A New Mechanism of Resistance of Human Immunodeficiency Virus Type 2 to Integrase Inhibitors: A 5-Amino-Acid Insertion in the Integrase C-Terminal Domain

Background: Integrase strand-transfer inhibitors (INSTI) are crucial for treatment of HIV-2 infection, due to limited available therapeutic options. Recently, bictegravir has been approved for HIV-1-infected patients but no data are currently available for HIV-2. Methods: We assessed phenotypic susceptibility to the five INSTI (bictegravir, cabotegravir, dolutegravir, elvitegravir and raltegravir) of 12 HIV-2 clinical isolates obtained from two antiretroviral-naive and 10 antiretroviral-experienced patients at virological failure of an INSTI-based regimen. 50% Inhibitory Concentrations (IC50) were determined. Phenotypic Inhibitory Quotients were determined after measurement of trough INSTI plasma concentrations. Results: Wild-type viruses were susceptible to the five INSTI with IC50 in the low nanomolar range. Bictegravir had lower IC50 than other INSTIs on HIV-2 isolates bearing major resistance-associated mutations (RAM, i.e. codons 143, 148 and 155). We identified a new INSTI-resistance profile, a 5-amino-acids insertion at codon 231 of HIV-2 integrase (231INS) in six patients at virological failure of a raltegravir-based regimen. Those patients had adequate raltegravir concentrations but harboured multi-resistant viruses with low genotypic susceptibility score (median=1.5). This insertion rendered isolates highly resistant to raltegravir and elvitegravir, and moderately resistant to dolutegravir and cabotegravir. Regarding bictegravir, two isolates remained susceptible and two had a slight increase in IC50 (3- to 5-fold-change). Conclusions: Our results confirm the potency of integrase inhibitors on wild-type integrase HIV-2 clinical isolates. In addition, we identified a new INSTI resistance pathway, 231INS, selected in highly antiretroviral-experienced patients with multi-resistant HIV-2 viruses. This highlights the need of a close follow-up of such patients initiating an INSTI-based regimen.