title: Clinical value of ultradeep HIV-1 genotyping and tropism testing in late presenters with advanced disease.
abstract: OBJECTIVE
  This article aims to investigate if the detection of preexisting drug-resistant minority variant (DRMV) and/or X4 HIV-1 variants could improve the efficacy of first-line combined antiretroviral therapy (ART) in late presenters.
  
  
  METHODS
  Post-hoc, combined analysis of two open-label, prospective, randomized clinical trials comparing first-line ART with efavirenz (EFV) vs. ritonavir-boosted protease inhibitor (PI/r)-based regimens in ART-naive, HIV-1-infected patients, with CD4 T-cell counts less than 100 cells/μl and wild-type HIV-1 by bulk sequencing.
  
  
  METHODS
  Pre-ART samples were reanalyzed for the presence of DRMVs and X4 HIV-1 using 454 sequencing. Kaplan-Meier curves and Cox regression were used to evaluate the association between X4 HIV and DRMVs and risk of virological failure.
  
  
  RESULTS
  From 141 evaluable patients, 57 received EFV, and 84 received PI/r, including first-line ART. Median pre-ART CD4 T-cell counts and HIV-1 RNA levels were 39 cells/μl and 257 424 copies/ml, respectively; 35.5% of patients had X4 HIV variants. Detection of DRMVs leading to an ART-specific cumulative HIVdb score of at least 10 increased the risk of virological failure in patients initiating EFV [log-rank P = 0.048, hazard ratio = 4.3 (95% confidence interval: 0.8, 25.0), P = 0.074], but not in those starting PI/r. Presence of X4 HIV did not affect virological outcomes, but was associated with impaired CD4 T-cell count recovery over 2 years (214 vs. 315 cells/μl with X4 vs. R5 HIV-1 tropism, respectively, P = 0.017).
  
  
  CONCLUSIONS
  Accounting for preexisting DRMVs may improve the outcomes of first-line nonnucleoside reverse transcriptase inhibitor-based ART in late presenters with advanced immune suppression. Presence of X4 HIV-1 at diagnosis predicts impaired immune restoration under ART.
authors.affiliation: aIrsiCaixa AIDS Research Institute, Universitat Autònoma de Barcelona, Badalona bHospital Clínic-IDIBAPS, University of Barcelona, Barcelona cUVIC-UCC, Vic dHospital Bellvitge-IDIBELL, University of Barcelona eHospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona fHIV Unit, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain. *Maria Casadellà and Christian Manzardo contributed equally to the writing of this article. †The ADVANZ and ADVANZ-3 investigators are listed under the Acknowledgements section.
authors.forename: Maria
authors.initials: M
authors.lastname: Casadellà
authors.forename: Christian
authors.initials: C
authors.lastname: Manzardo
authors.forename: Marc
authors.initials: M
authors.lastname: Noguera-Julian
authors.forename: Elena
authors.initials: E
authors.lastname: Ferrer
authors.forename: Pere
authors.initials: P
authors.lastname: Domingo
authors.forename: Susana
authors.initials: S
authors.lastname: Pérez-Álvarez
authors.forename: Daniel
authors.initials: D
authors.lastname: Podzamczer
authors.forename: Montserrat
authors.initials: M
authors.lastname: Plana
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: José M
authors.initials: JM
authors.lastname: Gatell
authors.forename: José M
authors.initials: JM
authors.lastname: Miró
authors.forename: Roger
authors.initials: R
authors.lastname: Paredes
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D024882:Drug Resistance, Viral; D005260:Female; D060005:Genotyping Techniques; D015658:HIV Infections / Q000175:diagnosis* / Q000821:virology*; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000302:isolation & purification* / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D056189:Viral Tropism
chemical_list: D044966:Anti-Retroviral Agents