human immunodeficiency virus; sub-subtype A6; transmission dynamics; genotypic drug resistance; subtyping tools
Abstract :
[en] The international spread of HIV-1 sub-subtype A6 raises concerns due to its association with contraindications for long-acting injectable formulations of cabotegravir (LA-CAB) and rilpivirine (LA-RPV). This study investigated its increasing proportion in Belgium, assessing transmission dynamics and potential migration links. Additionally, genotypic drug resistance in the Belgian HIV-1 sub-subtype A6 population were analyzed and four automatic subtyping tools were compared. A dataset of 4764 HIV-1 protease and reverse transcriptase (RT) sequences from newly diagnosed, treatment-naïve individuals in Belgium (2013-2022) was analyzed. A combination of phylogenetic analysis and online subtyping tools identified 136 sub-subtype A6 sequences. The increase in the proportion of HIV-1 sub-subtype A6 observed in Belgium since 2020 reflects changing transmission patterns, especially among Belgium-born men having sex with men, and cannot be solely linked to the recent influx of Ukrainian migrants. Of these sub-subtype A6 sequences, less than 10% showed LA-CAB + LA-RPV resistance, mainly due to E138A within RT. HIVdb and ANRS reliably assessed resistance in this therapy-naïve cohort, and HIVdb, COMET, and SmartGene ® produced concordant subtyping results. While algorithm choice has little
Disciplines :
Immunology & infectious disease
Author, co-author :
Mortier, Virginie; AIDS Reference Laboratory, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
Debaisieux, Laurent; AIDS Reference Laboratory, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), CUB Hôpital Erasme, Brussels, Belgium
De Geyter, Deborah; AIDS Reference Laboratory, Vrije Universiteit Brussel VUB, Brussels, Belgium
Delforge, Marie-Luce; AIDS Reference Laboratory, Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), CUB Hôpital Erasme, Brussels, Belgium
Depypere, Melissa; Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium ; AIDS Reference Laboratory, University Hospitals Leuven, Leuven, Belgium
Dessilly, Géraldine; AIDS Reference Laboratory, Medical Microbiology Unit, Université Catholique de Louvain, Brussels, Belgium
Kabamba-Mukadi, Benoît; AIDS Reference Laboratory, Medical Microbiology Unit, Université Catholique de Louvain, Brussels, Belgium
El Moussaoui, Khalid ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Bactériologie, mycologie, parasitologie, virologie et microbiologie
Mzougui, Samy ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Bactériologie, mycologie, parasitologie, virologie et microbiologie
Serrien, Ben; Department of Epidemiology and Public Health, Sciensano, Brussels, Belgium
Stoffels, Karolien; AIDS Reference Laboratory, Centre Hospitalier Universitaire St. Pierre, Brussels, Belgium
Van Beckhoven, Dominique; Department of Epidemiology and Public Health, Sciensano, Brussels, Belgium
Van Cutsem, Ellen; AIDS Reference Laboratory, Vrije Universiteit Brussel VUB, Brussels, Belgium
Van Den Bossche, Dorien; AIDS Reference Laboratory, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium ; Clinical Reference Laboratory, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
Van Den Wijngaert, Sigi; AIDS Reference Laboratory, Centre Hospitalier Universitaire St. Pierre, Brussels, Belgium
Vanroye, Fien; AIDS Reference Laboratory, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium ; Clinical Reference Laboratory, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
Padalko, Elizaveta; AIDS Reference Laboratory, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium ; Department of Medical Microbiology, Ghent University Hospital, Ghent, Belgium
Verhofstede, Chris; AIDS Reference Laboratory, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
Van Laethem, Kristel; Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium ; AIDS Reference Laboratory, University Hospitals Leuven, Leuven, Belgium
Hemelaar J. Elangovan R. Yun J. Dickson-Tetteh L. Fleminger I. Kirtley S. Williams B. Gouws-Williams E. Ghys P.D. Global and regional molecular epidemiology of HIV-1, 1990–2015: A systematic review, global survey, and trend analysis Lancet Infect. Dis. 2019 19 143 155 10.1016/S1473-3099(18)30647-9 30509777
Serwin K. Chaillon A. Scheibe K. Urbańska A. Aksak-Wąs B. Ząbek P. Siwak E. Cielniak I. Jabłonowska E. Wójcik-Cichy K. et al. Circulation of Human Immunodeficiency Virus 1 A6 Variant in the Eastern Border of the European Union-Dynamics of the Virus Transmissions Between Poland and Ukraine Clin. Infect. Dis. 2023 76 1716 1724 10.1093/cid/ciad058 36857116
Orkin C. Arasteh K. Gorgolas Hernandez-Mora M. Pokrovsky V. Overton E.T. Girard P.M. Oka S. Walmsley S. Bettacchi C. Brinson C. et al. Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection N. Engl. J. Med. 2020 382 1124 1135 10.1056/NEJMoa1909512
Swindells S. Andrade-Villanueva J.F. Richmond G.J. Rizzardini G. Baumgarten A. Masia M. Latiff G. Pokrovsky V. Bredeek F. Smith G. et al. Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression N. Engl. J. Med. 2020 382 1112 1123 10.1056/NEJMoa1904398 32130809
Overton E.T. Richmond G. Rizzardini G. Jaeger H. Orrell C. Nagimova F. Bredeek F. Deltoro M.G. Swindells S. Andrade-Villanueva J.F. et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: A randomised, multicentre, open-label, phase 3b, non-inferiority study Lancet 2021 396 1994 2005 10.1016/S0140-6736(20)32666-0
Landovitz R.J. Donnell D. Clement M.E. Hanscom B. Cottle L. Coelho L. Cabello R. Chariyalertsak S. Dunne E.F. Frank I. et al. Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women N. Engl. J. Med. 2021 385 595 608 10.1056/NEJMoa2101016
Delany-Moretlwe S. Hughes J.P. Bock P. Ouma S.G. Hunidzarira P. Kalonji D. Kayange N. Makhema J. Mandima P. Mathew C. et al. Cabotegravir for the prevention of HIV-1 in women: Results from HPTN 084, a phase 3, randomised clinical trial Lancet 2022 399 1779 1789 10.1016/S0140-6736(22)00538-4
Cutrell A.G. Schapiro J.M. Perno C.F. Kuritzkes D.R. Quercia R. Patel P. Polli J.W. Dorey D. Wang Y. Wu S. et al. Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: A multivariable analysis AIDS 2021 35 1333 1342 10.1097/QAD.0000000000002883
Désiré N. Cerutti L. Le Hingrat Q. Perrier M. Emler S. Calvez V. Descamps D. Marcelin A.-G. Hué S. Visseaux B. Characterization update of HIV-1 M subtypes diversity and proposal for subtypes A and D sub-subtypes reclassification Retrovirology 2018 15 80 10.1186/s12977-018-0461-y
Mendes Da Silva R.K. de Pina Araujo I.I.M. Maciera K.V. Morgado M.G. Guimaraes M.L. Genetic Characterization of a New HIV-1 Sub-Subtype A in Cabo Verde, Denominated A8 Viruses 2021 13 1093 10.3390/v13061093
Pineda-Pena A.C. Theys K. Stylianou D.C. Demetriades I. Abecasis A.B. Kostrikis L.G. HIV-1 Infection in Cyprus, the Eastern Mediterranean European Frontier: A Densely Sampled Transmission Dynamics Analysis from 1986 to 2012 Sci. Rep. 2018 8 1702 10.1038/s41598-017-19080-5
Kostaki E.G. Gova M. Adamis G. Xylomenos G. Chini M. Mangafas N. Lazanas M. Metallidis S. Tsachouridou O. Papastamopoulos V. et al. A Nationwide Study about the Dispersal Patterns of the Predominant HIV-1 Subtypes A1 and B in Greece: Inference of the Molecular Transmission Clusters Viruses 2020 12 1183 10.3390/v12101183 33086773
Diez-Fuertes F. Cabello M. Thomson M.M. Bayesian phylogeographic analyses clarify the origin of the HIV-1 subtype A variant circulating in former Soviet Union’s countries Infect. Genet. Evol. 2015 33 197 205 10.1016/j.meegid.2015.05.003 25952568
Vasylyeva T.I. Liulchuk M. Friedman S.R. Sazonova I. Faria N.R. Katzourakis A. Babii N. Scherbinska A. Thézé J. Pybus O.G. et al. Molecular epidemiology reveals the role of war in the spread of HIV in Ukraine Proc. Natl. Acad. Sci. USA 2018 115 1051 1056 10.1073/pnas.1701447115 29339468
Parczewski M. Jabłonowska E. Wójcik-Cichy K. Zhyvytsia D. Witak-Jędra M. Leszczyszyn-Pynka M. Aksak-Wąs B. Siwak E. Cielniak I. Olczak A. et al. Clinical Perspective on Human Immunodeficiency Virus Care of Ukrainian War Refugees in Poland Clin. Infect. Dis. 2023 76 1708 1715 10.1093/cid/ciad116
Fransen K. Buvé A. Nkengasong J. Laga M. van der Groen G. Longstanding presence in Belgians of multiple non-B HIV-1 subtypes Lancet 1996 347 1403 10.1016/S0140-6736(96)91042-9
Snoeck J. Van Laethem K. Hermans P. Van Wijngaerden E. Derdelinckx I. Schrooten Y. van de Vijver D.A.M.C. De Wit S. Clumeck N. Vandamme A.-M. Rising prevalence of HIV-1 non-B subtypes in Belgium: 1983–2001 J. Acquir. Immune Defic. Syndr. 2004 35 279 285 10.1097/00126334-200403010-00009
Deblonde A.S.B. De Rouck M. Montourcy M. Van Beckhoven D. Epidemiologie van hiv in België. Toestand op 31 December 2022 Sciensano Brussels, Belgium 2023
European Centre for Disease Prevention and Control WHO Regional Office for Europe HIV/AIDS Surveillance in Europe 2023–2022 Data ECDC Stockholm, Sweden 2023
Rhee S.Y. Gonzales M.J. Kantor R. Betts B.J. Ravela J. Shafer R.W. Human immunodeficiency virus reverse transcriptase and protease sequence database Nucleic Acids Res. 2003 31 298 303 10.1093/nar/gkg100
Liu T.F. Shafer R.W. Web resources for HIV type 1 genotypic-resistance test interpretation Clin. Infect. Dis. 2006 42 1608 1618 10.1086/503914
Struck D. Lawyer G. Ternes A.-M. Schmit J.-C. Bercoff D.P. COMET: Adaptive context-based modeling for ultrafast HIV-1 subtype identification Nucleic Acids Res. 2014 42 e144 10.1093/nar/gku739
Pineda-Pena A.C. Faria N.R. Imbrechts S. Libin P. Abecasis A.B. Deforche K. Gómez-López A. Camacho R.J. de Oliveira T. Vandamme A.-M. Automated subtyping of HIV-1 genetic sequences for clinical and surveillance purposes: Performance evaluation of the new REGA version 3 and seven other tools Infect. Genet. Evol. 2013 19 337 348 10.1016/j.meegid.2013.04.032
Hall T. BioEdit: A user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT Nucleic Acids Symp. Ser. 1999 41 95 98
Kuiken C. Korber B. Shafer R.W. HIV sequence databases AIDS Rev. 2003 5 52 61
Guindon S. Dufayard J.-F. Lefort V. Anisimova M. Hordijk W. Gascuel O. New algorithms and methods to estimate maximum-likelihood phylogenies: Assessing the performance of PhyML 3.0 Syst. Biol. 2010 59 307 321 10.1093/sysbio/syq010
Ragonnet-Cronin M. Hodcroft E. Hué S. Fearnhill E. Delpech V. Brown A.J.L. Lycett S. Automated analysis of phylogenetic clusters BMC Bioinform. 2013 14 317 10.1186/1471-2105-14-317
Beloukas A. Psarris A. Giannelou P. Kostaki E. Hatzakis A. Paraskevis D. Molecular epidemiology of HIV-1 infection in Europe: An overview Infect. Genet. Evol. 2016 46 180 189 10.1016/j.meegid.2016.06.033 27321440
Vinken L. Fransen K. Cuypers L. Alexiev I. Balotta C. Debaisieux L. Seguin-Devaux C. Ribas S.G. Gomes P. Incardona F. et al. Earlier Initiation of Antiretroviral Treatment Coincides With an Initial Control of the HIV-1 Sub-Subtype F1 Outbreak Among Men-Having-Sex-With-Men in Flanders, Belgium Front. Microbiol. 2019 10 613 10.3389/fmicb.2019.00613 30972053
Niculescu I. Paraschiv S. Paraskevis D. Abagiu A. Batan I. Banica L. Otelea D. Recent HIV-1 Outbreak Among Intravenous Drug Users in Romania: Evidence for Cocirculation of CRF14_BG and Subtype F1 Strains AIDS Res. Hum. Retroviruses 2015 31 488 495 10.1089/aid.2014.0189
Paraskevis D. Paraschiv S. Sypsa V. Nikolopoulos G. Tsiara C. Magiorkinis G. Psichogiou M. Flampouris A. Mardarescu M. Niculescu I. et al. Enhanced HIV-1 surveillance using molecular epidemiology to study and monitor HIV-1 outbreaks among intravenous drug users (IDUs) in Athens and Bucharest Infect. Genet. Evol. 2015 35 109 121 10.1016/j.meegid.2015.08.004
Ragonnet-Cronin M. Lycett S.J. Hodcroft E.B. Hué S. Fearnhill E. Brown A.E. Delpech V. Dunn D. Leigh Brown A.J. Transmission of Non-B HIV Subtypes in the United Kingdom Is Increasingly Driven by Large Non-Heterosexual Transmission Clusters J. Infect. Dis. 2016 213 1410 1418 10.1093/infdis/jiv758 26704616
Chaillon A. Avila-Ríos S. Wertheim J.O. Dennis A. García-Morales C. Tapia-Trejo D. Mejía-Villatoro C. Pascale J.M. Porras-Cortés G. Quant-Durán C.J. et al. Identification of major routes of HIV transmission throughout Mesoamerica Infect. Genet. Evol. 2017 54 98 107 10.1016/j.meegid.2017.06.021
Araujo P.M.M. Carvalho A. Pingarilho M. Abecasis A.B. Osório N.S. Characterization of a large cluster of HIV-1 A1 infections detected in Portugal and connected to several Western European countries Sci. Rep. 2019 9 7223 10.1038/s41598-019-43420-2 31076722
Hanke K. Faria N.R. Kühnert D. Yousef K.P. Hauser A. Meixenberger K. Hofmann A. Bremer V. Bartmeyer B. Pybus O. et al. Reconstruction of the Genetic History and the Current Spread of HIV-1 Subtype A in Germany J. Virol. 2019 93 10-1128 10.1128/JVI.02238-18
Rizzardini G. Overton E.T. Orkin C. Swindells S.M. Arasteh K. Hernández-Mora M.G.M. Pokrovsky V. Girard P.-M.M. Oka S.M. Andrade-Villanueva J.F. et al. Long-Acting Injectable Cabotegravir + Rilpivirine for HIV Maintenance Therapy: Week 48 Pooled Analysis of Phase 3 ATLAS and FLAIR Trials J. Acquir. Immune Defic. Syndr. 2020 85 498 506 10.1097/QAI.0000000000002466
Lapovok I. Laga V. Kazennova E. Bobkova M. HIV Type 1 Integrase Natural Polymorphisms in Viral Variants Circulating in FSU Countries Curr. HIV Res. 2017 15 318 326 10.2174/1570162X15666170815162052
Jeffrey J.L. Clair M.S. Wang P. Wang C. Li Z. Beloor J. Talarico C. Fridell R. Krystal M. White C.T. et al. Impact of Integrase Sequences from HIV-1 Subtypes A6/A1 on the In Vitro Potency of Cabotegravir or Rilpivirine Antimicrob. Agents Chemother. 2022 66 e0170221 10.1128/aac.01702-21
