World-wide variation in HIV-1 phenotypic susceptibility in untreated individuals: biologically relevant values for resistance testing

Objectives: To examine the natural phenotypic variability in drug susceptib ility among recombinant HIV-1 isolates from a large number of untreated HIV -positive individuals from wide-ranging geographic locations, and to use th is information to establish biologically relevant cut-off values for phenot ypic antiretroviral susceptibility testing. Methods: Phenotypic susceptibility to 14 antiretroviral agents was determin ed for HIV-1 samples from > 1000 treatment-naive individuals in seven clini cal trials. Samples were from the USA (n = 351), Germany (n = 306), Canada (n = 265), and South Africa (n = 358). Geometric mean fold-resistance and c onfidence intervals were determined relative to a standard laboratory wild- type virus. Results: Baseline fold-resistance was approximately log-normally distribute d for all antiretroviral agents examined. There was no evidence of large ge ographical differences in average antiviral susceptibility. Geometric mean fold-resistance for each of 14 antiviral agents was similar (+/- 0.5-fold) for samples derived from the USA, Canada, Germany, or South Africa. The non -nucleoside reverse transcriptase inhibitors (NNRTI) exhibited the broadest distribution of susceptibility; approximately 97.5% of all isolates had < 2.5-4.0, < 3.0-4.5, and < 5-10 fold-decrease in susceptibility to five prot ease inhibitors, six nucleoside analogues, and three NNRTI, respectively. N o consistent geographic pattern or clade effect (B versus C) in either the mean or the distribution of baseline antiretroviral susceptibility was obse rved. Conclusions: Phenotypic drug susceptibility of HIV-1 in untreated individua ls varies markedly from drug to drug, with broadly similar patterns world-w ide. These results have important implications in defining the 'normal rang e' of phenotypic susceptibility to antiretroviral agents and establish biol ogically relevant cut-off values for this phenotypic drug susceptibility te st. (C) 2001 Lippincott Williams & Wilkins.