title: Two different patterns of mutations are involved in the genotypic resistance score for atazanavir boosted versus unboosted by ritonavir in multiple failing patients.
abstract: OBJECTIVE
  The protease inhibitor atazanavir (ATV) can be used either boosted by ritonavir (ATV300/r) or unboosted (ATV400). To date, however, genotypic resistance scores (GRSs) have been developed only for boosted-ATV. We have determined GRS associated with virologic response (VR) for both ATV300/r and ATV400 in highly pre-treated HIV-1 infected patients.
  
  
  METHODS
  We analyzed the results of genotypic tests available 0-3 months before the initiation of an ATV-containing regimen in 159 patients with HIV-RNA >or= 500 copies/ml (ATV300/r group: 74; ATV400 group: 85) who were enrolled in the CARe study through an Early Access Program. The impact of baseline protease mutations on VR (>or= 1 log(10)copies/ml HIV-RNA decrease at 12-24 weeks) was analyzed using Fisher's exact test. Mutated protease amino acid positions (MPP) with p < 0.20 were retained for further analysis. The GRSs were determined by a step-by-step analysis using the chi(2) test for trend.
  
  
  RESULTS
  The GRSs for ATV300/r and ATV400 revealed differing sets of mutations. For ATV300/r, 12 MPPs (10C/I/V + 32I + 34Q + 46I/L + 53L + 54A/M/V + 82A/F/I/T + 84V + 90M - 15E/G/L/V - 69K/M/N/Q/R/T/Y - 72M/ T/V; p = 1.38 x 10(-9)) were the most strongly associated with VR (VR: 100%, 78.3%, 83.3%, 75% and 0% of patients with a score of -2/-1, 0, 1, 2, and >or= 3, respectively); the last three MPPs (I15/H69/I72) were associated with a better VR. For ATV400, nine MPPs (16E + 20I/M/R/T/V + 32I + 33F/I/V + 53L/Y + 64L/M/ V + 71I/T/V + 85V + 93L/M; p = 9.42 x 10(-8)) were most strongly associated with VR (VR: 83.3%, 66.7%, 5.9%, 0% of patients with 0, 1/2, 3, and >or= 4 MPP, respectively). Differences between GRSs for ATV300/r and ATV400 may be due to different ATV drug levels (boosted vs unboosted), favoring different pathways of escape from antiviral pressure.
  
  
  CONCLUSIONS
  Both GRSs were independent predictors of response in a multivariable logistic regression model. Nevertheless, cross-validation of these GRSs on different patient databases is required before their implementation in clinical practice.
authors.affiliation: Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.
authors.forename: M M
authors.initials: MM
authors.lastname: Santoro
authors.forename: A
authors.initials: A
authors.lastname: Bertoli
authors.forename: P
authors.initials: P
authors.lastname: Lorenzini
authors.forename: F
authors.initials: F
authors.lastname: Ceccherini-Silberstein
authors.forename: N
authors.initials: N
authors.lastname: Gianotti
authors.forename: C
authors.initials: C
authors.lastname: Mussini
authors.forename: C
authors.initials: C
authors.lastname: Torti
authors.forename: G
authors.initials: G
authors.lastname: Di Perri
authors.forename: G
authors.initials: G
authors.lastname: Barbarini
authors.forename: T
authors.initials: T
authors.lastname: Bini
authors.forename: S
authors.initials: S
authors.lastname: Melzi
authors.forename: P
authors.initials: P
authors.lastname: Caramello
authors.forename: R
authors.initials: R
authors.lastname: Maserati
authors.forename: P
authors.initials: P
authors.lastname: Narciso
authors.forename: V
authors.initials: V
authors.lastname: Micheli
authors.forename: A
authors.initials: A
authors.lastname: Antinori
authors.forename: C F
authors.initials: CF
authors.lastname: Perno
mesh_terms: D000595:Amino Acid Sequence; D023241:Antiretroviral Therapy, Highly Active; D000069446:Atazanavir Sulfate; D018791:CD4 Lymphocyte Count; D016009:Chi-Square Distribution; D003062:Codon; D024921:Drug Resistance, Multiple, Viral; D024882:Drug Resistance, Viral / Q000235:genetics*; D004357:Drug Synergism; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D008137:Longitudinal Studies; D008297:Male; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics; D009842:Oligopeptides / Q000627:therapeutic use; D011446:Prospective Studies; D011725:Pyridines / Q000627:therapeutic use; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D019438:Ritonavir / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load; D014766:Viremia / Q000188:drug therapy / Q000821:virology
chemical_list: D003062:Codon; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D012367:RNA, Viral; D000069446:Atazanavir Sulfate; D019438:Ritonavir