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; HIV Controllers Project Working Group for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCOORD

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, HIV Controllers Project Working Group for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCOORD

Department of Clinical Medicine

16 Citations (Scopus)

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Abstract

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
Number of pages	16
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0173893
Publication status	Published - Apr 2017

Keywords

Adult
Anti-HIV Agents/therapeutic use
Antiretroviral Therapy, Highly Active/methods
CD4 Lymphocyte Count/methods
CD4-Positive T-Lymphocytes/drug effects
CD8-Positive T-Lymphocytes/drug effects
Female
HIV Infections/drug therapy
HIV-1/immunology
Humans
Male
Viral Load/drug effects
Viremia/drug therapy
Virus Replication/immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllersFinal published version, 1.15 MBLicence: CC BY

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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., Estrada Perez, V., Leal, M., Mocroft, A., Garcia De Olalla, P., Ammassari, A., D'Arminio Monforte, A., Mussini, C., ... HIV Controllers Project Working Group for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCOORD (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

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, Estrada Perez, V, Leal, M, Mocroft, A, Garcia De Olalla, P, Ammassari, A, D'Arminio Monforte, A, Mussini, C, Segura, F, Castagna, A, Cavassini, M, Grabar, S, Morlat, P, De Wit, S, Lambotte, O, Meyer, L & HIV Controllers Project Working Group for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCOORD 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

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abstract = "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.",

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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 {Estrada Perez}, Vicente and Manuel Leal and Amanda Mocroft and {Garcia De Olalla}, Patricia and Adriana Ammassari and {D'Arminio Monforte}, Antonella 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 {HIV Controllers Project Working Group for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCOORD}",

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doi = "10.1371/journal.pone.0173893",

language = "English",

volume = "12",

journal = "PLoS Computational Biology",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "4",

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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 - Estrada Perez, Vicente

AU - Leal, Manuel

AU - Mocroft, Amanda

AU - Garcia De Olalla, Patricia

AU - Ammassari, Adriana

AU - D'Arminio Monforte, Antonella

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 - HIV Controllers Project Working Group for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCOORD

PY - 2017/4

Y1 - 2017/4

N2 - 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 - 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.

KW - Adult

KW - Anti-HIV Agents/therapeutic use

KW - Antiretroviral Therapy, Highly Active/methods

KW - CD4 Lymphocyte Count/methods

KW - CD4-Positive T-Lymphocytes/drug effects

KW - CD8-Positive T-Lymphocytes/drug effects

KW - Female

KW - HIV Infections/drug therapy

KW - HIV-1/immunology

KW - Humans

KW - Male

KW - Viral Load/drug effects

KW - Viremia/drug therapy

KW - Virus Replication/immunology

U2 - 10.1371/journal.pone.0173893

DO - 10.1371/journal.pone.0173893

M3 - Journal article

C2 - 28380038

SN - 1932-6203

VL - 12

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 4

M1 - e0173893

ER -

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

Abstract

Keywords

UN SDGs

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