Improved darunavir genotypic mutation score predicting treatment response for patients infected with HIRaben-1 subtype B and non-subtype B receiving a salvage regimen

A. De Luca, Philippe Flandre, D. Dunn, Maurizio Zazzi, Annemarie M J Wensing, Maria Mercedes Santoro, Huldrych F. Günthard, Linda Wittkop, T. Kordossis, Federico García, Antonella Castagna, Alessandro Cozzi-Lepri, Duncan Churchill, Stéphane De Wit, Norbert Brockmeyer, Arkaitz Imaz, Cristina Mussini, Niels Obel, Carlo Federico Perno, Bernardino RocaPeter Reiss, E. Schülter, C. Torti, Ard Van Sighem, Robert Zangerle, Diane Descamps, Amanda Mocroft, O. Kirk, Caroline Sabin, Stéphane de Wit, J. Casabona, Jose Miro, Giota Touloumi, Myriam Garrido, Ramon Teira, Ferdinand Wit, Josiane Warszawski, Laurence Meyer, Murielle Mary Krause, Murielle Mary Krause, Jade Ghosn, Catherine Leport, Maria Prins, Heiner C. Bucher, Diana Gibb, Gerd Fätkenheuer, Julia Del Amo, Claire Thorne, Christoph Stephan, Antoni Noguera-Julian, Barbara Bartmeyer, Barbara Bartmeyer, N. Chkhartishvili, Antoni Noguera-Julian, Andrea Antinori, A. D'Arminio Monforte, Luis Prieto, Pablo Rojo Conejo, Antoni Soriano-Arandes, Manuel Battegay, Roger Kouyos, Pat Tookey, Deborah Konopnick, Tessa Goetghebuer, Anders Sönnerborg, David Haerry, Stéphane de Wit, Dominique Costagliola, D. Raben, Genevieve Chene, F. Ceccherini-Silberstein, Huldrych Günthard, Ali Judd, Diana Barger, Christine Schwimmer, Monique Termote, Maria Campbell, Casper M. Frederiksen, Nina Friis-Møller, Jesper Kjaer, Rikke Salbøl Brandt, Juan Berenguer, Julia Bohlius, Vincent Bouteloup, Mary Anne Davies, Maria Dorrucci, Matthias Egger, Hansjakob Furrer, M. Guiguet, S. Grabar, Olivier Lambotte, Valériane Leroy, Sara Lodi, Sophie Matheron, Susana Monge, Fumiyo Nakagawa, Roger Paredes, A. N. Phillips, M. Puoti, Michael Schomaker, Colette Smit, Rodolphe Thiebaut, Rodolphe Thiebaut, Marc Van Der Valk, Natasha Wyss, Vincent Aubert, Manuel Battegay, E. Bernasconi, Jurg Boni, C. Burton-Jeangros, A. Calmy, M. Cavassini, G. Dollenmaier, Frederik Engsig, L. Elzi, Jan Fehr, Jacques Fellay, Hansjakob Furrer, C. Fux, Meri Gorgievski, H. Günthard, D. Haerry, Barbara Hasse, H. H. Hirsch, Matthias Hoffmann, Irene Hösli, C. Kahlert, L. Kaiser, Olivia Keiser, T. Klimkait, Roger Kouyos, H. Kovari, B. Ledergerber, G. Martinetti, B. Martinez de Tejada, Karin J. Metzner, N. Müller, D. Nadal, D. Nicca, Giuseppe Pantaleo, Andri Rauch, Stephan Regenass, Martin Rickenbach, C. Rudin, F. Schöni-Affolter, P. Schmid, J. Schüpbach, R. Speck, Philip E. Tarr, A. Telenti, A. Trkola, P. Vernazza, R. Weber, S. Yerly

Research output: Contribution to journalArticle

Abstract

Objectives: The objective of this studywas to improve the prediction of the impact of HIV-1 protease mutations in different viral subtypes on virological response to darunavir. Methods: 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). Results: 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 ormaraviroc or enfuvirtide in 53%. The predictionmodel 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 R2=0.47 [average squared error (ASE)=0.67, P>10-6]; 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 finalmodel outperformed models with existing interpretation systems in both training and validation sets. Conclusions: 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.

Original languageEnglish
Article numberdkv465
Pages (from-to)1352-1360
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume71
Issue number5
DOIs
Publication statusPublished - May 1 2016

Fingerprint

RNA
Mutation
HIV
HIV-1
HIV Protease
Therapeutics
Least-Squares Analysis
ROC Curve
Pharmaceutical Preparations
Linear Models
Databases
Weights and Measures
Darunavir
Datasets
Human immunodeficiency virus 1 p16 protease
enfuvirtide
Raltegravir Potassium

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Improved darunavir genotypic mutation score predicting treatment response for patients infected with HIRaben-1 subtype B and non-subtype B receiving a salvage regimen. / De Luca, A.; Flandre, Philippe; Dunn, D.; Zazzi, Maurizio; Wensing, Annemarie M J; Santoro, Maria Mercedes; Günthard, Huldrych F.; Wittkop, Linda; Kordossis, T.; García, Federico; Castagna, Antonella; Cozzi-Lepri, Alessandro; Churchill, Duncan; De Wit, Stéphane; Brockmeyer, Norbert; Imaz, Arkaitz; Mussini, Cristina; Obel, Niels; Perno, Carlo Federico; Roca, Bernardino; Reiss, Peter; Schülter, E.; Torti, C.; Van Sighem, Ard; Zangerle, Robert; Descamps, Diane; Mocroft, Amanda; Kirk, O.; Sabin, Caroline; de Wit, Stéphane; Casabona, J.; Miro, Jose; Touloumi, Giota; Garrido, Myriam; Teira, Ramon; Wit, Ferdinand; Warszawski, Josiane; Meyer, Laurence; Krause, Murielle Mary; Krause, Murielle Mary; Ghosn, Jade; Leport, Catherine; Prins, Maria; Bucher, Heiner C.; Gibb, Diana; Fätkenheuer, Gerd; Del Amo, Julia; Thorne, Claire; Stephan, Christoph; Noguera-Julian, Antoni; Bartmeyer, Barbara; Bartmeyer, Barbara; Chkhartishvili, N.; Noguera-Julian, Antoni; Antinori, Andrea; D'Arminio Monforte, A.; Prieto, Luis; Conejo, Pablo Rojo; Soriano-Arandes, Antoni; Battegay, Manuel; Kouyos, Roger; Tookey, Pat; Konopnick, Deborah; Goetghebuer, Tessa; Sönnerborg, Anders; Haerry, David; de Wit, Stéphane; Costagliola, Dominique; Raben, D.; Chene, Genevieve; Ceccherini-Silberstein, F.; Günthard, Huldrych; Judd, Ali; Barger, Diana; Schwimmer, Christine; Termote, Monique; Campbell, Maria; Frederiksen, Casper M.; Friis-Møller, Nina; Kjaer, Jesper; Brandt, Rikke Salbøl; Berenguer, Juan; Bohlius, Julia; Bouteloup, Vincent; Davies, Mary Anne; Dorrucci, Maria; Egger, Matthias; Furrer, Hansjakob; Guiguet, M.; Grabar, S.; Lambotte, Olivier; Leroy, Valériane; Lodi, Sara; Matheron, Sophie; Monge, Susana; Nakagawa, Fumiyo; Paredes, Roger; Phillips, A. N.; Puoti, M.; Schomaker, Michael; Smit, Colette; Thiebaut, Rodolphe; Thiebaut, Rodolphe; Van Der Valk, Marc; Wyss, Natasha; Aubert, Vincent; Battegay, Manuel; Bernasconi, E.; Boni, Jurg; Burton-Jeangros, C.; Calmy, A.; Cavassini, M.; Dollenmaier, G.; Engsig, Frederik; Elzi, L.; Fehr, Jan; Fellay, Jacques; Furrer, Hansjakob; Fux, C.; Gorgievski, Meri; Günthard, H.; Haerry, D.; Hasse, Barbara; Hirsch, H. H.; Hoffmann, Matthias; Hösli, Irene; Kahlert, C.; Kaiser, L.; Keiser, Olivia; Klimkait, T.; Kouyos, Roger; Kovari, H.; Ledergerber, B.; Martinetti, G.; Martinez de Tejada, B.; Metzner, Karin J.; Müller, N.; Nadal, D.; Nicca, D.; Pantaleo, Giuseppe; Rauch, Andri; Regenass, Stephan; Rickenbach, Martin; Rudin, C.; Schöni-Affolter, F.; Schmid, P.; Schüpbach, J.; Speck, R.; Tarr, Philip E.; Telenti, A.; Trkola, A.; Vernazza, P.; Weber, R.; Yerly, S.

In: Journal of Antimicrobial Chemotherapy, Vol. 71, No. 5, dkv465, 01.05.2016, p. 1352-1360.

Research output: Contribution to journalArticle

De Luca, A, Flandre, P, Dunn, D, Zazzi, M, Wensing, AMJ, Santoro, MM, Günthard, HF, Wittkop, L, Kordossis, T, García, F, Castagna, A, Cozzi-Lepri, A, Churchill, D, De Wit, S, Brockmeyer, N, Imaz, A, Mussini, C, Obel, N, Perno, CF, Roca, B, Reiss, P, Schülter, E, Torti, C, Van Sighem, A, Zangerle, R, Descamps, D, Mocroft, A, Kirk, O, Sabin, C, de Wit, S, Casabona, J, Miro, J, Touloumi, G, Garrido, M, Teira, R, Wit, F, Warszawski, J, Meyer, L, Krause, MM, Krause, MM, Ghosn, J, Leport, C, Prins, M, Bucher, HC, Gibb, D, Fätkenheuer, G, Del Amo, J, Thorne, C, Stephan, C, Noguera-Julian, A, Bartmeyer, B, Bartmeyer, B, Chkhartishvili, N, Noguera-Julian, A, Antinori, A, D'Arminio Monforte, A, Prieto, L, Conejo, PR, Soriano-Arandes, A, Battegay, M, Kouyos, R, Tookey, P, Konopnick, D, Goetghebuer, T, Sönnerborg, A, Haerry, D, de Wit, S, Costagliola, D, Raben, D, Chene, G, Ceccherini-Silberstein, F, Günthard, H, Judd, A, Barger, D, Schwimmer, C, Termote, M, Campbell, M, Frederiksen, CM, Friis-Møller, N, Kjaer, J, Brandt, RS, Berenguer, J, Bohlius, J, Bouteloup, V, Davies, MA, Dorrucci, M, Egger, M, Furrer, H, Guiguet, M, Grabar, S, Lambotte, O, Leroy, V, Lodi, S, Matheron, S, Monge, S, Nakagawa, F, Paredes, R, Phillips, AN, Puoti, M, Schomaker, M, Smit, C, Thiebaut, R, Thiebaut, R, Van Der Valk, M, Wyss, N, Aubert, V, Battegay, M, Bernasconi, E, Boni, J, Burton-Jeangros, C, Calmy, A, Cavassini, M, Dollenmaier, G, Engsig, F, Elzi, L, Fehr, J, Fellay, J, Furrer, H, Fux, C, Gorgievski, M, Günthard, H, Haerry, D, Hasse, B, Hirsch, HH, Hoffmann, M, Hösli, I, Kahlert, C, Kaiser, L, Keiser, O, Klimkait, T, Kouyos, R, Kovari, H, Ledergerber, B, Martinetti, G, Martinez de Tejada, B, Metzner, KJ, Müller, N, Nadal, D, Nicca, D, Pantaleo, G, Rauch, A, Regenass, S, Rickenbach, M, Rudin, C, Schöni-Affolter, F, Schmid, P, Schüpbach, J, Speck, R, Tarr, PE, Telenti, A, Trkola, A, Vernazza, P, Weber, R & Yerly, S 2016, 'Improved darunavir genotypic mutation score predicting treatment response for patients infected with HIRaben-1 subtype B and non-subtype B receiving a salvage regimen', Journal of Antimicrobial Chemotherapy, vol. 71, no. 5, dkv465, pp. 1352-1360. https://doi.org/10.1093/jac/dkv465
De Luca, A. ; Flandre, Philippe ; Dunn, D. ; Zazzi, Maurizio ; Wensing, Annemarie M J ; Santoro, Maria Mercedes ; Günthard, Huldrych F. ; Wittkop, Linda ; Kordossis, T. ; García, Federico ; Castagna, Antonella ; Cozzi-Lepri, Alessandro ; Churchill, Duncan ; De Wit, Stéphane ; Brockmeyer, Norbert ; Imaz, Arkaitz ; Mussini, Cristina ; Obel, Niels ; Perno, Carlo Federico ; Roca, Bernardino ; Reiss, Peter ; Schülter, E. ; Torti, C. ; Van Sighem, Ard ; Zangerle, Robert ; Descamps, Diane ; Mocroft, Amanda ; Kirk, O. ; Sabin, Caroline ; de Wit, Stéphane ; Casabona, J. ; Miro, Jose ; Touloumi, Giota ; Garrido, Myriam ; Teira, Ramon ; Wit, Ferdinand ; Warszawski, Josiane ; Meyer, Laurence ; Krause, Murielle Mary ; Krause, Murielle Mary ; Ghosn, Jade ; Leport, Catherine ; Prins, Maria ; Bucher, Heiner C. ; Gibb, Diana ; Fätkenheuer, Gerd ; Del Amo, Julia ; Thorne, Claire ; Stephan, Christoph ; Noguera-Julian, Antoni ; Bartmeyer, Barbara ; Bartmeyer, Barbara ; Chkhartishvili, N. ; Noguera-Julian, Antoni ; Antinori, Andrea ; D'Arminio Monforte, A. ; Prieto, Luis ; Conejo, Pablo Rojo ; Soriano-Arandes, Antoni ; Battegay, Manuel ; Kouyos, Roger ; Tookey, Pat ; Konopnick, Deborah ; Goetghebuer, Tessa ; Sönnerborg, Anders ; Haerry, David ; de Wit, Stéphane ; Costagliola, Dominique ; Raben, D. ; Chene, Genevieve ; Ceccherini-Silberstein, F. ; Günthard, Huldrych ; Judd, Ali ; Barger, Diana ; Schwimmer, Christine ; Termote, Monique ; Campbell, Maria ; Frederiksen, Casper M. ; Friis-Møller, Nina ; Kjaer, Jesper ; Brandt, Rikke Salbøl ; Berenguer, Juan ; Bohlius, Julia ; Bouteloup, Vincent ; Davies, Mary Anne ; Dorrucci, Maria ; Egger, Matthias ; Furrer, Hansjakob ; Guiguet, M. ; Grabar, S. ; Lambotte, Olivier ; Leroy, Valériane ; Lodi, Sara ; Matheron, Sophie ; Monge, Susana ; Nakagawa, Fumiyo ; Paredes, Roger ; Phillips, A. N. ; Puoti, M. ; Schomaker, Michael ; Smit, Colette ; Thiebaut, Rodolphe ; Thiebaut, Rodolphe ; Van Der Valk, Marc ; Wyss, Natasha ; Aubert, Vincent ; Battegay, Manuel ; Bernasconi, E. ; Boni, Jurg ; Burton-Jeangros, C. ; Calmy, A. ; Cavassini, M. ; Dollenmaier, G. ; Engsig, Frederik ; Elzi, L. ; Fehr, Jan ; Fellay, Jacques ; Furrer, Hansjakob ; Fux, C. ; Gorgievski, Meri ; Günthard, H. ; Haerry, D. ; Hasse, Barbara ; Hirsch, H. H. ; Hoffmann, Matthias ; Hösli, Irene ; Kahlert, C. ; Kaiser, L. ; Keiser, Olivia ; Klimkait, T. ; Kouyos, Roger ; Kovari, H. ; Ledergerber, B. ; Martinetti, G. ; Martinez de Tejada, B. ; Metzner, Karin J. ; Müller, N. ; Nadal, D. ; Nicca, D. ; Pantaleo, Giuseppe ; Rauch, Andri ; Regenass, Stephan ; Rickenbach, Martin ; Rudin, C. ; Schöni-Affolter, F. ; Schmid, P. ; Schüpbach, J. ; Speck, R. ; Tarr, Philip E. ; Telenti, A. ; Trkola, A. ; Vernazza, P. ; Weber, R. ; Yerly, S. / Improved darunavir genotypic mutation score predicting treatment response for patients infected with HIRaben-1 subtype B and non-subtype B receiving a salvage regimen. In: Journal of Antimicrobial Chemotherapy. 2016 ; Vol. 71, No. 5. pp. 1352-1360.
@article{e995e59116d34f08aaa6ebab162515b5,
title = "Improved darunavir genotypic mutation score predicting treatment response for patients infected with HIRaben-1 subtype B and non-subtype B receiving a salvage regimen",
abstract = "Objectives: The objective of this studywas to improve the prediction of the impact of HIV-1 protease mutations in different viral subtypes on virological response to darunavir. Methods: 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). Results: 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 ormaraviroc or enfuvirtide in 53{\%}. The predictionmodel 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 R2=0.47 [average squared error (ASE)=0.67, P>10-6]; 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 finalmodel outperformed models with existing interpretation systems in both training and validation sets. Conclusions: 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.",
author = "{De Luca}, A. and Philippe Flandre and D. Dunn and Maurizio Zazzi and Wensing, {Annemarie M J} and Santoro, {Maria Mercedes} and G{\"u}nthard, {Huldrych F.} and Linda Wittkop and T. Kordossis and Federico Garc{\'i}a and Antonella Castagna and Alessandro Cozzi-Lepri and Duncan Churchill and {De Wit}, St{\'e}phane and Norbert Brockmeyer and Arkaitz Imaz and Cristina Mussini and Niels Obel and Perno, {Carlo Federico} and Bernardino Roca and Peter Reiss and E. Sch{\"u}lter and C. Torti and {Van Sighem}, Ard and Robert Zangerle and Diane Descamps and Amanda Mocroft and O. Kirk and Caroline Sabin and {de Wit}, St{\'e}phane and J. Casabona and Jose Miro and Giota Touloumi and Myriam Garrido and Ramon Teira and Ferdinand Wit and Josiane Warszawski and Laurence Meyer and Krause, {Murielle Mary} and Krause, {Murielle Mary} and Jade Ghosn and Catherine Leport and Maria Prins and Bucher, {Heiner C.} and Diana Gibb and Gerd F{\"a}tkenheuer and {Del Amo}, Julia and Claire Thorne and Christoph Stephan and Antoni Noguera-Julian and Barbara Bartmeyer and Barbara Bartmeyer and N. Chkhartishvili and Antoni Noguera-Julian and Andrea Antinori and {D'Arminio Monforte}, A. and Luis Prieto and Conejo, {Pablo Rojo} and Antoni Soriano-Arandes and Manuel Battegay and Roger Kouyos and Pat Tookey and Deborah Konopnick and Tessa Goetghebuer and Anders S{\"o}nnerborg and David Haerry and {de Wit}, St{\'e}phane and Dominique Costagliola and D. Raben and Genevieve Chene and F. Ceccherini-Silberstein and Huldrych G{\"u}nthard and Ali Judd and Diana Barger and Christine Schwimmer and Monique Termote and Maria Campbell and Frederiksen, {Casper M.} and Nina Friis-M{\o}ller and Jesper Kjaer and Brandt, {Rikke Salb{\o}l} and Juan Berenguer and Julia Bohlius and Vincent Bouteloup and Davies, {Mary Anne} and Maria Dorrucci and Matthias Egger and Hansjakob Furrer and M. Guiguet and S. Grabar and Olivier Lambotte and Val{\'e}riane Leroy and Sara Lodi and Sophie Matheron and Susana Monge and Fumiyo Nakagawa and Roger Paredes and Phillips, {A. N.} and M. Puoti and Michael Schomaker and Colette Smit and Rodolphe Thiebaut and Rodolphe Thiebaut and {Van Der Valk}, Marc and Natasha Wyss and Vincent Aubert and Manuel Battegay and E. Bernasconi and Jurg Boni and C. Burton-Jeangros and A. Calmy and M. Cavassini and G. Dollenmaier and Frederik Engsig and L. Elzi and Jan Fehr and Jacques Fellay and Hansjakob Furrer and C. Fux and Meri Gorgievski and H. G{\"u}nthard and D. Haerry and Barbara Hasse and Hirsch, {H. H.} and Matthias Hoffmann and Irene H{\"o}sli and C. Kahlert and L. Kaiser and Olivia Keiser and T. Klimkait and Roger Kouyos and H. Kovari and B. Ledergerber and G. Martinetti and {Martinez de Tejada}, B. and Metzner, {Karin J.} and N. M{\"u}ller and D. Nadal and D. Nicca and Giuseppe Pantaleo and Andri Rauch and Stephan Regenass and Martin Rickenbach and C. Rudin and F. Sch{\"o}ni-Affolter and P. Schmid and J. Sch{\"u}pbach and R. Speck and Tarr, {Philip E.} and A. Telenti and A. Trkola and P. Vernazza and R. Weber and S. Yerly",
year = "2016",
month = "5",
day = "1",
doi = "10.1093/jac/dkv465",
language = "English",
volume = "71",
pages = "1352--1360",
journal = "Journal of Antimicrobial Chemotherapy",
issn = "0305-7453",
publisher = "Oxford University Press",
number = "5",

}

TY - JOUR

T1 - Improved darunavir genotypic mutation score predicting treatment response for patients infected with HIRaben-1 subtype B and non-subtype B receiving a salvage regimen

AU - De Luca, A.

AU - Flandre, Philippe

AU - Dunn, D.

AU - Zazzi, Maurizio

AU - Wensing, Annemarie M J

AU - Santoro, Maria Mercedes

AU - Günthard, Huldrych F.

AU - Wittkop, Linda

AU - Kordossis, T.

AU - García, Federico

AU - Castagna, Antonella

AU - Cozzi-Lepri, Alessandro

AU - Churchill, Duncan

AU - De Wit, Stéphane

AU - Brockmeyer, Norbert

AU - Imaz, Arkaitz

AU - Mussini, Cristina

AU - Obel, Niels

AU - Perno, Carlo Federico

AU - Roca, Bernardino

AU - Reiss, Peter

AU - Schülter, E.

AU - Torti, C.

AU - Van Sighem, Ard

AU - Zangerle, Robert

AU - Descamps, Diane

AU - Mocroft, Amanda

AU - Kirk, O.

AU - Sabin, Caroline

AU - de Wit, Stéphane

AU - Casabona, J.

AU - Miro, Jose

AU - Touloumi, Giota

AU - Garrido, Myriam

AU - Teira, Ramon

AU - Wit, Ferdinand

AU - Warszawski, Josiane

AU - Meyer, Laurence

AU - Krause, Murielle Mary

AU - Krause, Murielle Mary

AU - Ghosn, Jade

AU - Leport, Catherine

AU - Prins, Maria

AU - Bucher, Heiner C.

AU - Gibb, Diana

AU - Fätkenheuer, Gerd

AU - Del Amo, Julia

AU - Thorne, Claire

AU - Stephan, Christoph

AU - Noguera-Julian, Antoni

AU - Bartmeyer, Barbara

AU - Bartmeyer, Barbara

AU - Chkhartishvili, N.

AU - Noguera-Julian, Antoni

AU - Antinori, Andrea

AU - D'Arminio Monforte, A.

AU - Prieto, Luis

AU - Conejo, Pablo Rojo

AU - Soriano-Arandes, Antoni

AU - Battegay, Manuel

AU - Kouyos, Roger

AU - Tookey, Pat

AU - Konopnick, Deborah

AU - Goetghebuer, Tessa

AU - Sönnerborg, Anders

AU - Haerry, David

AU - de Wit, Stéphane

AU - Costagliola, Dominique

AU - Raben, D.

AU - Chene, Genevieve

AU - Ceccherini-Silberstein, F.

AU - Günthard, Huldrych

AU - Judd, Ali

AU - Barger, Diana

AU - Schwimmer, Christine

AU - Termote, Monique

AU - Campbell, Maria

AU - Frederiksen, Casper M.

AU - Friis-Møller, Nina

AU - Kjaer, Jesper

AU - Brandt, Rikke Salbøl

AU - Berenguer, Juan

AU - Bohlius, Julia

AU - Bouteloup, Vincent

AU - Davies, Mary Anne

AU - Dorrucci, Maria

AU - Egger, Matthias

AU - Furrer, Hansjakob

AU - Guiguet, M.

AU - Grabar, S.

AU - Lambotte, Olivier

AU - Leroy, Valériane

AU - Lodi, Sara

AU - Matheron, Sophie

AU - Monge, Susana

AU - Nakagawa, Fumiyo

AU - Paredes, Roger

AU - Phillips, A. N.

AU - Puoti, M.

AU - Schomaker, Michael

AU - Smit, Colette

AU - Thiebaut, Rodolphe

AU - Thiebaut, Rodolphe

AU - Van Der Valk, Marc

AU - Wyss, Natasha

AU - Aubert, Vincent

AU - Battegay, Manuel

AU - Bernasconi, E.

AU - Boni, Jurg

AU - Burton-Jeangros, C.

AU - Calmy, A.

AU - Cavassini, M.

AU - Dollenmaier, G.

AU - Engsig, Frederik

AU - Elzi, L.

AU - Fehr, Jan

AU - Fellay, Jacques

AU - Furrer, Hansjakob

AU - Fux, C.

AU - Gorgievski, Meri

AU - Günthard, H.

AU - Haerry, D.

AU - Hasse, Barbara

AU - Hirsch, H. H.

AU - Hoffmann, Matthias

AU - Hösli, Irene

AU - Kahlert, C.

AU - Kaiser, L.

AU - Keiser, Olivia

AU - Klimkait, T.

AU - Kouyos, Roger

AU - Kovari, H.

AU - Ledergerber, B.

AU - Martinetti, G.

AU - Martinez de Tejada, B.

AU - Metzner, Karin J.

AU - Müller, N.

AU - Nadal, D.

AU - Nicca, D.

AU - Pantaleo, Giuseppe

AU - Rauch, Andri

AU - Regenass, Stephan

AU - Rickenbach, Martin

AU - Rudin, C.

AU - Schöni-Affolter, F.

AU - Schmid, P.

AU - Schüpbach, J.

AU - Speck, R.

AU - Tarr, Philip E.

AU - Telenti, A.

AU - Trkola, A.

AU - Vernazza, P.

AU - Weber, R.

AU - Yerly, S.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Objectives: The objective of this studywas to improve the prediction of the impact of HIV-1 protease mutations in different viral subtypes on virological response to darunavir. Methods: 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). Results: 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 ormaraviroc or enfuvirtide in 53%. The predictionmodel 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 R2=0.47 [average squared error (ASE)=0.67, P>10-6]; 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 finalmodel outperformed models with existing interpretation systems in both training and validation sets. Conclusions: 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.

AB - Objectives: The objective of this studywas to improve the prediction of the impact of HIV-1 protease mutations in different viral subtypes on virological response to darunavir. Methods: 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). Results: 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 ormaraviroc or enfuvirtide in 53%. The predictionmodel 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 R2=0.47 [average squared error (ASE)=0.67, P>10-6]; 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 finalmodel outperformed models with existing interpretation systems in both training and validation sets. Conclusions: 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.

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U2 - 10.1093/jac/dkv465

DO - 10.1093/jac/dkv465

M3 - Article

VL - 71

SP - 1352

EP - 1360

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

SN - 0305-7453

IS - 5

M1 - dkv465

ER -