Dataset Information

Prevalence of Human Immunodeficiency Virus-1 Integrase Strand Transfer Inhibitor Resistance in British Columbia, Canada Between 2009 and 2016: A Longitudinal Analysis.

ABSTRACT: Background:Integrase strand transfer inhibitors (INSTIs) are highly efficacious and well tolerated antiretrovirals with fewer adverse side-effects relative to other classes of antiretrovirals. The use of INSTIs raltegravir, elvitegravir, and dolutegravir has increased dramatically over recent years. However, there is limited information about the evolution and prevalence of INSTI resistance mutations in clinical human immunodeficiency virus populations. Methods:Human immunodeficiency virus-1-positive individuals ?19 years were included if they received ?1 dispensed prescription of antiretroviral therapy (ART) in British Columbia between 2009 and 2016 (N = 9358). Physician-ordered drug resistance tests were analyzed and protease inhibitor (PI), reverse-transcriptase inhibitor (RT), and INSTI resistance were defined as having ?1 sample with a combined, cumulative score ?30 by Stanford HIV Drug Resistance Algorithm version 7.0.1. Results:Although most ART-treated individuals were tested for PI and RT resistance, INSTI resistance testing lagged behind the uptake of INSTIs among INSTI-treated individuals (11% in 2009; 34% in 2016). The prevalence of INSTI resistance was relatively low, but it increased from 1 to 7 per 1000 ART-treated individuals between 2009 and 2016 (P < .0001, R2 = 0.98). Integrase strand transfer inhibitor resistance mutations increased at integrase codons 66, 97, 140, 148, 155, and 263. Conclusions:The prevalence of INSTI resistance remains low compared with PI and RT resistance in ART-treated populations but is expanding with increased INSTI use.

SUBMITTER: Kamelian K

PROVIDER: S-EPMC6419991 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Prevalence of Human Immunodeficiency Virus-1 Integrase Strand Transfer Inhibitor Resistance in British Columbia, Canada Between 2009 and 2016: A Longitudinal Analysis.

Kamelian Kimia K Lepik Katherine J KJ Chau William W Yip Benita B Zhang Wendy W WW Lima Viviane Dias VD Robbins Marjorie A MA Woods Conan C Olmstead Andrea A Joy Jeffrey B JB Barrios Rolando R Harrigan P Richard PR

Open forum infectious diseases 20190212 3

<h4>Background</h4>Integrase strand transfer inhibitors (INSTIs) are highly efficacious and well tolerated antiretrovirals with fewer adverse side-effects relative to other classes of antiretrovirals. The use of INSTIs raltegravir, elvitegravir, and dolutegravir has increased dramatically over recent years. However, there is limited information about the evolution and prevalence of INSTI resistance mutations in clinical human immunodeficiency virus populations.<h4>Methods</h4>Human immunodeficie ...[more]

PMID: 30895202

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Project description:We previously showed that the simian immunodeficiency virus SIVmac239 is susceptible to human immunodeficiency virus (HIV) integrase (IN) strand transfer inhibitors (INSTIs) and that the same IN drug resistance mutations result in similar phenotypes in both viruses. Now we wished to determine whether tissue culture drug selection studies with SIV would yield the same resistance mutations as in HIV. Tissue culture selection experiments were performed using rhesus macaque peripheral blood mononuclear cells (PBMCs) infected with SIVmac239 viruses in the presence of increasing concentrations of dolutegravir (DTG), elvitegravir (EVG), and raltegravir (RAL). We now show that 22 weeks of selection pressure with DTG yielded a mutation at position R263K in SIV, similar to what has been observed in HIV, and that selections with EVG led to emergence of the E92Q substitution, which is a primary INSTI resistance mutation in HIV associated with EVG treatment failure. To study this at a biochemical level, purified recombinant SIVmac239 wild-type (WT) and E92Q, T97A, G118R, Y143R, Q148R, N155H, R263K, E92Q T97A, E92Q Y143R, R263K H51Y, and G140S Q148R recombinant substitution-containing IN enzymes were produced, and each of the characteristics strand transfer, 3'-processing activity, and INSTI inhibitory constants was assessed in cell-free assays. The results show that the G118R and G140S Q148R substitutions decreased Km' and Vmax'/Km' for strand transfer compared to those of the WT. RAL and EVG showed reduced activity against both viruses and against enzymes containing Q148R, E92Q Y143R, and G140S Q148R. Both viruses and enzymes containing Q148R and G140S Q148R showed moderate levels of resistance against DTG. This study further confirms that the same mutations associated with drug resistance in HIV display similar profiles in SIV.Our goal was to definitively establish whether HIV and simian immunodeficiency virus (SIV) share similar resistance pathways under tissue culture drug selection pressure with integrase strand transfer inhibitors and to test the effect of HIV-1 integrase resistance-associated mutations on SIV integrase catalytic activity and resistance to integrase strand transfer inhibitors. Clinically relevant HIV integrase resistance-associated mutations were selected in SIV in our tissue culture experiments. Not only do we report on the characterization of SIV recombinant integrase enzyme catalytic activities, we also provide the first research anywhere on the effect of mutations within recombinant integrase SIV enzymes on drug resistance.

Dataset Information

Prevalence of Human Immunodeficiency Virus-1 Integrase Strand Transfer Inhibitor Resistance in British Columbia, Canada Between 2009 and 2016: A Longitudinal Analysis.

Publications

Prevalence of Human Immunodeficiency Virus-1 Integrase Strand Transfer Inhibitor Resistance in British Columbia, Canada Between 2009 and 2016: A Longitudinal Analysis.

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