title: The preclinical discovery and development of dolutegravir for the treatment of HIV.
abstract: BACKGROUND
  Integration of the viral genome into the host cell chromatin is a central step in the replication cycle of HIV. Blocking the viral integrase (IN) enzyme therefore provides an attractive therapeutic strategy, as evidenced by the recent clinical approval of three IN strand transfer inhibitors. Dolutegravir is a therapy that is unique in its ability to evade HIV drug resistance in treatment-naïve patients.
  
  
  METHODS
  This review starts by providing a brief summary of the history of HIV-1 IN inhibitors. The authors follow this with details of the discovery and preclinical and clinical developments of dolutegravir. Finally, the authors provide details of dolutegravir's post-launch including the launch of the combination pill of dolutegravir, abacavir and lamivudine in August 2014.
  
  
  CONCLUSIONS
  The launch of raltegravir, the first IN inhibitor from Merck & Co., has created new hopes for the patient. Indeed, pharmaceutical companies have not lost courage by attempting to address the major drawbacks of this first-in-class molecule. And while the drug elvitegravir has been inserted into a four-drug combination pill providing a once-daily dosing alternative, dolutegravir has demonstrated superiority in terms of its efficacy and resistance.
authors.affiliation: a 1 Universite de lille, Pharmaceutical and Biological Sciences , 3, rue du Pr Laguesse, BP83, Lille 59006, France +33 0 3 62 28 36 94 ; philippe.cotelle@univ-lille1.fr.|b 2 Jean-Pierre Aubert Research Center UMR-S1172 INSERM, Onco and Neurochemistry team , 3, rue du Pr Laguesse, BP83, Lille 59006, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bailly
authors.affiliation: a 1 Universite de lille, Pharmaceutical and Biological Sciences , 3, rue du Pr Laguesse, BP83, Lille 59006, France +33 0 3 62 28 36 94 ; philippe.cotelle@univ-lille1.fr.|b 2 Jean-Pierre Aubert Research Center UMR-S1172 INSERM, Onco and Neurochemistry team , 3, rue du Pr Laguesse, BP83, Lille 59006, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Cotelle
mesh_terms: D000818:Animals; D015224:Dideoxynucleosides / Q000008:administration & dosage; D004338:Drug Combinations; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099227:Abacavir; D000099226:Dolutegravir
chemical_list: D015224:Dideoxynucleosides; D004338:Drug Combinations; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D019259:Lamivudine; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099227:Abacavir; D000099226:Dolutegravir
keywords: AIDS; HIV integrase; combination antiretroviral therapy; drug resistance; pharmacokinetics