Skip to main content

Advertisement

Log in

HIV-1 Integrase Inhibitors Resistance: Update of the Current Literature

  • HIV Medicine (CJ Yoon, Section editor)
  • Published:
Current Treatment Options in Infectious Diseases Aims and scope Submit manuscript

Opinion statement

Integrase strand transfer inhibitors (INSTIs) have become the most important class of anti-HIV-1 drugs used as third element of the classic three-agent regimen. In addition, they have become pillars of simplified therapeutic schemes. They represent a fundamental resource which cannot be misused. In particular, the most worrisome risk is the occurrence of class resistance that could prevent physicians from employing this impressive weapon in the anti-HIV-1 armamentarium. A precise insight into mechanisms and pathway of resistance is necessary to use these drugs wisely. Pending the advent of new-generation INSTIs, differences among the ones currently available must be kept in mind, especially the greater barrier to resistance displayed by dolutegravir when compared with raltegravir and elvitegravir.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. • Andreoni M, Marcotullio S, Puro V, De Carli G, Tambussi G, Nozza S, et al. An update on integrase inhibitors: new opportunities for a personalized therapy? The NEXTaim Project. New Microbiol; 2015: 443–90. A comprehensive review on several aspects of integrase inhibitors.

  2. Panel on Antiretroviral Guidelines for Adults. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf [Last accessed 31/10/2016]

  3. European AIDS Clinical, Society. EACS Guidelines Version 8.1 October 2016. Available at: http://www.eacsociety.org/files/guidelines_8.1-english.pdf [Last accessed 31/10/2016].

  4. Tsiang M, Jones GS, Goldsmith J, Mulato A, Hansen D, Kan E, et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob Agents Chemother 2016.

  5. Margolis DA, Brinson CC, Smith GH, de Vente J, Hagins DP, Eron JJ, et al. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis. 2015;15:1145–55.

    Article  CAS  PubMed  Google Scholar 

  6. Han YS, Mesplede T, Wainberg MA. Differences among HIV-1 subtypes in drug resistance against integrase inhibitors. Infect Genet Evol. 2016;S1567-1348(16):30271–4.

    Google Scholar 

  7. Lee FJ, Amin J, Carr A. Efficacy of initial antiretroviral therapy for HIV-1 infection in adults: a systematic review and meta-analysis of 114 studies with up to 144 weeks’ follow-up. PLoS One. 2014;9:e97482.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Raffi F, Esser S, Nunnari G, Perez-Valero I, Waters L. Switching regimens in virologically suppressed HIV-1-infected patients: evidence base and rationale for integrase strand transfer inhibitor (INSTI)-containing regimens. HIV Med. 2016;17(Suppl 5):3–16.

    Article  CAS  PubMed  Google Scholar 

  9. Park TE, Mohamed A, Kalabalik J, Sharma R. Review of integrase strand transfer inhibitors for the treatment of human immunodeficiency virus infection. Expert Rev Anti-Infect Ther. 2015;13:1195–212.

    Article  CAS  PubMed  Google Scholar 

  10. Podany AT, Scarsi KK, Fletcher CV. Comparative clinical pharmacokinetics and pharmacodynamics of HIV-1 integrase strand transfer inhibitors. Clin Pharmacokinet. Switzerland 2016.

  11. Geretti AM, Armenia D, Ceccherini-Silberstein F. Emerging patterns and implications of HIV-1 integrase inhibitor resistance. Curr Opin Infect Dis. 2012;25:677–86.

    Article  CAS  PubMed  Google Scholar 

  12. Xue W, Jin X, Ning L, Wang M, Liu H, Yao X. Exploring the molecular mechanism of cross-resistance to HIV-1 integrase strand transfer inhibitors by molecular dynamics simulation and residue interaction network analysis. J Chem Inf Model. 2013;53:210–22.

    Article  CAS  PubMed  Google Scholar 

  13. Mesplede T, Wainberg MA. Is resistance to dolutegravir possible when this drug is used in first-line therapy? Viruses. 2014;6:3377–85.

    Article  PubMed  PubMed Central  Google Scholar 

  14. • Wainberg MA, Han YS, Mesplede T. Might dolutegravir be part of a functional cure for HIV? Can J Microbiol. 2016;62:375–82. An intersting paper speculating upon the use of dolutegravir in strategies aimed at functional cure of HIV-1.

    Article  CAS  PubMed  Google Scholar 

  15. Wainberg MA, Han YS. HIV-1 resistance to dolutegravir: update and new insights. J Virus Erad. 2015;1:13–6.

    PubMed  PubMed Central  Google Scholar 

  16. Craigie R, Bushman FD. HIV DNA integration. Cold Spring Harb Perspect Med. 2012;2(7):a006890.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Jegede O, Babu J, Di Santo R, McColl DJ, Weber J, Quinones-Mateu M. HIV type 1 integrase inhibitors: from basic research to clinical implications. AIDS Rev. 2008;10:172–89.

    PubMed  Google Scholar 

  18. Vandegraaff N, Engelman A. Molecular mechanisms of HIV integration and therapeutic intervention. Expert Rev Mol Med. 2007;9:1–19.

    Article  PubMed  Google Scholar 

  19. Delelis O, Carayon K, Saib A, Deprez E, Mouscadet JF. Integrase and integration: biochemical activities of HIV-1 integrase. Retrovirology. 2008;5:114.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wu G, Abraham T, Saad N. Dolutegravir for the treatment of adult patients with HIV-1 infection. Expert Rev Anti-Infect Ther. 2014;12:535–44.

    Article  CAS  PubMed  Google Scholar 

  21. Hazuda DJ, Felock P, Witmer M, Wolfe A, Stillmock K, Grobler JA, et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science. 2000;287:646–50.

    Article  CAS  PubMed  Google Scholar 

  22. Hazuda DJ, Young SD, Guare JP, Anthony NJ, Gomez RP, Wai JS, et al. Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques. Science. 2004;305:528–32.

    Article  CAS  PubMed  Google Scholar 

  23. De Clercq E, Li G. Approved antiviral drugs over the past 50 years. Clin Microbiol Rev. 2016;29:695–747.

    Article  PubMed  Google Scholar 

  24. Sato M, Motomura T, Aramaki H, Matsuda T, Yamashita M, Ito Y, et al. Novel HIV-1 integrase inhibitors derived from quinolone antibiotics. J Med Chem. 2006;49:1506–8.

    Article  CAS  PubMed  Google Scholar 

  25. DeAnda F, Hightower KE, Nolte RT, Hattori K, Yoshinaga T, Kawasuji T, et al. Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics. PLoS One. 2013;8:e77448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bonadies G, Maraolo AE, Tambaro O, Palmiero G, Di Filippo G, Orlando R. Dolutegravir: successful experience in a challenging patient. AIDS. 2015;29:1269–71.

    Article  PubMed  Google Scholar 

  27. •• Wensing AM, Calvez V, Gunthard HF, Johnson VA, Paredes R, Pillay D, et al. Update of the drug resistance mutations in HIV-1. Top Antivir Med. 2015;23:132–41. An indispensabile guide to the universe of antiretroviral resistance.

    PubMed  Google Scholar 

  28. Hu Z, Kuritzkes DR. Effect of raltegravir resistance mutations in HIV-1 integrase on viral fitness. J Acquir Immune Defic Syndr. 2010;55:148–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Reigadas S, Masquelier B, Calmels C, Laguerre M, Lazaro E, Vandenhende M, et al. Structure-analysis of the HIV-1 integrase Y143C/R raltegravir resistance mutation in association with the secondary mutation T97A. Antimicrob Agents Chemother. 2011;55:3187–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hurt CB, Sebastian J, Hicks CB, Eron JJ. Resistance to HIV integrase strand transfer inhibitors among clinical specimens in the United States, 2009-2012. Clin Infect Dis. 2014;58:423–31.

    Article  CAS  PubMed  Google Scholar 

  31. Abram ME, Hluhanich RM, Goodman DD, Andreatta KN, Margot NA, Ye L, et al. Impact of primary elvitegravir resistance-associated mutations in HIV-1 integrase on drug susceptibility and viral replication fitness. Antimicrob Agents Chemother. 2013;57:2654–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wohl DA, Cohen C, Gallant JE, Mills A, Sax PE, Dejesus E, et al. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF versus single-tablet regimen efavirenz/emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. J Acquir Immune Defic Syndr. 2014;65:e118–20.

    Article  PubMed  Google Scholar 

  33. Clumeck N, Molina JM, Henry K, Gathe J, Rockstroh JK, DeJesus E, et al. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. J Acquir Immune Defic Syndr. 2014;65:e121–4.

    Article  PubMed  Google Scholar 

  34. White KL, Kulkarni R, McColl DJ, Rhee MS, Szwarcberg J, Cheng AK, et al. Week 144 resistance analysis of elvitegravir/cobicistat/emtricitabine/tenofovir DF versus efavirenz/emtricitabine/tenofovir DF in antiretroviral-naive patients. Antivir Ther. 2015;20:317–27.

    Article  CAS  PubMed  Google Scholar 

  35. Turner D, Brenner B, Wainberg MA. Relationships among various nucleoside resistance-conferring mutations in the reverse transcriptase of HIV-1. J Antimicrob Chemother. 2004;53:53–7.

    Article  CAS  PubMed  Google Scholar 

  36. Eron Jr JJ, Rockstroh JK, Reynes J, Andrade-Villanueva J, Ramalho-Madruga JV, Bekker LG, et al. Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial. Lancet Infect Dis. 2011;11:907–15.

    Article  CAS  PubMed  Google Scholar 

  37. Rockstroh JK, DeJesus E, Lennox JL, Yazdanpanah Y, Saag MS, Wan H, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr. 2013;63:77–85.

    Article  CAS  PubMed  Google Scholar 

  38. Mesplede T, Quashie PK, Zanichelli V, Wainberg MA. Integrase strand transfer inhibitors in the management of HIV-positive individuals. Ann Med. 2014;46:123–9.

    Article  CAS  PubMed  Google Scholar 

  39. Collin SE, Grant PM, Richardson ET, Zolopa AR. Integrating integrase inhibitors into an antiretroviral regimen. Current Treatment Options in Infectious Diseases. 2014;2:144–58.

    Article  Google Scholar 

  40. Kobayashi M, Yoshinaga T, Seki T, Wakasa-Morimoto C, Brown KW, Ferris R, et al. In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother. 2011;55:813–21.

    Article  CAS  PubMed  Google Scholar 

  41. Quashie PK, Mesplede T, Wainberg MA. Evolution of HIV integrase resistance mutations. Curr Opin Infect Dis. 2013;26:43–9.

    CAS  PubMed  Google Scholar 

  42. Quashie PK, Mesplede T, Han YS, Oliveira M, Singhroy DN, Fujiwara T, et al. 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;86:2696–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Anstett K, Fusco R, Cutillas V, Mesplede T, Wainberg MA. Dolutegravir-selected HIV-1 containing the N155H and R263K resistance substitutions does not acquire additional compensatory mutations under drug pressure that lead to higher-level resistance and increased replicative capacity. J Virol. 2015;89:10482–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wares M, Mesplede T, Quashie PK, Osman N, Han Y, Wainberg MA. The M50I polymorphic substitution in association with the R263K mutation in HIV-1 subtype B integrase increases drug resistance but does not restore viral replicative fitness. Retrovirology. 2014;11:7.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Quashie PK, Mesplede T, Han YS, Veres T, Osman N, Hassounah S, et al. Biochemical analysis of the role of G118R-linked dolutegravir drug resistance substitutions in HIV-1 integrase. Antimicrob Agents Chemother. 2013;57:6223–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Liang J, Mesplede T, Oliveira M, Anstett K, Wainberg MA. The combination of the R263K and T66I resistance substitutions in HIV-1 integrase is incompatible with high-level viral replication and the development of high-level drug resistance. J Virol. 2015;89:11269–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hightower KE, Wang R, Deanda F, Johns BA, Weaver K, Shen Y, et al. 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;55:4552–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wainberg MA, Mesplede T, Raffi F. What if HIV were unable to develop resistance against a new therapeutic agent? BMC Med. 2013;11:249.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Brenner BG, Wainberg MA. Clinical benefit of dolutegravir in HIV-1 management related to the high genetic barrier to drug resistance. Virus Res. 2016;S0168-1702(16):30283.

    Google Scholar 

  50. Hocqueloux L, Avettand-Fenoel V, Jacquot S, Prazuck T, Legac E, Melard A, et al. Long-term antiretroviral therapy initiated during primary HIV-1 infection is key to achieving both low HIV reservoirs and normal T cell counts. J Antimicrob Chemother. 2013;68:1169–78.

    Article  CAS  PubMed  Google Scholar 

  51. Castagna A, Maggiolo F, Penco G, Wright D, Mills A, Grossberg R, et al. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis. 2014;210:354–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hardy I, Brenner B, Quashie P, Thomas R, Petropoulos C, Huang W, et al. Evolution of a novel pathway leading to dolutegravir resistance in a patient harbouring N155H and multiclass drug resistance. J Antimicrob Chemother. 2015;70:405–11.

    Article  CAS  PubMed  Google Scholar 

  53. Munir S, Thierry E, Malet I, Subra F, Calvez V, Marcelin AG, et al. G118R and F121Y mutations identified in patients failing raltegravir treatment confer dolutegravir resistance. J Antimicrob Chemother. 2015;70:739–49.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alberto Enrico Maraolo MD.

Ethics declarations

Conflict of Interest

Alberto Enrico Maraolo declares that he has no conflict of interest, as reported in the disclosure form.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on HIV Medicine

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Maraolo, A.E. HIV-1 Integrase Inhibitors Resistance: Update of the Current Literature. Curr Treat Options Infect Dis 9, 44–51 (2017). https://doi.org/10.1007/s40506-017-0113-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40506-017-0113-0

Keywords

Navigation