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Current HIV Research

Editor-in-Chief

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

Research Article

Human Immunodeficiency Virus-1 Drug Resistance Mutations in Iranian Treatment-experienced Individuals

Author(s): Farah Bokharaei-Salim*, Khadijeh Khanaliha, Seyed Hamidreza Monavari, Seyed Jalal Kiani, Ahmad Tavakoli, Ensieh jafari, Sara Chavoshpour, Mohammad Hossein Razizadeh and Saeed Kalantari

Volume 22, Issue 1, 2024

Published on: 19 January, 2024

Page: [53 - 64] Pages: 12

DOI: 10.2174/011570162X273321240105081444

Price: $65

Abstract

Background: Human immunodeficiency virus-1 infection still remains a global health threat. While antiretroviral therapy is the primary treatment option, concerns about the emergence of drug-resistance mutations and treatment failure in HIV-infected patients persist.

Objective: In this study, we investigated the development of drug resistance in HIV-1-infected individuals receiving antiretroviral therapy for 6-10 years.

Methods: In this cross-sectional study, we evaluated 144 people living with HIV-1 who had received antiretroviral therapy for at least 6 years. Plasma specimens were collected, and the HIV-1 viral load and drug-resistance mutations were assessed using molecular techniques.

Results: The demographic and epidemiological characteristics of the participants were also analyzed: Twelve [8.3%) of the studied patients showed a viral load over 1000 copies per/mL, which indicates the suboptimal response to antiretroviral therapy. Significant correlations were found between viral load and CD4 count, as well as epidemiological factors, such as vertical transmission, history of imprisonment, and needle stick injuries. Drug resistance mutations were detected in 10 (83.3%) of patients who failed on antiretroviral therapy, with the most common mutations observed against nucleoside reverse transcriptase inhibitors (5 (41.7%)) and non-nucleoside reverse transcriptase inhibitors (9 (75%)). Phylogenetic analysis revealed that 12 patients who failed treatment were infected with CRF35_AD.

Conclusion: Our study provides important insights into the characteristics and development of drug resistance in HIV-1-infected individuals receiving long-term antiretroviral therapy in Iran. The findings underline the need for regular viral load monitoring, individualized treatment selection, and targeted interventions to optimize treatment outcomes and prevent the further spread of drug-resistant strains.

Graphical Abstract

[1]
van Heuvel Y, Schatz S, Rosengarten JF, Stitz J. Infectious RNA: Human immunodeficiency virus (HIV) biology, therapeutic intervention, and the quest for a vaccine. Toxins 2022; 14(2): 138.
[http://dx.doi.org/10.3390/toxins14020138] [PMID: 35202165]
[2]
Feinberg J, Keeshin S. Prevention and initial management of HIV infection. Ann Intern Med 2022; 175(6): ITC81-96.
[http://dx.doi.org/10.7326/AITC202206210] [PMID: 35696682]
[3]
Millar AJW, Cox SG. Surgical implications of HIV infection. Pediatr Surg Int 2022; 39(1): 39.
[http://dx.doi.org/10.1007/s00383-022-05333-6] [PMID: 36482099]
[4]
Urakovna NN, Sultanovna MG, Yunusovich MA, Fakhridinovna AM, Toshtemirovna XN, Vlademirovna BE. Epidemiological analysis of the human immunodeficiency virus. World Bulletin of Public Health 2023; 21: 95-8.
[5]
Rangwala HS, Anwar Z, Ovais MH, Fatima H, Siddiq MA. Rising HIV cases in Pakistan: Start of a pandemic? Ann Med Surg 2022; 82: 104791.
[http://dx.doi.org/10.1016/j.amsu.2022.104791] [PMID: 36268456]
[6]
Al-Tawfiq JA, Alhumaid S, Altawfiq KJ, Bearman G. 2022 World AIDS day: Past achievements and future optimism. New Microbes New Infect 2023; 51: 101067.
[http://dx.doi.org/10.1016/j.nmni.2022.101067] [PMID: 36593884]
[7]
Hargrave A, Mustafa AS, Hanif A, Tunio JH, Hanif SNM. Current status of HIV-1 vaccines. Vaccines 2021; 9(9): 1026.
[http://dx.doi.org/10.3390/vaccines9091026] [PMID: 34579263]
[8]
García Deltoro M. Rapid initiation of antiretroviral therapy after HIV diagnosis. AIDS Rev 2019; 21(2): 55-64.
[http://dx.doi.org/10.24875/AIDSRev.M19000027] [PMID: 31332395]
[9]
Kirichenko A, Kireev D, Lopatukhin A, et al. Prevalence of HIV-1 drug resistance in Eastern European and Central Asian countries. PLoS One 2022; 17(1): e0257731.
[http://dx.doi.org/10.1371/journal.pone.0257731] [PMID: 35061671]
[10]
Garshasbi S, Marjani A, Alipour A, et al. The frequency of HIV-1 infection and surveillance drug-resistant mutations determination among Iranians with high-risk behaviors, during 2014 to 2020. Iran J Microbiol 2021; 13(6): 878-86.
[http://dx.doi.org/10.18502/ijm.v13i6.8094] [PMID: 35222867]
[11]
Wang Y, Wu G, Wen Z, Lei H, Lin F. Highly active antiretroviral therapy-related effects on morphological connectivity in HIV. AIDS 2024; 38(2): 207-15.
[http://dx.doi.org/10.1097/QAD.0000000000003759] [PMID: 37861678]
[12]
Boender TS, Kityo CM, Boerma RS, et al. Accumulation of HIV-1 drug resistance after continued virological failure on first-line ART in adults and children in sub-Saharan Africa. J Antimicrob Chemother 2016; 71(10): 2918-27.
[http://dx.doi.org/10.1093/jac/dkw218] [PMID: 27342546]
[13]
Bokharaei-Salim F, Kalantari S, Gholamypour Z, et al. Investigation of the effects of a prevention of mother-to-child HIV transmission program among Iranian neonates. Arch Virol 2018; 163(5): 1179-85.
[http://dx.doi.org/10.1007/s00705-017-3661-1] [PMID: 29383588]
[14]
Agosto LM, Zhong P, Munro J, Mothes W. Highly active antiretroviral therapies are effective against HIV-1 cell-to-cell transmission. PLoS Pathog 2014; 10(2): e1003982.
[http://dx.doi.org/10.1371/journal.ppat.1003982] [PMID: 24586176]
[15]
Jarchi M, Bokharaei-Salim F, Esghaei M, et al. The frequency of HIV-1 infection in iranian children and determination of the transmitted drug resistance in treatment-naïve children. Curr HIV Res 2020; 17(6): 397-407.
[http://dx.doi.org/10.2174/1570162X17666191106111211] [PMID: 31702525]
[16]
Arrieta-Martínez JA, Estrada-Acevedo JI, Gómez CA, et al. Related factors to non-adherence to antiretroviral therapy in HIV/AIDS patients. Farm Hosp 2022; 46(6): 319-26.
[PMID: 36520570]
[17]
Kim SH, Gerver SM, Fidler S, Ward H. Adherence to antiretroviral therapy in adolescents living with HIV. AIDS 2014; 28(13): 1945-56.
[http://dx.doi.org/10.1097/QAD.0000000000000316] [PMID: 24845154]
[18]
Bokharaei-Salim F, Esghaei M, Khanaliha K, et al. HIV-1 reverse transcriptase and protease mutations for drug-resistance detection among treatment-experienced and naïve HIV-infected individuals. PLoS One 2020; 15(3): e0229275.
[http://dx.doi.org/10.1371/journal.pone.0229275] [PMID: 32119691]
[19]
Vahabpour R, Bokharaei-Salim F, Kalantari S, et al. HIV-1 genetic diversity and transmitted drug resistance frequency among Iranian treatment-naive, sexually infected individuals. Arch Virol 2017; 162(6): 1477-85.
[http://dx.doi.org/10.1007/s00705-017-3228-1] [PMID: 28181034]
[20]
Nasiri-Tajabadi Z, Bokharaei Salim F, Najafzadeh MJ, et al. A surveillance on protease inhibitor resistance-associated mutations among iranian hiv-1 patients. Arch Clin Infect Dis 2018; 13(6)
[http://dx.doi.org/10.5812/archcid.69153]
[21]
Wensing AM, Calvez V, Ceccherini-Silberstein F, et al. 2022 update of the drug resistance mutations in HIV-1. Top Antivir Med 2022; 30(4): 559-74.
[PMID: 36375130]
[22]
Bakhouch K, Oulad-Lahcen A, Bensghir R, et al. The prevalence of resistance-associated mutations to protease and reverse transcriptase inhibitors in treatment-naïve (HIV1)-infected individuals in Casablanca, Morocco. J Infect Dev Ctries 2009; 3(5): 380-91.
[http://dx.doi.org/10.3855/jidc.247] [PMID: 19759509]
[23]
Baesi K, Abbasian L, Farrokhi M, Gholami M, Mohraz M, McFarland W. HIV drug resistance among naïve HIV-infected patients in Iran. J Res Med Sci 2019; 24(1): 31.
[http://dx.doi.org/10.4103/jrms.JRMS_689_18] [PMID: 31143232]
[24]
Ghafari S, Memarnejadian A, Samarbaf-zadeh A, et al. Prevalence of HIV-1 transmitted drug resistance in recently infected, treatment-naïve persons in the Southwest of Iran, 2014-2015. Arch Virol 2017; 162(9): 2737-45.
[http://dx.doi.org/10.1007/s00705-017-3431-0] [PMID: 28589513]
[25]
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]
[26]
Habib Z, Bokharaei-Salim F, Kiani SJ, et al. Non detection of HIV-1 proviral DNA in PBMCs of the neonates born to Iranian HIV-infected mothers in PMTCT program. Arch Pediatr Infect Dis 2021; 9(2)
[http://dx.doi.org/10.5812/pedinfect.105098]
[27]
Marjani A, Bokharaei-Salim F, Jahanbakhshi F, et al. HIV-1 integrase drug-resistance mutations in Iranian treatment-experienced HIV-1-infected patients. Arch Virol 2020; 165(1): 115-25.
[http://dx.doi.org/10.1007/s00705-019-04463-y] [PMID: 31741096]
[28]
Zaccarelli M, Perno CF, Forbici F, et al. Using a database of HIV patients undergoing genotypic resistance test after HAART failure to understand the dynamics of M184V mutation. Antivir Ther 2003; 8(1): 51-6.
[http://dx.doi.org/10.1177/135965350300800107] [PMID: 12713064]
[29]
Hung M, Tokarsky EJ, Lagpacan L, Zhang L, Suo Z, Lansdon EB. Elucidating molecular interactions of L-nucleotides with HIV-1 reverse transcriptase and mechanism of M184V-caused drug resistance. Commun Biol 2019; 2(1): 469.
[http://dx.doi.org/10.1038/s42003-019-0706-x] [PMID: 31872074]
[30]
Brehm JH, Mellors JW, Sluis-Cremer N. Mechanism by which a glutamine to leucine substitution at residue 509 in the ribonuclease H domain of HIV-1 reverse transcriptase confers zidovudine resistance. Biochemistry 2008; 47(52): 14020-7.
[http://dx.doi.org/10.1021/bi8014778] [PMID: 19067547]
[31]
Menéndez-Arias L. Mechanisms of resistance to nucleoside analogue inhibitors of HIV-1 reverse transcriptase. Virus Res 2008; 134(1-2): 124-46.
[http://dx.doi.org/10.1016/j.virusres.2007.12.015] [PMID: 18272247]
[32]
Olearo F, Nguyen H, Bonnet F, et al. Impact of the M184V/I mutation on the efficacy of abacavir/lamivudine/dolutegravir therapy in HIV treatment-experienced patients. Open Forum Infect Dis 2019; 6(10): ofz330.
[http://dx.doi.org/10.1093/ofid/ofz330] [PMID: 31660328]
[33]
Bokharaei-Salim F, Jamshidi S, Nahand JS, et al. Evaluation of the expression pattern of 4 microRNAs and their correlation with cellular/viral factors in PBMCs of long term non-progressors and HIV infected naïve individuals. Curr HIV Res 2022; 20(1): 42-53.
[http://dx.doi.org/10.2174/1570162X19666210906143136] [PMID: 34493187]
[34]
Hull MW, Montaner JSG. Ritonavir-boosted protease inhibitors in HIV therapy. Ann Med 2011; 43(5): 375-88.
[http://dx.doi.org/10.3109/07853890.2011.572905] [PMID: 21501034]
[35]
Pasquau J, de Jesus SE, Arazo P, et al. Effectiveness and safety of dual therapy with rilpivirine and boosted darunavir in treatment-experienced patients with advanced HIV infection: A preliminary 24 week analysis (RIDAR study). BMC Infect Dis 2019; 19(1): 207.
[http://dx.doi.org/10.1186/s12879-019-3817-6] [PMID: 30819101]
[36]
Paredes R, Puertas MC, Bannister W, et al. A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy. J Infect Dis 2011; 204(5): 741-52.
[http://dx.doi.org/10.1093/infdis/jir385] [PMID: 21844300]
[37]
Sasadeusz J, Audsley J, Mijch A, et al. The anti-HIV activity of entecavir: A multicentre evaluation of lamivudine-experienced and lamivudine-naive patients. AIDS 2008; 22(8): 947-55.
[http://dx.doi.org/10.1097/QAD.0b013e3282ffde91] [PMID: 18453854]
[38]
Jiang D, Wang J, Zhao X, et al. Entecavir resistance mutations rtL180M/T184L/M204V combined with rtA200V lead to tenofovir resistance. Liver Int 2020; 40(1): 83-91.
[http://dx.doi.org/10.1111/liv.14241] [PMID: 31498528]
[39]
Guo JJ, Li QL, Shi XF, et al. Dynamics of hepatitis B virus resistance to entecavir in a nucleoside/nucleotide-naïve patient. Antiviral Res 2009; 81(2): 180-3.
[http://dx.doi.org/10.1016/j.antiviral.2008.09.004] [PMID: 18948142]
[40]
Metzner KJ, Bonhoeffer S, Fischer M, et al. Emergence of minor populations of human immunodeficiency virus type 1 carrying the M184V and L90M mutations in subjects undergoing structured treatment interruptions. J Infect Dis 2003; 188(10): 1433-43.
[http://dx.doi.org/10.1086/379215] [PMID: 14624368]
[41]
Lange CM, Hué S, Violari A, et al. Single genome analysis for the detection of linked multiclass drug resistance mutations in HIV-1-infected children after failure of protease inhibitor-based first-line therapy. J Acquir Immune Defic Syndr 2015; 69(2): 138-44.
[http://dx.doi.org/10.1097/QAI.0000000000000568] [PMID: 25923117]
[42]
Mascolini M, Boucher C, Larder B, Mellors J, Richman D. Key reports from the XV international HIV drug resistance workshop 2006. Antivir Ther 2007; 12(1): 131-46.
[http://dx.doi.org/10.1177/135965350701200118] [PMID: 17503758]
[43]
Bacheler LT, Anton ED, Kudish P, et al. Human immunodeficiency virus type 1 mutations selected in patients failing efavirenz combination therapy. Antimicrob Agents Chemother 2000; 44(9): 2475-84.
[http://dx.doi.org/10.1128/AAC.44.9.2475-2484.2000] [PMID: 10952598]
[44]
Rhee S-Y, Schapiro JM, Saladini F, Zazzi M, Khoo S, Shafer RW. Potential role of doravirine for the treatment of HIV-1-infected persons with transmitted drug resistance. AIDS Res Ther 2022; 20(1): 8.
[http://dx.doi.org/10.21203/rs.3.rs-1976150/v1]
[45]
Pham HT, Xiao MA, Principe MAV, Wong A, Mesplède T. Pharmaceutical, clinical, and resistance information on doravirine, a novel non-nucleoside reverse transcriptase inhibitor for the treatment of HIV-1 infection. Drugs Context 2020; 9: 1-11.
[http://dx.doi.org/10.7573/dic.2019-11-4] [PMID: 32180823]
[46]
Blevins SR, Hester EK, Chastain DB, Cluck DB. Doravirine: A return of the NNRTI class? Ann Pharmacother 2020; 54(1): 64-74.
[http://dx.doi.org/10.1177/1060028019869641] [PMID: 31416335]
[47]
Millar JR, Bengu N, Fillis R, et al. HIGH-FREQUENCY failure of combination antiretroviral therapy in paediatric HIV infection is associated with unmet maternal needs causing maternal NON-ADHERENCE. EClinicalMedicine 2020; 22: 100344.
[http://dx.doi.org/10.1016/j.eclinm.2020.100344] [PMID: 32510047]
[48]
Kuriakose S, George J, Dee N, Stoll P, Agan BK, Dewar RL, Eds. High level resistance to dolutegravir (DTG) after emergence of T97A mutation. Conference on Retroviruses and Opportunistic Infections (CROI).
[49]
Stellbrink HJ, Le Fevre E, Carr A, et al. Once-daily maraviroc versus tenofovir/emtricitabine each combined with darunavir/ritonavir for initial HIV-1 treatment. AIDS 2016; 30(8): 1229-38.
[http://dx.doi.org/10.1097/QAD.0000000000001058] [PMID: 26854810]
[50]
Deutschmann E, Bucher HC, Jaeckel S, et al. Prevalence of potential drug–drug interactions in patients of the Swiss HIV Cohort Study in the era of HIV integrase inhibitors. Clin Infect Dis 2021; 73(7): e2145-52.
[http://dx.doi.org/10.1093/cid/ciaa918] [PMID: 32634832]
[51]
Cattaneo D, Capetti A, Rizzardini G. Drug–drug interactions of a two-drug regimen of dolutegravir and lamivudine for HIV treatment. Expert Opin Drug Metab Toxicol 2019; 15(3): 245-52.
[http://dx.doi.org/10.1080/17425255.2019.1577821] [PMID: 30704313]
[52]
Hodge D, Hodel EM, Hughes E, Hazenberg P, Castillo SG, Gibbons S. Prevalence of potentially clinically significant drug-drug interactions with antiretrovirals against HIV over three decades: A systematic review of the literature. J Acquir Immune Defic Syndr 2022; 10: 1097.
[PMID: 36625857]
[53]
Mondleki E, Maartens G. Dolutegravir drug-drug interactions. S Afr Med J 2022; 112(3): 194-5.
[http://dx.doi.org/10.7196/SAMJ.2021.v112i3.16316]
[54]
Lewis JM, Stott KE, Monnery D, et al. Managing potential drug-drug interactions between gastric acid-reducing agents and antiretroviral therapy: Experience from a large HIV-positive cohort. Int J STD AIDS 2016; 27(2): 105-9.
[http://dx.doi.org/10.1177/0956462415574632] [PMID: 25721922]
[55]
Sajadi MM, Pulijala R, Redfield RR, Talwani R. Chronic immune activation and decreased CD4 cell counts associated with hepatitis C infection in HIV-1 natural viral suppressors. AIDS 2012; 26(15): 1879-84.
[http://dx.doi.org/10.1097/QAD.0b013e328357f5d1] [PMID: 22824629]
[56]
Grønborg HL, Jespersen S, Hønge BL, Jensen-Fangel S, Wejse C. Review of cytomegalovirus coinfection in HIV-infected individuals in Africa. Rev Med Virol 2017; 27(1): e1907.
[http://dx.doi.org/10.1002/rmv.1907] [PMID: 27714898]
[57]
Lindoso JAL, Moreira CHV, Cunha MA, Queiroz IT. Visceral leishmaniasis and HIV coinfection: Current perspectives. HIV/AIDS - Res Palliat Care 2018; 10: 193-201.
[http://dx.doi.org/10.2147/HIV.S143929]
[58]
de Castro S, Camarasa MJ. Polypharmacology in HIV inhibition: Can a drug with simultaneous action against two relevant targets be an alternative to combination therapy? Eur J Med Chem 2018; 150: 206-27.
[http://dx.doi.org/10.1016/j.ejmech.2018.03.007] [PMID: 29529501]
[59]
Hu R, Yan H, Liu M, et al. Brief report: Virologic and immunologic outcomes for HIV patients with coronavirus disease 2019. J Acquir Immune Defic Syndr 2021; 86(2): 213-8.
[http://dx.doi.org/10.1097/QAI.0000000000002540] [PMID: 33079905]
[60]
Cong B, Deng S, Wang X, Li Y. The role of respiratory co-infection with influenza or respiratory syncytial virus in the clinical severity of COVID-19 patients: A systematic review and meta-analysis. J Glob Health 2022; 12: 05040.
[http://dx.doi.org/10.7189/jogh.12.05040] [PMID: 36112521]
[61]
Donyavi T, Bokharaei-Salim F, Baghi HB, et al. Acute and post-acute phase of COVID-19: Analyzing expression patterns of miRNA-29a-3p, 146a-3p, 155-5p, and let-7b-3p in PBMC. Int Immunopharmacol 2021; 97: 107641.
[http://dx.doi.org/10.1016/j.intimp.2021.107641] [PMID: 33895478]
[62]
Garshasbi S, Bokharaei-Salim F, Khanaliha K, et al. SARS-CoV-2 infection in Iranian people living with human immunodeficiency virus-1 infection. Jundishapur J Microbiol 2022; 15(1)
[http://dx.doi.org/10.5812/jjm.121929]
[63]
Ambrosioni J, Blanco JL, Reyes-Urueña JM, et al. Overview of SARS-CoV-2 infection in adults living with HIV. Lancet HIV 2021; 8(5): e294-305.
[http://dx.doi.org/10.1016/S2352-3018(21)00070-9] [PMID: 33915101]
[64]
Noe S, Ochana N, Wiese C, et al. Humoral response to SARS-CoV-2 vaccines in people living with HIV. Infection 2022; 50(3): 617-23.
[http://dx.doi.org/10.1007/s15010-021-01721-7] [PMID: 34694595]
[65]
Ao L, Lu T, Cao Y, et al. Safety and immunogenicity of inactivated SARS-CoV-2 vaccines in people living with HIV. Emerg Microbes Infect 2022; 11(1): 1126-34.
[http://dx.doi.org/10.1080/22221751.2022.2059401] [PMID: 35369854]
[66]
Rock AE, DeMarais PL, Vergara-Rodriguez PT, Max BE. HIV-1 virologic rebound due to coadministration of divalent cations and bictegravir. Infect Dis Ther 2020; 9(3): 691-6.
[http://dx.doi.org/10.1007/s40121-020-00307-4] [PMID: 32623580]
[67]
Easterbrook PJ, Ives N, Waters A, et al. The natural history and clinical significance of intermittent viraemia in patients with initial viral suppression to < 400 copies/ml. AIDS 2002; 16(11): 1521-7.
[http://dx.doi.org/10.1097/00002030-200207260-00009] [PMID: 12131190]
[68]
Zamora FJ, Dowers E, Yasin F, Ogbuagu O. Dolutegravir and lamivudine combination for the treatment of HIV-1 infection. HIV AIDS 2019; 11: 255-63.
[69]
Lu CH, Bednarczyk EM, Catanzaro LM, Shon A, Xu JC, Ma Q. Pharmacokinetic drug interactions of integrase strand transfer inhibitors. Curr Res Pharmacol Drug Discov 2021; 2: 100044.
[http://dx.doi.org/10.1016/j.crphar.2021.100044] [PMID: 34909672]
[70]
Capetti AF, Astuti N, Cattaneo D, Rizzardini G. Pharmacokinetic drug evaluation of dolutegravir plus rilpivirine for the treatment of HIV. Expert Opin Drug Metab Toxicol 2017; 13(11): 1183-92.
[http://dx.doi.org/10.1080/17425255.2017.1361929] [PMID: 28854832]
[71]
He X. Integration of physical, chemical, mechanical, and biopharmaceutical properties in solid oral dosage form development. Developing solid oral dosage forms. Elsevier 2009; pp. 407-41.
[72]
Morsica G, Galli L, Messina E, et al. Risk of HIV viral rebound in HIV infected patients on direct acting antivirals (DAAs) treatment for HCV. PLoS One 2022; 17(2): e0262917.
[http://dx.doi.org/10.1371/journal.pone.0262917] [PMID: 35113890]
[73]
Havlir DV, Hellmann NS, Petropoulos CJ, et al. Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens. JAMA 2000; 283(2): 229-34.
[http://dx.doi.org/10.1001/jama.283.2.229] [PMID: 10634339]

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