title: Analysis of genotypic and phenotypic clinical cut-off levels for ritonavir-boosted saquinavir.
abstract: There is a need for new, clinically relevant interpretation algorithms for genotypic and phenotypic resistance for ritonavir-boosted saquinavir (SQV/r) at the current approved dosage [1000/100 mg twice a day (bid)]. Clinical cut-off levels, which correlate baseline measures of resistance with HIV RNA responses in large cohorts or clinical trials, are the ideal reference for developing such algorithms. Cut-off levels previously developed for unboosted saquinavir may no longer apply, as the plasma drug levels with SQV/r are significantly higher and may be able partially to overcome protease inhibitor-resistant HIV. Clinical cut-off levels for SQV/r, assessed in several cohort studies and clinical trials, also suggest that multiple genotypic mutations are required for complete loss of virological response. For phenotypic analysis of resistance, saquinavir cut-off levels 10-11-fold higher than the wild-type IC50 have best distinguished responders from non-responders in cohort studies. Using Virtual Phenotype, a 12.3-fold upper cut-off level was determined from analysis of large cohort databases. These genotypic and phenotypic algorithms need to be validated in larger prospective studies.
authors.affiliation: Department of Pharmacology, University of Liverpool, Liverpool, UK. microhaart@aol.com
authors.forename: A
authors.initials: A
authors.lastname: Hill
authors.forename: S
authors.initials: S
authors.lastname: Walmsley
authors.forename: B
authors.initials: B
authors.lastname: Clotet
authors.forename: J
authors.initials: J
authors.lastname: Molto
mesh_terms: D000465:Algorithms; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005838:Genotype; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009154:Mutation; D010641:Phenotype; D019438:Ritonavir / Q000494:pharmacology*; D019258:Saquinavir / Q000494:pharmacology*
chemical_list: D017320:HIV Protease Inhibitors; D019258:Saquinavir; D019438:Ritonavir