Format

Send to

Choose Destination
Clin Infect Dis. 2018 Nov 1. doi: 10.1093/cid/ciy940. [Epub ahead of print]

A new mechanism of resistance of HIV-2 to integrase inhibitors: a 5 amino-acids insertion in the integrase C-terminal domain.

Author information

1
IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Laboratoire de Virologie, Hôpital Bichat, AP-HP, Paris, France.
2
IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Laboratoire de Pharmacologie, Hôpital Bichat, AP-HP, Paris, France.
3
Service de Maladies Infectieuses, AP-HP Hôpital Pitié-Salpêtrière, Paris. Sorbonne Universités, Université Paris 6 - Pierre et Marie Curie, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France.
4
Hôpital Européen Georges Pompidou, Service d'Immunologie Clinique, Paris, France.
5
Hôpital St-Antoine, Service de Maladies Infectieuses et Tropicales, Paris, France.
6
Centre de Méthodologie et de Gestion, Université de Bordeaux, Bordeaux, France.
7
CHRU de Tours, Service de Médecine Interne et Maladies Infectieuses, Tours, France.
8
IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Service de Maladies Infectieuses et Tropicales, Hôpital Bichat, AP-HP, Paris, France.

Abstract

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-naïve 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.

PMID:
30383215
DOI:
10.1093/cid/ciy940

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center