Phenotypic analysis of HIV-1 E157Q integrase polymorphism and impact on virological outcome in patients initiating an integrase inhibitor-based regimen

Abstract

Objectives: To assess the phenotypic susceptibility of the E157Q polymorphism in HIV-1 integrase (IN) and thevirological outcome of patients infected with E157Q-mutated virus initiating an IN inhibitor (INI)-based regimen.Methods: This was a multicentre study assessing IN sequences from INI-naive patients among 17 FrenchHIV clinical centres. E157Q site-directed mutants in pNL4.3 and pCRF02_AG contexts were assessed in arecombinant phenotypic assay.Results: Prevalence of the E157Q polymorphism was 2.7% among 8528 IN sequences from INI-naive patientsand its distribution was 1.7%, 5.6% and 2.2% in B, CRF02_AG and various non-B subtypes, respectively. ThirtynineINI-naive patients with E157Q-mutated virus initiated an INI-based regimen. Among them, 15 had a viralload (VL)>50 copies/mL at initiation and virological suppression was maintained during the first year of followupin all but two exhibiting a viral blip. Twenty-four patients had a VL.50 copies/mL at the time of INI-based regimeninitiation. Among them eight were receiving a first-line regimen and the only two patients who did notreach VL,50 copies/mL at week 24 were receiving elvitegravir. The 16 remaining patients were ART experiencedin virological failure with drug-resistant viruses displaying several virological outcomes independently of the genotypicsusceptibility score. Phenotypic analyses showed a fold change in EC50 of 0.6, 0.9 and 1.9 for raltegravir,dolutegravir and elvitegravir, respectively, in a subtype B context, and 1.1, 1.9 and 2.4 for raltegravir, dolutegravirand elvitegravir, respectively, in a CRF02_AG context.Conclusions: Assessment of virological response in 39 patients initiating an INI-based regimen withE157Q-mutated virus, in combination with phenotypic analysis, suggests that particular attention should bepaid to antiretroviral-naive patients and dolutegravir should be preferentially used in these patients.