Single genome sequencing of HIV-1 gag and protease resistance mutations at virologic failure during the OK04 trial of simplified versus standard maintenance therapy

被引:14
作者
McKinnon, John E. [1 ]
Delgado, Rafael [2 ]
Pulido, Federico [2 ]
Shao, Wei [3 ]
Arribas, Jose R. [4 ]
Mellors, John W. [1 ]
机构
[1] Univ Pittsburgh, Dept Med, Div Infect Dis, Pittsburgh, PA 15260 USA
[2] Hosp 12 Octubre, Inst Invest, E-28041 Madrid, Spain
[3] NCI, ISP Adv Biomed Comp Ctr, SAIC Frederick, Frederick, MD 21701 USA
[4] Hosp La Paz, IdiPAZ, Unidad VIH, Serv Med Intern, Madrid, Spain
关键词
IMMUNODEFICIENCY-VIRUS TYPE-1; LOPINAVIR-RITONAVIR MONOTHERAPY; ANTIRETROVIRAL THERAPY; DRUG-RESISTANCE; CLEAVAGE SITES; VIRAL FITNESS; RANDOMIZED-TRIAL; IN-VIVO; HIV-1-INFECTED PATIENTS; REGIMEN SIMPLIFICATION;
D O I
10.3851/IMP1812
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
Background: Ritonavir-boosted lopinavir (LPV/RTV) alone has been evaluated as simplified maintenance therapy for HIV-1 infection, but there are concerns about greater potential for emergence of protease inhibitor (PI) resistance. The OK04 trial evaluated maintenance therapy with LPV/RTV alone versus standard therapy (ST) with two NRTIs plus LPV/RTV in 205 patients, of whom 15 had virological rebound by week 48 (11 versus 4 patients, respectively). We developed a single genome sequencing (SOS) assay of HIV-1 gag and protease to assess the emergence of low frequency drug-resistant variants during virological rebound. Methods: Plasma samples from 15 subjects at virological rebound were analysed by SGS of HIV-1 gag and protease genes. A total of 45 SOS sequences were planned per sample, providing 90% power to detect variants comprising >5% of the virus population. Results: Overall, 521 single sequences obtained from 13 patients (range 4-48 sequences/patient) revealed similar frequencies of major protease resistance mutations in samples from the LPV/RTV alone (3/11) and ST (3/4) arms (P=0.10), with a median number of minor protease resistance mutations of 3.0 versus 3.5, respectively (P=0.23). Median number of gag PI resistance mutations were similar between the LPV/RTV alone and ST arms at cleavage sites (3.0 versus 2.5; P=0.83), non-cleavage sites (21 versus 16.5; P=0.71) and the transframe protein-p6 pol region cleavage sites (4.0 versus 3.0; P=0.6). Conclusions: Although more subjects with simplified maintenance therapy with LPV/RTV alone had virological rebound compared to the ST arm, this was not associated with more frequent emergence of variants encoding PI resistance mutations in gag or protease detected by SGS.
引用
收藏
页码:725 / 732
页数:8
相关论文
共 49 条
[21]   Amino acid substitutions in Gag protein at non-cleavage sites are indispensable for the development of a high multitude of HIV-1 resistance against protease inhibitors [J].
Gatanaga, H ;
Suzuki, Y ;
Tsang, H ;
Yoshimura, K ;
Kavlick, MF ;
Nagashima, K ;
Gorelick, RJ ;
Mardy, S ;
Tang, C ;
Summers, MF ;
Mitsuya, H .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (08) :5952-5961
[22]  
GATHE JCY, 2007, 4 INT AIDS SOC C HIV
[23]   Randomized controlled study demonstrating failure of LPV/r monotherapy in HIV: the role of compartment and CD4-nadir [J].
Gutmann, Christine ;
Cusini, Alexia ;
Guenthard, Huldrych F. ;
Fux, Christoph ;
Hirschel, Bernard ;
Decosterd, Laurent-Arthur ;
Cavassini, Matthias ;
Yerly, Sabine ;
Vernazza, Pietro L. .
AIDS, 2010, 24 (15) :2347-2354
[24]  
Hogg R, 2008, LANCET, V372, P293, DOI 10.1016/S0140-6736(08)61113-7
[25]   Characterization of gag and pol sequences from long-term survivors of human immunodeficiency virus type 1 infection [J].
Huang, YX ;
Zhang, LQ ;
Ho, DD .
VIROLOGY, 1998, 240 (01) :36-49
[26]   Evolution of resistance to drugs in HIV-1-infected patients failing antiretroviral therapy [J].
Kantor, R ;
Shafer, RW ;
Follansbee, S ;
Taylor, J ;
Shilane, D ;
Hurley, L ;
Nguyen, DP ;
Katzenstein, D ;
Fessel, WJ .
AIDS, 2004, 18 (11) :1503-1511
[27]   Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136 [J].
Katlama, Christine ;
Valantin, Marc A. ;
Algarte-Genin, Michele ;
Duvivier, Claudine ;
Lambert-Niclot, Sidonie ;
Girard, Pierre M. ;
Molina, Jean M. ;
Hoen, Bruno ;
Pakianather, Sophie ;
Peytavin, Gilles ;
Marcelin, Anne G. ;
Flandre, Philippe .
AIDS, 2010, 24 (15) :2365-2374
[28]   Protease inhibitor resistance update: Where are we now? [J].
Kim, Rose ;
Baxter, John D. .
AIDS PATIENT CARE AND STDS, 2008, 22 (04) :267-277
[29]   Changes in human immunodeficiency virus type 1 Gag at positions L449 and P453 are linked to 150V protease mutants in vivo and cause reduction of sensitivity to amprenavir and improved viral fitness in vitro [J].
Maguire, MF ;
Guinea, R ;
Griffin, P ;
Macmanus, S ;
Elston, RC ;
Wolfram, J ;
Richards, N ;
Hanlon, MH ;
Porter, DJT ;
Wrin, T ;
Parkin, N ;
Tisdale, M ;
Furfine, E ;
Petropoulos, C ;
Snowden, BW ;
Kleim, JP .
JOURNAL OF VIROLOGY, 2002, 76 (15) :7398-7406
[30]   Association of Gag cleavage sites to protease mutations and to virological response in HIV-1 treated patients [J].
Malet, Isabelle ;
Roquebert, Benedicte ;
Dalban, Cecile ;
Wirden, Marc ;
Amellal, Bahia ;
Agher, Rachid ;
Simon, Anne ;
Katlama, Christine ;
Costagliola, Dominique ;
Calvez, Vincent ;
Marcelin, Anne-Genevieve .
JOURNAL OF INFECTION, 2007, 54 (04) :367-374