Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers

Fanny Chereau; Yoann Madec; Caroline Sabin; Niels Obel; Ezequiel Ruiz-Mateos; Georgios Chrysos; Sarah Fidler; Clara Lehmann; Robert Zangerle; Linda Wittkop; Peter Reiss; Osamah Hamouda; Vicente Estrada Perez; Manuel Leal; Amanda Mocroft; Patricia Garcia De Olalla; Adriana Ammassari; Antonella D.Arminio Monforte; Cristina Mussini; Ferran Segura; Antonella Castagna; Matthias Cavassini; Sophie Grabar; Philippe Morlat; Stéphane De Wit; Olivier Lambotte; Laurence Meyer; Ali Judd; Giota Touloumi; Josiane Warszawski; François Dabis; Murielle Mary Krause; Jade Ghosn; Catherine Leport; Ferdinand Wit; Maria Prins; Heiner Bucher; Diana Gibb; Gerd Fätkenheuer; Julia Del Amo; Claire Thorne; Ole Kirk; Christoph Stephan; Santiago Pérez-Hoyos; Barbara Bartmeyer; Nikoloz Chkhartishvili; Antoni Noguera-Julian; Andrea Antinori; Norbert Brockmeyer; Luis Prieto; Pablo Rojo Conejo; Antoni Soriano-Arandes; Manuel Battegay; Roger Kouyos; Pat Tookey; Jordi Casabona; Jose M. Miró; Deborah Konopnick; Tessa Goetghebuer; Anders Sönnerborg; Carlo Torti; Ramon Teira; Myriam Garrido; David Haerry; Jose Ma Miró; Dominique Costagliola; Antonella D'Arminio-Monforte; Dorthe Raben; Geneviève Chêne; Diana Barger; Christine Schwimmer; Monique Termote; Maria Campbell; Casper M. Frederiksen; Nina Friis-Møller; Jesper Kjaer; Rikke Salbøl Brandt; Juan Berenguer; Julia Bohlius; Vincent Bouteloup; Alessandro Cozzi-Lepri; Mary Anne Davies; Maria Dorrucci; David Dunn; Matthias Egger; Hansjakob Furrer; Marguerite Guiguet; Valériane Leroy; Sara Lodi; Sophie Matheron; Susana Monge; Fumiyo Nakagawa; Roger Paredes; Andrew Phillips; Massimo Puoti; Eliane Rohner; Michael Schomaker; Colette Smit; Jonathan Sterne; Rodolphe Thiebaut

doi:10.1371/journal.pone.0173893

Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers

Fanny Chereau, Yoann Madec, Caroline Sabin, Niels Obel, Ezequiel Ruiz-Mateos, Georgios Chrysos, Sarah Fidler, Clara Lehmann, Robert Zangerle, Linda Wittkop, Peter Reiss, Osamah Hamouda, Vicente Estrada Perez, Manuel Leal, Amanda Mocroft, Patricia Garcia De Olalla, Adriana Ammassari, Antonella D.Arminio Monforte, Cristina Mussini, Ferran SeguraAntonella Castagna, Matthias Cavassini, Sophie Grabar, Philippe Morlat, Stéphane De Wit, Olivier Lambotte, Laurence Meyer, Ali Judd, Giota Touloumi, Josiane Warszawski, François Dabis, Murielle Mary Krause, Jade Ghosn, Catherine Leport, Ferdinand Wit, Maria Prins, Heiner Bucher, Diana Gibb, Gerd Fätkenheuer, Julia Del Amo, Claire Thorne, Ole Kirk, Christoph Stephan, Santiago Pérez-Hoyos, Barbara Bartmeyer, Nikoloz Chkhartishvili, Antoni Noguera-Julian, Andrea Antinori, Norbert Brockmeyer, Luis Prieto, Pablo Rojo Conejo, Antoni Soriano-Arandes, Manuel Battegay, Roger Kouyos, Pat Tookey, Jordi Casabona, Jose M. Miró, Deborah Konopnick, Tessa Goetghebuer, Anders Sönnerborg, Carlo Torti, Ramon Teira, Myriam Garrido, David Haerry, Jose Ma Miró, Dominique Costagliola, Antonella D'Arminio-Monforte, Dorthe Raben, Geneviève Chêne, Diana Barger, Christine Schwimmer, Monique Termote, Maria Campbell, Casper M. Frederiksen, Nina Friis-Møller, Jesper Kjaer, Rikke Salbøl Brandt, Juan Berenguer, Julia Bohlius, Vincent Bouteloup, Alessandro Cozzi-Lepri, Mary Anne Davies, Maria Dorrucci, David Dunn, Matthias Egger, Hansjakob Furrer, Marguerite Guiguet, Valériane Leroy, Sara Lodi, Sophie Matheron, Susana Monge, Fumiyo Nakagawa, Roger Paredes, Andrew Phillips, Massimo Puoti, Eliane Rohner, Michael Schomaker, Colette Smit, Jonathan Sterne, Rodolphe Thiebaut

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Abstract

© 2017 Chereau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective: HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control. Methods: HICs were identified in COHERE on the basis of ≥5 consecutive viral loads (VL) ≤500 copies/mL over ≥1 year whilst ART-naive, with the last VL ≤500 copies/mL measured ≥5 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL >2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models. Results: We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds. Discussion: Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs.

Original language	English
Article number	e0173893
Journal	PLoS ONE
Volume	12
Issue number	4
DOIs	https://doi.org/10.1371/journal.pone.0173893
Publication status	Published - 1 Apr 2017

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10.1371/journal.pone.0173893

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Chereau, F., Madec, Y., Sabin, C., Obel, N., Ruiz-Mateos, E., Chrysos, G., Fidler, S., Lehmann, C., Zangerle, R., Wittkop, L., Reiss, P., Hamouda, O., Perez, V. E., Leal, M., Mocroft, A., De Olalla, P. G., Ammassari, A., Monforte, A. D. A., Mussini, C., ... Thiebaut, R. (2017). Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers. PLoS ONE, 12(4), [e0173893]. https://doi.org/10.1371/journal.pone.0173893

@article{b7f6fbde1e214836bce209cf1c82645b,

title = "Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers",

abstract = "{\textcopyright} 2017 Chereau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective: HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control. Methods: HICs were identified in COHERE on the basis of ≥5 consecutive viral loads (VL) ≤500 copies/mL over ≥1 year whilst ART-naive, with the last VL ≤500 copies/mL measured ≥5 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL >2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models. Results: We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds. Discussion: Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs.",

author = "Fanny Chereau and Yoann Madec and Caroline Sabin and Niels Obel and Ezequiel Ruiz-Mateos and Georgios Chrysos and Sarah Fidler and Clara Lehmann and Robert Zangerle and Linda Wittkop and Peter Reiss and Osamah Hamouda and Perez, {Vicente Estrada} and Manuel Leal and Amanda Mocroft and {De Olalla}, {Patricia Garcia} and Adriana Ammassari and Monforte, {Antonella D.Arminio} and Cristina Mussini and Ferran Segura and Antonella Castagna and Matthias Cavassini and Sophie Grabar and Philippe Morlat and {De Wit}, St{\'e}phane and Olivier Lambotte and Laurence Meyer and Ali Judd and Giota Touloumi and Josiane Warszawski and Fran{\c c}ois Dabis and Krause, {Murielle Mary} and Jade Ghosn and Catherine Leport and Ferdinand Wit and Maria Prins and Heiner Bucher and Diana Gibb and Gerd F{\"a}tkenheuer and {Del Amo}, Julia and Claire Thorne and Ole Kirk and Christoph Stephan and Santiago P{\'e}rez-Hoyos and Barbara Bartmeyer and Nikoloz Chkhartishvili and Antoni Noguera-Julian and Andrea Antinori and Norbert Brockmeyer and Luis Prieto and Conejo, {Pablo Rojo} and Antoni Soriano-Arandes and Manuel Battegay and Roger Kouyos and Pat Tookey and Jordi Casabona and Mir{\'o}, {Jose M.} and Deborah Konopnick and Tessa Goetghebuer and Anders S{\"o}nnerborg and Carlo Torti and Ramon Teira and Myriam Garrido and David Haerry and Mir{\'o}, {Jose Ma} and Dominique Costagliola and Antonella D'Arminio-Monforte and Dorthe Raben and Genevi{\`e}ve Ch{\^e}ne and Diana Barger and Christine Schwimmer and Monique Termote and Maria Campbell and Frederiksen, {Casper M.} and Nina Friis-M{\o}ller and Jesper Kjaer and Brandt, {Rikke Salb{\o}l} and Juan Berenguer and Julia Bohlius and Vincent Bouteloup and Alessandro Cozzi-Lepri and Davies, {Mary Anne} and Maria Dorrucci and David Dunn and Matthias Egger and Hansjakob Furrer and Marguerite Guiguet and Val{\'e}riane Leroy and Sara Lodi and Sophie Matheron and Susana Monge and Fumiyo Nakagawa and Roger Paredes and Andrew Phillips and Massimo Puoti and Eliane Rohner and Michael Schomaker and Colette Smit and Jonathan Sterne and Rodolphe Thiebaut",

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Chereau, F, Madec, Y, Sabin, C, Obel, N, Ruiz-Mateos, E, Chrysos, G, Fidler, S, Lehmann, C, Zangerle, R, Wittkop, L, Reiss, P, Hamouda, O, Perez, VE, Leal, M, Mocroft, A, De Olalla, PG, Ammassari, A, Monforte, ADA, Mussini, C, Segura, F, Castagna, A, Cavassini, M, Grabar, S, Morlat, P, De Wit, S, Lambotte, O, Meyer, L, Judd, A, Touloumi, G, Warszawski, J, Dabis, F, Krause, MM, Ghosn, J, Leport, C, Wit, F, Prins, M, Bucher, H, Gibb, D, Fätkenheuer, G, Del Amo, J, Thorne, C, Kirk, O, Stephan, C, Pérez-Hoyos, S, Bartmeyer, B, Chkhartishvili, N, Noguera-Julian, A, Antinori, A, Brockmeyer, N, Prieto, L, Conejo, PR, Soriano-Arandes, A, Battegay, M, Kouyos, R, Tookey, P, Casabona, J, Miró, JM, Konopnick, D, Goetghebuer, T, Sönnerborg, A, Torti, C, Teira, R, Garrido, M, Haerry, D, Miró, JM, Costagliola, D, D'Arminio-Monforte, A, Raben, D, Chêne, G, Barger, D, Schwimmer, C, Termote, M, Campbell, M, Frederiksen, CM, Friis-Møller, N, Kjaer, J, Brandt, RS, Berenguer, J, Bohlius, J, Bouteloup, V, Cozzi-Lepri, A, Davies, MA, Dorrucci, M, Dunn, D, Egger, M, Furrer, H, Guiguet, M, Leroy, V, Lodi, S, Matheron, S, Monge, S, Nakagawa, F, Paredes, R, Phillips, A, Puoti, M, Rohner, E, Schomaker, M, Smit, C, Sterne, J & Thiebaut, R 2017, 'Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers', PLoS ONE, vol. 12, no. 4, e0173893. https://doi.org/10.1371/journal.pone.0173893

TY - JOUR

T1 - Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers

AU - Chereau, Fanny

AU - Madec, Yoann

AU - Sabin, Caroline

AU - Obel, Niels

AU - Ruiz-Mateos, Ezequiel

AU - Chrysos, Georgios

AU - Fidler, Sarah

AU - Lehmann, Clara

AU - Zangerle, Robert

AU - Wittkop, Linda

AU - Reiss, Peter

AU - Hamouda, Osamah

AU - Perez, Vicente Estrada

AU - Leal, Manuel

AU - Mocroft, Amanda

AU - De Olalla, Patricia Garcia

AU - Ammassari, Adriana

AU - Monforte, Antonella D.Arminio

AU - Mussini, Cristina

AU - Segura, Ferran

AU - Castagna, Antonella

AU - Cavassini, Matthias

AU - Grabar, Sophie

AU - Morlat, Philippe

AU - De Wit, Stéphane

AU - Lambotte, Olivier

AU - Meyer, Laurence

AU - Judd, Ali

AU - Touloumi, Giota

AU - Warszawski, Josiane

AU - Dabis, François

AU - Krause, Murielle Mary

AU - Ghosn, Jade

AU - Leport, Catherine

AU - Wit, Ferdinand

AU - Prins, Maria

AU - Bucher, Heiner

AU - Gibb, Diana

AU - Fätkenheuer, Gerd

AU - Del Amo, Julia

AU - Thorne, Claire

AU - Kirk, Ole

AU - Stephan, Christoph

AU - Pérez-Hoyos, Santiago

AU - Bartmeyer, Barbara

AU - Chkhartishvili, Nikoloz

AU - Noguera-Julian, Antoni

AU - Antinori, Andrea

AU - Brockmeyer, Norbert

AU - Prieto, Luis

AU - Conejo, Pablo Rojo

AU - Soriano-Arandes, Antoni

AU - Battegay, Manuel

AU - Kouyos, Roger

AU - Tookey, Pat

AU - Casabona, Jordi

AU - Miró, Jose M.

AU - Konopnick, Deborah

AU - Goetghebuer, Tessa

AU - Sönnerborg, Anders

AU - Torti, Carlo

AU - Teira, Ramon

AU - Garrido, Myriam

AU - Haerry, David

AU - Miró, Jose Ma

AU - Costagliola, Dominique

AU - D'Arminio-Monforte, Antonella

AU - Raben, Dorthe

AU - Chêne, Geneviève

AU - Barger, Diana

AU - Schwimmer, Christine

AU - Termote, Monique

AU - Campbell, Maria

AU - Frederiksen, Casper M.

AU - Friis-Møller, Nina

AU - Kjaer, Jesper

AU - Brandt, Rikke Salbøl

AU - Berenguer, Juan

AU - Bohlius, Julia

AU - Bouteloup, Vincent

AU - Cozzi-Lepri, Alessandro

AU - Davies, Mary Anne

AU - Dorrucci, Maria

AU - Dunn, David

AU - Egger, Matthias

AU - Furrer, Hansjakob

AU - Guiguet, Marguerite

AU - Leroy, Valériane

AU - Lodi, Sara

AU - Matheron, Sophie

AU - Monge, Susana

AU - Nakagawa, Fumiyo

AU - Paredes, Roger

AU - Phillips, Andrew

AU - Puoti, Massimo

AU - Rohner, Eliane

AU - Schomaker, Michael

AU - Smit, Colette

AU - Sterne, Jonathan

AU - Thiebaut, Rodolphe

PY - 2017/4/1

Y1 - 2017/4/1

N2 - © 2017 Chereau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective: HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control. Methods: HICs were identified in COHERE on the basis of ≥5 consecutive viral loads (VL) ≤500 copies/mL over ≥1 year whilst ART-naive, with the last VL ≤500 copies/mL measured ≥5 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL >2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models. Results: We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds. Discussion: Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs.

AB - © 2017 Chereau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective: HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control. Methods: HICs were identified in COHERE on the basis of ≥5 consecutive viral loads (VL) ≤500 copies/mL over ≥1 year whilst ART-naive, with the last VL ≤500 copies/mL measured ≥5 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL >2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models. Results: We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds. Discussion: Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs.

U2 - 10.1371/journal.pone.0173893

DO - 10.1371/journal.pone.0173893

M3 - Article

VL - 12

IS - 4

M1 - e0173893

ER -

Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers

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