title: Genetic barrier to resistance for dolutegravir.
abstract: Dolutegravir is a novel integrase strand-transfer inhibitor that displays potent in vitro activity and a remarkably different resistance profile. Its robust pharmacokinetic/pharmacodynamic properties - long plasma t1/2, high plasma inhibition quotient, and slow dissociation rate from the integrase complex - suggest it should present a high barrier to resistance development. This has been confirmed in pivotal phase III studies of initial therapy, with none out of 1,118 treated individuals selecting resistance-associated mutations at the integrase or reverse transcriptase. In integrase-naive subjects with virological failure, a rescue intervention with dolutegravir has shown significantly higher rates of virological suppression than raltegravir, as well as significantly lower rates of selection of resistance both at the integrase and against the optimized background. Unexpectedly, a mutation rarely selected in this scenario (R263K) induces a fitness cost that prevents HIV-1 from evading drug pressure, and accumulation of further secondary mutations does not occur and has not been able to compensate the replication capacity deficit in the aftermath of the appearance of a single drug resistance mutation. Therefore, both in vitro and in vivo, it leads the virus to a previously unnoticed evolutionary pathway with low chances to develop resistance to both dolutegravir and other families of antiretrovirals present in the background. This high genetic barrier to resistance development in early stages of antiretroviral treatment can help preserve future treatment options in patients who fail antiretroviral therapy.
authors.affiliation: HIV Unit and "Lluita contra la SIDA Fndn", Univ Hosp Germans Trias i Pujol, Badalona, Spain and Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llibre
authors.affiliation: HIV Unit, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Pulido
authors.affiliation: Microbiology Dpt., Instituto de Investigación Biosanitaria IBS, Hospitales Universitarios de Granada, Granada, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: García
authors.affiliation: Infectious Diseases Unit, Consorcio Hospital General Universitario de Valencia, Valencia, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: García Deltoro
authors.affiliation: Infectious Diseases, Hospital Clinic IDIBAPS, Barcelona, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Blanco
authors.affiliation: Laboratory of Molecular Microbiology, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Delgado
mesh_terms: D017326:Clinical Trials, Phase III as Topic; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects*; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir
chemical_list: D019428:HIV Integrase Inhibitors; D054303:HIV Reverse Transcriptase; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir