Patterns of resistance and cross-resistance to human immunodeficiency virus type 1 reverse transcriptase inhibitors in patients treated with the nonnucleoside reverse transcriptase inhibitor loviride

Human immunodeficiency virus type 1 (HIV-1) strains resistant to nonnucleos ide reverse transcriptase inhibitors (NNRTIs) may easily be selected for in vitro and in vivo under a suboptimal therapy regimen. Although cross-resis tance is extensive within this class of compounds, newer NNRTIs were report ed to retain activity against laboratory strains containing defined resista nce associated mutations. We have characterized HIV-1 resistance to lovirid e and the extent of cross-resistance to nevirapine, delavirdine, efavirenz, HBY-097, and tivirapine in a set of 24 clinical samples from patients trea ted with long-term loviride monotherapy by using a recombinant virus assay. Genotypic changes associated,vith resistance were analyzed by population s equencing. Overall, phenotypic resistance to loviride ranged from 0.04 to 3 .47 log(10)-fold. Resistance aas observed in samples from patients who had discontinued loviride for up to 27 months. Cross-resistance to the other co mpounds was extensive; however, fold resistance to efavirenz was significan tly lower than fold resistance to nevirapine. No genotypic changes were det ected in three samples; these were sensitive to all of the NNRTIs tested. T he most common genotypic change was the K103N substitution. The range of ph enotypic resistance in samples containing the K103N substitution could not be predicted from a genotypic analysis of known NNRTI resistance-associated mutations. The Y181C substitution was detected in one isolate which was re sistant to loviride and delavirdine but sensitive to efavirenz, HBY-097, an d tivirapine. Our data indicate that the available newer NNRTIs which retai n activity against some HIV-1 strains selected by other compounds of this c lass in vitro may have compromised clinical efficacy in some patients pretr eated with NNRTI.