De Luca, Andrea ORCID: 0000-0002-9561-9193, Flandre, Philippe ORCID: 0000-0002-2612-3522, Dunn, David ORCID: 0000-0003-1836-4446, Zazzi, Maurizio ORCID: 0000-0002-0344-6281, Wensing, Annemarie, Santoro, Maria Mercedes, Gunthard, Huldrych F., Wittkop, Linda ORCID: 0000-0003-2403-0960, Kordossis, Theodoros, Garcia, Federico ORCID: 0000-0001-7611-781X, Castagna, Antonella, Cozzi-Lepri, Alessandro, Churchill, Duncan, De Wit, Stephane, Brockmeyer, Norbert H., Imaz, Arkaitz, Mussini, Cristina, Obel, Niels, Perno, Carlo Federico, Roca, Bernardino, Reiss, Peter, Schulter, Eugen, Torti, Carlo, van Sighem, Ard, Zangerle, Robert and Descamps, Diane (2016). Improved darunavir genotypic mutation score predicting treatment response for patients infected with HIV-1 subtype B and non-subtype B receiving a salvage regimen. J. Antimicrob. Chemother., 71 (5). S. 1352 - 1361. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2091

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Abstract

The objective of this study was to improve the prediction of the impact of HIV-1 protease mutations in different viral subtypes on virological response to darunavir. Darunavir-containing treatment change episodes (TCEs) in patients previously failing PIs were selected from large European databases. HIV-1 subtype B-infected patients were used as the derivation dataset and HIV-1 non-B-infected patients were used as the validation dataset. The adjusted association of each mutation with week 8 HIV RNA change from baseline was analysed by linear regression. A prediction model was derived based on best subset least squares estimation with mutational weights corresponding to regression coefficients. Virological outcome prediction accuracy was compared with that from existing genotypic resistance interpretation systems (GISs) (ANRS 2013, Rega 9.1.0 and HIVdb 7.0). TCEs were selected from 681 subtype B-infected and 199 non-B-infected adults. Accompanying drugs were NRTIs in 87%, NNRTIs in 27% and raltegravir or maraviroc or enfuvirtide in 53%. The prediction model included weighted protease mutations, HIV RNA, CD4 and activity of accompanying drugs. The model's association with week 8 HIV RNA change in the subtype B (derivation) set was R(2)aEuroS=aEuroS0.47 [average squared error (ASE)aEuroS=aEuroS0.67, PaEuroS < aEuroS10(-6)]; in the non-B (validation) set, ASE was 0.91. Accuracy investigated by means of area under the receiver operating characteristic curves with a binary response (above the threshold value of HIV RNA reduction) showed that our final model outperformed models with existing interpretation systems in both training and validation sets. A model with a new darunavir-weighted mutation score outperformed existing GISs in both B and non-B subtypes in predicting virological response to darunavir.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
De Luca, AndreaUNSPECIFIEDorcid.org/0000-0002-9561-9193UNSPECIFIED
Flandre, PhilippeUNSPECIFIEDorcid.org/0000-0002-2612-3522UNSPECIFIED
Dunn, DavidUNSPECIFIEDorcid.org/0000-0003-1836-4446UNSPECIFIED
Zazzi, MaurizioUNSPECIFIEDorcid.org/0000-0002-0344-6281UNSPECIFIED
Wensing, AnnemarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Santoro, Maria MercedesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gunthard, Huldrych F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wittkop, LindaUNSPECIFIEDorcid.org/0000-0003-2403-0960UNSPECIFIED
Kordossis, TheodorosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia, FedericoUNSPECIFIEDorcid.org/0000-0001-7611-781XUNSPECIFIED
Castagna, AntonellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cozzi-Lepri, AlessandroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Churchill, DuncanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Wit, StephaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brockmeyer, Norbert H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Imaz, ArkaitzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mussini, CristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Obel, NielsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perno, Carlo FedericoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roca, BernardinoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reiss, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulter, EugenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torti, CarloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Sighem, ArdUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zangerle, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Descamps, DianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-277723
DOI: 10.1093/jac/dkv465
Journal or Publication Title: J. Antimicrob. Chemother.
Volume: 71
Number: 5
Page Range: S. 1352 - 1361
Date: 2016
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2091
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ONCE-DAILY DARUNAVIR/RITONAVIR; TREATMENT-EXPERIENCED PATIENTS; VIROLOGICAL RESPONSE; HIV-1-INFECTED PATIENTS; TREATMENT-NAIVE; ANTIRETROVIRAL TREATMENT; RESISTANCE PROFILE; PROTEASE; EFFICACY; THERAPYMultiple languages
Infectious Diseases; Microbiology; Pharmacology & PharmacyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/27772

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