Plasma HIV viral rebound following protocol-indicated cessation of ART commenced in primary and chronic HIV infection

Elizabeth Hamlyn, Fiona M Ewings, Kholoud Porter, David A Cooper, Giuseppe Tambussi, Mauro Schechter, Court Pedersen, Jason F Okulicz, Myra McClure, Abdel Babiker, Jonathan Weber, Sarah Fidler, INSIGHT SMART and SPARTAC Investigators, A Breckenridge, P Clayden, C Conlon, F Conradie, J Kaldor, F Maggiolo, F Ssali, D A Cooper, P Kaleebu, G Ramjee, M Schechter, G Tambussi, J Weber, S Fidler, A Babiker, T Peto, A McLaren, V Beral, G Chene, J Hakim, A Babiker, K Porter, M Thomason, F Ewings, M Gabriel, D Johnson, K Thompson, A Cursley, K Donegan, E Fossey, P Kelleher, K Lee, B Murphy, D Nock, R Phillips, J Frater, L Ohm Laursen, N Robinson, P Goulder, H Brown, M McClure, D Bonsall, O Erlwein, A Helander, S Kaye, M Robinson, L Cook, G Adcock, P Ahmed, N Paton, S Fidler, A Kelleher, R Moore, R McFarlane, N Roth, R Finlayson, B Kiem Tee, T Read, M Kelly, N Doong, M Bloch, C Workman, P Grey, D A Cooper, A Kelleher, M Law, M Schechter, P Gama, M Mercon, M Barbosa de Souza, C Beppu Yoshida, J R Grangeiro da Silva, A Sampaio Amaral, D Fernandes de Aguiar, M de Fátima Melo, R Quaresma Garrido, G Tambussi, S Nozza, M Pogliaghi, S Chiappetta, L Della Torre, E Gasparotto, G D'Offizi, C Vlassi, A Corpolongo, R Wood, J Pitt, C Orrell, F Cilliers, R Croxford, K Middelkoop, L G Bekker, C Heiberg, J Aploon, N Killa, E Fielder, T Buhler, H Rees, F Venter, T Palanee, W Stevens, C Ingram, M Majam, M Papathanasopoulos, G Ramjee, S Gappoo, J Moodley, A Premrajh, L Zako, H Grosskurth, A Kamali, P Kaleebu, U Bahemuka, J Mugisha, H F Njaj, J M Miro, M López-Dieguez, C Manzardo, J A Arnaiz, T Pumarola, M Plana, M Tuset, M C Ligero, M T García, T Gallart, J M Gatell, M Fisher, K Hobbs, N Perry, D Pao, D Maitland, L Heald, F Mulcahy, G Courtney, S O'Dea, D Reidy, C Leen, G Scott, L Ellis, S Morris, P Simmonds, B Gazzard, D Hawkins, C Higgs, J Anderson, S Mguni, I Williams, N De Esteban, P Pellegrino, A Arenas-Pinto, D Cornforth, J Turner, J Ainsworth, A Waters, M Johnson, S Kinloch, A Carroll, P Byrne, Z Cuthbertson, C Orkin, J Hand, C De Souza, J Weber, S Fidler, E Hamlyn, E Thomson, J Fox, K Legg, S Mullaney, A Winston, S Wilson, P Ambrose, S Taylor, G Gilleran, S Keeling, A Becker, C Boocock, J D Lundgren, K B Jensen, D C Gey, L Borup, M Pearson, P O Jansson, B G Jensen, J Tverland, H Juncker-Benzon, Z Fox, A N Phillips, J H Darbyshire, A G Babiker, A J Palfreeman, S L Fleck, W Dodds, E King, B Cordwell, F van Hooff, Y Collaco-Moraes, B J Angus, D A Cooper, S Emery, F M Drummond, S A Connor, C S Satchell, S Gunn, S Oka, M A Delfino, K Merlin, C McGinley, F Gordin, E Finley, D Dietz, C Chesson, M Vjecha, B Standridge, J D Neaton, G Bartsch, A DuChene, M George, B Grund, M Harrison, E Krum, G Larson, C Miller, R Nelson, J Neuhaus, M P Roediger, T Schultz, R Prineas, C Campbell, Z M Zhang, G Perez, A Lifson, D Duprez, J Hoy, C Lahart, D Perlman, R Price, R Prineas, F Rhame, J Sampson, J Worley, M Rein, R DerSimonian, B A Brody, E S Daar, N N Dubler, T R Fleming, D J Freeman, J P Kahn, K M Kim, G Medoff, J F Modlin, R Moellering Jr, B E Murray, B Pick, M L Robb, D O Scharfstein, J Sugarman, A Tsiatis, C Tuazon, L Zoloth, K Klingman, Elizabeth Hamlyn, Fiona M Ewings, Kholoud Porter, David A Cooper, Giuseppe Tambussi, Mauro Schechter, Court Pedersen, Jason F Okulicz, Myra McClure, Abdel Babiker, Jonathan Weber, Sarah Fidler, INSIGHT SMART and SPARTAC Investigators, A Breckenridge, P Clayden, C Conlon, F Conradie, J Kaldor, F Maggiolo, F Ssali, D A Cooper, P Kaleebu, G Ramjee, M Schechter, G Tambussi, J Weber, S Fidler, A Babiker, T Peto, A McLaren, V Beral, G Chene, J Hakim, A Babiker, K Porter, M Thomason, F Ewings, M Gabriel, D Johnson, K Thompson, A Cursley, K Donegan, E Fossey, P Kelleher, K Lee, B Murphy, D Nock, R Phillips, J Frater, L Ohm Laursen, N Robinson, P Goulder, H Brown, M McClure, D Bonsall, O Erlwein, A Helander, S Kaye, M Robinson, L Cook, G Adcock, P Ahmed, N Paton, S Fidler, A Kelleher, R Moore, R McFarlane, N Roth, R Finlayson, B Kiem Tee, T Read, M Kelly, N Doong, M Bloch, C Workman, P Grey, D A Cooper, A Kelleher, M Law, M Schechter, P Gama, M Mercon, M Barbosa de Souza, C Beppu Yoshida, J R Grangeiro da Silva, A Sampaio Amaral, D Fernandes de Aguiar, M de Fátima Melo, R Quaresma Garrido, G Tambussi, S Nozza, M Pogliaghi, S Chiappetta, L Della Torre, E Gasparotto, G D'Offizi, C Vlassi, A Corpolongo, R Wood, J Pitt, C Orrell, F Cilliers, R Croxford, K Middelkoop, L G Bekker, C Heiberg, J Aploon, N Killa, E Fielder, T Buhler, H Rees, F Venter, T Palanee, W Stevens, C Ingram, M Majam, M Papathanasopoulos, G Ramjee, S Gappoo, J Moodley, A Premrajh, L Zako, H Grosskurth, A Kamali, P Kaleebu, U Bahemuka, J Mugisha, H F Njaj, J M Miro, M López-Dieguez, C Manzardo, J A Arnaiz, T Pumarola, M Plana, M Tuset, M C Ligero, M T García, T Gallart, J M Gatell, M Fisher, K Hobbs, N Perry, D Pao, D Maitland, L Heald, F Mulcahy, G Courtney, S O'Dea, D Reidy, C Leen, G Scott, L Ellis, S Morris, P Simmonds, B Gazzard, D Hawkins, C Higgs, J Anderson, S Mguni, I Williams, N De Esteban, P Pellegrino, A Arenas-Pinto, D Cornforth, J Turner, J Ainsworth, A Waters, M Johnson, S Kinloch, A Carroll, P Byrne, Z Cuthbertson, C Orkin, J Hand, C De Souza, J Weber, S Fidler, E Hamlyn, E Thomson, J Fox, K Legg, S Mullaney, A Winston, S Wilson, P Ambrose, S Taylor, G Gilleran, S Keeling, A Becker, C Boocock, J D Lundgren, K B Jensen, D C Gey, L Borup, M Pearson, P O Jansson, B G Jensen, J Tverland, H Juncker-Benzon, Z Fox, A N Phillips, J H Darbyshire, A G Babiker, A J Palfreeman, S L Fleck, W Dodds, E King, B Cordwell, F van Hooff, Y Collaco-Moraes, B J Angus, D A Cooper, S Emery, F M Drummond, S A Connor, C S Satchell, S Gunn, S Oka, M A Delfino, K Merlin, C McGinley, F Gordin, E Finley, D Dietz, C Chesson, M Vjecha, B Standridge, J D Neaton, G Bartsch, A DuChene, M George, B Grund, M Harrison, E Krum, G Larson, C Miller, R Nelson, J Neuhaus, M P Roediger, T Schultz, R Prineas, C Campbell, Z M Zhang, G Perez, A Lifson, D Duprez, J Hoy, C Lahart, D Perlman, R Price, R Prineas, F Rhame, J Sampson, J Worley, M Rein, R DerSimonian, B A Brody, E S Daar, N N Dubler, T R Fleming, D J Freeman, J P Kahn, K M Kim, G Medoff, J F Modlin, R Moellering Jr, B E Murray, B Pick, M L Robb, D O Scharfstein, J Sugarman, A Tsiatis, C Tuazon, L Zoloth, K Klingman

Abstract

Objectives: The magnitude of HIV viral rebound following ART cessation has consequences for clinical outcome and onward transmission. We compared plasma viral load (pVL) rebound after stopping ART initiated in primary (PHI) and chronic HIV infection (CHI).

Design: Two populations with protocol-indicated ART cessation from SPARTAC (PHI, n = 182) and SMART (CHI, n = 1450) trials.

Methods: Time for pVL to reach pre-ART levels after stopping ART was assessed in PHI using survival analysis. Differences in pVL between PHI and CHI populations 4 weeks after stopping ART were examined using linear and logistic regression. Differences in pVL slopes up to 48 weeks were examined using linear mixed models and viral burden was estimated through a time-averaged area-under-pVL curve. CHI participants were categorised by nadir CD4 at ART stop.

Results: Of 171 PHI participants, 71 (41.5%) rebounded to pre-ART pVL levels, at a median of 50 (95% CI 48-51) weeks after stopping ART. Four weeks after stopping treatment, although the proportion with pVL ≥ 400 copies/ml was similar (78% PHI versus 79% CHI), levels were 0.45 (95% CI 0.26-0.64) log(10) copies/ml lower for PHI versus CHI, and remained lower up to 48 weeks. Lower CD4 nadir in CHI was associated with higher pVL after ART stop. Rebound for CHI participants with CD4 nadir >500 cells/mm(3) was comparable to that experienced by PHI participants.

Conclusions: Stopping ART initiated in PHI and CHI was associated with viral rebound to levels conferring increased transmission risk, although the level of rebound was significantly lower and sustained in PHI compared to CHI.

Conflict of interest statement

Competing Interests: JO is a PLoS ONE Editorial Board member. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. No other conflict of interest is declared.

Figures

Figure 1. pVL after ART stop in…
Figure 1. pVL after ART stop in primary (PHI) and chronic HIV infection (CHI).
a. median (IQR) pVL up to 48 weeks after ART stop. b. predicted pVL over 4–48 weeks after ART stop, based on a representative participant (male infected through sex with men, aged 40 years and with CD4 count 600 cells/mm3 at ART stop; values in brackets are the 95% CI). CI = confidence intervals, IQR = interquartile range, pLV = plasma viral load.
Figure 2. pVL after ART stop in…
Figure 2. pVL after ART stop in primary (PHI) and chronic HIV infection (CHI), with CHI participants categorised by nadir CD4 count.
a. median (IQR) pVL up to 48 weeks after ART stop. b. predicted pVL over 4–48 weeks after ART stop, based on a representative participant (male infected through sex between men, aged 40 years and CD4 count 600 cells/mm3 at ART stop; values in brackets are the 95% CI). CI = confidence intervals, IQR = interquartile range, pLV = plasma viral load.

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