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      Primary resistance to integrase strand transfer inhibitors in patients infected with diverse HIV-1 subtypes in sub-Saharan Africa

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          Abstract

          To investigate the prevalence and patterns of major and accessory resistance mutations associated with integrase strand transfer inhibitors (INSTIs), across diverse HIV-1 subtypes in sub-Saharan Africa.

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          Resistance to HIV integrase strand transfer inhibitors among clinical specimens in the United States, 2009-2012.

          B Hurt, Joseph Sebastian, J Eron … (2014)
          Data on integrase inhibitor resistance come primarily from clinical trials and in vitro studies. We examined results of all clinically indicated integrase genotypic resistance tests (GRTs) performed at a US national referral lab from 2009 through 2012. Integrase sequences and demographic data were compiled with paired protease-reverse transcriptase (PR-RT) GRT results, when available. Analyses utilized the Stanford HIV Drug Resistance Database. "Major" integrase mutations included T66AIK, E92QV, F121Y, Y143CHR, S147G, Q148HKR, and N155H; multiple accessory mutations were also assessed. Among 3294 sequences from 3012 patients, 471 patients had viruses with ≥ 1 raltegravir or elvitegravir resistance mutation (15.6%). Q148 and N155 pathways were equally represented (both n = 197); 84 had Y143 mutations. Q148 rarely occurred without accessory mutations (n = 3). Among 224 patients with serial integrase GRTs, 22 with baseline wild-type acquired a major mutation, after a median 224 days between tests (interquartile range, 148-335 days). Major mutations were observed to persist up to 462 days. Most (62%) had paired PR-RT results. Patients with integrase-resistant viruses were older and more likely to have PR-RT mutations (both P < .001). Among those with PR-RT data, 42 patients had 4-class resistance (2.3%). Sex, geographic region, and test year were not associated with integrase resistance. High-level dolutegravir resistance was predicted in 12% of patients with raltegravir- or elvitegravir-resistant viruses (2% of all patients). Approximately 1 in 6 US patients undergoing integrase GRT for clinical decision making harbors significant resistance, with Q148 and N155 pathways equally common. Dolutegravir is likely to have full or partial activity against most variants observed.
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            Emergent drug resistance with integrase strand transfer inhibitor-based regimens

            P Harrigan, Katherine J Lepik, Wendy W. Zhang … (2017)
            To estimate the incidence of and risk factors for emergent resistance to integrase strand transfer inhibitor (INSTI) and nucleoside(-tide) reverse transcriptase inhibitors (NRTI) in HIV-1-infected adults receiving an INSTI and two NRTIs.
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              Natural variation of HIV-1 group M integrase: Implications for a new class of antiretroviral inhibitors

              Soo-Yon Rhee, Tommy Liu, Mark Kiuchi … (2008)
              HIV-1 integrase is the third enzymatic target of antiretroviral (ARV) therapy. However, few data have been published on the distribution of naturally occurring amino acid variation in this enzyme. We therefore characterized the distribution of integrase variants among more than 1,800 published group M HIV-1 isolates from more than 1,500 integrase inhibitor (INI)-naïve individuals. Polymorphism rates equal or above 0.5% were found for 34% of the central core domain positions, 42% of the C-terminal domain positions, and 50% of the N-terminal domain positions. Among 727 ARV-naïve individuals in whom the complete pol gene was sequenced, integrase displayed significantly decreased inter- and intra-subtype diversity and a lower Shannon's entropy than protease or RT. All primary INI-resistance mutations with the exception of E157Q – which was present in 1.1% of sequences – were nonpolymorphic. Several accessory INI-resistance mutations including L74M, T97A, V151I, G163R, and S230N were also polymorphic with polymorphism rates ranging between 0.5% to 2.0%.
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                Author and article information

                Journal
                Title: Journal of Antimicrobial Chemotherapy
                Publisher: Oxford University Press (OUP)
                ISSN (Print): 0305-7453
                ISSN (Electronic): 1460-2091
                Publication date Created: May 2018
                Publication date Created: May 01 2018
                Publication date Created: February 14 2018
                Publication date Other: May 2018
                Publication date (Print): May 01 2018
                Publication date (Electronic): February 14 2018
                Volume: 73
                Issue: 5
                Pages: 1167-1172
                Affiliations
                [1 ]Department of Global Health, Academic Medical Center of the University of Amsterdam, and Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands
                [2 ]Joep Lange Institute, Department of Global Health, Academic Medical Centre of the University of Amsterdam, Amsterdam, The Netherlands
                [3 ]Eijkman-Oxford Clinical Research Unit, Jakarta, Indonesia, and Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
                [4 ]Infectious Diseases Unit & IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain
                [5 ]Universitat de Vic-Universitat Central de Catalunya, C. Sagrada Família 7, 08500 Vic, Catalonia, Spain
                Article
                DOI: 10.1093/jac/dky005
                PubMed ID: 29462322
                SO-VID: 75b6306b-7c88-4cbc-9c14-2f2a8e50b9b4
                Copyright © © 2018
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                https://academic.oup.com/journals/pages/about_us/legal/notices

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