The dynamics of appearance and disappearance of HIV-1 integrase mutations during and after withdrawal of raltegravir therapy

被引:29
作者
Ferns, Ruth Bridget [1 ]
Kirk, Stuart [2 ]
Bennett, Julie [2 ]
Williams, Ian [3 ,4 ]
Edwards, Simon [4 ]
Pillay, Deenan
机构
[1] UCL, Div Infect & Immun, Ctr Virol, London W1T 4JF, England
[2] Univ Coll London Hosp NHS Fdn, Dept Virol, London, England
[3] UCL, Sch Med, Ctr Sexual Hlth & HIV Res, London W1N 8AA, England
[4] Mortimer Market Ctr, Camden Provider Serv, London, England
关键词
HIV-1; integrase mutations; raltegravir resistance; IMMUNODEFICIENCY-VIRUS TYPE-1; TREATMENT-EXPERIENCED PATIENTS; INHIBITOR RALTEGRAVIR; PHASE-II; TREATMENT-NAIVE; RESISTANCE; INFECTION; GENE; GS-9137; TRIAL;
D O I
10.1097/QAD.0b013e32832ec4ae
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Objectives: To monitor HIV-1 integrase resistance mutations during raltegravir (RAL) therapy, including the impact of RAL interruption. Design and method: An analysis of viral load and the HIV-1 integrase gene evolution in 26 HIV-1 treatment-experienced patients undergoing RAL therapy. Results: Initial suppression of viral load was observed in all patients; however, four patients failed to maintain suppression and subsequently developed resistance at viral load rebound. Mutations Q148R (2 months) followed by G140A/Q148R and then G140A/Y143CHR/Q148R/G163R were detected in the virus from one patient, and these reverted to wild type when treatment was withdrawn, although clonal analysis identified maintenance of RAL resistance minority species at this time point. RAL treatment was restarted after 6 months, and 2 weeks later, Y143CY/G163RG mutations appeared. In three other patients, viruses with N155H emerged at viral rebound either alone (2 months), followed by V1511 (8 months) or alone (10 months), or together with V1511/G163RG (7 months). Loss of virus with the N155H mutation occurred in these patients when RAL therapy was terminated, despite maintenance of reverse transcriptase/polymerase resistance mutations. Conclusion: Complete viral suppression was important in order to prevent resistance emerging. RAL-resistance mutations were detected in the presence of other antiviral treatments, and the reverse of these mutations following RAL cessation suggests that a fitness deficit was conferred by these mutants. The observation that following RAL interruption virus rebound was with previously existing reverse transcriptase/polymerase mutations in the absence of integrase mutations implies that it is pre-RAL-archived viruses that re-emerge. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
引用
收藏
页码:2159 / 2164
页数:6
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