title: Virologic failures on initial boosted-PI regimen infrequently possess low-level variants with major PI resistance mutations by ultra-deep sequencing.
abstract: BACKGROUND
  It is unknown whether HIV-positive patients experiencing virologic failure (VF) on boosted-PI (PI/r) regimens without drug resistant mutations (DRM) by standard genotyping harbor low-level PI resistant variants. CASTLE compared the efficacy of atazanavir/ritonavir (ATV/r) with lopinavir/ritonavir (LPV/r), each in combination with TVD in ARV-naïve subjects.
  
  
  OBJECTIVE
  To determine if VF on an initial PI/r-based regimen possess low-level resistant variants that may affect a subsequent PI-containing regimen.
  
  
  RESULTS
  Patients experiencing VF on a Tenofovir/Emtricitabine+PI/r regimen were evaluated by ultra deep sequencing (UDS) for mutations classified/weighted by Stanford HIVdb. Samples were evaluated for variants to 0.4% levels. 36 VF subjects were evaluated by UDS; 24 had UDS for PI and RT DRMs. Of these 24, 19 (79.2%) had any DRM by UDS. The most common UDS-detected DRM were NRTI in 18 subjects: M184V/I (11), TAMs(7) & K65R(4); PI DRMs were detected in 9 subjects: M46I/V(5), F53L(2), I50V(1), D30N(1), and N88S(1). The remaining 12 subjects, all with VLs<10,000, had protease gene UDS, and 4 had low-level PI DRMs: F53L(2), L76V(1), I54S(1), G73S(1). Overall, 3/36(8.3%) subjects had DRMs identified with Stanford-HIVdb weights >12 for ATV or LPV: N88S (at 0.43% level-mutational load 1,828) in 1 subject on ATV; I50V (0.44%-mutational load 110) and L76V (0.52%-mutational load 20) in 1 subject each, both on LPV. All VF samples remained phenotypically susceptible to the treatment PI/r.
  
  
  CONCLUSIONS
  Among persons experiencing VF without PI DRMs with standard genotyping on an initial PI/r regimen, low-level variants possessing major PI DRMs were present in a minority of cases, occurred in isolation, and did not result in phenotypic resistance. NRTI DRMs were detected in a high proportion of subjects. These data suggest that PIs may remain effective in subjects experiencing VF on a PI/r-based regimen when PI DRMs are not detected by standard or UDS genotyping.
authors.affiliation: Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America. Max.lataillade@BMS.com
authors.forename: Max
authors.initials: M
authors.lastname: Lataillade
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chiarella
authors.forename: Rong
authors.initials: R
authors.lastname: Yang
authors.forename: Michelle
authors.initials: M
authors.lastname: DeGrosky
authors.forename: Jonathan
authors.initials: J
authors.lastname: Uy
authors.forename: Daniel
authors.initials: D
authors.lastname: Seekins
authors.forename: Birgitte
authors.initials: B
authors.lastname: Simen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: St John
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Moreno
authors.forename: Michael
authors.initials: M
authors.lastname: Kozal
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000069446:Atazanavir Sulfate; D024882:Drug Resistance, Viral / Q000235:genetics*; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D061466:Lopinavir / Q000627:therapeutic use; D009154:Mutation / Q000187:drug effects / Q000235:genetics*; D009842:Oligopeptides / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D019438:Ritonavir / Q000627:therapeutic use; D019562:Viral Load / Q000187:drug effects* / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D019438:Ritonavir