Clinical Trial

. 2013 Oct 23;8(10):e76582.

doi: 10.1371/journal.pone.0076582. eCollection 2013.

The immunological and virological consequences of planned treatment interruptions in children with HIV infection

Nigel Klein¹, Delali Sefe, Ilaria Mosconi, Marisa Zanchetta, Hannah Castro, Marianne Jacobsen, Hannah Jones, Stefania Bernardi, Deenan Pillay, Carlo Giaquinto, A Sarah Walker, Diana M Gibb, Anita De Rossi; Paediatric European Network for Treatment of AIDS 11 Trial Team

Collaborators, Affiliations

Collaborators

Paediatric European Network for Treatment of AIDS 11 Trial Team:
J-P Aboulker, J Ananworanich, A Babiker, E Belfrage, S Bernardi, S Blanche, A-B Bohlin, R Bologna, D M Burger, K Butler, G Castelli-Gattinara, H Castro, P Clayden, A Compagnucci, J H Darbyshire, M Debré, A Faye, R de Groot, M della Negra, D Duiculescu, C Giaquinto, D M Gibb, I Grosch-Wörner, M Hainault, L Harper, N Klein, M Lallemant, J Levy, H Lyall, M Marczynska, M Mardarescu, M J Mellado Peña, D Nadal, T Niehues, C Peckham, D Pillay, J T Ramos Amador, L Rosado, R Rosso, C Rudin, Y Saidi, H J Scherpbier, M Sharland, M Stevanovic, C Thorne, P A Tovo, G Tudor-Williams, N Valerius, A S Walker, S Welch, U Wintergerst, J-P Aboulker, A Babiker, D M Burger, A Compagnucci, J H Darbyshire, M Debré, C Giaquinto, D M Gibb, H Castro, L Harper, N Klein, M Lallemant, H Lyall, L Mofenson, J Moye, D Nadal, Y Saïdi, D M Burger, T R Cressey, E Jacqz-Aigrain, S Khoo, J M Tréluyer, A De Rossi, N Klein, J Moye, N Ngo-Giang-Huong, M A Muñoz Fernandez, D Pillay, C Hill, P Lepage, A Pozniak, S Vella, J-P Aboulker, A Compagnucci, G Hadjou, S Léonardo, Y Riault, Y Saïdi, A Babiker, L Buck, J H Darbyshire, L Farrelly, S Forcat, D M Gibb, H Castro, L Harper, L Harrison, J Horton, D Johnson, S Moore, C Taylor, A S Walker, S Chalermpantmetagul, T R Cressey, R Peongjakta, S Chailert, F Fregonese, G Jourdain, M Lallemant, N Ngo-Giang-Huong, D Butler, C Carlton, D Collins, G Kao, L Mofenson, J Moye, S Van Buskirk, S Watson, S Corradini, D Floret, T T Le Thi, F Monpoux, J Cottalorda, J C Lefebvre, S Mellul, N Boudjoudi, G Firtion, M Denon, F Picard, A Faye, D Beniken, F Damond, G Alexandre, J Tricoire, F Nicot, A Krivine, D Rivaux, M L Chaix, U Wintergerst, G Notheis, G Strotmann, S Schlieben, C Giaquinto, O Rampon, M Zanchetta, R Rosso, F Ginocchio, C Viscoli, G Castelli-Gattinara, S Bernardi, A Martino, G Pontrelli, C Concato, A Mazza, G Rossetti, M Marczynska, S Dobosz, A Oldakowska, J Popielska, M Kaflik, J Stanczak, G Stanczack, T Dyda, M I González Tomé, R Delgado García, M T Fernandez Gonzalez, M José Mellado Peña, P Martín-Fontelos, R Piñeiro Pérez, M Penin, I Garcia Mellado, A F Medina, B Ascencion, J T Ramos Amador, I Garcia Bermejo, J A Garcia Vela, I Martin Rubio, D Gurbindo, M L Navarro Gomez, J L Jimenez, M A Muñoz-Fernandez, A Garcia Torre, M I José Gómez, M C García Rodriguez, D Moreno Pérez, E Núñez Cuadros, F Asensi-Botet, A Pérez, M D Pérez Tamarit, M Gobernado Serrano, A Gonzales Molina, C Kalhert, D Nadal, M Dobrovoljac, C Berger, G Nobile, S Reinhard, J Schupbach, T Bunupuradah, J Ananworanich, T Puthanakit, C Pancharoen, O Butterworth, C Phasomsap, T Jupimai, S Ubolyam, P Phanuphak, Chiang Mai, S Kanjanavanit, T Namwong, D Chutima, M Raksasang, H Lyall, G Tudor-Williams, C Foster, D Hamadache, S Campbell, C Newbould, C Monrose, D Patel, S Kaye, H Lyall, P Seery, D Hamadache, A Wildfire, V Novelli, D M Gibb, N Klein, D Shingadia, K Moshal, J Flynn, M Clapson, L Farrelly, A Allen, L Spencer, M Depala, M Jacobsen, P McMaster, M Phipps, J Orendi, C Farmer, S Liebeschuetz, O Sodeinde, D Shingadia, S Wong, S Welch, Y Heath, S Scott, K Gandhi, P Lewis, J Daglish, D Pillay, L Weiner, M Famiglietti, S Rana, P Yu, J Roa, A Puga, A Haerry, A Inma

Affiliation

¹ Institute of Child Health, University College London, London, United Kingdom.

PMID: 24194841
PMCID: PMC3806774
DOI: 10.1371/journal.pone.0076582

Clinical Trial

The immunological and virological consequences of planned treatment interruptions in children with HIV infection

Nigel Klein et al. PLoS One. 2013.

. 2013 Oct 23;8(10):e76582.

doi: 10.1371/journal.pone.0076582. eCollection 2013.

Authors

Collaborators

Paediatric European Network for Treatment of AIDS 11 Trial Team:
J-P Aboulker, J Ananworanich, A Babiker, E Belfrage, S Bernardi, S Blanche, A-B Bohlin, R Bologna, D M Burger, K Butler, G Castelli-Gattinara, H Castro, P Clayden, A Compagnucci, J H Darbyshire, M Debré, A Faye, R de Groot, M della Negra, D Duiculescu, C Giaquinto, D M Gibb, I Grosch-Wörner, M Hainault, L Harper, N Klein, M Lallemant, J Levy, H Lyall, M Marczynska, M Mardarescu, M J Mellado Peña, D Nadal, T Niehues, C Peckham, D Pillay, J T Ramos Amador, L Rosado, R Rosso, C Rudin, Y Saidi, H J Scherpbier, M Sharland, M Stevanovic, C Thorne, P A Tovo, G Tudor-Williams, N Valerius, A S Walker, S Welch, U Wintergerst, J-P Aboulker, A Babiker, D M Burger, A Compagnucci, J H Darbyshire, M Debré, C Giaquinto, D M Gibb, H Castro, L Harper, N Klein, M Lallemant, H Lyall, L Mofenson, J Moye, D Nadal, Y Saïdi, D M Burger, T R Cressey, E Jacqz-Aigrain, S Khoo, J M Tréluyer, A De Rossi, N Klein, J Moye, N Ngo-Giang-Huong, M A Muñoz Fernandez, D Pillay, C Hill, P Lepage, A Pozniak, S Vella, J-P Aboulker, A Compagnucci, G Hadjou, S Léonardo, Y Riault, Y Saïdi, A Babiker, L Buck, J H Darbyshire, L Farrelly, S Forcat, D M Gibb, H Castro, L Harper, L Harrison, J Horton, D Johnson, S Moore, C Taylor, A S Walker, S Chalermpantmetagul, T R Cressey, R Peongjakta, S Chailert, F Fregonese, G Jourdain, M Lallemant, N Ngo-Giang-Huong, D Butler, C Carlton, D Collins, G Kao, L Mofenson, J Moye, S Van Buskirk, S Watson, S Corradini, D Floret, T T Le Thi, F Monpoux, J Cottalorda, J C Lefebvre, S Mellul, N Boudjoudi, G Firtion, M Denon, F Picard, A Faye, D Beniken, F Damond, G Alexandre, J Tricoire, F Nicot, A Krivine, D Rivaux, M L Chaix, U Wintergerst, G Notheis, G Strotmann, S Schlieben, C Giaquinto, O Rampon, M Zanchetta, R Rosso, F Ginocchio, C Viscoli, G Castelli-Gattinara, S Bernardi, A Martino, G Pontrelli, C Concato, A Mazza, G Rossetti, M Marczynska, S Dobosz, A Oldakowska, J Popielska, M Kaflik, J Stanczak, G Stanczack, T Dyda, M I González Tomé, R Delgado García, M T Fernandez Gonzalez, M José Mellado Peña, P Martín-Fontelos, R Piñeiro Pérez, M Penin, I Garcia Mellado, A F Medina, B Ascencion, J T Ramos Amador, I Garcia Bermejo, J A Garcia Vela, I Martin Rubio, D Gurbindo, M L Navarro Gomez, J L Jimenez, M A Muñoz-Fernandez, A Garcia Torre, M I José Gómez, M C García Rodriguez, D Moreno Pérez, E Núñez Cuadros, F Asensi-Botet, A Pérez, M D Pérez Tamarit, M Gobernado Serrano, A Gonzales Molina, C Kalhert, D Nadal, M Dobrovoljac, C Berger, G Nobile, S Reinhard, J Schupbach, T Bunupuradah, J Ananworanich, T Puthanakit, C Pancharoen, O Butterworth, C Phasomsap, T Jupimai, S Ubolyam, P Phanuphak, Chiang Mai, S Kanjanavanit, T Namwong, D Chutima, M Raksasang, H Lyall, G Tudor-Williams, C Foster, D Hamadache, S Campbell, C Newbould, C Monrose, D Patel, S Kaye, H Lyall, P Seery, D Hamadache, A Wildfire, V Novelli, D M Gibb, N Klein, D Shingadia, K Moshal, J Flynn, M Clapson, L Farrelly, A Allen, L Spencer, M Depala, M Jacobsen, P McMaster, M Phipps, J Orendi, C Farmer, S Liebeschuetz, O Sodeinde, D Shingadia, S Wong, S Welch, Y Heath, S Scott, K Gandhi, P Lewis, J Daglish, D Pillay, L Weiner, M Famiglietti, S Rana, P Yu, J Roa, A Puga, A Haerry, A Inma

Affiliation

¹ Institute of Child Health, University College London, London, United Kingdom.

PMID: 24194841
PMCID: PMC3806774
DOI: 10.1371/journal.pone.0076582

Abstract

Objectives: To evaluate the immunological and viral consequences of planned treatment interruptions (PTI) in children with HIV.

Design: This was an immunological and virological sub-study of the Paediatric European Network for Treatment of AIDS (PENTA) 11 trial, which compared CD4-guided PTI of antiretroviral therapy (ART) with continuous therapy (CT) in children.

Methods: HIV-1 RNA and lymphocyte subsets, including CD4 and CD8 cells, were quantified on fresh samples collected during the study; CD45RA, CD45RO and CD31 subpopulations were evaluated in some centres. For 36 (18 PTI, 18 CT) children, immunophenotyping was performed and cell-associated HIV-1 DNA analysed on stored samples to 48 weeks.

Results: In the PTI group, CD4 cell count fell rapidly in the first 12 weeks off ART, with decreases in both naïve and memory cells. However, the proportion of CD4 cells expressing CD45RA and CD45RO remained constant in both groups. The increase in CD8 cells in the first 12 weeks off ART in the PTI group was predominantly due to increases in RO-expressing cells. PTI was associated with a rapid and sustained increase in CD4 cells expressing Ki67 and HLA-DR, and increased levels of HIV-1 DNA.

Conclusions: PTI in children is associated with rapid changes in CD4 and CD8 cells, likely due to increased cell turnover and immune activation. However, children off treatment may be able to maintain stable levels of naïve CD4 cells, at least in proportion to the memory cell pool, which may in part explain the observed excellent CD4 cell recovery with re-introduction of ART.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

**Figure 1. Change in HIV-1 RNA, CD4 and CD8 cells from baseline in the PTI group.**
Change in HIV-1 RNA from baseline for all children in the trial in the PTI (planned treatment interruption) group off ART (antiretroviral therapy) and children in the substudy in the PTI group off ART (a). Change in CD4 and CD8 from baseline for all children in the trial in the PTI (planned treatment interruption) group off ART (antiretroviral therapy) and in the CT (continuous ART) group (b). Changes from baseline were estimated using normal regression of actual measurements adjusting for baseline using the overall mean at randomisation as the reference category.

**Figure 2. Changes in CD45RA, CD45RO and CD45A+CD31+ cells.**
Changes in absolute numbers of CD45RA cells (a), CD45RO cells (b) and CD4 RA and RO cells as a % of CD4 cells, for children in the trial where of CD4 sub-populations were evaluated (including the children in the substudy) (c). Change in CD45RA+ CD31+ cells from baseline for children in the substudy (d). CT = continuous ART (antiretroviral therapy), PTI = planned treatment interruption (off ART). Changes from baseline were estimated using normal regression of actual measurements adjusting for baseline using the overall mean at randomisation as the reference category.

**Figure 3. Change in CD8 RA and RO cells from baseline.**
Change in CD8 RA and RO cells from baseline for children in the substudy. CT = continuous ART (antiretroviral therapy), PTI = planned treatment interruption (off ART). Changes from baseline were estimated using normal regression of actual measurements adjusting for baseline using the overall mean at randomisation as the reference category.

**Figure 4. Change in % Ki67, HLA-DR and LPS from baseline.**
Change in % Ki67 (a) and % HLA-DR (b) in CD45RA- CD31- cells and in LPS (c) from baseline for children in the substudy. CT = continuous ART (antiretroviral therapy), PTI = planned treatment interruption (off ART). Changes from baseline were estimated using normal regression of actual measurements adjusting for baseline using the overall mean at randomisation as the reference category.

**Figure 5. Relative change in HIV DNA copies/10⁶ PBMC from baseline.**
Relative change in HIV DNA copies/10⁶ PBMC from baseline for children in the substudy. CT = continuous ART (antiretroviral therapy), PTI = planned treatment interruption (off ART), PBMC = peripheral blood mononuclear cells.

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References

1. Paediatric European Network for Treatment of AIDS (2010) Response to planned treatment interruptions in HIV infection varies across childhood. AIDS 24: 231–241. - PubMed
1. Bunupuradah T, Duong T, Compagnucci A, McMaster P, Bernardi S, et al, on behalf of the PENTA 11 Extension Study Group (2013) Outcomes after reinitiating antiretroviral therapy in children randomized to planned treatment interruptions in the PENTA 11 Study. AIDS 27: 579–589. - PubMed
1. Ananworanich J, Gayet-Ageron A, Le Braz M, Prasithsirikul W, Chetchotisakd P, et al. (2006) CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomised trial. Lancet 368: 459–465. - PubMed
1. Danel C, Moh R, Minga A, Anzian A, Ba-Gomis O, et al. (2006) CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet 367: 1981–9. - PubMed
1. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, et al (2006) CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 355: 2283–96. - PubMed

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The immunological and virological consequences of planned treatment interruptions in children with HIV infection

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The immunological and virological consequences of planned treatment interruptions in children with HIV infection

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Conflict of interest statement

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