Safety and Efficacy of Dolutegravir in Treatment-Experienced Subjects With Raltegravir-Resistant HIV Type 1 Infection: 24-Week Results of the VIKING Study

Integrase inhibitors (INIs) represent a class of drugs for the treatment of human immunodeficiency virus (HIV)–infected individuals, blocking HIV genome integration into the host cell DNA [1]. They have been shown to be highly effective for the treatment of antiretroviral-naive and antiretroviral-experienced subjects, as demonstrated first with raltegravir (RAL) and more recently with elvitegravir (EVG) [2–6]. However, these first-generation INIs share common resistance pathways. In clinical studies of RAL, subjects with virologic failure and reduced RAL susceptibility typically harbored virus with 1 of 3 signature mutational pathways (ie, N155H, Q148H/K/R, or Y143C/H/R) in the integrase gene [7]. Continuing RAL treatment in these circumstances may lead to the addition of secondary mutations or pathway evolution; N155H may evolve to Y143 or Q148 pathways [4]. In addition, EVG does not appear to have activity against RAL-resistant isolates, and RAL does not appear to have activity against EVG-resistant isolates [8–10]. Therefore, there is a need for an INI with a high barrier to resistance and activity in subjects with human immunodeficiency virus type 1 (HIV-1) resistant to EVG and RAL. Dolutegravir (DTG) is a new HIV-1 INI that has demonstrated good efficacy and safety in treatment-naive, HIV-infected individuals [11]. In vitro studies demonstrate limited cross-resistance between DTG and RAL or EVG, with no or minimal impact on DTG fold-change against Q148 single mutants or against viruses with Y143 or N155 signature mutations regardless of RAL-associated secondary mutations [12, 13]. However, the DTG fold-change increased for Q148H/K/R as secondary RAL resistance–associated mutations increased. On the basis of these in vitro findings, this phase IIb pilot study was conducted to assess and demonstrate the activity of DTG in HIV-1–infected individuals with RAL-resistant viral isolates.