NEVIRAPINE RESISTANCE MUTATIONS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 SELECTED DURING THERAPY

Drug susceptibility and mutations in the reverse transcriptase (RT) ge ne were analyzed with 167 virus isolates from 38 patients treated with nevirapine, a potent nonnucleoside inhibitor of human immunodeficienc y virus type 1 (HIV-1) RT. Resistant isolates emerged quickly and unif ormly in all patients administered nevirapine either as monotherapy or in combination with zidovudine (AZT). Resistance developed as early a s 1 week, indicating rapid turnover of the virus population. The devel opment of resistance was associated with the loss of antiviral drug ac tivity as measured by CD4 lymphocyte counts and levels of HIV p24 anti gen and RNA in serum. In addition to mutations at amino acid residues 103, 106, and 181 that had been identified by selection in cell cultur e, mutations at residues 108, 188, and 190 were also found in the pati ent isolates. Sequences from patient clones documented cocirculating m ixtures of populations of different mutants. The most common mutation with monotherapy, tyrosine to cysteine at residue 181, was prevented f rom emerging by coadministration of AZT, which resulted in the selecti on of alternative mutations. The observations documented that, under s elective drug pressure, the circulating virus population can change ra pidly, and many alternative mutants can emerge, often in complex mixtu res. The addition of a second RT inhibitor, AZT, significantly altered the pattern of mutations in the circulating population of HIV.