, R263K. Among 12 (26.1%) raltegravir treated patients treatment failure was observed; major InI drug resistance mutations (G140S, Q148H and N155H, V151I, E92EQ, V151I, G163R) were noted in four of these cases (8.3% of the total InI-treated patients). 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 raltegravir.ConclusionsIn InI treatment naive patients polymorphic integrase sequence variation was common, with no major resistance mutants. In the treatment failing patients selection of drug resistance occurred rapidly and followed the typical drug resistance pathways. Preexisting integrase polymorphisms were not associated with the treatment failure.

Prevalence of resistance to integrase strand-transfer inhibitors (INSTIs) among untreated HIV-1 infected patients in Morocco

“…Importantly the major resistance mutations with reduced susceptibility to RAL, EVG and DTG were totally absent. The absence of such mutations in our study is consistent with the results of several studies in treatment-naïve patients [ 19 , 20 , 31 – 35 ] and with the fact that the transmission of the drug resistance is unlikely in populations previously unexposed to INIs treatment [ 36 ]. Only three secondary drug resistance mutations included in Stanford list were observed in 4 strains.…”

Antiviral Activity of Bictegravir and Cabotegravir against Integrase Inhibitor-Resistant SIVmac239 and HIV-1

“…Previous studies have shown that tissue culture selections in primary cells with DTG yielded the R263K mutation (25) that was also detected after 24 weeks in 4 treatment-experienced patients who failed DTG as a first-line INSTI in the SAILING study (32). R263K was also rarely observed in several patients who had received RAL (31,(33)(34)(35)(36)(37) and in tissue culture selections with EVG (38). Selection studies in CBMCs showed the consistent emergence of M50I, H51Y, or E138K as secondary/accessory substitutions to R263K under DTG pressure (25).…”

Effect of HIV-1 Subtype C integrase mutations implied using molecular modeling and docking data

“…Compared to the European study our frequency of accessory mutations were less but were higher than the one reported from USA [ 37 ]. Among the RAL treated individuals the major IN resistance mutations reported were G140S, Q148H and N155H, V151I, E92EQ, V151I, G163R [ 1 ]. These major mutations were not present in any of our study strains.…”

“…The enzyme integrase (IN) is a key retroviral enzyme that plays a significant role in the replication of the virus in its susceptible host [ 1 ]. The HIV-1 pol gene encodes for the IN enzyme, the reverse transcriptase enzyme (RT) and Protease (Pr).…”