Abstract
The use of integrase inhibitors (INI) is increasing in antiretroviral therapies (ART) and INI are not all equal regarding genetic barrier to resistance. The aim of this manuscript was to review main in vivo and in vitro knowledge about two particular integrase resistance-associated mutations: R263K and E157Q. The R263K mutation was the first mutation rarely found selected at time of virological failure in patients failing a first-line dolutegravir-based treatment. Further in vitro studies on R263K mutants showed a moderate increase in phenotypic resistance level and a drastic reduction in viral replicative capacity. No compensatory mutations were evidenced. The E157Q mutation is polymorphic, found between 1.7% and 5.6% of viral sequences issued from ART-naïve patients depending on the viral subtype; as well as acquired resistance emerging at failure of a raltegravir-based regimen in two case reports. We reported data on phenotypic resistance level of E157Q mutants and virological response of patients harboring a E157Q virus initiating an INI-based regimen, showing that dolutegravir might be the most recommended INI in such patients. These findings show that there is still a need for a better understanding of resistance mechanisms to INI and emphasized the importance of genotypic background in viral evolution under drug pressure.
Highlights
Human Immunodeficiency Virus (HIV) integrase inhibitors (INI) are the most common drug class recommended by the different international guidelines as third agent of the combined antiretroviral therapy
E157Q integrase mutation is of interest too, since it is both polymorphic, with variable prevalence in INI-naïve patients depending on the viral subtype [3], and selected at virological failure (VF) of a RAL-based regimen in two case reports [4,5] and described in a case report of a non virological response to a DTG-based regimen [6]
Integrase E157Q substitution has been described as a polymorphism present in 2.4% of viral sequences obtained from combined antiretroviral therapy (cART)-naïve patients in the ARCA Italian database and in 5.0% in the last
Summary
Human Immunodeficiency Virus (HIV) integrase inhibitors (INI) are the most common drug class recommended by the different international guidelines as third agent of the combined antiretroviral therapy (cART). There is still data to provide regarding resistance mechanisms to the most recent, second-generation INI, dolutegravir (DTG). In this manuscript, we have reviewed main in vivo and in vitro knowledge about two integrase resistance-associated mutations: R263K and E157Q. E157Q integrase mutation is of interest too, since it is both polymorphic, with variable prevalence in INI-naïve patients depending on the viral subtype [3], and selected at virological failure (VF) of a RAL-based regimen in two case reports [4,5] and described in a case report of a non virological response to a DTG-based regimen [6]
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