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
Authors:   The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) Study Group in EuroCoord, Chappell Elizabeth , Riordan Andrew , Jourdain Gonzague , Soriano-Arandes Antoni , Ene Luminita , Scherpbier Henriette J , Warszawski Josiane , Collins Intira J , 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 Lars , Giaquinto Carlo , Gibb Diana M , Marczynska Magdalena , Okhonskaia Liubov , Klimkait Thomas , Lallemant Marc , Ngo-Giang-Huong Nicole , Kiseleva Galyna , Malyuta Ruslan , Volokha Alla , Goetghebuer Tessa , Hainaut Marc , Delforge Marc , Warszawski Josiane , 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 , Bicëtre Le Kremlin , Fourcade Corinne , Heller-Roussin Brigitte , Runel-Belliard Camille , Tricoire Joëlle , Chirouze Catherine , Reliquet Véronique , Brouard Jacques , Kebaili Kamila , Fialaire Pascale , Lalande Muriel , Königs Christoph , Schultze-Strasser Stephan , Baumann U , Niehues T , Neubert J , Kobbe R , Berlin Charite , Feiterna-Sperling C , Königs C , Buchholz B , Notheis G , Spoulou Vana , 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 , Rampon Osvalda , Donà Daniele , Romano Amelia , Dodi Icilio , Maccabruni Anna , Consolini Rita , Bernardi Stefania , Tchidjou Kuekou Hyppolite , Genovese Orazio , Olmeo Paolina , Cristiano Letizia , Mazza Antonio , Gabiano Clara , Garazzino Silvia , Pellegatta Antonio , Pajkrt D , Scherpbier H J , Weijsenfeld A M , de Boer C G , Jurriaans S , Back N K T , Zaaijer H L , Berkhout B , Cornelissen M T E , Schinkel C J , Wolthers K C , Fraaij P L A , van Rossum A M C , van der Knaap L C , Visser E G , Koopmans M P G , van Kampen J J A , Pas S D , Henriet S S V , van de Flier M , van Aerde K , Strik-Albers R , Rahamat-Langendoen J , Stelma F F , Schölvinck E H , de Groot-de Jonge H , Niesters H G M , van Leer-Buter C C , Knoester M , Bont L J , Geelen S P M , Wolfs T F W , Nauta N , Ang C W , van Houdt R , Pettersson A M , Vandenbroucke-Grauls C M J E , Reiss P , Bezemer D O , van Sighem A I , Smit C , Wit F W M N , Boender T S , 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 Jolanta , Pokorska-Śpiewak Maria , Ołdakowska Agnieszka , Zawadka Konrad , Coupland Urszula , DorobaLaura Marques Małgorzata , Teixeira Carla , Fernandes Alexandre , Prata Filipa , Ene Luminita , Okhonskaia Liubov , Voronin Evgeny , Miloenko Milana , Labutina Svetlana , Tomás Ramos José , Prieto Luis , Guillén Sara , Luisa Navarro María , Saavedra Jesús , Santos Mar , Angeles Muñoz Mª , Ruiz Beatriz , Mc Phee Carolina Fernandez , de Ory Santiago Jimenez , Alvarez Susana , Ángel Roa Miguel , Beceiro José , Martínez Jorge , Badillo Katie , Apilanez Miren , Pocheville Itziar , Garrote Elisa , Colino Elena , Gómez Sirvent Jorge , Garzón Mónica , Román Vicente , Montesdeoca Abián , Mateo Mercedes , José Muñoz María , Angulo Raquel , Neth Olaf , Falcón Lola , Terol Pedro , Luis Santos Juan , Moreno David , Lendínez Francisco , Grande Ana , José Romero Francisco , Lillo Miguel , Losada Begoña , Herranz Mercedes , Bustillo Matilde , Guerrero Carmelo , Collado Pilar , Antonio Couceiro José , Pérez Amparo , Isabel Piqueras Ana , Bretón Rafael , Segarra Inmaculada , Gavilán César , Jareño Enrique , Montesinos Elena , Dapena Marta , Álvarez Cristina , Gloria Andrés Ana , Marugán Víctor , Ochoa Carlos , Alfayate Santiago , Isabel Menasalvas Ana , de Miguel Elisa , Aebi-Popp K , Asner S , Aubert V , Battegay M , Baumann M , Bernasconi E , Böni J , Brazzola P , Bucher H C , Calmy A , Cavassini M , Ciuffi A , Duppenthaler A , Dollenmaier G , Egger M , Elzi L , Fehr J , Fellay J , Francini K , Furrer H , Fux C A , Grawe C , Günthard H F , Haerry D , Hasse B , Hirsch H H , Hoffmann M , Hösli I , Kahlert C , Kaiser L , Keiser O , Klimkait T , Kovari H , Kouyos R D , Ledergerber B , Martinetti G , de Tejada B Martinez , Metzner K J , Müller N , Nicca D , Paioni P , Pantaleo G , Polli Ch , Posfay-Barbe K , Rauch A , Rudin C , Schmid P , Scherrer A U , Speck R , Tarr P , Thanh Lecompte M , Trkola A , Vernazza P , Wagner N , Wandeler G , Weber R , Wyler C A , Yerly S , Techakunakorn Pornchai , Hansudewechakul Rawiwan , Kham Chiang , Wanchaitanawong Vanichaya , Theansavettrakul Sookchai , Sai Mae , Nanta Sirisak , Ngampiyaskul Chaiwat , Phanomcheong Siriluk , Hongsiriwon Suchat , Karnchanamayul Warit , Kwanchaipanich Ratchanee , Kanjanavanit Suparat , Kamonpakorn Nareerat , Nantarukchaikul Maneeratn , Layangool Prapaisri , Mekmullica Jutarat , Lucksanapisitkul Paiboon , Watanayothin Sudarat , Lertpienthum Narong , Warachit Boonyarat , Hanpinitsak Sansanee , Potchalongsin Sathit , Thanasiri Pimpraphai , Krikajornkitti Sawitree , Attavinijtrakarn Pornsawan , Srirojana Sakulrat , Bunjongpak Suthunya , Puangsombat Achara , Na-Rajsima Sathaporn , Ananpatharachai Pornchai , Akarathum Noppadon , Phuket Vachira , Lawtongkum Weerasak , Kheunjan Prapawan , Suriyaboon Thitiporn , Saipanya Airada , Than-in-at Kanchana , Jaisieng Nirattiya , Suaysod Rapeepan , Chailoet Sanuphong , Naratee Naritsara , Kawilapat Suttipong , Kaleeva T , Baryshnikova Y , Soloha S , Bashkatova N , Raus I , Glutshenko O , Ruban Z , Prymak N , Kiseleva G , Bailey H , Bamford Alasdair , Butler Karina , Doerholt Katja , Doherty Conor , Foster Caroline , Francis Kate , Harrison Ian , Kenny Julia , Klein Nigel , Letting Gillian , McMaster Paddy , Murau Fungai , Nsangi Edith , Peters Helen , Prime Katia , Riordan Andrew , Shackley Fiona , Shingadia Delane , Storey Sharon , Thorne Claire , Tudor-Williams Gareth , Turkova Anna , Welch Steve , Jeannie Collins Intira , Cook Claire , Crichton Siobhan , Dobson Donna , Fairbrother Keith , M Gibb Diana , Harper Lynda , Judd Ali , Le Prevost Marthe , Van Looy Nadine , Peters Helen , Thorne Claire , Butler K , Walsh A , Thrasyvoulou L , Welch S , 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 , Klein N , Shingadia D , 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 , McMaster P , 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 , Riordan A , Ibberson L , Shackley F , Faust S N , Hancock J , Doerholt K , Prime K , Sharland M , Storey S , Lyall H , Monrose C , Seery P , Tudor-Williams G , Menson E , Callaghan A , Bridgwood A , McMaster P , Evans J , Blake E , Yannoulias A , Chappell Elizabeth , Critchton Siobhan , Jeannie Collins Intira , Duff Charlotte , Giaquinto Carlo , Goodall Ruth , Gomezpena Daniel , Judd Ali , Lundin Rebecca , Mangiarini Laura , Nardone Alessandra , Thorne Claire 
Published: March 2019

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 &lt;18 years at ART initiation, with sustained viral suppression (VS) (≤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 &lt; .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.