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J Acquir Immune Defic Syndr. 2015 Sep 1;70(1):42-53. doi: 10.1097/QAI.0000000000000671.

HIV-1 Drug Resistance and Second-Line Treatment in Children Randomized to Switch at Low Versus Higher RNA Thresholds.

Collaborators (552)

Brouwers P, Costello D, Ferguson E, Fiscus S, Hodge J, Hughes M, Jennings C, Melvin A, McKinney R, Mofenson L, Warshaw W, Smith E, Spector S, Stiehm E, Toye M, Yogev R, Aboulker JP, Babiker A, Castro H, Compagnucci A, Giaquinto C, Darbyshire J, Debré M, Gibb DM, Harper L, Harrison L, Tudor-Williams G, Saidi Y, Walker AS, Brody B, Hill C, Lepage P, Modlin J, Poziak A, Rein M, Robb M, Fleming T, Vella S, Kim KM, Garrahan JP, Bologna R, Mecikovsky D, Pineda N, Sen L, Mangano A, Marino S, Galvez C, Deluchi G, Zöhrer B, Zenz W, Daghofer E, Pfurtscheller K, Pabst B, Gomez MP, McNeil P, Jervis M, Whyms I, Kwolfe D, Scott S, Mussi-Pinhata MM, Issac ML, Cervi MC, Negrini BV, Matsubara TC, de Souza CB, Gabaldi JC, Oliveira RH, Sapia MC, Abreu T, Evangelista L, Pala A, Fernandes I, Farias I, Melo Mde F, Carreira H, Lira LM, della Negra M, Queiroz W, Lian YC, Pacola DP, Pinto J, Ferreira F, Kakehasi F, Martins L, Diniz A, Lobato V, Diniz M, Hill C, Cleto S, Costa S, Romeiro J, Dollfus C, Tabone MD, Courcoux MF, Vaudre G, Dehée A, Schnuriger A, Le Gueyades N, De Bortoli C, Méchinaud F, Reliquet V, Arias J, Rodallec A, André E, Falconi I, Le Pelletier A, Monpoux F, Cottalorda J, Mellul S, Lachassinne E, Galimand J, Rouzioux C, Chaix ML, Benabadji Z, Pourrat M, Firtion G, Rivaux D, Denon D, Boudjoudi N, Nganzali F, Krivine A, Méritet JF, Delommois G, Norgeux C, Guérin C, Floch C, Marty L, Hichou H, Tournier V, Faye A, Le Moal I, Sellier M, Dehache L, Damond F, Leleu J, Beniken D, Alexandre-Castor G, Neubert J, Niehues T, Laws HJ, Huck K, Gudowius S, Bellert S, Ortwin A, Notheis G, Wintergerst U, Hoffman F, Werthmann A, Seyboldt S, Schneider L, Bucholz B, Feiterna-Sperling C, Peiser C, Nickel R, Schmitz T, Piening T, Müller C, Warncke G, Wigger M, Neubauer R, Butler K, Chang AL, Belger T, Menon A, O'Connell M, Barrett L, Rochford A, Goode M, Hayes E, McDonagy S, Walsh A, Doyle A, Fanning J, O'Connor M, Byrne M, O'Sullivan N, Hyland E, Giacomet V, Viganò A, Zuccotti GV, Trabattoni D, Berzi A, Badolato R, Schumacher F, Bennato V, Brusati M, Sorlini A, Spinelli E, Filisetti M, Bertulli C, Rampon O, Giaquinto C, Zanchetta M, Mazza A, Stringari G, Rossetti G, Bernardi S, Martino A, Castelli Gattinara G, Palma P, Pontrelli G, Tchidjou H, Furcas A, Frillici C, Mazzei A, Zoccano A, Concato C, Duiculescu D, Oprea C, Tardei G, Abaab F, Mardarescu M, Draghicenoiu R, Otelea D, Alecsandru L, Matusa R, Rugina S, Ilie M, Netescu S, Florea C, Voicu E, Poalelungi D, Belmega C, Vladau L, Chiriac A, Ramos Amador JT, Gonzalez Tomé MI, Rojo Conejo P, Fernandez M, Delgado Garcia R, Ferrari JM, Garcia Lopez M, Mellado Peña MJ, Martin Fontelos P, Jimenez Nacher I, Muñoz Fernandez MA, Jimenez JL, García Torre A, Penin M, Pineiro Perez R, Garcia Mellado I, Finn A, LaJeunesse M, Hutchison E, Usher J, Ball L, Dunn M, Sharland M, Doerholt K, Storey S, Donaghy S, Wells C, Buckberry K, Rice P, McMaster P, Butler P, Farmer C, Shenton J, Haley H, Orendi J, Stroobant J, Navarante L, Archer P, Mazhude C, Scott D, O'Connell R, Wong J, Boddy G, Shackley F, Lakshman R, Hobbs J, Ball G, Kudesia G, Bane J, Painter D, Sloper K, Shah V, Cheng A, Aali A, Ball C, Hawkins S, Nayagam D, Waters A, Doshi S, Liebeschuetz S, Sodiende B, Shingadia D, Wong S, Swan J, Shah Z, Collinson A, Hayes C, King J, O'Connor K, Tudor-Williams G, Lyall H, Fidler K, Walters S, Foster C, Hadamache D, Newbould C, Monrose C, Campbell S, Yeung S, Cohen J, Martinez-Allier N, Tatum G, Gordon A, Kaye S, Muir D, Patel D, Novelli V, Gibb D, Shingadia D, Moshal K, Lambert J, Klein N, Flynn J, Farrelly L, Clapson M, Spencer L, Depala M, Jacobsen M, Segal S, Pollard A, Yeadon S, Peng Y, Dong T, Peng Y, Jeffries K, Snelling M, Smyth A, Smith J, Ward B, Jungmann E, Ryan C, Swaby K, Buckton A, Smidt E, Abrams EJ, Champion S, Fernandez AD, Calo D, Garrovillo L, Swaminathan K, Alford T, Frere M, Navarra J, Borkowsky W, Deygoo S, Hastings T, Akleh S, Ilmet T, Melvin A, Mohan K, Bowen G, Emmanuel PJ, Lujan-Zimmerman J, Rodriguez C, Johnson S, Marion A, Graisbery C, Casey D, Lewis G, Guzman-Cottrill J, Croteau R, Acevedo-Flores M, Gonzalez M, Angeli L, Fabregas L, Valentin P, Weiner L, Contello KA, Holz W, Butler M, Nachman S, Kelly MA, Ferraro DM, Rana S, Reed C, Yeagley E, Malheiro A, Roa J, Neely M, Kovacs A, Spencer L, Homans J, Rodriguez Lozano Y, Puga A, Talero G, Sellers R, Lawrence R, Weinberg GA, Murante B, Laverty S, Deveikis A, Batra J, Chen T, Michalik D, Deville J, Elkins K, Marks S, Jackson J, Alvarez J, Palm J, Fineanganofo I, Keuth M, Deveikis L, Tomosada W, Van Dyke R, Alchediak T, Silio M, Borne C, Bradford S, Eloby-Childress S, Nguyen K, Rathore MH, Alvarez A, Mirza A, Mahmoudi S, Burke M, Febo IL, Lugo L, Santos R, Church JA, Dunaway T, Rodier C, Flynn P, Patel N, DiScenza S, Donohoe M, Luzuriaga K, Picard D, Kline M, Paul ME, Shearer WT, McMullen-Jackson C, Yogev R, Chadwick E, Cagwin E, Kabat K, Dieudonne A, Palumbo P, Johnson J, Gaur S, Cerracchio L, Foca M, Jurgrau A, Vasquez Bonilla S, Silva G, Gershon A, Sullivan J, Bryson Y, Frenkel L, Fiscus S, Nelson J, Aboulker JP, Compagnucci A, Hadjou G, Léonardo S, Riault Y, Saïdi Y, Babiker A, Buck L, Darbyshire JH, Farrelly L, Forcat S, Gibb DM, Castro H, Harper L, Harrison L, Horton J, Johnson D, Taylor C, Walker AS, Collins D, Buskirk S, Kamara P, Nesel C, Johnson M, Ferreira A, Hodge J, Tutko J, Sprenger H, Hughes M, Warshaw M, Britto P, Powell C, Harrison L, DerSimonian R, Handelsman E, Aboulker JP, Ananworanich J, Babiker A, Belfrage E, Bernardi S, Blanche S, Bohlin AB, Bologna R, Burger D, Butler K, Castelli-Gattinara G, Castro H, Clayden P, Compagnucci A, Cressey T, Darbyshire JH, Debré M, De Groot R, Della Negra M, De Rossi A, Duicelescu D, Faye A, Giacomet V, Giaquinto C, Gibb DM, Grosch-Wörner I, Hainault M, Klein N, Lallemant M, Levy J, Lyall H, Marczynska M, Marques L, Mardarescu M, Mellado Pena MJ, Nadal D, Nastouli E, Naver L, Niehues T, Noquera A, Peckham C, Pillay D, Popieska J, Ramos Amador JT, Rojo Conejo P, Rosado L, Rosso R, Rudin C, Saïdi Y, Scherpbier H, Sharland M, Stevanovic M, Thorne C, Tovo PA, Tudor-Williams G, Turkova A, Valerius N, Volokha A, Walker AS, Welch S, Wintergerst U.

Abstract

BACKGROUND:

The PENPACT-1 trial compared virologic thresholds to determine when to switch to second-line antiretroviral therapy (ART). Using PENPACT-1 data, we aimed to describe HIV-1 drug resistance accumulation on first-line ART by virologic threshold.

METHODS:

PENPACT-1 had a 2 × 2 factorial design, randomizing HIV-infected children to start protease inhibitor (PI) versus nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART, and switch at a 1000 copies/mL versus 30,000 copies/mL threshold. Switch criteria were not achieving the threshold by week 24, confirmed rebound above the threshold thereafter, or Center for Disease Control and Prevention stage C event. Resistance tests were performed on samples ≥1000 copies/mL before switch, resuppression, and at 4-years/trial end.

RESULTS:

Sixty-seven children started PI-based ART and were randomized to switch at 1000 copies/mL (PI-1000), 64 PIs and 30,000 copies/mL (PI-30,000), 67 NNRTIs and 1000 copies/mL (NNRTI-1000), and 65 NNRTI and 30,000 copies/mL (NNRTI-30,000). Ninety-four (36%) children reached the 1000 copies/mL switch criteria during 5-year follow-up. In 30,000 copies/mL threshold arms, median time from 1000 to 30,000 copies/mL switch criteria was 58 (PI) versus 80 (NNRTI) weeks (P = 0.81). In NNRTI-30,000, more nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations accumulated than other groups. NNRTI mutations were selected before switching at 1000 copies/mL (23% NNRTI-1000, 27% NNRTI-30,000). Sixty-two children started abacavir + lamivudine, 166 lamivudine + zidovudine or stavudine, and 35 other NRTIs. The abacavir + lamivudine group acquired fewest NRTI mutations. Of 60 switched to second-line, 79% PI-1000, 63% PI-30,000, 64% NNRTI-1000, and 100% NNRTI-30,000 were <400 copies/mL 24 weeks later.

CONCLUSIONS:

Children on first-line NNRTI-based ART who were randomized to switch at a higher virologic threshold developed the most resistance, yet resuppressed on second-line. An abacavir + lamivudine NRTI combination seemed protective against development of NRTI resistance.

PMID:
26322666
PMCID:
PMC4556171
DOI:
10.1097/QAI.0000000000000671
[Indexed for MEDLINE]
Free PMC Article

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