Resistance to HIV Integrase Strand Transfer Inhibitors among Clinical Specimens in the United States, 2009-2012

As the newest class of antiretrovirals (ARVs), integrase strand transfer inhibitors (INSTIs) have assumed an important role in treating human immunodeficiency virus (HIV) infection. Raltegravir became part of a preferred initial regimen in the United States for HIV-infected adults [1] within 2 years of Food and Drug Administration (FDA) approval [2], owing to its demonstrated efficacy and favorable safety profile in treatment-experienced [3] and -naive patients [4]. The second drug in the class, elvitegravir [5, 6], is a component of an alternative INSTI-based regimen for treatment-naive patients [7], in a fixed-dose combination tablet with tenofovir disoproxil fumarate, emtricitabine, and the pharmacologic booster cobicistat [8]. Dolutegravir, a second-generation INSTI, was approved by the FDA in August 2013 [9]. Despite the potency, tolerability, and durability of first-generation INSTIs, resistance mutations are detected in up to 60% of patients with virologic failure in clinical trials studying highly treatment-experienced patients, and up to 8% in studies of initial therapy [10, 11]. Three principal mutation pathways reduce susceptibility to raltegravir: Y143CHR, Q148HKR, and N155H. These codons are located in close proximity to integrase's active site, and each mutation significantly reduces viral fitness [12]. Certain compensatory mutations can partially or fully restore viral replicative capacity: T97A rescues catalytic function in the presence of Y143 mutants, similar to G140ACS or E138AK for Q148 mutants [13]. In the case of N155H, its main accessory mutation, E92QV, further reduces susceptibility without restoring fitness—a fact that helps explain why N155 mutants are frequently replaced by Q148 ± G140 [14] in vivo. Interestingly, E92Q is the most common initial mutation to arise during failure of elvitegravir-based regimens, followed by N155H and Q148R [15]. Due to unique interactions between active site residues and raltegravir, substitutions at Y143 unaccompanied by additional mutations have no effect on in vitro susceptibility to dolutegravir [16] and little [17] to no [18] effect on elvitegravir. Indeed, dolutegravir retains activity against all single-mutation variants [16, 19, 20]. Patients continued on failing raltegravir-containing regimens may accumulate multiple mutations over time [21]—a scenario that can reduce susceptibilities to other INSTIs, including dolutegravir. In 2 studies of dolutegravir among patients who failed raltegravir (VIKING-2 and -3), the greatest reduction in dolutegravir susceptibility occurred when Q148 was accompanied by ≥2 other major mutations. However, a reduced but measurable antiretroviral effect was still observed in most patients [19, 20]. Two recently identified mutations, G118R and R263K, each confer low-level resistance to dolutegravir [22, 23]. Both have been reported in vivo [24, 25]. Although much is known about the mutation pathways affecting INSTIs, all such data come from in vitro experiments or clinical trials. In this report, we focus on integrase genotypic resistance tests (GRTs) sent to a US national referral laboratory, in order to characterize the profile of INSTI resistance among specimens obtained for clinical decision making. Our principal aims were to (1) describe the prevalence of INSTI resistance and the patterns of mutations resulting from INSTI failures in a clinical population; (2) determine the association between integrase and protease–reverse transcriptase (PR-RT) mutations among patients with paired GRTs; and (3) assess the frequency of mutation patterns likely to impact dolutegravir susceptibility among patients harboring viruses with resistance to first-generation INSTIs.