title: A randomized controlled trial to evaluate antiretroviral salvage therapy guided by rules-based or phenotype-driven HIV-1 genotypic drug-resistance interpretation with or without concentration-controlled intervention: the Resistance and Dosage Adapted Regimens (RADAR) study.
abstract: BACKGROUND
  It is not well defined whether concentration-controlled intervention (CCI) and rules-based human immunodeficiency virus (HIV) type 1 genotype drug-resistance interpretation (GI) or virtual phenotype drug-resistance interpretation (VPI) may improve the outcome of HIV salvage therapy.
  
  
  METHODS
  In a prospective, randomized, controlled trial, patients were randomized (on a factorial basis) to change treatment after either GI or VPI, and they then were further randomized to the control arm (no CCI) or the CCI arm. Protease inhibitor (PI) and nonnucleoside reverse-transcriptase inhibitor (NNRTI) trough concentration (Ctrough) values were determined at weeks 1, 4, 12, and 24 of the study.
  
  
  RESULTS
  Among 230 patients, virological benefit (defined by an HIV RNA load of <400 copies/mL at week 24) was not statistically different, either between patients in the GI and VPI arms or between patients in the CCI and control arms. A virological benefit was found for patients in the CCI arm, compared with patients in the control arm, but this benefit was not statistically significant (56.8% vs. 64.3% at week 4 and 63.6% vs. 74% at week 12). Dosage adaptation was possible for only a fraction of patients, because of low rates of treatment adherence or patient refusal to increase dosages. In the logistic regression analysis, independent predictors of virological response at week 24 were a PI Ctrough value and/or an NNRTI Ctrough value in the higher quartiles (or above cutoff levels) and a low number of PIs previously received. Moreover, receipt of a regimen that contained PIs boosted with ritonavir was an independent predictor of virological response.
  
  
  CONCLUSIONS
  The present study did not support the routine use of CCI for patients undergoing salvage treatment, probably as a result of existing difficulties associated with its clinical application. However, a higher Ctrough value appeared to be correlated with treatment response. No major differences were found between VPI or GI when they are used together with expert advice for the selection of salvage treatment combinations.
authors.affiliation: Institute for Infectious and Tropical Diseases, Brescia, Italy. torti.carlo@libero.it
authors.forename: Carlo
authors.initials: C
authors.lastname: Torti
authors.forename: Eugenia
authors.initials: E
authors.lastname: Quiros-Roldan
authors.forename: Mario
authors.initials: M
authors.lastname: Regazzi
authors.forename: Andrea
authors.initials: A
authors.lastname: De Luca
authors.forename: Francesco
authors.initials: F
authors.lastname: Mazzotta
authors.forename: Andrea
authors.initials: A
authors.lastname: Antinori
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Ladisa
authors.forename: Valeria
authors.initials: V
authors.lastname: Micheli
authors.forename: Anna
authors.initials: A
authors.lastname: Orani
authors.forename: Andrea
authors.initials: A
authors.lastname: Patroni
authors.forename: Paola
authors.initials: P
authors.lastname: Villani
authors.forename: Sergio
authors.initials: S
authors.lastname: Lo Caputo
authors.forename: Francesca
authors.initials: F
authors.lastname: Moretti
authors.forename: Simona
authors.initials: S
authors.lastname: Di Giambenedetto
authors.forename: Filippo
authors.initials: F
authors.lastname: Castelnuovo
authors.forename: Paolo
authors.initials: P
authors.lastname: Maggi
authors.forename: Carmine
authors.initials: C
authors.lastname: Tinelli
authors.forename: Giampiero
authors.initials: G
authors.lastname: Carosi
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D016879:Salvage Therapy
chemical_list: D019380:Anti-HIV Agents