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Current HIV Research

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ISSN (Print): 1570-162X
ISSN (Online): 1873-4251

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Research Article

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

Author(s): Murat Sayan*, Figen Sarigul Yildirim, Sila Akhan, Ilkay Karaoglan and Halis Akalin

Volume 20, Issue 2, 2022

Published on: 25 March, 2022

Page: [184 - 192] Pages: 9

DOI: 10.2174/1570162X20666220303104509

Price: $65

Abstract

Background and Objective: 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).

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: HIV, drug resistance, INSTI, raltegravir, elvitegravir, dolutegravir.

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[1]
UNAIDS data 2020 2020. Available from: http://www.unaids.org/en/dataanalysis/datatools/aidsinfo/ (accessed; March 19, 2021).
[2]
Panel on antiretroviral guidelines for adults and adolescents. Guidelines for the use of antiretroviral agents in hiv-1-infected adults and adolescents. Department of Health and Human Services. 2021. Available from: http://www.aidsinfo.nih. gov/ContentFiles/AdultandAdolescentGL.pdf (accessed; March 19, 2021).
[3]
European AIDS clinical society (EACS) Guidelines. (2020): Version 10.1, October 2017. 2020. Available from: http://www. eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.htlm (accessed; March 30, 2021).
[4]
Saag MS, Gandhi RT, Hoy JF, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2020 Recommendations of the International Antiviral Society-USA Panel. JAMA 2020; 324(16): 1651-69.
[http://dx.doi.org/10.1001/jama.2020.17025] [PMID: 33052386]
[5]
Engelman A, Mizuuchi K, Craigie R. HIV-1 DNA integration: Mechanism of viral DNA cleavage and DNA strand transfer. Cell 1991; 67(6): 1211-21.
[http://dx.doi.org/10.1016/0092-8674(91)90297-C] [PMID: 1760846]
[6]
U.S. Food and drug administration. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/resources-information-approved-drugs (accessed: April, 2021).
[7]
European medicines agency - Europa EU. Available from: https://www.ema.europa.eu/en/medicines/download-medicine-data (accessed: April 20, 2021).
[8]
Merck Sharp & Dohme Corp. Isentress package insert. 2017. Available from: http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi. pdf (accessed: April 20, 2021).
[9]
Greig SL, Deeks ED. Abacavir/dolutegravir/lamivudine single-tablet regimen: A review of its use in HIV-1 infection. Drugs 2015; 75(5): 503-14.
[http://dx.doi.org/10.1007/s40265-015-0361-6] [PMID: 25698454]
[10]
Tsiang M, Jones GS, Goldsmith J, et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob Agents Chemother 2016; 60(12): 7086-97.
[http://dx.doi.org/10.1128/AAC.01474-16] [PMID: 27645238]
[11]
Kovač L, Časar Z. A literature review of the patent application publications on cabotegravir - an HIV integrase strand transfer inhibitor. Expert Opin Ther Pat 2020; 30(3): 195-208.
[http://dx.doi.org/10.1080/13543776.2020.1717470] [PMID: 31944142]
[12]
Sarıgül F, User U, Oztoprak N. Comparison of immunological and virological recovery of raltegravir, elvitegravir, and dolutegravir in HIV-1 infected naive patients. Acta Med Mediter 2019; 35(6): 3077-84.
[13]
Brooks KM, Sherman EM, Egelund EF, et al. Integrase inhibitors: After 10 years of experience, is the best yet to come? Pharmacotherapy 2019; 39(5): 576-98.
[http://dx.doi.org/10.1002/phar.2246] [PMID: 30860610]
[14]
Anstett K, Brenner B, Mesplede T, Wainberg MA. HIV drug resistance against strand transfer integrase inhibitors. Retrovirology 2017; 14(1): 36.
[http://dx.doi.org/10.1186/s12977-017-0360-7] [PMID: 28583191]
[15]
General directorate of public health. Statistical data of communicable diseases department: HIV/AIDS. Ankara: T.C. Ministry of Health. Available from: http://www.thsk.gov.tr/component/k2/353- istatiksel-veriler/bulasici-hastaliklar-dairebaskanligi-istatiksel-veriler.html (accessed: April 22, 2020).
[16]
Erdinc FS, Dokuzoguz B, Unal S, et al. Multicentric Hiv Study Group. Temporal trends in the epidemiology of HIV in Turkey. Curr HIV Res 2020; 18(4): 258-66.
[http://dx.doi.org/10.2174/1570162X18666200427223823] [PMID: 32342820]
[17]
IMS Health Turkey. 2021. Available from: www.imshealth.com/portal/site/imshealth (accessed: March 24, 2021).
[18]
Ceccherini-Silberstein F, Malet I, Fabeni L, et al. Specific HIV-1 integrase polymorphisms change their prevalence in untreated versus antiretroviral-treated HIV-1-infected patients, all naive to integrase inhibitors. J Antimicrob Chemother 2010; 65(11): 2305-18.
[http://dx.doi.org/10.1093/jac/dkq326] [PMID: 20817922]
[19]
Sayan M, Gündüz A, Ersöz G, et al. Integrase strand transfer inhibitors (INSTIs) resistance mutations in HIV-1 infected Turkish patients. HIV Clin Trials 2016; 17(3): 109-13.
[http://dx.doi.org/10.1080/15284336.2016.1153303] [PMID: 27125365]
[20]
Bennett DE, Camacho RJ, Otelea D, et al. Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update. PLoS One 2009; 4(3): e4724.
[http://dx.doi.org/10.1371/journal.pone.0004724] [PMID: 19266092]
[21]
Tzou PL, Rhee SY, Descamps D, et al. Integrase strand transfer inhibitor (INSTI)-resistance mutations for the surveillance of transmitted HIV-1 drug resistance. J Antimicrob Chemother 2020; 75(1): 170-82.
[http://dx.doi.org/10.1093/jac/dkz417] [PMID: 31617907]
[22]
HIV Stanford Drug Resistance Database, INSTI Resistance Notes, HIVdb version 9.0. Available from: https://hivdb.stanford.edu/dr-summary/resistance-notes/INSTI/ (accessed: April 22, 2021).
[23]
Nichols G, Mills A, Grossberg R, et al. Antiviral activity of dolutegravir in subjects with failure on an integrase inhibitor-based regimen: Week 24 phase 3 results from VIKING-3. J Int AIDS Soc 2012; 15(4): 18112.
[http://dx.doi.org/10.7448/IAS.15.6.18112]
[24]
Casadellà M, van Ham PM, Noguera-Julian M, et al. SPREAD programme. Primary resistance to integrase strand-transfer inhibitors in Europe. J Antimicrob Chemother 2015; 70(10): 2885-8.
[http://dx.doi.org/10.1093/jac/dkv202] [PMID: 26188038]
[25]
Doyle T, Dunn DT, Ceccherini-Silberstein F, et al. Integrase inhibitor (INI) genotypic resistance in treatment-naive and raltegravir-experienced patients infected with diverse HIV-1 clades. J Antimicrob Chemother 2015; 70(11): 3080-6.
[http://dx.doi.org/10.1093/jac/dkv243] [PMID: 26311843]
[26]
Rossetti B, Di Giambenedetto S, Torti C, et al. Antiviral response cohort analysis (ARCA) collaborative group. Evolution of transmitted HIV-1 drug resistance and viral subtypes circulation in Italy from 2006 to 2016. HIV Med 2018; 19(9): 619-28.
[http://dx.doi.org/10.1111/hiv.12640] [PMID: 29932313]
[27]
Lai J, Liu Y, Han X, et al. Low frequency of integrase inhibitor resistance mutations among therapy-naïve HIV patients in Southeast China. Drug Des Devel Ther 2021; 15: 889-94.
[http://dx.doi.org/10.2147/DDDT.S286863] [PMID: 33679129]
[28]
Tsai HC, Chen IT, Tsai KW, Lee SS, Chen YS. Prevalence of HIV-1 integrase strand transfer inhibitor resistance in treatment-naïve voluntary counseling and testing clients by population sequencing and Illumina next-generation sequencing in Taiwan. Infect Drug Resist 2020; 13: 4519-29.
[http://dx.doi.org/10.2147/IDR.S273704] [PMID: 33364799]
[29]
Scutari R, Alteri C, Vicenti I, et al. Evaluation of HIV-1 integrase resistance emergence and evolution in patients treated with integrase inhibitors. J Glob Antimicrob Resist 2020; 20: 163-9.
[http://dx.doi.org/10.1016/j.jgar.2019.07.015] [PMID: 31330378]
[30]
Nguyen T, Fofana DB, Lê MP, et al. Prevalence and clinical impact of minority resistant variants in patients failing an integrase inhibitor-based regimen by ultra-deep sequencing. J Antimicrob Chemother 2018; 73(9): 2485-92.
[http://dx.doi.org/10.1093/jac/dky198] [PMID: 29873733]
[31]
Orta-Resendiz A, Rodriguez-Diaz RA, Angulo-Medina LA, Hernandez-Flores M, Soto-Ramirez LE. HIV-1 acquired drug resistance to integrase inhibitors in a cohort of antiretroviral therapy multi-experienced Mexican patients failing to raltegravir: A cross-sectional study. AIDS Res Ther 2020; 17(1): 6.
[http://dx.doi.org/10.1186/s12981-020-0262-y] [PMID: 32041622]
[32]
Wohl DA, Cohen C, Gallant JE, et al. GS-US-236-0102 Study Team. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF versus single-tablet regimen efavirenz/emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: Analysis of week 144 results. J Acquir Immune Defic Syndr 2014; 65(3): e118-20.
[http://dx.doi.org/10.1097/QAI.0000000000000057] [PMID: 24256630]
[33]
Eron JJ, Cooper DA, Steigbigel RT, et al. Efficacy and safety of raltegravir for treatment of HIV for 5 years in the BENCHMRK studies: Final results of two randomised, placebo-controlled trials. Lancet Infect Dis 2013; 13(7): 587-96.
[http://dx.doi.org/10.1016/S1473-3099(13)70093-8] [PMID: 23664333]
[34]
Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: Final 5-year results from STARTMRK. J Acquir Immune Defic Syndr 2013; 63(1): 77-85.
[http://dx.doi.org/10.1097/QAI.0b013e31828ace69] [PMID: 23412015]
[35]
Geretti AM, Armenia D, Ceccherini-Silberstein F. Emerging patterns and implications of HIV-1 integrase inhibitor resistance. Curr Opin Infect Dis 2012; 25(6): 677-86.
[http://dx.doi.org/10.1097/QCO.0b013e32835a1de7] [PMID: 23086187]
[36]
Abram ME, Hluhanich RM, Goodman DD, et al. Impact of primary elvitegravir resistance-associated mutations in HIV-1 integrase on drug susceptibility and viral replication fitness. Antimicrob Agents Chemother 2013; 57(6): 2654-63.
[http://dx.doi.org/10.1128/AAC.02568-12] [PMID: 23529738]
[37]
Blanco JL, Varghese V, Rhee SY, Gatell JM, Shafer RW. HIV-1 integrase inhibitor resistance and its clinical implications. J Infect Dis 2011; 203(9): 1204-14.
[http://dx.doi.org/10.1093/infdis/jir025] [PMID: 21459813]
[38]
Métifiot M, Vandegraaff N, Maddali K, et al. Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143. AIDS 2011; 25(9): 1175-8.
[http://dx.doi.org/10.1097/QAD.0b013e3283473599] [PMID: 21505303]
[39]
Van Wesenbeeck L, Rondelez E, Feyaerts M, et al. Cross-resistance profile determination of two second-generation HIV-1 integrase inhibitors using a panel of recombinant viruses derived from raltegravir-treated clinical isolates. Antimicrob Agents Chemother 2011; 55(1): 321-5.
[http://dx.doi.org/10.1128/AAC.01733-09] [PMID: 20956600]
[40]
Mesplède T, Quashie PK, Wainberg MA. Resistance to HIV integrase inhibitors. Curr Opin HIV AIDS 2012; 7(5): 401-8.
[http://dx.doi.org/10.1097/COH.0b013e328356db89] [PMID: 22789986]
[41]
Fourati S, Charpentier C, Amiel C, et al. Cross-resistance to elvitegravir and dolutegravir in 502 patients failing on raltegravir: A French national study of raltegravir-experienced HIV-1-infected patients. J Antimicrob Chemother 2015; 70(5): 1507-12.
[http://dx.doi.org/10.1093/jac/dku535] [PMID: 25558077]
[42]
Malet I, Thierry E, Wirden M, et al. Combination of two pathways involved in raltegravir resistance confers dolutegravir resistance. J Antimicrob Chemother 2015; 287(10): 2870-80.
[PMID: 26205139]
[43]
Castagna A, Maggiolo F, Penco G, et al. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis 2014; 210(3): 354-62.
[http://dx.doi.org/10.1093/infdis/jiu051] [PMID: 24446523]
[44]
Hardy I, Brenner B, Quashie P, et al. Evolution of a novel pathway leading to dolutegravir resistance in a patient harbouring N155H and multiclass drug resistance. J Antimicrob Chemother 2015; 70(2): 405-11.
[http://dx.doi.org/10.1093/jac/dku387] [PMID: 25281399]
[45]
Mesplède T, Quashie PK, Zanichelli V, Wainberg MA. Integrase strand transfer inhibitors in the management of HIV-positive individuals. Ann Med 2014; 46(3): 123-9.
[http://dx.doi.org/10.3109/07853890.2014.883169] [PMID: 24579911]
[46]
Quashie PK, Sloan RD, Wainberg MA. Novel therapeutic strategies targeting HIV integrase. BMC Med 2012; 10(1): 34.
[http://dx.doi.org/10.1186/1741-7015-10-34] [PMID: 22498430]
[47]
Clotet B, Feinberg J, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet 2014; 383(9936): 2222-31.
[http://dx.doi.org/10.1016/S0140-6736(14)60084-2] [PMID: 24698485]
[48]
Fulcher JA, Du Y, Zhang TH, Sun R, Landovitz RJ. The emergence of integrase resistance mutations during initial therapy containing dolutegravir. Clin Infect Dis 2018; 67(5): 791-4.
[http://dx.doi.org/10.1093/cid/ciy228]
[49]
Kobayashi M, Yoshinaga T, Seki T, et al. In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother 2011; 55(2): 813-21.
[http://dx.doi.org/10.1128/AAC.01209-10] [PMID: 21115794]
[50]
Castagna A, Ferrara M, Galli L, et al. Long-term efficacy of dolutegravir in treatment-experienced subjects failing therapy with HIV-1 integrase strand inhibitor-resistant virus. J Antimicrob Chemother 2018; 73(1): 177-82.
[PMID: 29077927]
[51]
Modica S, Rossetti B, Lombardi F, et al. Prevalence and determinants of resistance mutations in HIV-1-infected patients exposed to integrase inhibitors in a large Italian cohort. HIV Med 2019; 20(2): 137-46.
[http://dx.doi.org/10.1111/hiv.12692] [PMID: 30461149]

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