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Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients with HIV previously receiving episodic therapy: a randomized trial.
SMART Study Group, El-Sadr WM, Grund B, Neuhaus J, Babiker A, Cohen CJ, Darbyshire J, Emery S, Lundgren JD, Phillips A, Neaton JD.Collaborators (651)Lazovski J, Belloso WH, Losso MH, Benetucci JA, Aquilia S, Bittar V, Bogdanowicz EP, Cahn PE, Casiró AD, Cassetti I, Contarelli JM, Corral JA, Crinejo A, Daciuk L, David DO, Guaragna G, Ishida MT, Krolewiecki A, Laplume HE, Lasala MB, Lourtau L, Lupo SH, Maranzana A, Masciottra F, Michaan M, Ruggieri L, Salazar E, Sánchez M, Somenzini C, Hoy JF, Rogers GD, Allworth AM, Anderson JS, Armishaw J, K Barnes K, A Carr A, Chiam A, Chuah JC, Curry MC, Dever RL, Donohue WA, Doong NC, Dwyer DE, Dyer J, Eu B, Ferguson VW, French MA, Garsia RJ, Gold J, Hudson JH, Jeganathan S, Konecny P, Leung J, McCormack CL, Mc-Murchie M, Medland N, Moore R, Orth D, Piper M, Read T, Roney JJ, Roth N, Shaw DR, Silvers J, Smith DJ, Street AC, Vale RJ, Wendt NA, Wood H, Youds DW, Zillman J, Rieger A, Tozeau V, Aichelburg A, Vetter N, Clumeck N, Dewit S, de Roo A, Kabeya K, Leonard P, Lynen L, Moutschen M, O'Doherty E, Pereira LC Jr, Souza TN, Schechter M, Zajdenverg R, Almeida MM, Araujo F, Bahia F, Brites C, Caseiro MM, Casseb J, Etzel A, Falco GG, Filho EC, Flint SR, Gonzales CR, Madruga JV, Passos LN, Reuter T, Sidi LC, Toscano AL, Zarowny D, Cherban E, Cohen J, Conway B, Dufour C, Ellis M, Foster A, Haase D, Haldane H, Houde M, Kato C, Klein M, Lessard B, Martel A, Martel C, McFarland N, Paradis E, Piche A, Sandre R, Schlech W, Schmidt S, Smaill F, Thompson B, Trottier S, Vezina S, Walmsley S, Wolff Reyes MJ, Northland R, Ostergaard L, Pedersen C, Nielsen H, Hergens L, Loftheim IR, Jensen KB, Raukas M, Zilmer K, Justinen J, Ristola M, Girard PM, Landman R, Abel S, Abgrall S, Amat K, Auperin L, Barruet R, Benalycherif A, Benammar N, Bensalem M, Bentata M, Besnier JM, Blanc M, Bouchaud O, Cabié A, Chavannet P, Chennebault JM, Dargere S, de la Tribonniere X, Debord T, Decaux N, Delgado J, Dupon M, Durant J, Frixon-Marin V, Genet C, Gérard L, Gilquin J, Hoen B, Jeantils V, Kouadio H, Leclercq P, Michon CP, Nau P, Pacanowski J, Piketty C, Poizot-Martin I, Raymond I, Salmon D, Schmit JL, Serini MA, Simon A, Tassi S, Touam F, Verdon R, Weinbreck P, Weiss L, Yazdanpanah Y, Yeni P, Fätkenheuer G, Staszewski S, Bergmann F, Bitsch S, Bogner JR, Brockmeyer N, Esser S, Goebel FD, Hartmann M, Klinker H, Lehmann C, Lennemann T, Plettenberg A, Potthof A, Rockstroh J, Ross B, Stoehr A, Wasmuth JC, Wiedemeyer K, Winzer R, Hatzakis A, Touloumi G, Antoniadou A, Daikos GL, Dimitrakaki A, Gargalianos-Kakolyris P, Karafoulidou A, Katsambas A, Katsarou O, Kontos AN, Kordossis T, Lazanas MK, Panagopoulos P, Panos G, Paparizos V, Papastamopoulos V, Petrikkos G, Skoutelis A, Tsogas N, Xylomenos G, Bergin CJ, Mooka B, Pollack S, Mamorksy MG, Agmon-Levin N, Karplus R, Kedem E, Maayan S, Shahar E, Sthoeger Z, Turner D, Yust I, Tambussi G, Rusconi V, Abeli C, Bechi M, Biglino A, Butini L, Carosi G, Casari S, Corpolongo A, De Gioanni M, Di Pietro M, D'Offizi G, Esposito R, Mazzotta F, Montroni M, Nardini G, Nozza S, Quirino T, Raise E, Honda M, Ishisaka M, Caplinskas S, Uzdaviniene V, Schmit JC, Staub T, Himmich H, Marhoum El Filali K, Mills GD, Blackmore T, Masters JA, Morgan J, Pithie A, Brunn J, Ormasssen V, La Rosa A, Guerra O, Espichan M, Gutierrez L, Mendo F, Salazar R, Knytz B, Horban A, Bakowska E, Beniowski M, Gasiorowski J, Kwiatkowski J, Antunes F, Castro RS, Doroana M, Horta A, Mansinho K, Miranda AC, Pinto IV, Valadas E, Vera J, Rakhmanova A, Vinogradov E, Yakovlev A, Zakharova N, Wood R, Orrel C, Gatell J, Arnaiz JA, Carrillo R, Clotet B, Dalmau D, González A, Jordano Q, Jou A, Knobel H, Larrousse M, Mata R, Moreno JS, Oretaga E, Pena JN, Pulido F, Rubio R, Sanz J, Viciana P, Hirschel B, Spyche R, Battegay M, Bernasconi E, Bottone S, Cavassini M, Christen A, Franc C, Furrer HJ, Gayet-Ageron A, Genné D, Hochstrasser S, Magenta L, Moens C, Müller N, Nüesch R, Phanuphak P, Ruxrungtham K, Pumpradit W, Chetchotisakd P, Dangthongde S, Kiertiburanakul S, Klinbuayaem V, Klinbuayaem P, Nonenoy S, Piyavong B, Prasithsirikul W, Raksakulkarn P, Gazzard BG, Ainsworth JG, Anderson J, Barber TJ, Brook MG, Chadwick DR, Chikohora M, Churchill DR, Cornforth D, Easterbrook PJ, Fox PA, Fox R, Gomez PA, Gompels MM, Harris GM, Herman S, Jackson AG, Jebakumar SP, Johnson MA, Kinghorn GR, Kuldanek KA, Larbalestier N, Leen C, Lumsden M, Maher T, Mantell J, Maw R, McKernan S, McLean L, Morris S, Muromba L, Orkin CM, Palfreeman AJ, Peters BS, Peto TE, Portsmouth SD, Rajamanoharan S, Ronan A, Schwenk A, Slinn MA, Stroud CJ, Thomas RC, Wansbrough-Jones MH, Whiles HJ, Williams E, Williams IG, Youle M, Abrams DI, Acosta EA, Adams S, Adamski A, Andrews L, Antoniskis D, Aragon DR, Arduino R, Artz R, Bailowitz J, Barnett BJ, Baroni C, Barron M, Baxter JD, Beers D, Beilke M, Bemenderfer D, Bernard A, Besch CL, Bessesen MT, Bethel JT, Blue S, Blum JD, Boarden S, Bolan RK, Borgman JB, Brar I, Braxton BK, Bredeek UF, Brennan R, Britt DE, Brockelman J, Brown S, Bruzzese V, Bulgin-Coleman D, Bullock DE, Cafaro V, Campbell B, Caras S, Carroll J, Casey KK, Chiang F, Childress G, Cindrich RB, Clark C, Climo M, Cohen C, Coley J, Condoluci DV, Contreras R, Corser J, Cozzolino J, Crane LR, Daley L, Dandridge D, D'Antuono V, Darcourt Rizo Patron JG, DeHovitz JA, DeJesus E, DesJardin J, Diaz-Linares M, Dietrich C, Dodson P, Dolce E, Elliott K, Erickson D, Estes M, Faber LL, Falbo J, Farrough MJ, Farthing CF, Ferrell-Gonzalez P, Flynn H, Frank C, Frank M, Freeman KF, French N, Friedland G, Fujita N, Gahagan L, Genther K, Gilson I, Goetz MB, Goodwin E, Graziano F, Guity CK, Gulick P, Gunderson ER, Hale CM, Hannah K, Henderson H, Hennessey K, Henry WK, Higgins DT, Hodder SL, Horowitz HW, Howe-Pittman M, Hubbard J, Hudson R, Hunter H, Hutelmyer C, Insignares MT, Jackson L, Jenny L, John M, Johnson DL, Johnson G, Johnson J, Johnson L, Kaat J, Kaczmarski J, Kagan S, Kantor C, Kempner T, Kieckhaus K, Kimmel N, Klaus BM, Klimas N, Koeppe JR, Koirala J, Kopka J, Kostman JR, Kozal MJ, Kumar A, Labriola A, Lampiris H, Lamprecht C, Lattanzi KM, Lee J, Leggett J, Long C, Loquere A, Loveless K, Lucasti CJ, Luskin-Hawk R, MacVeigh M, Makohon LH, Mannheimer S, Markowitz NP, Marks C, Martinez N, Martorell C, McFeaters E, McGee B, McIntyre DM, McKee J, McManus E, Melecio LG, Melton D, Mercado S, Merrifield E, Mieras JA, Mogyoros M, Moran FM, Murphy K, Mushatt D, Mutic S, Nadeem I, Nahass R, Nixon D, O'Brien S, Ognjan A, O'Hearn M, O'Keefe K, Okhuysen PC, Oldfield E, Olson D, Orenstein R, Ortiz R, Osterberger J, Owen W, Parpart F, Pastore-Lange V, Paul S, Pavlatos A, Pearce DD, Pelz R, Perez G, Peterson S, Pierone G Jr, Pitrak D, Powers SL, Pujet HC, Raaum JW, Ravishankar J, Reeder J, Regevik N, Reilly NA, Reyelt C, Riddell J 4th, Rimland D, Robinson ML, Rodriguez AE, Rodriguez-Barradas MC, Rodriguez Derouen V, Roland R, Rosmarin C, Rossen WL, Rouff JR, Sampson JH, Sands M, Savini C, Schrader S, Schulte MM, Scott C, Scott R, Seedhom H, Sension M, Sheble-Hall A, Sheridan A, Shuter J, Slater LN, Slotten R, Slowinski D, Smith M, Snap S, Somboonwit C, States DM, Stewart M, Stringer G, Sullivan J, Summers KK, Swanson K, Sweeto IB, Szabo S, Tedaldi EM, Telzak EE, Temesgen Z, Thomas D, Thompson MA, Thompson S, Ting Hong Bong C, Tobin C, Uy J, Vaccaro A, Vasco LM, Vecino I, Verlinghieri GK, Visnegarwala F, Wade BH, Watson V, Weis SE, Weise JA, Weissman S, Wilkin AM, Williams L, Witter JH, Wojtusic L, Wright TJ, Yeh V, Young B, Zeana C, Zeh J, Savio E, Vacarezza M.
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 x 10(9) 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 x 10(9) cells/L (95% CI, 0.136 to 0.167 x 10(9) 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 x 10(9) 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 < or =400 copies/mL after 6 months), but CD4+ cell counts after 6 months remained 0.140 x 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.
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PMID: 18765698 [PubMed - indexed for MEDLINE]