title: Improved prediction of salvage antiretroviral therapy outcomes using ultrasensitive HIV-1 drug resistance testing.
abstract: BACKGROUND
  The clinical relevance of ultrasensitive human immunodeficiency virus type 1 (HIV-1) genotypic resistance testing in antiretroviral treatment (ART)-experienced individuals remains unknown.
  
  
  METHODS
  This was a retrospective, multicentre, cohort study in ART-experienced, HIV-1-infected adults who initiated salvage ART including, at least 1 ritonavir-boosted protease inhibitor, raltegravir or etravirine. Presalvage ART Sanger and 454 sequencing of plasma HIV-1 were used to generate separate genotypic sensitivity scores (GSS) using the HIVdb, ANRS, and REGA algorithms. Virological failure (VF) was defined as 2 consecutive HIV-1 RNA levels ≥200 copies/mL at least 12 weeks after salvage ART initiation, whereas subjects remained on the same ART. The ability of Sanger and 454-GSS to predict VF was assessed by receiver operating characteristic (ROC) curves and survival analyses.
  
  
  RESULTS
  The study included 132 evaluable subjects; 28 (21%) developed VF. Using HIVdb, 454 predicted VF better than Sanger sequencing in the ROC curve analysis (area under the curve: 0.69 vs 0.60, Delong test P = .029). Time to VF was shorter for subjects with 454-GSS < 3 vs 454-GSS ≥ 3 (Log-rank P = .003) but not significantly different between Sanger-GSS < 3 and ≥3. Factors independently associated with increased risk of VF in multivariate Cox regression were a 454-GSS < 3 (HR = 4.6, 95 CI, [1.5, 14.0], P = .007), and the number of previous antiretrovirals received (HR = 1.2 per additional drug, 95 CI, [1.1, 1.3], P = .001). Equivalent findings were obtained with the ANRS and REGA algorithms.
  
  
  CONCLUSIONS
  Ultrasensitive HIV-1 genotyping improves GSS-based predictions of virological outcomes of salvage ART relative to Sanger sequencing. This may improve the clinical management of ART-experienced subjects living with HIV-1.
  
  
  BACKGROUND
  NCT01346878.
authors.affiliation: IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona Universitat Autònoma de Barcelona, Cerdanyola del Vallès.
authors.forename: Christian
authors.initials: C
authors.lastname: Pou
authors.affiliation: IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona Universitat Autònoma de Barcelona, Cerdanyola del Vallès Universitat de Vic-Universitat Central de Catalunya, Vic.
authors.forename: Marc
authors.initials: M
authors.lastname: Noguera-Julian
authors.affiliation: IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona Universitat Autònoma de Barcelona, Cerdanyola del Vallès.
authors.forename: Susana
authors.initials: S
authors.lastname: Pérez-Álvarez
authors.affiliation: Microbiology and Molecular Biology Department, Hospital Universitario San Cecilio, Granada.
authors.forename: Federico
authors.initials: F
authors.lastname: García
authors.affiliation: Laboratory of Molecular Microbiology, Instituto de Investigación Biomedica Hospital 12 de Octubre (i + 12), Madrid.
authors.forename: Rafael
authors.initials: R
authors.lastname: Delgado
authors.affiliation: HIV/AIDS Department, Hospital Universitari MútuaTerrassa Universitat de Barcelona, Terrassa.
authors.forename: David
authors.initials: D
authors.lastname: Dalmau
authors.affiliation: Roche Diagnostics, SL, Sant Cugat del Vallès.
authors.forename: Miguel
authors.initials: M
authors.lastname: Álvarez-Tejado
authors.affiliation: ABL SA, Barcelona, Spain ABL SA, Luxembourg, Luxembourg.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Gonzalez
authors.affiliation: ABL SA, Barcelona, Spain ABL SA, Luxembourg, Luxembourg.
authors.forename: Chalom
authors.initials: C
authors.lastname: Sayada
authors.affiliation: Microbiology and Molecular Biology Department, Hospital Universitario San Cecilio, Granada.
authors.forename: Natalia
authors.initials: N
authors.lastname: Chueca
authors.affiliation: Laboratory of Molecular Microbiology, Instituto de Investigación Biomedica Hospital 12 de Octubre (i + 12), Madrid.
authors.forename: Federico
authors.initials: F
authors.lastname: Pulido
authors.affiliation: HIV/AIDS Department, Hospital Universitari MútuaTerrassa.
authors.forename: Laura
authors.initials: L
authors.lastname: Ibáñez
authors.affiliation: IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona Universitat Autònoma de Barcelona, Cerdanyola del Vallès.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez
authors.affiliation: IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona Universitat Autònoma de Barcelona, Cerdanyola del Vallès.
authors.forename: Maria
authors.initials: M
authors.lastname: Casadellà
authors.affiliation: Universitat Autònoma de Barcelona, Cerdanyola del Vallès HIV Unit, Internal Medicine Department, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain.
authors.forename: José R
authors.initials: JR
authors.lastname: Santos
authors.affiliation: IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona Universitat Autònoma de Barcelona, Cerdanyola del Vallès.
authors.forename: Lidia
authors.initials: L
authors.lastname: Ruiz
authors.affiliation: IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona Universitat Autònoma de Barcelona, Cerdanyola del Vallès Universitat de Vic-Universitat Central de Catalunya, Vic HIV Unit, Internal Medicine Department, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain.
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.affiliation: IrsiCaixa AIDS Research Institute - HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona Universitat Autònoma de Barcelona, Cerdanyola del Vallès Universitat de Vic-Universitat Central de Catalunya, Vic HIV Unit, Internal Medicine Department, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Paredes
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D015331:Cohort Studies; D024882:Drug Resistance, Viral; D005260:Female; D060005:Genotyping Techniques / Q000379:methods*; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests / Q000379:methods; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D016879:Salvage Therapy / Q000379:methods*; D017211:Treatment Failure
chemical_list: D044966:Anti-Retroviral Agents
keywords: HIV-1; antiretroviral drug resistance; deep sequencing; genotypic susceptibility score; salvage antiretroviral therapy