Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy

Efavirenz (also known as DMP 266 or SUSTIVA) is a potent nonnucleoside inhi bitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and of HIV-1 replication in vitro and in vivo. Most patients on efavirenz-containing regimens have sustained antiviral responses; howeve r, rebounds in plasma viral load have been observed in some patients in ass ociation with the emergence of mutant strains of HIV-1, Virus isolates from the peripheral blood mononuclear cells (PBMCs) of patients with such treat ment failures, as well as recombinant viruses incorporating viral sequences derived from patient plasma, show reduced in vitro susceptibility to efavi renz in association with mutations in the RT gene encoding K103N, Y188L, or G190S/E substitutions. Patterns of RT gene mutations and in vitro suscepti bility were similar in plasma virus and in viruses isolated from PBMCs. Var iant strains of HIV-1 constructed by site-directed mutagenesis confirmed th e role of K103N, G190S, and Y188L substitutions in reduced susceptibility t o efavirenz. Further, certain secondary mutations (V106I, V108I, Y181C, Y18 8H, P225H, and F227L) conferred little resistance to efavirenz as single mu tations but enhanced the level of resistance of viruses carrying these muta tions in combination with K103N or Y188L. Viruses with K103N or Y188L mutat ions, regardless of the initial selecting nonnucleoside RT inhibitor (NNRT1 ), exhibited cross-resistance to all of the presently available NNRT1s (efa virenz, nevirapine, and delavirdine). Some virus isolates from nevirapine o r delavirdine treatment failures that lacked K103N or Y188L mutations remai ned susceptible to efavirenz in vitro, although the clinical significance o f this finding is presently unclear.