Resistance associated mutations to dolutegravir (S/GSK1349572) in HIV-infected patients--impact of HIV subtypes and prior raltegravir experience

Abstract

Dolutegravir (S/GSK1349572) is a second-generation HIV-1 integrase inhibitor (INI) in advanced clinical development. It has shown good antiviral activity in most patients with prior raltegravir failure, although changes at the integrase codon 148, particularly when combined with other mutations, confer reduced susceptibility and may impair dolutegravir activity. Mutations believed to be associated with dolutegravir resistance at positions 92, 101, 124, 148, 153, and 193 were assessed in patients either INI-naïve or experiencing failure to raltegravir-based regimens. The integrase coding region was sequenced using an in-house nested-PCR protocol. HIV-1 subtyping was carried out using the Stanford algorithm. A total of 638 plasma samples were analyzed from 535 INI-naïve and 103 raltegravir-experienced patients. Non-B subtypes were recognized in 20.8% patients. Mutations L101I and T124A were significantly more prevalent in patients with non-B subtypes (66.9% vs. 45.7% for L101I; 61.7% vs. 25.9% for T124A; and 39.1% vs. 12.7% for L101I+T124A; p<0.001 in all cases). E92Q and Q148H/R were only seen in raltegravir-experienced patients and exclusively infected with subtype B (1.9% vs. 0%, p=0.026, for E92Q and 12.6% vs. 0%, p<0.001, for Q148H/R). On the contrary, T124A was more frequent in INI-naïve than raltegravir-experienced patients (35.1% vs. 24.3%, p=0.040). S153Y/F was absent in this dataset. Polymorphic changes L101I and T124A were more frequent in HIV-1 non-B than B subtypes. T124A was more frequent in INI-naïve patients but E92Q and Q148H/R were only seen in raltegravir-experienced individuals. Thus, both HIV-1 subtype and raltegravir exposure may influence the antiviral activity of dolutegravir.