title: Dolutegravir, the Second-Generation of Integrase Strand Transfer Inhibitors (INSTIs) for the Treatment of HIV.
abstract: The integrase strand transfer inhibitors (INSTIs) are the newest antiretroviral class in the HIV treatment armamentarium. Dolutegravir (DTG) is the only second-generation INSTI with FDA approval (2013). It has potential advantages in comparison to first-generation INSTI's, including unboosted daily dosing, limited cross resistance with raltegravir and elvitegravir, and a high barrier to resistance. Clinical trials have evaluated DTG as a 50-mg daily dose in both treatment-naïve and treatment-experienced, INSTI-naïve participants. In those treatment-naïve participants with baseline viral load <100,000 copies/mL, DTG combined with abacavir and lamivudine was non-inferior and superior to fixed-dose combination emtricitabine/tenofovir/efavirenz. DTG was also superior to the protease inhibitor regimen darunavir/ritonavir in treatment-naïve participants regardless of baseline viral load. Among treatment-experienced patients naïve to INSTI, DTG (50 mg daily) demonstrated both non-inferiority and superiority when compared to the first-generation INSTI raltegravir (400 mg twice daily) regardless of the background regimen. No phenotypically significant DTG resistance has been demonstrated in INSTI-naïve participant trials. The VIKING trials evaluated DTG's ability to treat persons with HIV with prior INSTI exposure. VIKING demonstrated twice-daily DTG was more efficacious than daily dosing when treating participants receiving and failing first-generation INSTI regimens. DTG maintained potency against single mutations from any of the three major INSTI pathways (Y143, H155, Q148); however, the Q148 mutation with two or more additional mutations significantly reduced its potency. The long-acting formulation of DTG, GSK1265744LA, is the next innovation in this second-generation INSTI class, holding promise for the future of HIV prevention and treatment.
authors.affiliation: Duke University, DUMC 3499, Durham, NC, 27710, USA. dorothy.dow@duke.edu.|Kilimanjaro Christian Medical Centre, Moshi, Tanzania. dorothy.dow@duke.edu.|Division of Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA. dorothy.dow@duke.edu.
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Dow
authors.affiliation: Kilimanjaro Christian Medical Centre, Moshi, Tanzania.|Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC, USA.|Duke Global Health Institute, Duke University, Durham, NC, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Bartlett
keywords: Antiretroviral therapy (ART); Dolutegravir (DTG); GSK1265744LA; HIV; Integrase strand transfer inhibitor (INSTI); Nanoparticle formulation