title: Plasma drug levels, genotypic resistance, and virological response to a nelfinavir plus saquinavir-containing regimen.
abstract: OBJECTIVE
  To determine the importance of resistance and drug levels in the response to a dual-protease inhibitor (PI) combination.
  
  
  METHODS
  Prospective study of 62 HIV-positive patients who switched to a salvage regimen including nelfinavir plus saquinavir. Virological response was defined as a decrease in viraemia > 0.5 log10 after 24 weeks. Optimal PI levels were defined as those above the protein binding-corrected 95% inhibitory concentration (IC95), as estimated in the presence of 50% human serum.
  
  
  RESULTS
  Baseline median HIV load was 4.78 log10 copies/ml. The median number of mutations in the protease gene was nine (range, 2-25), predominantly at residues 82 (52%), and 90 (40%). After 24 weeks, 45% of patients had responded and 19% were < 50 copies/ml. A higher number of mutations in the protease gene (12 versus 8;P = 0.001), and the L90M mutation (36% versus 67%; P = 0.001) were associated with treatment failure. Trough levels of nelfinavir and saquinavir were two- and fivefold, respectively, greater than those reached when used as the only PI (2480 and 260 ng/ml, respectively), and they were above the estimated protein-corrected IC95 in 96% and 32% of cases. Thus, the Cmin : IC95 ratio ranged from 0.1 to 10 for nelfinavir and from 0.12 to 3.24 for saquinavir. Suboptimal PI levels were associated with a poorer response, but there was no correlation between optimal drug levels and a better response.
  
  
  CONCLUSIONS
  Genotypic resistance predicts the virological response to a nelfinavir-saquinavir salvage regimen. Our data suggest that higher than optimal drug levels could be necessary to control the replication of many PI-resistant viruses.
authors.affiliation: Department of Infectious Diseases, Ramon y Cajal Hospital, Madrid, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Casado
authors.forename: Santiago
authors.initials: S
authors.lastname: Moreno
authors.forename: Kurt
authors.initials: K
authors.lastname: Hertogs
authors.forename: Fernando
authors.initials: F
authors.lastname: Dronda
authors.forename: Antonio
authors.initials: A
authors.lastname: Antela
authors.forename: Pascale
authors.initials: P
authors.lastname: Dehertogh
authors.forename: María J
authors.initials: MJ
authors.lastname: Perez-Elías
authors.forename: Ana
authors.initials: A
authors.lastname: Moreno
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D016333:HIV Protease / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019888:Nelfinavir / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D016879:Salvage Therapy; D019258:Saquinavir / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D011480:Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D016333:HIV Protease; D019888:Nelfinavir; D019258:Saquinavir