title: Improved darunavir genotypic mutation score predicting treatment response for patients infected with HIV-1 subtype B and non-subtype B receiving a salvage regimen.
abstract: OBJECTIVE
  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.
  
  
  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 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) = 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 final model 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.
authors.affiliation: Division of Infectious Diseases, Siena University Hospital, Siena, Italy Department of Medical Biotechnologies, University of Siena, Siena, Italy andrea.deluca@unisi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: De Luca
authors.affiliation: INSERM UMR-S 1136, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Flandre
authors.affiliation: MRC Clinical Trials Unit at University College London, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Dunn
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Siena, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zazzi
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Wensing
authors.affiliation: University of Rome Tor Vergata, Rome, Italy.
authors.forename: Maria Mercedes
authors.initials: MM
authors.lastname: Santoro
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Switzerland and Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.affiliation: Inserm U897, ISPED, Université de Bordeaux, CHU Bordeaux, France/Cohere in Eurocoord RCC, Bordeaux, France.
authors.forename: Linda
authors.initials: L
authors.lastname: Wittkop
authors.affiliation: University of Athens, Athens, Greece.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Kordossis
authors.affiliation: Hospital San Cecilio, Granada, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Garcia
authors.affiliation: San Raffaele Hospital, Milan, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Castagna
authors.affiliation: University College London, London, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cozzi-Lepri
authors.affiliation: Brighton and Sussex University Hospitals NHS Trust, Brighton, UK.
authors.forename: Duncan
authors.initials: D
authors.lastname: Churchill
authors.affiliation: St Pierre University Hospital, Brussels, Belgium.
authors.forename: Stéphane
authors.initials: S
authors.lastname: De Wit
authors.affiliation: Department of Dermatology and Venereology, Center for Sexual Health and Medicine, Ruhr University Bochum, Bochum, Germany and Competence Network for HIV/AIDS, Ruhr University Bochum, Bochum, Germany.
authors.forename: Norbert H
authors.initials: NH
authors.lastname: Brockmeyer
authors.affiliation: Bellvitge University Hospital, Barcelona, Catalonia, Spain.
authors.forename: Arkaitz
authors.initials: A
authors.lastname: Imaz
authors.affiliation: University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mussini
authors.affiliation: Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Obel
authors.affiliation: INMI 'L. Spallanzani', Rome, Italy.
authors.forename: Carlo Federico
authors.initials: CF
authors.lastname: Perno
authors.affiliation: University of Valencia, Castellon, Spain.
authors.forename: Bernardino
authors.initials: B
authors.lastname: Roca
authors.affiliation: Stichting HIV Monitoring, Amsterdam, The Netherlands, and Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands/Cohere in Eurocoord RCC, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Reiss
authors.affiliation: University of Cologne, Cologne, Germany.
authors.forename: Eugen
authors.initials: E
authors.lastname: Schülter
authors.affiliation: University Magna Graecia, Catanzaro, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Torti
authors.affiliation: Stichting HIV Monitoring, Amsterdam, The Netherlands.
authors.forename: Ard
authors.initials: A
authors.lastname: van Sighem
authors.affiliation: Universitätsklinik für Dermatologie und Venerologie, Innsbruck, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Zangerle
authors.affiliation: AP-HP, Hôpital Bichat-Claude Bernard, Laboratoire de Virologie, IAME, UMR_1137, INSERM, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Descamps
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000069454:Darunavir / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D005060:Europe; D005260:Female; D060005:Genotyping Techniques / Q000379:methods*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D016333:HIV Protease / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests / Q000379:methods; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D000069454:Darunavir
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