Cross-resistance to elvitegravir and dolutegravir in 502 patients failing on raltegravir: a French national study of raltegravir-experienced HIV-1-infected patients
Authors: Fourati Slim , Charpentier Charlotte , Amiel Corinne , Morand-Joubert Laurence , Reigadas Sandrine , Trabaud Mary-Anne , Delaugerre Constance , Nicot Florence , Rodallec Audrey , Maillard Anne , Mirand Audrey , Jeulin Hélène , Montès Brigitte , Barin Francis , Bettinger Dominique , Le Guillou-Guillemette Hélène , Vallet Sophie , Signori-Schmuck Anne , Descamps Diane , Calvez Vincent , Flandre Philippe , Marcelin Anne-Genevieve ,   on behalf of the ANRS AC11 Resistance Study Group, Lagier E. , Roussel C. , Le Guillou H. , Alloui C. , Bettinger D. , Pallier C. , Fleury H. , Reigadas S. , Bellecave P. , Recordon-Pinson P. , Payan C. , Vallet S. , Vabret A. , Henquell C. , Mirand A. , Bouvier-Alias M. , de Rougemont A. , Dos Santos G. , Morand P. , Signori-Schmuck A. , Bocket L. , Rogez S. , Andre P. , Tardy J. C. , Trabaud M. A. , Tamalet C. , Delamare C. , Montes B. , Schvoerer E. , Ferre V. , André-Garnier E. , Cottalorda J. , Guinard J. , Guiguon A. , Descamps D. , Brun-Vézinet F. , Charpentier C. , Visseaux B. , Peytavin G. , Krivine A. , Si-Mohamed A. , Avettand-Fenoel V. , Marcelin A. G. , Calvez V. , Lambert-Niclot S. , Soulié C. , Wirden M. , Morand-Joubert L. , Delaugerre C. , Chaix M. L. , Amiel C. , Schneider V. , Giraudeau G. , Brodard V. , Maillard A. , Plantier J. C. , Chaplain C. , Bourlet T. , Fafi-Kremer S. , Stoll-Keller F. , Schmitt M. P. , Barth H. , Yerly S. , Poggi C. , Izopet J. , Raymond S. , Barin F. , Chaillon A. , Marque-Juillet S. , Roque-Afonso A. M. , Haïm-Boukobza S. , Flandre P. , Grudé M. , Assoumou L. , Costagliola D. , Allegre T. , Schmit J. L. , Chennebault J. M. , Bouchaud O. , Magy-Bertrand N. , Delfraissy J. F. , Dupon M. , Morlat P. , Neau D. , Ansart S. , Jaffuel S. , Verdon R. , Jacomet C. , Lévy Y. , Dominguez S. , Chavanet P. , Piroth L. , Cabié A. , Leclercq P. , Ajana F. , Cheret A. , Weinbreck P. , Cotte L. , Poizot-Martin I. , Ravaud I. , Christian B. , Truchetet F. , Grandidier M. , Reynes J. , May T. , Goehringer F. , Raffi F. , Dellamonica P. , Prazuck T. , Hocqueloux L. , Yéni P. , Landman R. , Launay O. , Weiss L. , Viard J. P. , Katlama C. , Simon A. , Girard P.M. , Meynard J. L. , Molina J. M. , Pialoux G. , Hoen B. , Goeger-Sow M. T. , Lamaury I. , Beaucaire G. , Jaussaud R. , Rouger C. , Michelet C. , Borsa-Lebas F. , Caron F. , Khuong M. A. , Lucht F. , Rey D. , Calmy A. , Marchou B. , Gras G. , Greder-Belan A. , Vittecoq D. , Teicher E. 
Published: January 2015

Abstract

Objectives
The objectives of this study were to determine the prevalence and patterns of resistance to integrase strand transfer inhibitors (INSTIs) in patients experiencing virological failure on raltegravir-based ART and the impact on susceptibility to INSTIs (raltegravir, elvitegravir and dolutegravir).

Patients and methods
Data were collected from 502 treatment-experienced patients failing a raltegravir-containing regimen in a multicentre study. Reverse transcriptase, protease and integrase were sequenced at failure for each patient. INSTI resistance-associated mutations investigated were those included in the last ANRS genotypic algorithm (v23).

Results
Among the 502 patients, at failure, median baseline HIV-1 RNA (viral load) was 2.9 log10 copies/mL. Patients had been previously exposed to a median of five NRTIs, one NNRTI and three PIs. Seventy-one percent harboured HIV-1 subtype B and the most frequent non-B subtype was CRF02_AG (13.3%). The most frequent mutations observed were N155H/S (19.1%), Q148G/H/K/R (15.4%) and Y143C/G/H/R/S (6.7%). At failure, viruses were considered as fully susceptible to all INSTIs in 61.0% of cases, whilst 38.6% were considered as resistant to raltegravir, 34.9% to elvitegravir and 13.9% to dolutegravir. In the case of resistance to raltegravir, viruses were considered as susceptible to elvitegravir in 11% and to dolutegravir in 64% of cases. High HIV-1 viral load at failure (P &lt; 0.001) and low genotypic sensitivity score of the associated treatment with raltegravir (P &lt; 0.001) were associated with the presence of raltegravir-associated mutations at failure. Q148 mutations were selected more frequently in B subtypes versus non-B subtypes (P = 0.004).

Conclusions
This study shows that a high proportion of viruses remain susceptible to dolutegravir in the case of failure on a raltegravir-containing regimen.