Universität zu Köln

Doyle, Tomas, Dunn, David T., Ceccherini-Silberstein, Francesca, De Mendoza, Carmen, Garcia, Frederico, Smit, Erasmus, Fearnhill, Esther, Marcelin, Anne-Genevieve ORCID: 0000-0003-4808-8999, Martinez-Picado, Javier ORCID: 0000-0002-4916-2129, Kaiser, Rolf and Geretti, Anna Maria (2015). Integrase inhibitor (INI) genotypic resistance in treatment-naive and raltegravir-experienced patients infected with diverse HIV-1 clades. J. Antimicrob. Chemother., 70 (11). S. 3080 - 3087. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2091

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Abstract

Objectives: The aim of this study was to characterize the prevalence and patterns of genotypic integrase inhibitor (INI) resistance in relation to HIV-1 clade. Methods: The cohort comprised 533 INI-naive subjects and 255 raltegravir recipients with viraemia who underwent integrase sequencing in routine care across Europe, including 134/533 (25.1%) and 46/255 (18.0%), respectively, with non-B clades (A, C, D, F, G, CRF01, CRF02, other CRFs, complex). Results: No major INI resistance-associated mutations (RAMs) occurred in INI-naive subjects. Among raltegravir recipients with viraemia (median 3523 HIV-1 RNA copies/mL), 113/255 (44.3%) had one or more major INI RAMs, most commonly N155H (45/255, 17.6%), Q148H/R/K+G140S/A (35/255, 13.7%) and Y143R/C/H (12/255, 4.7%). In addition, four (1.6%) raltegravir recipients showed novel mutations at recognized resistance sites (E92A, S147I, N155D, N155Q) and novel mutations at other integrase positions that were statistically associated with raltegravir exposure (K159Q/R, I161L/M/T/V, E170A/G). Comparing subtype B with non-B clades, Q148H/R/K occurred in 42/209 (20.1%) versus 2/46 (4.3%) subjects (P = 0.009) and G140S/A occurred in 36/209 (17.2%) versus 1/46 (2.2%) subjects (P = 0.005). Intermediate-to high-level cross-resistance to twice-daily dolutegravirwas predicted in 40/255 (15.7%) subjects, more commonly in subtype B versus non-B clades (39/209, 18.7% versus 1/46, 2.2%; P = 0.003). A glycine (G) to serine (S) substitution at integrase position 140 required one nucleotide change in subtype B and two nucleotide changes in all non-B clades. Conclusions: No major INI resistance mutations occurred in INI-naive subjects. Reduced occurrence of Q148H/R/K+ G140S/A was seen in non-B clades versus subtype B, and was explained by the higher genetic barrier to the G140S mutation observed in all non-B clades analysed.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Doyle, Tomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Dunn, David T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ceccherini-Silberstein, Francesca UNSPECIFIED UNSPECIFIED UNSPECIFIED De Mendoza, Carmen UNSPECIFIED UNSPECIFIED UNSPECIFIED Garcia, Frederico UNSPECIFIED UNSPECIFIED UNSPECIFIED Smit, Erasmus UNSPECIFIED UNSPECIFIED UNSPECIFIED Fearnhill, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Marcelin, Anne-Genevieve UNSPECIFIED orcid.org/0000-0003-4808-8999 UNSPECIFIED Martinez-Picado, Javier UNSPECIFIED orcid.org/0000-0002-4916-2129 UNSPECIFIED Kaiser, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Geretti, Anna Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-388789
DOI:	10.1093/jac/dkv243
Journal or Publication Title:	J. Antimicrob. Chemother.
Volume:	70
Number:	11
Page Range:	S. 3080 - 3087
Date:	2015
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2091
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ONCE-DAILY DOLUTEGRAVIR; TWICE-DAILY RALTEGRAVIR; CROSS-RESISTANCE; DOUBLE-BLIND; GENETIC BARRIERS; DRUG-RESISTANCE; ELVITEGRAVIR; ADULTS; S/GSK1349572; RITONAVIR Multiple languages Infectious Diseases; Microbiology; Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38878