Quentin Le Hingrat1,2, Gilles Collin1,2, Minh Lê1,3, Gilles Peytavin1,3, Benoit Visseaux1,2, Mélanie Bertine1,2, Roland Tubiana4,5, Marina Karmochkine6, Nadia Valin7, Fidéline Collin8,9, Adrien Lemaignen10, Louis Bernard10, Florence Damond1,2, Sophie Matheron1,11, Diane Descamps1,2, Charlotte Charpentier1,2. 1. Infections Antimicrobials Modelling Evolution, Unité Mixte de Recherche (UMR) 1137, Institut national de la santé et de la recherche médicale (INSERM), Université Paris Diderot, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital St-Antoine, Paris. 2. Laboratoire de Virologie, Hôpital St-Antoine, Paris. 3. Laboratoire de Pharmacologie, Hôpital Bichat, AP-HP, Hôpital St-Antoine, Paris. 4. Service de Maladies Infectieuses, Hôpital Pitié-Salpêtrière, AP-HP, Hôpital St-Antoine, Paris. 5. Sorbonne Universités, Université Paris 6-Pierre et Marie Curie, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique (UMRS 1136), Hôpital St-Antoine, Paris. 6. Service d'Immunologie Clinique, Hôpital Européen Georges Pompidou, Hôpital St-Antoine, Paris. 7. Service de Maladies Infectieuses et Tropicales, Hôpital St-Antoine, Paris. 8. Bordeaux Population Health Center, UMR 1219, INSERM, AP-HP, Paris, France. 9. Centre Hospitalier Universitaire de Bordeaux, AP-HP, Paris, France. 10. Service de Médecine Interne et Maladies Infectieuses, Centre Hospitalier Universitaire de Tours, AP-HP, Paris, France. 11. Service de Maladies Infectieuses et Tropicales, Hôpital Bichat, AP-HP, Paris, France.
Abstract
BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are crucial for the treatment of human immunodeficiency virus (HIV) type 2 infection, due to limited available therapeutic options. Recently, bictegravir has been approved for HIV-1, but no data are currently available for HIV-2. METHODS: We assessed the phenotypic susceptibility of 12 HIV-2 clinical isolates, obtained from 2 antiretroviral-naive and 10 antiretroviral-experienced patients, to 5 INSTIs (bictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir) at the virological failure of an INSTI-based regimen. The 50% inhibitory concentrations (IC50s) were determined. Phenotypic inhibitory quotients were determined using trough INSTI plasma concentrations. RESULTS: Wild-type viruses were susceptible to the 5 INSTIs, with IC50s in the nanomolar range. Bictegravir had a lower IC50 than the other INSTIs on those HIV-2 isolates bearing major, resistance-associated mutations (codons 143, 148, and 155). We identified a new resistance profile-a 5-amino-acid insertion at codon 231 of the HIV-2 integrase (231INS)-in 6 patients at the virological failure of a raltegravir-based regimen. Those patients had adequate raltegravir concentrations, but harbored multiresistant viruses with low genotypic susceptibility scores (median = 1.5). This insertion rendered isolates highly resistant to raltegravir and elvitegravir, and moderately resistant to dolutegravir and cabotegravir. Regarding bictegravir, 2 isolates remained susceptible and 2 had a slight increase in IC50 (3- to 5-fold change). CONCLUSIONS: Our results confirm the potency of INSTI on HIV-2 clinical isolates with wild-type integrase. In addition, we identified a new resistance pathway, 231INS, selected in antiretroviral-experienced patients with multiresistant HIV-2 viruses. This highlights the need of close follow-up of those patients initiating an INSTI-based regimen.
BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are crucial for the treatment of human immunodeficiency virus (HIV) type 2 infection, due to limited available therapeutic options. Recently, bictegravir has been approved for HIV-1, but no data are currently available for HIV-2. METHODS: We assessed the phenotypic susceptibility of 12 HIV-2 clinical isolates, obtained from 2 antiretroviral-naive and 10 antiretroviral-experienced patients, to 5 INSTIs (bictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir) at the virological failure of an INSTI-based regimen. The 50% inhibitory concentrations (IC50s) were determined. Phenotypic inhibitory quotients were determined using trough INSTI plasma concentrations. RESULTS: Wild-type viruses were susceptible to the 5 INSTIs, with IC50s in the nanomolar range. Bictegravir had a lower IC50 than the other INSTIs on those HIV-2 isolates bearing major, resistance-associated mutations (codons 143, 148, and 155). We identified a new resistance profile-a 5-amino-acid insertion at codon 231 of the HIV-2 integrase (231INS)-in 6 patients at the virological failure of a raltegravir-based regimen. Those patients had adequate raltegravir concentrations, but harbored multiresistant viruses with low genotypic susceptibility scores (median = 1.5). This insertion rendered isolates highly resistant to raltegravir and elvitegravir, and moderately resistant to dolutegravir and cabotegravir. Regarding bictegravir, 2 isolates remained susceptible and 2 had a slight increase in IC50 (3- to 5-fold change). CONCLUSIONS: Our results confirm the potency of INSTI on HIV-2 clinical isolates with wild-type integrase. In addition, we identified a new resistance pathway, 231INS, selected in antiretroviral-experienced patients with multiresistant HIV-2 viruses. This highlights the need of close follow-up of those patients initiating an INSTI-based regimen.
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