CONCOMITANT COMBINATION THERAPY FOR HIV-INFECTION PREFERABLE OVER SEQUENTIAL THERAPY WITH 3TC AND NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS

Exposure to 3TC of HIV-1 mutant strains containing non-nucleoside reve rse transcriptase inhibitor (NNRTI)-specific mutations in their revers e transcriptase (RT) easily selected for double-mutant viruses that ha d acquired the characteristic 184-Ile mutation in their RT in addition to the NNRTI-specific mutations, Conversely, exposure of 3TC-resistan t 184-Val mutant HIV-1 strains to nine different NNRTIs resulted in th e rapid emergence of NNRTI-resistant virus strains at a time that was not more delayed than when wild-type HIV-1(IIIB) was exposed to the sa me compounds. The RTs of these resistant virus strains had acquired th e NNRTI-characteristic mutations in addition to the preexisting 184-Va l mutation, Surprisingly, when the 184-Ile mutant HIV-1 was exposed to a variety of NNRTIs, the 188-His mutation invariably occurred concomi tantly with the 184-Ile mutation in the HIV-1 RT, Breakthrough of this double-mutant virus was markedly accelerated as compared with the mut ant virus selected from the wild-type or 184-Val mutant HIV-1 strain, The double (184-Ile + 188-His) mutant virus showed a much more profoun d resistance profile against the NNRTIs than the 188-His HIV-1 mutant, In contrast with the sequential chemotherapy, concomitant combination treatment of HIV-1-infected tells with 3TC and a variety of NNRTIs re sulted in a dramatic delay of virus breakthrough and resistance develo pment.