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1. Prevalence and Clinical Outcomes of Poor Immune Response Despite Virologically Suppressive Antiretroviral Therapy Among Children and Adolescents With Human Immunodeficiency Virus in Europe and Thailand: Cohort Study

Author

Chappell, E., Riordan, A., Jourdain, G., Soriano-Arandes, A., Ene, L., Scherpbier, H., Warszawski, J., Collins, I., Smit, C., Marques, L., Klein, N., Guillén, S., Judd, A., Thorne, C., Goodall, R., Königs, C., Spoulou, V., Prata, F., Goetghebuer, T., Chiappini, E., Galli, L., Naver, L., Giaquinto, C., Gibb, D., Marczynska, M., Okhonskaia, L., Klimkait, T., Lallemant, M., Ngo-Giang-Huong, N., Kiseleva, G., Malyuta, R., Volokha, A., Hainaut, M., Delforge, M., Le Chenadec, J., Ramos, E., Dialla, O., Wack, T., Laurent, C., Ait Si Selmi, L., Leymarie, I., Ait Benali, F., Brossard, M., Boufassa, L., Floch-Tudal, C., Firtion, G., Hau, I., Chace, A., Bolot, P., Blanche, S., Levine, M., Bicëtre, L., Fourcade, C., Heller-Roussin, B., Runel-Belliard, C., Tricoire, J., Chirouze, C., Reliquet, V., Brouard, J., Kebaili, K., Fialaire, P., Lalande, M., Schultze-Strasser, S., Baumann, U., Niehues, T., Neubert, J., Kobbe, R., Berlin, C., Feiterna-Sperling, C., Buchholz, B., Notheis, G., de Martino, M., Angelo Tovo, P., Patrizia, O., Larovere, D., Ruggeri, M., Faldella, G., Baldi, F., Badolato, R., Montagnani, C., Venturini, E., Lisi, C., Di Biagio, A., Taramasso, L., Giacomet, V., Erba, P., Esposito, S., Lipreri, R., Salvini, F., Tagliabue, C., Cellini, M., Bruzzese, E., Lo Vecchio, A., Rampon, O., Donà, D., Romano, A., Dodi, I., Maccabruni, A., Consolini, R., Bernardi, S., Tchidjou Kuekou, H., Genovese, O., Olmeo, P., Cristiano, L., Mazza, A., Gabiano, C., Garazzino, S., Pellegatta, A., Pajkrt, D., Weijsenfeld, A., de Boer CG, Jurriaans, S., Back, N., Zaaijer, H., Berkhout, B., Cornelissen, M., Schinkel, C., Wolthers, K., Fraaij, P., van Rossum AMC, van der Knaap LC, Visser, E., Koopmans, M., van Kampen JJA, Pas, S., Henriet, S., van de Flier, M., van Aerde, K., Strik-Albers, R., Rahamat-Langendoen, J., Stelma, F., Schölvinck, E., de Groot-de Jonge, H., Niesters, H., van Leer-Buter CC, Knoester, M., Bont, L., Geelen, S., Wolfs, T., Nauta, N., Ang, C., van Houdt, R., Pettersson, A., Vandenbroucke-Grauls, C., Reiss, P., Bezemer, D., van Sighem AI, Wit, F., Boender, T., Zaheri, S., Hillebregt, M., de Jong, A., Bergsma, D., Grivell, S., Jansen, A., Raethke, M., Meijering, R., de Groot, L., van den Akker, M., Bakker, Y., Claessen, E., El Berkaoui, A., Koops, J., Kruijne, E., Lodewijk, C., Munjishvili, L., Peeck, B., Ree, C., Regtop, R., Ruijs, Y., Rutkens, T., Schoorl, M., Timmerman, A., Tuijn, E., Veenenberg, L., van der Vliet, S., Wisse, A., Woudstra, T., Tuk, B., Popielska, J., Pokorska-Śpiewak, M., Ołdakowska, A., Zawadka, K., Coupland, U., DorobaLaura Marques, M., Teixeira, C., Fernandes, A., Voronin, E., Miloenko, M., Labutina, S., Tomás Ramos, J., Prieto, L., Luisa Navarro, M., Saavedra, J., Santos, M., Angeles Muñoz, M., Ruiz, B., Mc Phee CF, de Ory SJ, Alvarez, S., Ángel Roa, M., Beceiro, J., Martínez, J., Badillo, K., Apilanez, M., Pocheville, I., Garrote, E., Colino, E., Gómez Sirvent, J., Garzón, M., Román, V., Montesdeoca, A., Mateo, M., José Muñoz, M., Angulo, R., Neth, O., Falcón, L., Terol, P., Luis Santos, J., Moreno, D., Lendínez, F., Grande, A., José Romero, F., Lillo, M., Losada, B., Herranz, M., Bustillo, M., Guerrero, C., Collado, P., Antonio Couceiro, J., Pérez, A., Isabel Piqueras, A., Bretón, R., Segarra, I., Gavilán, C., Jareño, E., Montesinos, E., Dapena, M., Álvarez, C., Gloria Andrés, A., Marugán, V., Ochoa, C., Alfayate, S., Isabel Menasalvas, A., de Miguel, E., Aebi-Popp, K., Asner, S., Aubert, V., Battegay, M., Baumann, M., Bernasconi, E., Böni, J., Brazzola, P., Bucher, H., Calmy, A., Cavassini, M., Ciuffi, A., Duppenthaler, A., Dollenmaier, G., Egger, M., Elzi, L., Fehr, J., Fellay, J., Francini, K., Furrer, H., Fux, C., Grawe, C., Günthard, H., Haerry, D., Hasse, B., Hirsch, H., Hoffmann, M., Hösli, I., Kahlert, C., Kaiser, L., Keiser, O., Kovari, H., Kouyos, R., Ledergerber, B., Martinetti, G., de Tejada BM, Metzner, K., Müller, N., Nicca, D., Paioni, P., Pantaleo, G., Polli, C., Posfay-Barbe, K., Rauch, A., Rudin, C., Schmid, P., Scherrer, A., Speck, R., Tarr, P., Thanh Lecompte, M., Trkola, A., Vernazza, P., Wagner, N., Wandeler, G., Weber, R., Wyler, C., Yerly, S., Techakunakorn, P., Hansudewechakul, R., Kham, C., Wanchaitanawong, V., Theansavettrakul, S., Sai, M., Nanta, S., Ngampiyaskul, C., Phanomcheong, S., Hongsiriwon, S., Karnchanamayul, W., Kwanchaipanich, R., Kanjanavanit, S., Kamonpakorn, N., Nantarukchaikul, M., Layangool, P., Mekmullica, J., Lucksanapisitkul, P., Watanayothin, S., Lertpienthum, N., Warachit, B., Hanpinitsak, S., Potchalongsin, S., Thanasiri, P., Krikajornkitti, S., Attavinijtrakarn, P., Srirojana, S., Bunjongpak, S., Puangsombat, A., Na-Rajsima, S., Ananpatharachai, P., Akarathum, N., Phuket, V., Lawtongkum, W., Kheunjan, P., Suriyaboon, T., Saipanya, A., Than-In-At, K., Jaisieng, N., Suaysod, R., Chailoet, S., Naratee, N., Kawilapat, S., Kaleeva, T., Baryshnikova, Y., Soloha, S., Bashkatova, N., Raus, I., Glutshenko, O., Ruban, Z., Prymak, N., Bailey, H., Bamford, A., Butler, K., Doerholt, K., Doherty, C., Foster, C., Francis, K., Harrison, I., Kenny, J., Letting, G., Mcmaster, P., Murau, F., Nsangi, E., Peters, H., Prime, K., Shackley, F., Shingadia, D., Storey, S., Tudor-Williams, G., Turkova, A., Welch, S., Jeannie Collins, I., Cook, C., Crichton, S., Dobson, D., Fairbrother, K., M Gibb D, Harper, L., Le Prevost, M., Van Looy, N., Walsh, A., Thrasyvoulou, L., Bernatoniene, J., Manyika, F., Sharpe, G., Subramaniam, B., Sloper, K., Fidler, K., Hague, R., Price, V., Clapson, M., Flynn, J., Cardoso, A., Abou-Rayyah, M., Gurtin, D., Yeadon, S., Segal, S., Ball, C., Hawkins, S., Dowie, M., Bandi, S., Percival, E., Eisenhut, M., Duncan, K., Clough, S., Anguvaa, L., Conway, S., Flood, T., Pickering, A., Murphy, C., Daniels, J., Lees, Y., Thompson, F., Williams, B., Pope, S., Cliffe, L., Smyth, A., Southall, S., Freeman, A., Freeman, H., Christie, S., Gordon, A., Rogahn, D., Clarke, L., Jones, L., Offerman, B., Greenberg, M., Benson, C., Ibberson, L., Faust, S., Hancock, J., Sharland, M., Lyall, H., Monrose, C., Seery, P., Menson, E., Callaghan, A., Bridgwood, A., Evans, J., Blake, E., Yannoulias, A., Critchton, S., Duff, C., Gomezpena, D., Lundin, R., Mangiarini, L., Nardone, A., Posfay Barbe, Klara, Universidad de Alcalá - University of Alcalá (UAH), Department of Sciences for Woman and Child's Health, Università degli Studi di Firenze = University of Florence (UniFI), Épidémiologie clinique, santé mère-enfant et VIH en Asie du Sud-Est (IRD_PHPT), Harvard University-Chiang Mai University (CMU), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier de Saint-Denis [Ile-de-France], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), service de maladies infectieuses CHU J Minjoz Besancon, Service des maladies infectieuses et tropicales [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Pédiatrie Médicale [Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'hématologie : Immuno-Hématologie pédiatrique et transplantation de moelle osseuse, Hôpital Debrousse, Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Universitätsklinikum Frankfurt, Infectious Diseases, San Martino Hospital, Università degli studi di Genova = University of Genoa (UniGe), Department of Maternal and Pediatric Sciences, University of Milan, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Maternal-Infantile Department, Unit of Paediatrics and Oncohematology, University Hospital of Parma, Department of Infectious Diseases, IRCCS S. Matteo, Department of Paediatrics, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Dipartimento di Ingegneria [Benevento], Università degli Studi del Sannio, University of Twente, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratory for Infectious Diseases and Perinatal Screening, Center for Infectious Disease Control, National Institute for Public Health and the Environment [Bilthoven] (RIVM), Architecture et réactivité de l'ARN (ARN), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Synthèse, Structure et Propriétés de Matériaux Fonctionnels (STEP), SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé (SYMMES), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Département Interfaces pour l'énergie, la Santé et l'Environnement (DIESE), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Stichting HIV Monitoring, Universidade Federal do Ceará = Federal University of Ceará (UFC), Departamento de Química Orgánica, Universidade de Vigo, Polytechnical University of Valencia, Fac Biol, Dept Genet, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Service des maladies infectieuses, Hôpitaux Universitaires de Genève (HUG), University of Basel (Unibas), Dysfonctions métaboliques et diabètes: Mécanismes et approches thérapeutiques, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), University Heart Centre Freiburg - Bad Krozingen, Prapokklao Hospital [Chanthaburi, Thailand], Nakornping Hospital [Chiang Mai, Thailand], Samutsakhon Hospital [Samutsakhon, Thailand], Kalasin Hospital [Kalasin, Thailand], Sanpatong Hospital [Chiang Mai, Thailand], Chiang Mai University (CMU), Microbiology Department, St. Jame's Hospital, University of Edinburgh, Infectious Diseases and Microbiology Unit, Great Ormond Street Hospital for Children [London] (GOSH)-Institute of Child Health, European Synchrotron Radiation Facility (ESRF), Centre for Ecology and Hydrology [Bangor] (CEH), Natural Environment Research Council (NERC), Jet Propulsion Laboratory (JPL), NASA-California Institute of Technology (CALTECH), University of London [London], London South Bank University (LSBU), Dipartimento di Pediatria, Azienda Ospedaliera di Padova, Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) Study Group in EuroCoord, Florence University, Harvard University [Cambridge]-Chiang Mai University (CMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), University of Genoa (UNIGE), Catholic University of Rome, University of Twente [Netherlands], Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), University of the Basque Country [Bizkaia] (UPV/EHU), Université Nice Sophia Antipolis (... - 2019) (UNS), Pediatrics, Virology, Chappell, Elizabeth, Riordan, Andrew, Jourdain, Gonzague, Soriano-Arandes, Antoni, Ene, Luminita, J Scherpbier, Henriette, Warszawski, Josiane, J Collins, Intira, Smit, Colette, Marques, Laura, Klein, Nigel, Guillén, Sara, Judd, Ali, Thorne, Claire, Goodall, Ruth, Königs, Christoph, Spoulou, Vana, Prata, Filipa, Goetghebuer, Tessa, Chiappini, Elena, Galli, Luisa, Naver, Lar, Giaquinto, Carlo, M Gibb, Diana, Marczynska, Magdalena, Okhonskaia, Liubov, Klimkait, Thoma, Lallemant, Marc, Ngo-Giang-Huong, Nicole, Kiseleva, Galyna, Malyuta, Ruslan, Volokha, Alla, Hainaut, Marc, Delforge, Marc, Le Chenadec, Jerome, Ramos, Elisa, Dialla, Olivia, Wack, Thierry, Laurent, Corine, Ait Si Selmi, Lamya, Leymarie, Isabelle, Ait Benali, Fazia, Brossard, Maud, Boufassa, Leila, Floch-Tudal, Corinne, Firtion, Ghislaine, Hau, Isabelle, Chace, Anne, Bolot, Pascal, Blanche, Stéphane, Levine, Martine, Kremlin Bicëtre, Le, Fourcade, Corinne, Heller-Roussin, Brigitte, Runel-Belliard, Camille, Tricoire, Joëlle, Chirouze, Catherine, Reliquet, Véronique, Brouard, Jacque, Kebaili, Kamila, Fialaire, Pascale, Lalande, Muriel, Schultze-Strasser, Stephan, Baumann, U, Niehues, T, Neubert, J, Kobbe, R, Berlin, Charite, Feiterna-Sperling, C, Königs, C, Buchholz, B, Notheis, G, de Martino, Maurizio, Angelo Tovo, Pier, Patrizia, Osimani, Larovere, Domenico, Ruggeri, Maurizio, Faldella, Giacomo, Baldi, Francesco, Badolato, Raffaele, Montagnani, Carlotta, Venturini, Elisabetta, Lisi, Catiuscia, Di Biagio, Antonio, Taramasso, Lucia, Giacomet, Vania, Erba, Paola, Esposito, Susanna, Lipreri, Rita, Salvini, Filippo, Tagliabue, Claudia, Cellini, Monica, Bruzzese, Eugenia, LO VECCHIO, Andrea, Paediatric Infectious Diseases / Rheumatology / Immunology, Amsterdam institute for Infection and Immunity, AII - Infectious diseases, Amsterdam Reproduction & Development (AR&D), APH - Aging & Later Life, Infectious diseases, and Global Health

Subjects
0301 basic medicine, medicine.medical_treatment, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], HIV Infections, Rate ratio, Cohort Studies, 0302 clinical medicine, Pregnancy, Antiretroviral Therapy, Highly Active, Prevalence, 030212 general & internal medicine, Child, poor immune response, ddc:618, Immunosuppression, Viral Load, Hepatitis B, Thailand, 3. Good health, Europe, Thailand/epidemiology, Infectious Diseases, Cohort, Coinfection, Female, Cohort study, Adult, Microbiology (medical), viral suppression, medicine.medical_specialty, Adolescent, Anti-HIV Agents, antiretroviral therapy, 030106 microbiology, Europe/epidemiology, 03 medical and health sciences, children, Acquired immunodeficiency syndrome (AIDS), SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, HIV, Aged, Settore MED/38 - Pediatria Generale e Specialistica, business.industry, Immunity, medicine.disease, HIV Infections/drug therapy/epidemiology, CD4 Lymphocyte Count, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Anti-HIV Agents/therapeutic use, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background In human immunodeficiency virus (HIV)–positive adults, low CD4 cell counts despite fully suppressed HIV-1 RNA on antiretroviral therapy (ART) have been associated with increased risk of morbidity and mortality. We assessed the prevalence and outcomes of poor immune response (PIR) in children receiving suppressive ART. Methods Sixteen cohorts from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) contributed data. Children Results Of 2318 children included, median age was 6.4 years and 68% had advanced/severe immunosuppression at ART initiation. At 1 year of VS, 12% had PIR. In multivariable analysis, PIR was associated with older age and worse immunological stage at ART start, hepatitis B coinfection, and residing in Thailand (all P ≤ .03). Rates of AIDS/death (95% confidence interval) per 100 000 person-years were 1052 (547, 2022) among PIR versus 261 (166, 409) among immune responders; rate ratio of 4.04 (1.83, 8.92; P < .001). Conclusions One in eight children in our cohort experienced PIR despite sustained VS. While the overall rate of AIDS/death was low, children with PIR had a 4-fold increase in risk of event as compared with immune responders.

Published
2020
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2. Outcomes of second-line antiretroviral therapy among children living with HIV : a global cohort analysis

Author

The Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration, Patel, K., Mofenson, L., Bekker, L.G., Vicari, M., Essajee, S., Penazzato, M., Collins, I.J., Wools-Kaloustian, K., Davies, M.A., Leroy, V., Goodall, R., Smith, C., Vreeman, R., Slogrove, A., Williams, P., Crichton, S., Seage, G., Thahane, L., Kazembe, P.N., Lukhele, B., Mwita, L., Kekitiinwa-Rukyalekere, A., Wanless, S., Matshaba, M.S., Goetghebuer, T., Thorne, C., Josiane Warszawski, J., Luisa Galli, L., Geelen, S., Gibb, D.M., Giaquinto, C., Marczynska, M., Marques, M., Prata, F., Ene, L., Okhonskaia, L., Rojo, P., Noguera-Julian, A., Naver, L., Rudin, C., and Jourdain, Gonzague

Abstract

Introduction : Limited data describe outcomes on second-line antiretroviral therapy (ART) among children globally. Our objective was to contribute data on outcomes among children living with HIV after initiation of second-line ART in the context of routine care within a large global cohort collaboration. Methods : Patient-level data from 1993 through 2015 from 11 paediatric HIV cohorts were pooled. Characteristics at switch and through two years of follow-up were summarized for children who switched to second-line ART after starting a standard first-line regimen in North America, Latin America, Europe, Asia, Southern Africa (South Africa & Botswana) and the rest of sub-Saharan Africa (SSA). Cumulative incidences of mortality and loss to follow-up (LTFU) were estimated using a competing risks framework. Results : Of the 85,389 children on first-line ART, 3,555 (4%) switched to second-line after a median of 2.8 years on ART (IQR: 1.6, 4.7); 69% were from Southern Africa or SSA and 86% of second-line regimens were protease inhibitor-based. At switch, median age was 8.4 years and 50% had a prior AIDS diagnosis. Median follow-up after switch to second-line ranged from 1.8 years in SSA to 5.3 years in North America. Median CD4 counts at switch to second-line ranged from 235 cells/mm(3) in SSA to 828 cells/mm(3) in North America. Improvements in CD4 counts were observed over two years of follow-up, particularly in regions with lower CD4 counts at second-line switch. Improvements in weight-for-age z-scores were not observed during follow-up. Cumulative incidence of LTFU at two years was

Published
2020

3. Prevalence and Clinical Outcomes of Poor Immune Response Despite Virologically Suppressive Antiretroviral Therapy Among Children and Adolescents With Human Immunodeficiency Virus in Europe and Thailand: Cohort Study

Author

Smit C, Marques L, Klein N, Gulllen S, Judd A, Thorne C, Goodall R, Konigs C, Spoulou V, Prata F, Goetghebuer T, Chiappini E, Galli L, Naver L, Giaquinto C, Gibb D, Marczynska M, Okhonskaia L, Klimkait T, Lallernant M, Ngo-Giang-Huong N, Kiseleva G, Malyuta R, Volokha A, and European Pregnancy Paediat HIV Coh

Subjects
viral suppression, children, antiretroviral therapy, HIV, poor immune response
Abstract

Background. In human immunodeficiency virus (HIV)-positive adults, low CD4 cell counts despite fully suppressed HIV-1 RNA on antiretroviral therapy (ART) have been associated with increased risk of morbidity and mortality. We assessed the prevalence and outcomes of poor immune response (PIR) in children receiving suppressive ART. Methods. Sixteen cohorts from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) contributed data. Children = 400 copies/mL) for >= 1 year were included. The prevalence of PIR (defined as World Health Organization advanced/severe immunosuppression for age) at 1 year of VS was described. Factors associated with PIR were assessed using logistic regression. Rates of acquired immunodeficiency syndrome (AIDS) or death on suppressive ART were calculated by PIR status. Results. Of 2318 children included, median age was 6.4 years and 68% had advanced/severe immunosuppression at ART initiation. At 1 year of VS, 12% had PIR. In multivariable analysis, PIR was associated with older age and worse immunological stage at ART start, hepatitis B coinfection, and residing in Thailand (all P=.03). Rates of AIDS/death (95% confidence interval) per 100 000 person-years were 1052 (547, 2022) among PIR versus 261 (166, 409) among immune responders; rate ratio of 4.04 (1.83, 8.92; P

Published
2020

4. Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand

Author

Goetghebuer T, Hainaut M, Van der Kelen E, Delforge M, Warszawski J, Le Chenadec J, Ramos E, Dialla O, Wack T, Laurent C, Selmi L, Leymarie I, Benali F, Brossard M, Boufassa L, Floch-Tudal C, Firtion G, Hau I, Chace A, Bolot P, Blanche S, Granier M, Labrune P, Lachassine E, Dollfus C, Levine M, Fourcade C, Heller-Roussin B, Runel-Belliard C, Tricoire J, Monpoux F, Chirouze C, Reliquet V, Brouard J, Kebaili K, Fialaire P, Lalande M, Mazingue F, Partisani M, Koenigs C, Schultze-Strasser S, Baumann U, Niehues T, Neubert J, Kobbe R, Feiterna-Sperling C, Buchholz B, Notheis G, Spoulou V, Tovo P, Galli L, Chiappini E, Patrizia O, Larovere D, Ruggeri M, Faldella G, Baldi F, Badolato R, Montagnani C, Venturini E, Lisi C, Di Biagio A, Taramasso L, Giacomet V, Erba P, Esposito S, Lipreri R, Salvini F, Tagliabue C, Cellini M, Bruzzese E, Lo Vecchio A, Rampon O, Dona D, Romano A, Dodi I, Maccabruni A, Consolini R, Bernardi S, Genovese O, Olmeo P, Cristiano L, Mazza A, Garazzino S, Pellegatta A, Pajkrt D, Scherpbier H, Weijsenfeld A, van der Plas A, Jurriaans S, Back N, Zaaijer H, Berkhout B, Cornelissen M, Schinkel C, Wolthers K, Fraaij P, van Rossum A, van der Knaap L, Visser E, Boucher C, Koopmans M, van Kampen J, Pas S, Henriet S, de Flier M, van Aerde K, Strik-Albers R, Rahamat-Langendoen J, Stelma F, Scholvinck E, de Groot-de Jonge H, Niesters H, van Leer-Buter C, Knoester M, Bont L, Geelen S, Wolfs T, Nauta N, Ang C, van Houdt R, Pettersson A, Vandenbroucke-Grauls C, Reiss P, Bezemer D, van Sighem A, Smit C, Wit F, Boender T, Zaheri S, Hillebregt M, de Jong A, Bergsma D, Grivell S, Jansen A, Raethke M, Meijering R, de Groot L, van den Akker M, Bakker Y, Claessen E, El Berkaoui A, Koops J, Kruijne E, Lodewijk C, Munjishvili L, Peeck B, Ree C, Regtop R, Ruijs Y, Rutkens T, Schoorl M, Timmerman A, Tuijn E, Veenenberg L, van der Vliet S, Wisse A, Woudstra T, Tuk B, Marczynska M, Oldakowska A, Popielska J, Coupland U, Doroba M, Marques L, Teixeira C, Fernandes A, Prata F, Ene L, Gingaras C, Radoi R, Okhonskaia L, Voronin E, Miloenko M, Labutina S, Soler-Palacin P, Antoinette Frick M, Perez-Hoyos S, Mur A, Lopez N, Mendez M, Mayol L, Vallmanya T, Calavia O, Garcia L, Coll M, Pineda V, Rius N, Rovira N, Duenas J, Fortuny C, Noguera-Julian A, Jose Mellado M, Escosa L, Garcia Hortelano M, Sainz T, Isabel Gonzalez-Tome M, Rojo P, Blazquez D, Tomas Ramos J, Prieto L, Guillen S, Luisa Navarro M, Saavedra J, Santos M, Angeles Munoz M, Ruiz B, Fernandez Mc Phee C, Jimenez de Ory S, Alvarez S, Angel Roa M, Beceiro J, Martinez J, Badillo K, Apilanez M, Pocheville I, Garrote E, Colino E, Gomez Sirvent J, Garzon M, Roman V, Montesdeoca A, Mateo M, Jose Munoz M, Angulo R, Neth O, Falcon L, Terol P, Luis Santos J, Moreno D, Lendinez F, Grande A, Jose Romero F, Perez C, Lillo M, Losada B, Herranz M, Bustillo M, Guerrero C, Collado P, Antonio Couceiro J, Perez A, Isabel Piqueras A, Breton R, Segarra I, Gavilan C, Jareno E, Montesinos E, Dapena M, Alvarez C, Gloria Andres A, Marugan V, Ochoa C, Alfayate S, Isabel Menasalvas A, de Miguel E, Naver L, Soeria-Atmadja S, Hagas V, Aebi-Popp K, Asner S, Aubert V, Battegay M, Baumann M, Bernasconi E, Boni J, Brazzola P, Bucher H, Calmy A, Cavassini M, Ciuffi A, Duppenthaler A, Dollenmaier G, Egger M, Elzi L, Fehr J, Fellay J, Francini K, Furrer H, Fux C, Grawe C, Gunthard H, Haerry D, Hasse B, Hirsch H, Hoffmann M, Hosli I, Kahlert C, Kaiser L, Keiser O, Klimkait T, Kovari H, Kouyos R, Ledergerber B, Martinetti G, de Tejada M, Metzner K, Muller, Nicca D, Paioni P, Pantaleo G, Polli C, Posfay-Barbe K, Rauch A, Rudin C, Schmid P, Scherrer A, Speck R, Tarr P, Lecompte T, Trkola A, Vernazza P, Wagner N, Wandeler G, Weber R, Wyler C, Yerly S, Techakunakorn P, Prachanukroh C, Hansudewechakul R, Wanchaitanawong V, Theansavettrakul S, Nanta S, Ngampiyaskul C, Phanomcheong S, Hongsiriwon S, Karnchanamayul W, Chacheongsao B, Kwanchaipanich R, Kanjanavanit S, Prapinklao S, Kamonpakorn N, Nantarukchaikul M, Adulyadej B, Layangool P, Mekmullica J, Lucksanapisitkul P, Watanayothin S, Lertpienthum N, Warachit B, Hanpinitsak S, Potchalongsin S, Thanasiri P, Krikajornkitti S, Attavinijtrakarn P, Srirojana S, Bunjongpak S, Puangsombat A, Na-Rajsima S, Ananpatharachai P, Akarathum N, Phuket V, Lawtongkum W, Kheunjan P, Suriyaboon T, Saipanya A, Than-in-at K, Jaisieng N, Suaysod R, Chailoet S, Naratee N, Kawilapat S, Kaleeva T, Baryshnikova Y, Soloha S, Bashkatova N, Raus I, Glutshenko O, Ruban Z, Prymak N, Kiseleva G, Bailey H, Lyall H, Butler K, Doerholt K, Foster C, Klein N, Menson E, Riordan A, Shingadia D, Tudor-Williams G, Tookey P, Welch S, Collins I, Cook C, Dobson D, Fairbrother K, Gibb D, Judd A, Harper L, Parrott F, Tostevin A, Van Looy N, Walsh A, Scott S, Vaughan Y, Laycock N, Bernatoniene J, Finn A, Hutchison L, Sharpe G, Williams A, Lyall E, Seery P, Lewis P, Miles K, Subramaniam B, Hutchinson L, Ward P, Sloper K, Gopal G, Doherty C, Hague R, Price V, Bamford A, Bundy H, Clapson M, Flynn J, Novelli V, Ainsley-Walker P, Tovey P, Gurtin D, Garside J, Fall A, Porter D, Segal S, Ball C, Hawkins S, Chetcuti P, Dowie M, Bandi S, McCabe A, Eisenhut M, Handforth J, Roy P, Flood T, Pickering A, Liebeschuetz S, Kavanagh C, Murphy C, Rowson K, Tan T, Daniels J, Lees Y, Kerr E, Thompson F, Le Provost M, Cliffe L, Smyth A, Stafford S, Freeman A, Reddy T, Fidler K, Christie S, Gordon A, Rogahn D, Harris S, Collinson A, Jones L, Offerman B, Van Someren V, Benson C, Riddell A, O'Connor R, Brown N, Ibberson L, Shackley F, Faust S, Hancock J, Donaghy S, Prime K, Sharland M, Storey S, Gorman S, Monrose C, Walters S, Cross R, Broomhall J, Scott D, Stroobant J, Bridgwood A, McMaster P, Evans J, Gardiner T, Jones R, Gardiner K, European Pregnancy Paediat HIV Coh, Stichting HIV Monitoring, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Department of Sciences for Woman and Child's Health, Florence University, Dipartimento di Pediatria, Azienda Ospedaliera di Padova, Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Pediatrics, and Virology

Subjects
Male, 0301 basic medicine, Time Factors, HIV, antiretroviral therapy, children, second-line, switch, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Drug Resistance, INFANTS, HIV Infections, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, Interquartile range, Antiretroviral Therapy, Highly Active, ADOLESCENTS, Cumulative incidence, Viral, Treatment Failure, 030212 general & internal medicine, Child, ComputingMilieux_MISCELLANEOUS, Antiretroviral therapy, Children, Second-line, Switch, Age Factors, Anti-HIV Agents, Child, Preschool, Drug Resistance, Viral, Drug Substitution, Europe, Female, Humans, Infant, Reverse Transcriptase Inhibitors, Thailand, Viral Load, Reverse-transcriptase inhibitor, Immunosuppression, OPEN-LABEL, VIROLOGICAL FAILURE, 3. Good health, Infectious Diseases, Viral load, medicine.drug, Microbiology (medical), medicine.medical_specialty, Efavirenz, Nevirapine, SCALE-UP, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Highly Active, Preschool, business.industry, HIV-1 DRUG-RESISTANCE, ADULTS, 030112 virology, RANDOMIZED-TRIAL, Regimen, INFECTED CHILDREN, VIRAL LOAD, chemistry, business
Abstract

Background. Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand.Methods. Children aged = 2 nucleoside reverse transcriptase inhibitors p[NRTIs] plus nonnucleoside reverse transcriptase inhibitor p[NNRTI] or boosted protease inhibitor p[PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of >= 1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks.Results. Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch.Conclusions. One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch.

Published
2017
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5. CD4 recovery following antiretroviral treatment interruptions in children and adolescents with HIV infection in Europe and Thailand

Author

Galli, L., Crichton, S., Buzzoni, C., Goetghebuer, T., Jourdain, Gonzague, Judd, A., Klein, N., Mellado, M., Noguera-Julian, A., Kahlert, C. R., Spoulou, V., Scherpbier, H., Marques, L., Collins, I. J., Gibb, D. M., Tome, M. G., Warszawski, J., Dollfus, C., Konigs, C., Prata, F., Chiappini, E., Naver, L., Giaquinto, C., Thorne, C., Marczynska, M., Okhonskaia, L., Borkird, T., Attavinijtrakarn, P., Malyuta, R., Volokha, A., Ene, L., Goodall, R., and EPPICC Study Group

Subjects
paediatric, treatment interruption, antiretroviral therapy
Abstract

Objectives The aim of the study was to explore factors associated with CD4 percentage (CD4%) reconstitution following treatment interruptions (TIs) of antiretroviral therapy (ART). Methods Data from paediatric HIV-infected cohorts across 17 countries in Europe and Thailand were pooled. Children on combination ART (cART; at least three drugs from at least two classes) for > 6 months before TI of >= 30 days while aged CD4% at restart of ART (r-ART) and in the long term (up to 24 months after r-ART) following the first TI was modelled using asymptotic regression. Results In 779 children with at least one TI, the median age at first TI was 10.1 [interquartile range (IQR) 6.4, 13.6] years and the mean CD4% was 27.3% [standard deviation (SD) 11.0%]; the median TI duration was 9.0 (IQR 3.5, 22.5) months. In regression analysis, the mean CD4% was 19.2% [95% confidence interval (CI) 18.3, 20.1%] at r-ART, and 27.1% (26.2, 27.9%) in the long term, with half this increase in the first 6 months. r-ART and long-term CD4% values were highest in female patients and in children aged TI. Long-term CD4% was highest in those with a TI lasting 1 to = 25% (all P < 0.001). The effect of CD4% nadir during the TI differed significantly (P = 0.038) by viral suppression at the start of the TI; in children with CD4% nadir TI, recovery was better in those virally suppressed prior to the TI; viral suppression was not associated with recovery in children with CD4% nadir >= 25%. Conclusions After restart of ART following TI, most children reconstituted well immunologically. Nevertheless, several factors predicted better immunological reconstitution, including younger age and higher nadir CD4% during TI.

Published
2019

6. Predictors of faster virological suppression in early treated infants with perinatal HIV from Europe and Thailand

Author

Chan, M. K., Goodall, R., Judd, A., Klein, N., Chiappini, E., Klimkait, T., Ngo-Giang-Huong, Nicole, Palma, P., Rossi, P., Thorne, C., Turkova, A., Zangari, P., Rojo, P., Babiker, A. G. A., Fraaij, P. L., Pajkrt, D., Marques, L., Collins, I. J., Gibb, D. M., Gonzalez-Tome, M. I., Ramos, J. T., Navarro, M. L., Noguera-Julian, A., Warszawski, J., Konigs, C., Spoulou, V., Prata, F., Goetghebuer, T., Galli, L., Naver, L., Giaquinto, C., Marczynska, M., Okhonskaia, L., Malyuta, R., Volokha, A., Ene, L., Gibb, D., Watters, S., Chan, M., McCoy, L., Babiker, A., Marcelin, A. G., Calvez, V., Munoz, M. A., Wahren, B., Foster, C., Cotton, M., Robb, M., Ananworanich, J., Claiden, P., Pillay, D., Persaud, D., De Boer, R. J., Schroter, J., Anelone, A. J. N., Puthanakit, T., Ceci, A., Giannuzzi, V., Luzuriaga, K., Chomont, N., Cameron, M., Cancrini, C., Yates, A., Kuhn, L., Violari, A., Otwombe, K., Pepponi, I., Rocchi, F., Rinaldi, S., Tagarro, A., Lain, M. G., Vaz, P., Lopez, E., Nhampossa, T., EPPICC study group, and EPIICAL study groups

Subjects
early combination antiretroviral therapy, predictors, infants, perinatal HIV, virological suppression
Abstract

Objective: To identify predictors of faster time to virological suppression among infants starting combination antiretroviral therapy (cART) early in infancy. Design: Cohort study of infants from Europe and Thailand included in studies participating in the European Pregnancy and Paediatric HIV Cohort Collaboration. Methods: Infants with perinatal HIV starting cART aged less than 6 months with at least 1 viral load measurement within 15 months of cART initiation were included. Multi-variable interval-censored flexible parametric proportional hazards models were used to assess predictors of faster virological suppression, with timing of suppression assumed to lie in the interval between last viral load at least 400 and first viral load less than 400 copies/ml. Results: Of 420 infants, 59% were female and 56% from Central/Western Europe, 26% United Kingdom/Ireland, 15% Eastern Europe and 3% Thailand; 46 and 54% started a boosted protease inhibitor-based or nonnucleoside reverse transcriptase inhibitor-based regimen, respectively. At cART initiation, the median age, CD4(+) % and viral load were 2.9 [interquartile range (IQR): 1.4-4.1] months, 34 (IQR: 24-45)% and 5.5 (IQR: 4.5-6.0) log(10) copies/ml, respectively. Overall, an estimated 89% (95% confidence interval: 86-92%) achieved virological suppression within 12 months of cART start. In multivariable analysis, younger age [adjusted hazard ratio (aHR): 0.84 per month older; P < 0.001], higher CD4(+) % (aHR: 1.11 per 10% higher; P=0.010) and lower log(10) viral load (aHR: 0.85 per log(10) higher; P < 0.001) at cART initiation independently predicted faster virological suppression. Conclusion: We observed a significant independent effect of age at cART initiation, even within a narrow 6 months window from birth. These findings support the earliest feasible cART initiation in infants and suggest that early therapy influences key virological and immunological parameters that could have important consequences for long-term health.

Published
2019

7. CD4 recovery following antiretroviral treatment interruptions in children and adolescents with HIV infection in Europe and Thailand

Author

Galli, L. Crichton, S. Buzzoni, C. Goetghebuer, T. and Jourdain, G. Judd, A. Klein, N. Jose Mellado, M. and Noguera-Julian, A. Kahlert, C. R. Spoulou, V. Scherpbier, H. and Marques, L. Collins, I. J. Gibb, D. M. Gonzalez Tome, Mi and Warszawski, J. Dollfus, C. Koenigs, C. Prata, F. and Chiappini, E. Naver, L. Giaquinto, C. Thorne, C. and Marczynska, M. Okhonskaia, L. Borkird, T. Attavinijtrakarn, P. Malyuta, R. Volokha, A. Ene, L. Goodall, R. and European Pregnancy Paediat HIV

Abstract

Objectives The aim of the study was to explore factors associated with CD4 percentage (CD4%) reconstitution following treatment interruptions (TIs) of antiretroviral therapy (ART). Methods Data from paediatric HIV-infected cohorts across 17 countries in Europe and Thailand were pooled. Children on combination ART (cART; at least three drugs from at least two classes) for > 6 months before TI of >= 30 days while aged CD4% at restart of ART (r-ART) and in the long term (up to 24 months after r-ART) following the first TI was modelled using asymptotic regression. Results In 779 children with at least one TI, the median age at first TI was 10.1 [interquartile range (IQR) 6.4, 13.6] years and the mean CD4% was 27.3% [standard deviation (SD) 11.0%]; the median TI duration was 9.0 (IQR 3.5, 22.5) months. In regression analysis, the mean CD4% was 19.2% [95% confidence interval (CI) 18.3, 20.1%] at r-ART, and 27.1% (26.2, 27.9%) in the long term, with half this increase in the first 6 months. r-ART and long-term CD4% values were highest in female patients and in children aged TI. Long-term CD4% was highest in those with a TI lasting 1 to = 25% (all P < 0.001). The effect of CD4% nadir during the TI differed significantly (P = 0.038) by viral suppression at the start of the TI; in children with CD4% nadir TI, recovery was better in those virally suppressed prior to the TI; viral suppression was not associated with recovery in children with CD4% nadir >= 25%. Conclusions After restart of ART following TI, most children reconstituted well immunologically. Nevertheless, several factors predicted better immunological reconstitution, including younger age and higher nadir CD4% during TI.

Published
2019

8. Incidence of switching to second-line antiretroviral therapy and associated factors in children with HIV : an international cohort collaboration [plus Supplementary appendix]

Author

The Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration, Collins, I.J., Wools-Kaloustian, K., Goodall, R., Smith, C., Abrams, E.J., Ben-Farhat, J., Balkan, S., Davies, M.A., Edmonds, A., Leroy, V., Nuwagaba-Biribonwoha, H., Patel, K., Paul, M.E., Pinto, J., Conejo, P.R., Sohn, A., Van Dyke, R., Vreeman, R., Maxwell, N., Timmerman, V., Duff, C., Judd, A., Seage, G., Williams, P., Gibb, D.M., Bekker, L.G., Mofenson, L., Vicari, M., Essajee, S., Mohapi, E.Q., Kazembe, P.N., Hlatshwayo, M., Lumumba, M., Kekitiinwa-Rukyalekere, A., Wanless, S., Matshaba, M.S., Goetghebuer, T., Thorne, C., Warszawski, J., Galli, L., Geelen, S., Giaquinto, C., Marczynska, M., Marques, L., Prata, F., Ene, L., Okhonskaia, L., Noguera-Julian, A., Naver, L., Rudin, C., and Jourdain, Gonzague

Abstract

Background : Estimates of incidence of switching to second-line antiretroviral therapy (ART) among children with HIV are necessary to inform the need for paediatric second-line formulations. We aimed to quantify the cumulative incidence of switching to second-line ART among children in an international cohort collaboration. Methods : In this international cohort collaboration study, we pooled individual patient-level data for children younger than 18 years who initiated ART (two or more nucleoside reverse-transcriptase inhibitors [NRTI] plus a non-NRTI [NNRTI] or boosted protease inhibitor) between 1993 and 2015 from 12 observational cohort networks in the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration. Patients who were reported to be horizontally infected with HIV and those who were enrolled in trials of treatment monitoring, switching, or interruption strategies were excluded. Switch to second-line ART was defined as change of one or more NRTI plus either change in drug class (NNRTI to protease inhibitor or vice versa) or protease inhibitor change, change from single to dual protease inhibitor, or addition of a new drug class. We used cumulative incidence curves to assess time to switching, and multivariable proportional hazards models to explore patient-level and cohort-level factors associated with switching, with death and loss to follow-up as competing risks. Findings : At the data cutoff of Sept 16, 2015, 182 747 children with HIV were included in the CIPHER dataset, of whom 93 351 were eligible, with 83 984 (90.0%) from sub-Saharan Africa. At ART initiation, the median patient age was 3.9 years (IQR 1.6-6.9) and 82 885 (88.8%) patients initiated NNRTI-based and 10 466 (11.2%) initiated protease inhibitor-based regimens. Median duration of follow-up after ART initiation was 26 months (IQR 9-52). 3883 (4.2%) patients switched to second-line ART after a median of 35 months (IQR 20-57) of ART. The cumulative incidence of switching at 3 years was 3.1% (95% CI 3.0-3.2), but this estimate varied widely depending on the cohort monitoring strategy, from 6.8% (6.5-7.2) in settings with routine monitoring of CD4 (CD4% or CD4 count) and viral load to 0.8% (0.6-1.0) in settings with clinical only monitoring. In multivariable analyses, patient-level factors associated with an increased likelihood of switching were male sex, older age at ART initiation, and initial NNRTI-based regimen (p

Published
2019

9. Safety of zidovudine/lamivudine scored tablets in children with HIV infection in Europe and Thailand

Author

Bailey, H., Thompson, L., Childs, T., Jeannie, I., Tostevin, A., Goodall, R., Goetghebuer, T., Spoulou, V., Galli, L., Marczynska, M., Marques, L., Ene, L., Samarina, A., Rosenberg, V., Dodonov, K., Okhonskaia, L., Julian, A. N., Conejo, P. R., Amador, J. T. R., Naver, L., Jourdain, G., Thorne, C., Giaquinto, Carlo, Judd, A., Voronin, E., Tookey, P., and Collins, I. J.

Subjects
Pharmacology, Anti-HIV Agents, Pharmacoepidemiology and Prescription, Antiretroviral therapy, Children, HIV, NRTIs, Pharmacovigilance, Child, Europe, HIV Infections, Humans, Lamivudine, Tablets, Thailand, Zidovudine, Pharmacology (medical), virus diseases, General Medicine, 030204 cardiovascular system & hematology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030212 general & internal medicine
Abstract

Background Zidovudine (ZDV) has been associated with risk of haematological toxicity. Safety data from clinical trials is generally limited to 48 weeks. We assessed the short- and mid-term toxicity of ZDV/lamivudine (3TC) fixed-dose combination scored tablets in HIV-infected children followed in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) network. Methods Fourteen cohorts provided data on patients 24 months). Clinical adverse events and reasons for tablet discontinuation were described. Results Of 541 patients on ZDV/3TC, 388 (72%) had weight and dose data available, of whom 350 (90%) weighed ≥14 kg and were eligible for tablet use; 161 (41%) were aged

Published
2016

10. Long-term trends in mortality and AIDS-defining events after combination ART initiation among children and adolescents with perinatal HIV infection in 17 middle- and high-income countries in Europe and Thailand: A cohort study

Author

European Pregnancy and Paediatric HIV Cohort Collaboration (EPPI, Judd, A, Chappell, E, Turkova, A, Le Coeur, S, Noguera-Julian, A, Goetghebuer, T, Doerholt, K, Galli, L, Pajkrt, D, Marques, L, Collins, IJ, Gibb, DM, González Tome, MI, Navarro, M, Warszawski, J, Königs, C, Spoulou, V, Prata, F, Chiappini, E, Naver, L, Giaquinto, C, Thorne, C, Marczynska, M, Okhonskaia, L, Posfay-Barbe, K, Ounchanum, P, Techakunakorn, P, Kiseleva, G, Malyuta, R, Volokha, A, Ene, L, and Goodall, R

Subjects
AIDS, WESTERN_EUROPE, ADOLESCENTS, THAILAND, virus diseases, Medicine, CHILDREN, CHILD_MORTALITY, PERINATAL_MORTALITY, YOUTHS, CENTRAL_AND_EASTERN_EUROPE
Abstract

BACKGROUND: Published estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand. METHODS AND FINDINGS: Children with perinatal HIV aged 6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4-9.3) years; 35% of children aged 400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time. CONCLUSIONS: In our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred =6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at >6 months after initiation of cART.

Published
2018

11. The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis

Author

Slogrove, A.L. (Amy L.), Schomaker, M. (Michael), Davies, M.-A. (Mary-Ann), Williams, P. (Paige), Balkan, S. (Suna), Ben-Farhat, J. (Jihane), Calles, N. (Nancy), Chokephaibulkit, K. (Kulkanya), Duff, C. (Charlotte), Eboua, T.F. (Tanoh François), Kekitiinwa-Rukyalekere, A. (Adeodata), Maxwell, N. (Nicola), Pinto, J. (Jorge), Seage, G. (George), Teasdale, C.A. (Chloe A.), Wanless, S. (Sebastian), Warszawski, J. (Josiane), Wools-Kaloustian, K. (Kara), Yotebieng, M. (Marcel), Timmerman, V. (Venessa), Collins, I.J. (Intira J.), Goodall, R. (Ruth), Smith, C. (Colette), Patel, K. (Kunjal), Paul, M. (Mary), Gibb, D.M., Vreeman, R. (Rachel), Abrams, E.J. (Elaine J.), Hazra, R. (Rohan), Van Dyke, R. (Russell), Bekker, L.-G. (Linda-Gail), Mofenson, L. (Lynne), Vicari, M. (Marissa), Essajee, S. (Shaffiq), Penazzato, M. (Martina), Anabwani, G. (Gabriel), Q. Mohapi, E. (Edith), N. Kazembe, P. (Peter), Hlatshwayo, M. (Makhosazana), Lumumba, M. (Mwita), Goetghebuer, T. (Tessa), Thorne, C. (Claire), Galli, L. (Luisa), van Rossum, A. (Annemarie), Giaquinto, C. (Carlo), Marczynska, M. (Magdalena), Marques, L.C. (Laura), Prata, F. (Filipa), Ene, L. (Luminita), Okhonskaia, L. (Liubov), Rojo, P. (Pablo), Fortuny, C. (Claudia), Nave´r, L., Rudin, C. (Christoph), Le Coeur, S. (Sophie), Volokha, A. (Alla), Rouzier, V. (Vanessa), Succi, R. (Regina), Sohn, A. (Annette), Kariminia, A. (Azar), Edmonds, A. (Andrew), Lelo, P. (Patricia), Ayaya, S. (Samuel), Ongwen, P. (Patricia), Jefferys, L.F. (Laura F.), Phiri, S. (Sam), Mubiana-Mbewe, M. (Mwangelwa), Sawry, S. (Shobna), Renner, L. (Lorna), Sylla, M. (Mariam), Abzug, M.J. (Mark J.), Levin, M. (Myron), Oleske, J. (James), Chernoff, M. (Miriam), Traite, S. (Shirley), Purswani, M. (Murli), Chadwick, E.G. (Ellen G.), Judd, A. (Ali), Leroy, V. (Valériane), Slogrove, A.L. (Amy L.), Schomaker, M. (Michael), Davies, M.-A. (Mary-Ann), Williams, P. (Paige), Balkan, S. (Suna), Ben-Farhat, J. (Jihane), Calles, N. (Nancy), Chokephaibulkit, K. (Kulkanya), Duff, C. (Charlotte), Eboua, T.F. (Tanoh François), Kekitiinwa-Rukyalekere, A. (Adeodata), Maxwell, N. (Nicola), Pinto, J. (Jorge), Seage, G. (George), Teasdale, C.A. (Chloe A.), Wanless, S. (Sebastian), Warszawski, J. (Josiane), Wools-Kaloustian, K. (Kara), Yotebieng, M. (Marcel), Timmerman, V. (Venessa), Collins, I.J. (Intira J.), Goodall, R. (Ruth), Smith, C. (Colette), Patel, K. (Kunjal), Paul, M. (Mary), Gibb, D.M., Vreeman, R. (Rachel), Abrams, E.J. (Elaine J.), Hazra, R. (Rohan), Van Dyke, R. (Russell), Bekker, L.-G. (Linda-Gail), Mofenson, L. (Lynne), Vicari, M. (Marissa), Essajee, S. (Shaffiq), Penazzato, M. (Martina), Anabwani, G. (Gabriel), Q. Mohapi, E. (Edith), N. Kazembe, P. (Peter), Hlatshwayo, M. (Makhosazana), Lumumba, M. (Mwita), Goetghebuer, T. (Tessa), Thorne, C. (Claire), Galli, L. (Luisa), van Rossum, A. (Annemarie), Giaquinto, C. (Carlo), Marczynska, M. (Magdalena), Marques, L.C. (Laura), Prata, F. (Filipa), Ene, L. (Luminita), Okhonskaia, L. (Liubov), Rojo, P. (Pablo), Fortuny, C. (Claudia), Nave´r, L., Rudin, C. (Christoph), Le Coeur, S. (Sophie), Volokha, A. (Alla), Rouzier, V. (Vanessa), Succi, R. (Regina), Sohn, A. (Annette), Kariminia, A. (Azar), Edmonds, A. (Andrew), Lelo, P. (Patricia), Ayaya, S. (Samuel), Ongwen, P. (Patricia), Jefferys, L.F. (Laura F.), Phiri, S. (Sam), Mubiana-Mbewe, M. (Mwangelwa), Sawry, S. (Shobna), Renner, L. (Lorna), Sylla, M. (Mariam), Abzug, M.J. (Mark J.), Levin, M. (Myron), Oleske, J. (James), Chernoff, M. (Miriam), Traite, S. (Shirley), Purswani, M. (Murli), Chadwick, E.G. (Ellen G.), Judd, A. (Ali), and Leroy, V. (Valériane)

Abstract

Background: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in “real-life” settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. Methods and findings: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]

Published
2018
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12. The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis

Author

Slogrove, AL, Schomaker, M, Davies, MA, Williams, P, Balkan, S, Ben-Farhat, J, Calles, N, Chokephaibulkit, K, Duff, C, Eboua, TF, Kekitiinwa-Rukyalekere, A, Maxwell, N, Pinto, J, Seage, G, Teasdale, CA, Wanless, S, Warszawski, J, Wools-Kaloustian, K, Yotebieng, M, Timmerman, V, Collins, IJ, Goodall, R, Smith, C, Patel, KN, Paul, M, Gibb, D, Vreeman, R, Abrams, EJ, Hazra, R, Van Dyke, R, Bekker, LG, Mofenson, L, Vicari, M, Essajee, S, Penazzato, M, Anabwani, G, Mohapi, EQ, Kazembe, PN, Hlatshwayo, M, Lumumba, M, Goetghebuer, T, Thorne, C, Galli, L, van Rossum, Annemarie, Giaquinto, C, Marczynska, M, Marques, L (Lemelinda), Prata, F, Ene, L, Okhonskaia, L, Rojo, P, Fortuny, C, Naver, L, Rudin, C, Le Coeur, S, Volokha, A, Rouzier, V, Succi, R, Sohn, A, Kariminia, A, Edmonds, A, Lelo, P, Ayaya, S, Ongwen, P, Jefferys, LF, Phiri, S, Mubiana-Mbewe, M, Sawry, S, Renner, L, Sylla, M, Abzug, MJ, Levin, M, Oleske, J, Chernoff, M, Traite, S, Purswani, M, Chadwick, EG, Judd, A, Leroy, V, Slogrove, AL, Schomaker, M, Davies, MA, Williams, P, Balkan, S, Ben-Farhat, J, Calles, N, Chokephaibulkit, K, Duff, C, Eboua, TF, Kekitiinwa-Rukyalekere, A, Maxwell, N, Pinto, J, Seage, G, Teasdale, CA, Wanless, S, Warszawski, J, Wools-Kaloustian, K, Yotebieng, M, Timmerman, V, Collins, IJ, Goodall, R, Smith, C, Patel, KN, Paul, M, Gibb, D, Vreeman, R, Abrams, EJ, Hazra, R, Van Dyke, R, Bekker, LG, Mofenson, L, Vicari, M, Essajee, S, Penazzato, M, Anabwani, G, Mohapi, EQ, Kazembe, PN, Hlatshwayo, M, Lumumba, M, Goetghebuer, T, Thorne, C, Galli, L, van Rossum, Annemarie, Giaquinto, C, Marczynska, M, Marques, L (Lemelinda), Prata, F, Ene, L, Okhonskaia, L, Rojo, P, Fortuny, C, Naver, L, Rudin, C, Le Coeur, S, Volokha, A, Rouzier, V, Succi, R, Sohn, A, Kariminia, A, Edmonds, A, Lelo, P, Ayaya, S, Ongwen, P, Jefferys, LF, Phiri, S, Mubiana-Mbewe, M, Sawry, S, Renner, L, Sylla, M, Abzug, MJ, Levin, M, Oleske, J, Chernoff, M, Traite, S, Purswani, M, Chadwick, EG, Judd, A, and Leroy, V

Published
2018

13. Outcomes of etravirine-based antiretroviral treatment in treatment-experienced children and adolescents living with HIV in Europe and Thailand.

Author

European Pregnancy And Paediatric Infections Cohort Collaboration Eppicc, Lyons A, Thompson L, Chappell E, Ene L, Galli L, Goetghebuer T, Jourdain G, Noguera-Julian A, Kahlert CR, Königs C, Kosalaraksa P, Lumbiganon P, Marczyńska M, Marques L, Navarro M, Naver L, Okhonskaia L, Prata F, Puthanakit T, Ramos JT, Samarina A, Thorne C, Voronin E, Turkova A, Giaquinto C, Judd A, and Collins IJ

Subjects
Adolescent, Anti-Retroviral Agents, CD4 Lymphocyte Count, Child, Humans, Nitriles, Pyrimidines, Thailand, Treatment Outcome, Viral Load, Anti-HIV Agents, HIV Infections, Pyridazines
Abstract

Background: Etravirine (ETR) is approved as a component of second or third-line antiretroviral treatment (ART) for children living with HIV. We assessed the outcomes of ETR-based ART in children in routine care in Europe and Thailand., Methods: Data on children aged <18 years at ETR start were pooled from 17 observational cohorts. Characteristics at ETR start, immunological and virological outcomes at 12 months, discontinuations, adverse events (AEs) and serious adverse events (SAEs) were described. Follow-up was censored at ETR discontinuation, death or last visit., Results: 177 children ever received ETR. At ETR start, median [IQR] age was 15 [12,16] years, CD4 count 480 [287, 713] cells/mm 3 , 70% had exposure to ≥3 ART classes and 20% had viral load (VL) <50 copies/mL. 95% received ETR in combination with ≥1 potent drug class, mostly protease inhibitor-based regimens. Median time on ETR was 24 [7, 48] months. Amongst those on ETR at 12 months ( n =141), 69% had VL<50 copies/mL. Median CD4 increase since ETR start ( n =83) was 147 [16, 267] cells/mm 3 . Overall, 81 (46%) discontinued ETR by last follow-up. Median time to discontinuation was 23 [8, 47] months. Common reasons for discontinuation were treatment simplification (19%), treatment failure (16%) and toxicity (12%). Eight children (5%) had AEs causally associated with ETR, all dermatological/hypersensitivity reactions. Two were SAEs, both Stevens-Johnson Syndrome in children on regimens containing ETR and darunavir and were causally related to either drugs; both resolved following ART discontinuation., Conclusion: Children receiving ETR were predominantly highly treatment-experienced, over two-thirds were virally suppressed at 12 months.

Published
2022
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14. The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis.

Author

Slogrove AL, Schomaker M, Davies MA, Williams P, Balkan S, Ben-Farhat J, Calles N, Chokephaibulkit K, Duff C, Eboua TF, Kekitiinwa-Rukyalekere A, Maxwell N, Pinto J, Seage G 3rd, Teasdale CA, Wanless S, Warszawski J, Wools-Kaloustian K, Yotebieng M, Timmerman V, Collins IJ, Goodall R, Smith C, Patel K, Paul M, Gibb D, Vreeman R, Abrams EJ, Hazra R, Van Dyke R, Bekker LG, Mofenson L, Vicari M, Essajee S, Penazzato M, Anabwani G, Q Mohapi E, N Kazembe P, Hlatshwayo M, Lumumba M, Goetghebuer T, Thorne C, Galli L, van Rossum A, Giaquinto C, Marczynska M, Marques L, Prata F, Ene L, Okhonskaia L, Rojo P, Fortuny C, Naver L, Rudin C, Le Coeur S, Volokha A, Rouzier V, Succi R, Sohn A, Kariminia A, Edmonds A, Lelo P, Ayaya S, Ongwen P, Jefferys LF, Phiri S, Mubiana-Mbewe M, Sawry S, Renner L, Sylla M, Abzug MJ, Levin M, Oleske J, Chernoff M, Traite S, Purswani M, Chadwick EG, Judd A, and Leroy V

Subjects
Adolescent, Child, Epidemiological Monitoring, Female, Follow-Up Studies, Humans, Infant, Newborn, International Cooperation, Internationality, Longitudinal Studies, Male, Anti-Retroviral Agents therapeutic use, Disease Transmission, Infectious prevention & control, Disease Transmission, Infectious statistics & numerical data, Global Health statistics & numerical data, HIV Infections epidemiology, HIV Infections mortality, HIV Infections therapy, HIV Infections transmission
Abstract

Background: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia., Methods and Findings: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria., Conclusion: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.

Published
2018
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15. Long-term trends in mortality and AIDS-defining events after combination ART initiation among children and adolescents with perinatal HIV infection in 17 middle- and high-income countries in Europe and Thailand: A cohort study.

Author

Judd A, Chappell E, Turkova A, Le Coeur S, Noguera-Julian A, Goetghebuer T, Doerholt K, Galli L, Pajkrt D, Marques L, Collins IJ, Gibb DM, González Tome MI, Navarro M, Warszawski J, Königs C, Spoulou V, Prata F, Chiappini E, Naver L, Giaquinto C, Thorne C, Marczynska M, Okhonskaia L, Posfay-Barbe K, Ounchanum P, Techakunakorn P, Kiseleva G, Malyuta R, Volokha A, Ene L, and Goodall R

Subjects
Acquired Immunodeficiency Syndrome drug therapy, Acquired Immunodeficiency Syndrome mortality, Acquired Immunodeficiency Syndrome virology, Adolescent, Child, Child, Preschool, Cohort Studies, Drug Therapy, Combination mortality, Europe epidemiology, HIV Infections virology, Humans, Infant, Infant, Newborn, Risk Factors, Thailand epidemiology, Anti-Retroviral Agents administration & dosage, Disease Progression, Drug Therapy, Combination statistics & numerical data, HIV Infections drug therapy, HIV Infections mortality
Abstract

Background: Published estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand., Methods and Findings: Children with perinatal HIV aged <18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013. Rates of death and first AIDS-defining events were calculated. Baseline and time-updated risk factors for early/late (≤/>6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4-9.3) years; 35% of children aged <5 years had a CD4 lymphocyte percentage <15% in 1997-2003, which fell to 15% of children in 2011 onwards (p < 0.001). Similarly, 53% and 18% of children ≥5 years had a CD4 count <200 cells/mm3 in 1997-2003 and in 2011 onwards, respectively (p < 0.001). Median follow-up was 5.6 (2.9-8.7) years. Of 94 deaths and 237 first AIDS-defining events, 43 (46%) and 100 (42%) were within 6 months of initiating cART, respectively. Multivariable predictors of early death were: being in the first year of life; residence in Russia, Ukraine, or Thailand; AIDS at cART start; initiating cART on a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen; severe immune suppression; and low BMI-for-age z-score. Current severe immune suppression, low current BMI-for-age z-score, and current viral load >400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time., Conclusions: In our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred ≤6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at >6 months after initiation of cART.

Published
2018
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