Resistance mutations selected in vivo under therapy with anti-HIV drug HBY097 differ from resistance pattern selected in vitro

The quinoxaline derivative HEY 097, an orally active nonnucleoside inhibito r of HIV-1 reverse transcriptase (NNRTI), showed an efficient suppression o f viral load in a dose-escalating phase I study with mean trough concentrat ions increasing from 137-1299 ug/l [Rubsamen-Waigmann et al., Lancet 349:15 17]. Half-maximal inhibitory concentrations (IC,,) for viruses grown from t he patients at entry of the study were 0.1-3 nM, except for one patient who had a virus with reduced susceptibility to HEY 097 at entry (IC50: 160 nM) . During therapy, only two patients developed a virus with a moderately inc reased IC50 (2.2 and 15 nM). This reduced susceptibility was associated wit h the known NNRTI-resistance mutation K double right arrow N at position 10 3, in contrast to resistance selection in vitro, which had yielded predomin ant mutations at positions 179 and 190. The Tyr mutation at position 181, i nducing high resistance for other NNRTIs, was never observed. The resistant virus at study entry (IC50 = 160 nM) had a mutation at position 103 as wel l, combined with an AZT resistance mutation (K double right arrow R) at pos ition 70, suggesting that nucleoside-resistance mutations may help increasi ng resistance to HEY 097. This is in line with our in vitro selection studi es, where resistance mutations at the 'nucleoside sites' 74 and 75 increase d the resistance phenotype of NNRTI mutations. Our findings highlight the c rucial importance of IC50 determinations from cultured virus for determinat ion of phenotypic resistance development during therapy and demonstrate tha t in vivo resistance development cannot be predicted from in vitro selectio n. (C) 1999 Elsevier Science B.V. All rights reserved.