Skip to main content
SpringerLink
Log in

Dolutegravir: First Global Approval

  • R&D Insight Report
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Dolutegravir, an orally administered HIV-1 integrase strand transfer inhibitor (INSTI), is under development by ViiV Healthcare. Like other drugs belonging in the INSTI class of antiretroviral agents, dolutegravir binds to the integrase site of HIV-1 and blocks the strand transfer integration step, thereby preventing the replication of HIV-1. Dolutegravir is being developed as an unboosted once-daily therapy for use in combination with other antiretroviral agents for the treatment of both treatment-naïve and treatment-experienced patients with HIV-1 infection. Dolutegravir has been approved in the USA for the treatment of HIV-1 infection in combination with other antiretroviral agents and has been filed for approval in the EU and Canada. Phase III development is underway in North America, Europe, South Africa, South America, Australia and Taiwan. This article summarizes the milestones in the development of dolutegravir leading to this first approval for the treatment of HIV-1 infection in both therapy-naïve and -experienced patients.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Messiaen P, Wensing AMJ, Fun A, et al. Clinical use of HIV integrase inhibitors: a systematic review and meta-analysis. PLoS ONE [Electronic Resource]. 2013;8(1):e52562.

    Article  CAS  Google Scholar 

  2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 23 Aug 2013.

  3. Mesplede T, Quashie PK, Wainberg MA. Resistance to HIV integrase inhibitors. Curr Opin HIV AIDS. 2012;7(5):401–8.

    Article  PubMed  CAS  Google Scholar 

  4. Abram ME, Hluhanich RM, Goodman DD, 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(6):2654–63.

    Article  PubMed  CAS  Google Scholar 

  5. Powderly WG. Integrase inhibitors in the treatment of HIV-1 infection. J Antimicrob Chemother. 2010;65(12):2485–8.

    Article  PubMed  CAS  Google Scholar 

  6. ViiV Healthcare. US prescribing information for Tivicay (dolutegravir). 2013. http://www.viivhealthcare.com/media/58599/us_tivicay.pdf. Accessed 23 Aug 2013.

  7. Eron JJ, Clotet B, Durant J, et al. Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study. J Infect Dis. 2013;207(5):740–8.

    Article  PubMed  CAS  Google Scholar 

  8. Williams I, Churchill D, Anderson J, et al. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy. HIV Med. 2012;13(Suppl. 2):1–85.

    Google Scholar 

  9. EACS European AIDS Clinical Society. Guidelines Version 6.1. 2012. http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. Accessed 10 Sep 2013.

  10. Wainberg MA, Mesplede T, Quashie PK. The development of novel HIV integrase inhibitors and the problem of drug resistance. Curr Opin Virol. 2012;2(5):656–62.

    Article  PubMed  CAS  Google Scholar 

  11. Tang MW, Shafer RW. HIV-1 antiretroviral resistance: scientific principles and clinical applications. Drugs. 2012;72(9):e1–25.

    Article  PubMed  Google Scholar 

  12. Geretti AM, Armenia D, Ceccherini-Silberstein F. Emerging patterns and implications of HIV-1 integrase inhibitor resistance. Curr Opin Infect Dis. 2012;25(6):677–86.

    Article  PubMed  CAS  Google Scholar 

  13. Lenz JCC, Rockstroh JK. S/GSK1349572, a new integrase inhibitor for the treatment of HIV: promises and challenges. Expert Opin Investig Drugs. 2011;20(4):537–48.

    PubMed  CAS  Google Scholar 

  14. Karmon SL, Markowitz M. Next-generation integrase inhibitors: where to after raltegravir? Drugs. 2013;73(3):213–28.

    Article  PubMed  Google Scholar 

  15. U.S. Food and Drug Administration. FDA approves new drug to treat HIV infection. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm. Accessed 23 Aug 2013.

  16. ViiV Healthcare. ViiV Healthcare announces regulatory submissions for dolutegravir in the EU, US and Canada. 2012. http://www.viivhealthcare.com/media/press-releases/2012/december/viiv-healthcare-announces-regulatory-submissions-for-dolutegravir-in-the-eu-us-and-canada.aspx. Accessed 10 Sep 2013.

  17. ViiV Healthcare. ViiV Healthcare announces U.S. approval of Tivicay(Rm) (dolutegravir) for the treatment of HIV-1. 2013. http://www.viivhealthcare.com/media/press-releases/2013/august/viiv-healthcare-announces-us-approval-of-tivicay%C2%AE-dolutegravir-for-the-treatment-of-hiv-1.aspx. Accessed 10 Sep 2013.

  18. ViiV Healthcare Ltd. Shionogi and ViiV Healthcare announce new agreement to commercialise and develop integrase inhibitor portfolio. 2012. http://www.viivhealthcare.com/media/press-releases/2012/october/shionogi-and-viiv-healthcare-announce-new-agreement-to-commercialise-and-develop-integrase-inhibitor-portfolio.aspx. Accessed 10 Sep 2013.

  19. ViiV Healthcare. ViiV Healthcare launches: A new specialist HIV company dedicated to delivering advances in HIV treatment and care. 2009. http://www.viivhealthcare.com/media/press-releases/2012/october/shionogi-and-viiv-healthcare-announce-new-agreement-to-commercialise-and-develop-integrase-inhibitor-portfolio.aspx. Accessed 10 Sep 2013.

  20. Sato A. In vitro passage of drug resistant HIV-1 against a next generation integrase inhibitor (INI), S/GSK1349572. In: 49th interscience conference on antimicrobial agents and chemotherapy. 2009:abstr. H-932.

  21. Underwood MR, Johns BA, Sato A, et al. The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J Acquir Immune Defic Syndr. 2012;61(3):297–301.

    Article  PubMed  CAS  Google Scholar 

  22. Seki T, Kobayashi M, Miki S, et al. High barrier to resistance for dolutegravir (DTG, S/GSK1349572) against raltegravir resistant Y143 mutants: An in vitro passage study. Antivir Ther. 2012;17:A62.

    Google Scholar 

  23. Vavro C, Hasan S, Madsen H, et al. Prevalent polymorphisms in wild-type HIV-1 integrase are unlikely to engender drug resistance to dolutegravir (S/GSK1349572). Antimicrob Agents Chemother. 2013;57(3):1379–84.

    Article  PubMed  CAS  Google Scholar 

  24. Kobayashi M, Seki T, Yoshinaga T, et al. Antiviral activity in vitro of the INI, dolutegravir, against raltegravir-resistant HIV-2 mutants [abstract no. 691]. In: 19th conference on retroviruses and opportunistic infections, Washington, DC, Mar 5–8 2012.

  25. Vavro CL, Dudas KC, Hasan S, et al. Dolutegravir treatment of HIV subjects with raltegravir resistance: integrase resistance evolution in cohort II of the VIKING study. Antivir Ther. 2012;17:A13.

    Google Scholar 

  26. Stellbrink H-J, Reynes J, Lazzarin A, et al. Dolutegravir in antiretroviral-naive adults with HIV-1: 96-week results from a randomized dose-ranging study. AIDS. 2013;27(11):1771–8.

    Article  PubMed  CAS  Google Scholar 

  27. ViiV Healthcare. Dolutegravir studies [ClinicalTrials.gov]. 2013. http://clinicaltrials.gov/ct2/results?term=dolutegravir&pg=2. Accessed 26 Aug 2013.

  28. GlaxoSmithKline. GSK1349572 studies [ClinicalTrials.gov]. 2013. http://clinicaltrials.gov/ct2/results?term=GSK1349572&Search=Search. Accessed 26 Aug 2013.

  29. Greener BN, Adams J, Patterson K, et al. Single and multiple dose dolutegravir pharmacokinetics in the genital tract and colorectum of HIV- men and women [abstract no. 531]. In: 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, Mar 3–6 2013.

  30. Patel P, Song I, Borland J, et al. Pharmacokinetics of a dolutegravir pediatric granule formulation in healthy adult subjects [abstract no. 985]. In: 19th conference on retroviruses and opportunistic infections; 2012 Mar 5–8, Seattle, WA, 2012.

  31. Min S, Song I, Borland J, et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother. 2010;54(1):254–8.

    Article  PubMed  CAS  Google Scholar 

  32. Song I, Borland J, Chen S, et al. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother. 2012;56(3):1627–9.

    Article  PubMed  CAS  Google Scholar 

  33. Castellino S, Moss L, Wagner D, et al. Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans. Antimicrob Agents Chemother. 2013;57(8):3536–46.

    Article  PubMed  CAS  Google Scholar 

  34. Reese MJ, Savina PM, Generaux GT, et al. In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor. Drug Metab Dispos. 2013;41(2):353–61.

    Article  PubMed  CAS  Google Scholar 

  35. Song I, Min SS, Borland J, et al. The effect of lopinavir/ritonavir and darunavir/ritonavir on the HIV integrase inhibitor S/GSK1349572 in healthy participants. J Clin Pharmacol. 2011;51(2):237–42.

    Article  PubMed  CAS  Google Scholar 

  36. Song I, Borland J, Min S, et al. Effects of etravirine alone and with ritonavir-boosted protease inhibitors on the pharmacokinetics of dolutegravir. Antimicrob Agents Chemother. 2011;55(7):3517–21.

    Article  PubMed  CAS  Google Scholar 

  37. Song I, Borland J, Chen S, et al. Effect of atazanavir and atazanavir/ritonavir on the pharmacokinetics of the next-generation HIV integrase inhibitor, S/GSK1349572. Br J Clin Pharmacol. 2011;72(1):103–8.

    Article  PubMed  CAS  Google Scholar 

  38. Song I, Min SS, Borland J, et al. Lack of interaction between the HIV integrase inhibitor S/GSK1349572 and tenofovir in healthy subjects. JAIDS. 2010;55(3):365–7.

    Google Scholar 

  39. Patel P, Song I, Borland J, et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers. J Antimicrob Chemother. 2011;66(7):1567–72.

    Article  PubMed  CAS  Google Scholar 

  40. Dooley KE, Sayre P, Borland J, et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr. 2013;62(1):21–7.

    Article  PubMed  CAS  Google Scholar 

  41. Song I, Mark S, Borland J, et al. Dolutegravir has no effect on pharmacokinetics of methadone or oral contraceptives with norgestimate and ethinyl estradiol [abstract no. 535]. In: 20th Conference on Retroviruses and Opportunistic Infections; 2013 Mar 3–6; Atlanta, GA.

  42. Raffi F, Rachlis A, Stellbrink H-J, et al. 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(9868):735–43.

    Article  PubMed  CAS  Google Scholar 

  43. Raffi F, Jaeger H, Motta D, et al. Dolutegravir is non-inferior to raltegravir and shows durable response through 96 weeks: results from the SPRING-2 trial [TULBPE17]. In: 7th International AIDS Society Conference on HIV Pathogenesis and Treatment; 2013 Jun 30–Jul 03, Kuala Lumpur.

  44. Walmsey S, Antela A, Clumeck N, et al. Dolutegravir + abacavir/lamivudine once daily statistically superior to tenofovir/emtricitabine/efavirenz: 48-week results—SINGLE [abstract H-556b] [abstract no. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2012 Sept 9–12; San Francisco, CA.

  45. ViiV Healthcare. Dolutegravir compared to darunavir/ritonavir, each in combination with dual nucleoside reverse transcriptase inhibitors (NRTIs) in ART-naive subjects (FLAMINGO) [ClinicalTrials.gov identifier NCT01449929]. 2013. http://clinicaltrials.gov/ct2/results?term=dolutegravir&pg=1. Accessed 26 Aug 2013.

  46. Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir (DTG) is superior to raltegravir (RAL) in ART-experienced, integrase naive subjects: week 48 results from SAILING (ING111762) [WELBB03]. In: 7th International AIDS Society Conference on HIV Pathogenesis and Treatment; 2013 Jun 30–Jul 03, Kuala Lumpur.

  47. Pozniak A, Mingrone H, Shuldyakov A, et al. Dolutegravir vs raltegravir in ART-experienced, integrase-naive subjects: 24-week interim results from SAILING (ING111762) [abstract no. 179LB]. In: 20th Conference on Retroviruses and Opportunistic Infections; 2013 Mar 3–6, Atlanta, GA.

  48. Cahn P, Pozniak AL, Mingrone H, et al. 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(9893):700–8.

    Article  PubMed  CAS  Google Scholar 

  49. Cahn P, Pozniak AL, Shuldyakov A, et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase- inhibitor-naive adults with HIV: week 48 results from the randomised, double- blind, non-inferiority SAILING study. World Wide Web [online]. 2013 Jul 10.

  50. Nichols G, Mills A, Grossberg R, et al. Antiviral activity of dolutegravir in subjects with failure on an integrase inhibitor-based regimen: week 24 phase 3 results from VIKING-3 [abstract no. O232]. In: 11th International Congress on Drug Therapy in HIV Infection; 2012 Nov 11–15; Glasgow.

  51. Nichols G, Lazzrin A, Maggiolo F, et al. Phase 3 assessment of dolutegravir (DTG) 50 mg twice daily in HIV-1 infected subjects with raltegravir (RAL) and/or elvitegravir (EVG) resistence in VIKING-3: week 24 results of all 183 patients enrolled [abstract no. TULBPE19]. In: 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; 2013 Jun 30–Jul 3; Kuala Lumpur.

  52. van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012;12(2):111–8.

    Article  PubMed  Google Scholar 

  53. Min S, Sloan L, DeJesus E, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS. 2011;25(14):1737–45.

    Article  PubMed  CAS  Google Scholar 

  54. Eron Jr J, Rockstroh J, Pozniak A, et al. Dolutegravir treatment response by baseline viral load and NRTI backbone in treatment-naive HIV-infected individuals [poster no. P204]. 11th International Congress on Drug Therapy in HIV Infection. JIAS. 2013; 15(Suppl. 4):18264.

  55. Brinson C, Walmsley S, Arasteh K, et al. Dolutegravir treatment response and safety by key subgroups in treatment-naive HIV + individuals [abstract no. 554]. In: 20th Conference on Retroviruses and Opportunistic Infections; 2013 Mar 3–6; Atlanta (GA), Atlanta.

  56. Chen S, Min SS, Peppercorn A, et al. Effect of a single supratherapeutic dose of dolutegravir on cardiac repolarization. Pharmacother J Human Pharmacol Drug Ther. 2012;32(4):333–9.

    Article  CAS  Google Scholar 

  57. ViiV Healthcare. A trial comparing GSK1349572 50 mg plus abacavir/lamivudine once daily to Atripla (also called the SINGLE trial) [Clinicaltrials.gov identifier NCT01263015]. 2013. http://clinicaltrials.gov/ct2/results?term=dolutegravir&pg=1. Accessed 26 Aug 2013.

  58. Viiv Healthcare. Study assessing dolutegravir in HIV-1 infected subjects with virus resistant to raltegravir and/or elivitegravir (VIKING-4) [ClinicalTrials.gov identifier NCT01568892]. 2013. http://clinicaltrials.gov/ct2/results?term=dolutegravir&pg=1. Accessed 26 Aug 2013.

  59. ViiV Healthcare. A study to assess dolutegravir in HIV-infected subjects with treatment failure on an integrase inhibitor containing regimen (VIKING-3) [ClinicalTrials.gov identifier NCT01328041]. 2013. http://clinicaltrials.gov/ct2/results?term=dolutegravir&pg=1. Accessed 26 Aug 2013.

  60. ViiV Healthcare. A pilot study assessing the integrase inhibitor GSK1349572 in HIV-infected persons with virus resistant to raltegravir [ClinicalTrials.gov identifier NCT00950859]. 2013. http://clinicaltrials.gov/ct2/results?term=dolutegravir&pg=2. Accessed 26 Aug 2013.

  61. Viiv Healthcare. A study to determine safety and efficacy of dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) in human immunodeficiency virus (HIV)-1 infected antiretroviral therapy (ART) naïve women (ARIA) [ClinicalTrials.gov identifier NCT01910402]. 2013. http://clinicaltrials.gov/ct2/results?term=dolutegravir&pg=1. Accessed 26 Aug 2013.

  62. ViiV Healthcare. Dolutegravir Expanded Access Study (DEAP) [ClinicalTrials.gov identifier NCT01536873]. 2013. http://clinicaltrials.gov/ct2/results?term=dolutegravir&pg=1. Accessed 26 Aug 2013.

Download references

Author information

Authors and Affiliations

  1. Adis R & D Insight, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, 0754, Auckland, New Zealand

    Anita D. Ballantyne

  2. Adis, Auckland, New Zealand

    Caroline M. Perry

Authors
  1. Anita D. Ballantyne
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Caroline M. Perry
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anita D. Ballantyne.

Additional information

This profile has been extracted and modified from the Adis R&D Insight drug pipeline database. Adis R&D Insight tracks drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ballantyne, A.D., Perry, C.M. Dolutegravir: First Global Approval. Drugs 73, 1627–1637 (2013). https://doi.org/10.1007/s40265-013-0121-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-013-0121-4

Keywords

Search

Navigation