BMC Medicine | |
What if HIV were unable to develop resistance against a new therapeutic agent? | |
Francois Raffi3  Thibault Mesplède2  Mark A Wainberg1  | |
[1] Departments of Medicine and Microbiology, Jewish General Hospital, McGill University, Montreal, QC, Canada;McGill University AIDS Centre, Montreal, QC, Canada;Division of Infectious Diseases, Nantes University Hospital, Nantes, France | |
关键词: Drug resistance; Viral fitness; HIV prevention strategies; Dolutegravir; Antiretroviral therapy; Integrase inhibitors; Human immunodeficiency virus type 1; | |
Others : 855342 DOI : 10.1186/1741-7015-11-249 |
|
received in 2013-11-06, accepted in 2013-11-07, 发布年份 2013 | |
【 摘 要 】
Background
The HIV integrase inhibitor, Dolutegravir (DTG), was recently approved by the Food and Drug Administration in the United States and is the only HIV drug that has not selected for resistance mutations in the clinic when used as part of first-line therapy. This has led to speculation that DTG might have a higher genetic barrier for the development of drug resistance than the other compounds that are used in therapy.
Discussion
In this Opinion article, we speculate that this is due to greatly diminished replication capacity on the part of viruses that might become resistant to DTG when the drug is used in initial therapy and that DTG might be able to be used in HIV prevention and eradication strategies. We also note that no compensatory mutation that might restore viral replication fitness to HIV in the aftermath of the appearance of a single drug resistance mutation has yet to be observed.
Summary
DTG is a valuable addition to the anti-HIV armamentarium of drugs and its long-term utility may potentially exceed its obvious use in treatment of HIV disease.
【 授权许可】
2013 Wainberg et al.; licensee BioMed Central Ltd.
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
20140722032849456.pdf | 1180KB | download | |
55KB | Image | download |
【 图 表 】
【 参考文献 】
- [1]Walmsley S, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutiérrez F, Hocqueloux L, Maggiolo F, Sandkovsky U, Granier C, Pappa K, Wynne B, Min S, Nichols G, SINGLE Investigators: Dolutegravir plus abacavir/lamivudine for the treatment of HIV infection. N Engl J Med 2013, 369:1807-1818.
- [2]Wainberg MA, Zaharatos GJ, Brenner BG: Development of antiretroviral drug resistance. N Engl J Med 2011, 365:637-646.
- [3]Gupta RK, Jordan MR, Sultan BJ, Hill A, Davis DH, Gregson J, Sawyer AW, Hamers RL, Ndembi N, Pillay D, Bertagnolio S: Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis. Lancet 2012, 380:1250-1258.
- [4]Mesplede T, Quashie PK, Wainberg MA: Resistance to HIV integrase inhibitors. Curr Opin HIV AIDS 2012, 7:401-408.
- [5]Ni XJ, Delilis O, Charpentier C, Storto A, Collin G, Damond F, Descamps D, Mouscadet JF: G140S/Q148R and N155H mutations render HIV-2 integrase resistant to raltegravir whereas Y143C does not. Retrovirology 2011, 8:68. BioMed Central Full Text
- [6]Sax PE, DeJesus E, Mills A, Zolopa A, Cohen C, Wohl D, Gallant JE, Liu HC, Zhong L, Yale K, White K, Kearney BP, Szwarcberg J, Quirk E, Cheng AK, GS-US-236–0102 Study Team: Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, doubleblind, phase 3 trial, analysis of results after 48 weeks. Lancet 2012, 379:2439-2448. Erratum in: Lancet 2012, 380:730
- [7]DeJesus E, Rockstroh JK, Henry K, Molina JM, Gathe J, Ramanathan S, Wei X, Yale K, Szwarcberg J, White K, Cheng AK, Kearney BP, GS-236-0103 Study Team: Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, doubleblind, phase 3, non-inferiority trial. Lancet 2012, 379:2429-2438.
- [8]Molina JM, Lamarca A, Andrade-Villanueva J, Clotet B, Clumeck N, Liu YP, Zhong L, Margot N, Cheng AK, Chuck SL: Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study. Lancet Infect Dis 2012, 12:27-35.
- [9]Raffi F, Wainberg MA: Multiple choices for HIV therapy with integrase strand transfer inhibitors. Retrovirology 2012, 9:110. BioMed Central Full Text
- [10]Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C, Bloch M, Podzamczer D, Pokrovsky V, Pulido F, Almond S, Margolis D, Brennan C, Min S, the SPRING-2 Study Group: Once-daily dolutegravir versus raltegravir in antiretroviral naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet 2013, 381:735-743.
- [11]Clotet B, Khuong M-A, Antinori A, van Lunzen J, Dumitru I, Pokrovskiy V, Fehr J, Ortiz R, Saag M, Feinberg J, Harris J, Brennan C, Min S, Cuffe R: Once-daily dolutegravir versus darunavir/ritonavir in antiretroviral naïve subjects: 48 week subgroup analyses from FLAMINGO. Abstract LBPS4/6. 14th European AIDS Conference. October 16–19, 2013, Brussels, Belgium; 2013
- [12]Mesplède T, Quashie PK, Osman N, Han Y, Singhroy DN, Lie Y, Petropoulos CJ, Huang W, Wainberg MA: Viral fitness cost prevents HIV-1 from evading dolutegravir drug pressure. Retrovirology 2013, 10:22. BioMed Central Full Text
- [13]Quashie PK, Mesplède T, Han YS, Oliveira M, Singhroy DN, Fujiwara T, Underwood MR, Wainberg MA: Characterization of the R263K mutation in HIV-1 integrase that confers low-level resistance to the second-generation integrase strand transfer inhibitor dolutegravir. J Virol 2012, 86:2696-2705.
- [14]Hightower KE, Wang R, Deanda F, Johns BA, Weaver K, Shen Y, Tomberlin GH, Carter HL 3rd, Broderick T, Sigethy S, Seki T, Kobayashi M, Underwood MR: Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes. Antimicrob Agents Chemother 2011, 55:4552-4559.
- [15]Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, Andrade-Villanueva JF, Richmond G, Buendia CB, Fourie J, Ramgopal M, Hagins D, Felizarta F, Madruga J, Reuter T, Newman T, Small CB, Lombaard J, Grinsztejn B, Dorey D, Underwood M, Griffith S, Min S, extended SAILING Study Team: Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet 2013, 382:700-708.
- [16]Underwood MR, Vavro CL, Haney R, Horton J: Epidemiology of dolutegravir (DTG) resistance in ~700 raltegravir-resistant isolates. Abstract 85. International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies. June 4–8, 2013, Toronto, Canada