Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients with HIV previously receiving episodic therapy

A randomized trial

The SMART Study Group

Research output: Contribution to journalArticleResearchpeer-review

114 Citations (Scopus)

Abstract

Background: Episodic use of antiretroviral therapy guided by CD4 + cell counts is inferior to continuous antiretroviral therapy. Objective: To determine whether reinitiating continuous antiretroviral therapy in patients who received episodic treatment reduces excess risk for opportunistic disease or death. Design: Randomized, controlled trial. Setting: Sites in 33 countries. Patients: 5472 HIV-infected individuals with CD4 + cell counts greater than 0.350 × 109 cells/L enrolled from January 2002 to January 2006. Intervention: Episodic or continuous antiretroviral therapy initially, followed by continuous therapy in participants previously assigned to episodic treatment. Measurements: Opportunistic disease or death was the primary outcome. Results: Eighteen months after the recommendation to reinitiate continuous therapy, mean CD4+ cell counts were 0.152 × 109 cells/L (95% CI, 0.136 to 0.167 × 109 cells/L) less in participants previously assigned to episodic treatment (P < 0.001). The proportion of follow-up time spent with CD4+ cell counts of 0.500 × 109 cells/L or more and HIV RNA levels of 400 copies/mL or less was 29% for participants initially assigned to episodic therapy and 66% for those assigned to continuous therapy. Participants who reinitiated continuous therapy experienced rapid suppression of HIV RNA levels (89.7% with HIV RNA levels ≤400 copies/mL after 6 months), but CD4+ cell counts after 6 months remained 0.140 × 10 9 cells/L below baseline. The hazard ratio (episodic versus continuous treatment) for opportunistic disease or death decreased after the recommendation to reinitiate continuous therapy (from 2.5 [CI, 1.8 to 3.5] to 1.4 [CI, 1.0 to 2.0]; P = 0.033 for difference). The residual excess risk was attributable to failure to reinitiate therapy by some participants and slow recovery of CD4+ cell counts for those who reinitiated therapy. Limitation: Follow-up was too short to assess the full effect of switching from episodic to continuous antiretroviral therapy. Conclusion: Reinitiating continuous antiretroviral therapy in patients previously assigned to episodic treatment reduced excess risk for opportunistic disease or death, but excess risk remained. Episodic antiretroviral therapy, as used in the SMART study, should be avoided.

Original languageEnglish
Pages (from-to)289-299
Number of pages11
JournalAnnals of Internal Medicine
Volume149
Issue number5
DOIs
Publication statusPublished - 2 Sep 2008

Cite this

@article{d0e8fee3f5cb442b80922988ccc1356c,
title = "Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients with HIV previously receiving episodic therapy: A randomized trial",
abstract = "Background: Episodic use of antiretroviral therapy guided by CD4 + cell counts is inferior to continuous antiretroviral therapy. Objective: To determine whether reinitiating continuous antiretroviral therapy in patients who received episodic treatment reduces excess risk for opportunistic disease or death. Design: Randomized, controlled trial. Setting: Sites in 33 countries. Patients: 5472 HIV-infected individuals with CD4 + cell counts greater than 0.350 × 109 cells/L enrolled from January 2002 to January 2006. Intervention: Episodic or continuous antiretroviral therapy initially, followed by continuous therapy in participants previously assigned to episodic treatment. Measurements: Opportunistic disease or death was the primary outcome. Results: Eighteen months after the recommendation to reinitiate continuous therapy, mean CD4+ cell counts were 0.152 × 109 cells/L (95{\%} CI, 0.136 to 0.167 × 109 cells/L) less in participants previously assigned to episodic treatment (P < 0.001). The proportion of follow-up time spent with CD4+ cell counts of 0.500 × 109 cells/L or more and HIV RNA levels of 400 copies/mL or less was 29{\%} for participants initially assigned to episodic therapy and 66{\%} for those assigned to continuous therapy. Participants who reinitiated continuous therapy experienced rapid suppression of HIV RNA levels (89.7{\%} with HIV RNA levels ≤400 copies/mL after 6 months), but CD4+ cell counts after 6 months remained 0.140 × 10 9 cells/L below baseline. The hazard ratio (episodic versus continuous treatment) for opportunistic disease or death decreased after the recommendation to reinitiate continuous therapy (from 2.5 [CI, 1.8 to 3.5] to 1.4 [CI, 1.0 to 2.0]; P = 0.033 for difference). The residual excess risk was attributable to failure to reinitiate therapy by some participants and slow recovery of CD4+ cell counts for those who reinitiated therapy. Limitation: Follow-up was too short to assess the full effect of switching from episodic to continuous antiretroviral therapy. Conclusion: Reinitiating continuous antiretroviral therapy in patients previously assigned to episodic treatment reduced excess risk for opportunistic disease or death, but excess risk remained. Episodic antiretroviral therapy, as used in the SMART study, should be avoided.",
author = "El-Sadr, {W. M.} and B. Grund and Neaton, {J. D.} and J. Neuhaus and Cohen, {C. J.} and J. Darbyshire and A. Babiker and S. Emery and Lundgren, {J. D.} and A. Phillips and Jensen, {K. B.} and Gey, {D. C.} and L. Borup and M. Pearson and Jansson, {P. O.} and Jensen, {B. G.} and J. Tverland and H. Juncker-Benzon and Z. Fox and Phillips, {A. N.} and Babiker, {A. G.} and Palfreeman, {A. J.} and Fleck, {S. L.} and W. Dodds and E. King and B. Cordwell and {van Hooff}, F. and Y. Collaco-Moraes and Angus, {B. J.} and Cooper, {D. A.} and Drummond, {F. M.} and Connor, {S. A.} and Satchell, {C. S.} and S. Gunn and S. Oka and Delfino, {M. A.} and K. Merlin and C. McGinley and F. Gordin and E. Finley and D. Dietz and C. Chesson and M. Vjecha and B. Standridge and G. Bartsch and A. Duchene and M. George and M. Harrison and E. Krum and G. Larson and C. Miller and R. Nelson and Roediger, {M. P.} and T. Schultz and R. Prineas and C. Campbell and Zhang, {Z. M.} and G. Perez and A. Lifson and D. Duprez and J. Hoy and C. Lahart and D. Perlman and R. Price and F. Rhame and J. Sampson and J. Worley and M. Rein and R. Dersimonian and Brody, {B. A.} and Daar, {E. S.} and Dubler, {N. N.} and Fleming, {T. R.} and Freeman, {D. J.} and Kahn, {J. P.} and Kim, {K. M.} and G. Medoff and Modlin, {J. F.} and R. Moellering and Murray, {B. E.} and B. Pick and Robb, {M. L.} and Scharfstein, {D. O.} and J. Sugarman and A. Tsiatis and C. Tuazon and L. Zoloth and K. Klingman and S. Lehrman and J. Lazovski and Belloso, {W. H.} and Losso, {M. H.} and Benetucci, {J. A.} and S. Aquilia and V. Bittar and Bogdanowicz, {E. P.} and Cahn, {P. E.} and Casir{\'o}, {A. D.} and I. Cassetti and Contarelli, {J. M.} and Corral, {J. A.} and A. Crinejo and L. Daciuk and David, {D. O.} and G. Guaragna and Ishida, {M. T.} and A. Krolewiecki and Laplume, {H. E.} and Lasala, {M. B.} and L. Lourtau and Lupo, {S. H.} and A. Maranzana and F. Masciottra and M. Michaan and L. Ruggieri and E. Salazar and M. S{\'a}nchez and C. Somenzini and J. Hoy and Rogers, {G. D.} and Allworth, {A. M.} and Anderson, {J. St C.} and J. Armishaw and K. Barnes and A. Carr and A. Chiam and Chuah, {J. C.P.} and Curry, {M. C.} and Dever, {R. L.} and Donohue, {W. A.} and Doong, {N. C.} and Dwyer, {D. E.} and J. Dyer and B. Eu and Ferguson, {V. W.} and French, {M. A.H.} and Garsia, {R. J.} and J. Gold and Hudson, {J. H.} and S. Jeganathan and P. Konecny and J. Leung and McCormack, {C. L.} and M. Mc-Murchie and N. Medland and Moore, {R. J.} and Moussa, {M. B.} and D. Orth and M. Piper and T. Read and Roney, {J. J.} and N. Roth and Shaw, {D. R.} and J. Silvers and Smith, {D. J.} and Street, {A. C.} and Vale, {R. J.} and Wendt, {N. A.} and H. Wood and Youds, {D. W.} and J. Zillman and A. Rieger and V. Tozeau and A. Aichelburg and N. Vetter and N. Clumeck and S. Dewit and {de Roo}, A. and K. Kabeya and P. Leonard and L. Lynen and M. Moutschen and E. O’doherty and Pereira, {L. C.} and Souza, {T. N.L.} and M. Schechter and R. Zajdenverg and Almeida, {M. M.T.B.} and F. Araujo and F. Bahia and C. Brites and Caseiro, {M. M.} and J. Casseb and A. Etzel and Falco, {G. G.} and Filho, {E. C.J.} and Flint, {S. R.} and Gonzales, {C. R.} and Madruga, {J. V.R.} and Passos, {L. N.} and T. Reuter and Sidi, {L. C.} and Toscano, {A. L.C.} and D. Zarowny and E. Cherban and J. Cohen and B. Conway and C. Dufour and M. Ellis and A. Foster and D. Haase and H. Haldane and M. Houde and C. Kato and M. Klein and B. Lessard and A. Martel and C. Martel and N. McFarland and E. Paradis and A. Piche and R. Sandre and W. Schlech and S. Schmidt and F. Smaill and B. Thompson and S. Trottier and S. Vezina and S. Walmsley and {Wolff Reyes}, {M. J.} and R. Northland and L. Ostergaard and C. Pedersen and H. Nielsen and L. Hergens and Loftheim, {I. R.} and M. Raukas and K. Zilmer and J. Justinen and M. Ristola and Girard, {P. M.} and R. Landman and S. Abel and S. Abgrall and K. Amat and L. Auperin and R. Barruet and A. Benalycherif and N. Benammar and M. Bensalem and M. Bentata and Besnier, {J. M.} and M. Blanc and O. Bouchaud and A. Cabi{\'e} and P. Chavannet and Chennebault, {J. M.} and S. Dargere and {de la Tribonniere}, X. and T. Debord and {The SMART Study Group}",
year = "2008",
month = "9",
day = "2",
doi = "10.7326/0003-4819-149-5-200809020-00003",
language = "English",
volume = "149",
pages = "289--299",
journal = "Annals of Internal Medicine",
issn = "0003-4819",
publisher = "American College of Physicians",
number = "5",

}

Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients with HIV previously receiving episodic therapy : A randomized trial. / The SMART Study Group.

In: Annals of Internal Medicine, Vol. 149, No. 5, 02.09.2008, p. 289-299.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients with HIV previously receiving episodic therapy

T2 - A randomized trial

AU - El-Sadr, W. M.

AU - Grund, B.

AU - Neaton, J. D.

AU - Neuhaus, J.

AU - Cohen, C. J.

AU - Darbyshire, J.

AU - Babiker, A.

AU - Emery, S.

AU - Lundgren, J. D.

AU - Phillips, A.

AU - Jensen, K. B.

AU - Gey, D. C.

AU - Borup, L.

AU - Pearson, M.

AU - Jansson, P. O.

AU - Jensen, B. G.

AU - Tverland, J.

AU - Juncker-Benzon, H.

AU - Fox, Z.

AU - Phillips, A. N.

AU - Babiker, A. G.

AU - Palfreeman, A. J.

AU - Fleck, S. L.

AU - Dodds, W.

AU - King, E.

AU - Cordwell, B.

AU - van Hooff, F.

AU - Collaco-Moraes, Y.

AU - Angus, B. J.

AU - Cooper, D. A.

AU - Drummond, F. M.

AU - Connor, S. A.

AU - Satchell, C. S.

AU - Gunn, S.

AU - Oka, S.

AU - Delfino, M. A.

AU - Merlin, K.

AU - McGinley, C.

AU - Gordin, F.

AU - Finley, E.

AU - Dietz, D.

AU - Chesson, C.

AU - Vjecha, M.

AU - Standridge, B.

AU - Bartsch, G.

AU - Duchene, A.

AU - George, M.

AU - Harrison, M.

AU - Krum, E.

AU - Larson, G.

AU - Miller, C.

AU - Nelson, R.

AU - Roediger, M. P.

AU - Schultz, T.

AU - Prineas, R.

AU - Campbell, C.

AU - Zhang, Z. M.

AU - Perez, G.

AU - Lifson, A.

AU - Duprez, D.

AU - Hoy, J.

AU - Lahart, C.

AU - Perlman, D.

AU - Price, R.

AU - Rhame, F.

AU - Sampson, J.

AU - Worley, J.

AU - Rein, M.

AU - Dersimonian, R.

AU - Brody, B. A.

AU - Daar, E. S.

AU - Dubler, N. N.

AU - Fleming, T. R.

AU - Freeman, D. J.

AU - Kahn, J. P.

AU - Kim, K. M.

AU - Medoff, G.

AU - Modlin, J. F.

AU - Moellering, R.

AU - Murray, B. E.

AU - Pick, B.

AU - Robb, M. L.

AU - Scharfstein, D. O.

AU - Sugarman, J.

AU - Tsiatis, A.

AU - Tuazon, C.

AU - Zoloth, L.

AU - Klingman, K.

AU - Lehrman, S.

AU - Lazovski, J.

AU - Belloso, W. H.

AU - Losso, M. H.

AU - Benetucci, J. A.

AU - Aquilia, S.

AU - Bittar, V.

AU - Bogdanowicz, E. P.

AU - Cahn, P. E.

AU - Casiró, A. D.

AU - Cassetti, I.

AU - Contarelli, J. M.

AU - Corral, J. A.

AU - Crinejo, A.

AU - Daciuk, L.

AU - David, D. O.

AU - Guaragna, G.

AU - Ishida, M. T.

AU - Krolewiecki, A.

AU - Laplume, H. E.

AU - Lasala, M. B.

AU - Lourtau, L.

AU - Lupo, S. H.

AU - Maranzana, A.

AU - Masciottra, F.

AU - Michaan, M.

AU - Ruggieri, L.

AU - Salazar, E.

AU - Sánchez, M.

AU - Somenzini, C.

AU - Hoy, J.

AU - Rogers, G. D.

AU - Allworth, A. M.

AU - Anderson, J. St C.

AU - Armishaw, J.

AU - Barnes, K.

AU - Carr, A.

AU - Chiam, A.

AU - Chuah, J. C.P.

AU - Curry, M. C.

AU - Dever, R. L.

AU - Donohue, W. A.

AU - Doong, N. C.

AU - Dwyer, D. E.

AU - Dyer, J.

AU - Eu, B.

AU - Ferguson, V. W.

AU - French, M. A.H.

AU - Garsia, R. J.

AU - Gold, J.

AU - Hudson, J. H.

AU - Jeganathan, S.

AU - Konecny, P.

AU - Leung, J.

AU - McCormack, C. L.

AU - Mc-Murchie, M.

AU - Medland, N.

AU - Moore, R. J.

AU - Moussa, M. B.

AU - Orth, D.

AU - Piper, M.

AU - Read, T.

AU - Roney, J. J.

AU - Roth, N.

AU - Shaw, D. R.

AU - Silvers, J.

AU - Smith, D. J.

AU - Street, A. C.

AU - Vale, R. J.

AU - Wendt, N. A.

AU - Wood, H.

AU - Youds, D. W.

AU - Zillman, J.

AU - Rieger, A.

AU - Tozeau, V.

AU - Aichelburg, A.

AU - Vetter, N.

AU - Clumeck, N.

AU - Dewit, S.

AU - de Roo, A.

AU - Kabeya, K.

AU - Leonard, P.

AU - Lynen, L.

AU - Moutschen, M.

AU - O’doherty, E.

AU - Pereira, L. C.

AU - Souza, T. N.L.

AU - Schechter, M.

AU - Zajdenverg, R.

AU - Almeida, M. M.T.B.

AU - Araujo, F.

AU - Bahia, F.

AU - Brites, C.

AU - Caseiro, M. M.

AU - Casseb, J.

AU - Etzel, A.

AU - Falco, G. G.

AU - Filho, E. C.J.

AU - Flint, S. R.

AU - Gonzales, C. R.

AU - Madruga, J. V.R.

AU - Passos, L. N.

AU - Reuter, T.

AU - Sidi, L. C.

AU - Toscano, A. L.C.

AU - Zarowny, D.

AU - Cherban, E.

AU - Cohen, J.

AU - Conway, B.

AU - Dufour, C.

AU - Ellis, M.

AU - Foster, A.

AU - Haase, D.

AU - Haldane, H.

AU - Houde, M.

AU - Kato, C.

AU - Klein, M.

AU - Lessard, B.

AU - Martel, A.

AU - Martel, C.

AU - McFarland, N.

AU - Paradis, E.

AU - Piche, A.

AU - Sandre, R.

AU - Schlech, W.

AU - Schmidt, S.

AU - Smaill, F.

AU - Thompson, B.

AU - Trottier, S.

AU - Vezina, S.

AU - Walmsley, S.

AU - Wolff Reyes, M. J.

AU - Northland, R.

AU - Ostergaard, L.

AU - Pedersen, C.

AU - Nielsen, H.

AU - Hergens, L.

AU - Loftheim, I. R.

AU - Raukas, M.

AU - Zilmer, K.

AU - Justinen, J.

AU - Ristola, M.

AU - Girard, P. M.

AU - Landman, R.

AU - Abel, S.

AU - Abgrall, S.

AU - Amat, K.

AU - Auperin, L.

AU - Barruet, R.

AU - Benalycherif, A.

AU - Benammar, N.

AU - Bensalem, M.

AU - Bentata, M.

AU - Besnier, J. M.

AU - Blanc, M.

AU - Bouchaud, O.

AU - Cabié, A.

AU - Chavannet, P.

AU - Chennebault, J. M.

AU - Dargere, S.

AU - de la Tribonniere, X.

AU - Debord, T.

AU - The SMART Study Group

PY - 2008/9/2

Y1 - 2008/9/2

N2 - Background: Episodic use of antiretroviral therapy guided by CD4 + cell counts is inferior to continuous antiretroviral therapy. Objective: To determine whether reinitiating continuous antiretroviral therapy in patients who received episodic treatment reduces excess risk for opportunistic disease or death. Design: Randomized, controlled trial. Setting: Sites in 33 countries. Patients: 5472 HIV-infected individuals with CD4 + cell counts greater than 0.350 × 109 cells/L enrolled from January 2002 to January 2006. Intervention: Episodic or continuous antiretroviral therapy initially, followed by continuous therapy in participants previously assigned to episodic treatment. Measurements: Opportunistic disease or death was the primary outcome. Results: Eighteen months after the recommendation to reinitiate continuous therapy, mean CD4+ cell counts were 0.152 × 109 cells/L (95% CI, 0.136 to 0.167 × 109 cells/L) less in participants previously assigned to episodic treatment (P < 0.001). The proportion of follow-up time spent with CD4+ cell counts of 0.500 × 109 cells/L or more and HIV RNA levels of 400 copies/mL or less was 29% for participants initially assigned to episodic therapy and 66% for those assigned to continuous therapy. Participants who reinitiated continuous therapy experienced rapid suppression of HIV RNA levels (89.7% with HIV RNA levels ≤400 copies/mL after 6 months), but CD4+ cell counts after 6 months remained 0.140 × 10 9 cells/L below baseline. The hazard ratio (episodic versus continuous treatment) for opportunistic disease or death decreased after the recommendation to reinitiate continuous therapy (from 2.5 [CI, 1.8 to 3.5] to 1.4 [CI, 1.0 to 2.0]; P = 0.033 for difference). The residual excess risk was attributable to failure to reinitiate therapy by some participants and slow recovery of CD4+ cell counts for those who reinitiated therapy. Limitation: Follow-up was too short to assess the full effect of switching from episodic to continuous antiretroviral therapy. Conclusion: Reinitiating continuous antiretroviral therapy in patients previously assigned to episodic treatment reduced excess risk for opportunistic disease or death, but excess risk remained. Episodic antiretroviral therapy, as used in the SMART study, should be avoided.

AB - Background: Episodic use of antiretroviral therapy guided by CD4 + cell counts is inferior to continuous antiretroviral therapy. Objective: To determine whether reinitiating continuous antiretroviral therapy in patients who received episodic treatment reduces excess risk for opportunistic disease or death. Design: Randomized, controlled trial. Setting: Sites in 33 countries. Patients: 5472 HIV-infected individuals with CD4 + cell counts greater than 0.350 × 109 cells/L enrolled from January 2002 to January 2006. Intervention: Episodic or continuous antiretroviral therapy initially, followed by continuous therapy in participants previously assigned to episodic treatment. Measurements: Opportunistic disease or death was the primary outcome. Results: Eighteen months after the recommendation to reinitiate continuous therapy, mean CD4+ cell counts were 0.152 × 109 cells/L (95% CI, 0.136 to 0.167 × 109 cells/L) less in participants previously assigned to episodic treatment (P < 0.001). The proportion of follow-up time spent with CD4+ cell counts of 0.500 × 109 cells/L or more and HIV RNA levels of 400 copies/mL or less was 29% for participants initially assigned to episodic therapy and 66% for those assigned to continuous therapy. Participants who reinitiated continuous therapy experienced rapid suppression of HIV RNA levels (89.7% with HIV RNA levels ≤400 copies/mL after 6 months), but CD4+ cell counts after 6 months remained 0.140 × 10 9 cells/L below baseline. The hazard ratio (episodic versus continuous treatment) for opportunistic disease or death decreased after the recommendation to reinitiate continuous therapy (from 2.5 [CI, 1.8 to 3.5] to 1.4 [CI, 1.0 to 2.0]; P = 0.033 for difference). The residual excess risk was attributable to failure to reinitiate therapy by some participants and slow recovery of CD4+ cell counts for those who reinitiated therapy. Limitation: Follow-up was too short to assess the full effect of switching from episodic to continuous antiretroviral therapy. Conclusion: Reinitiating continuous antiretroviral therapy in patients previously assigned to episodic treatment reduced excess risk for opportunistic disease or death, but excess risk remained. Episodic antiretroviral therapy, as used in the SMART study, should be avoided.

UR - http://www.scopus.com/inward/record.url?scp=51049084622&partnerID=8YFLogxK

U2 - 10.7326/0003-4819-149-5-200809020-00003

DO - 10.7326/0003-4819-149-5-200809020-00003

M3 - Article

VL - 149

SP - 289

EP - 299

JO - Annals of Internal Medicine

JF - Annals of Internal Medicine

SN - 0003-4819

IS - 5

ER -