Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy

Abstract

Drug susceptibility and mutations in the reverse transcriptase (RT) gene were analyzed with 167 virus isolates from 38 patients treated with nevirapine, a potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) RT. Resistant isolates emerged quickly and uniformly in all patients administered nevirapine either as monotherapy or in combination with zidovudine (AZT). Resistance developed as early as 1 week, indicating rapid turnover of the virus population. The development of resistance was associated with the loss of antiviral drug activity as measured by CD4 lymphocyte counts and levels of HIV p24 antigen and RNA in serum. In addition to mutations at amino acid residues 103, 106, and 181 that had been identified by selection in cell culture, mutations at residues 108, 188, and 190 were also found in the patient isolates. Sequences from patient clones documented cocirculating mixtures of populations of different mutants. The most common mutation with monotherapy, tyrosine to cysteine at residue 181, was prevented from emerging by coadministration of AZT, which resulted in the selection of alternative mutations. The observations documented that, under selective drug pressure, the circulating virus population can change rapidly, and many alternative mutants can emerge, often in complex mixtures. The addition of a second RT inhibitor, AZT, significantly altered the pattern of mutations in the circulating population of HIV.

Non‐nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability

“…Genotypic analysis has shown mutations in the HIV-1 RT gene Y181C and/or V106A depending upon the virus strain and cell line employed. The most common resistance-associated mutation (RAM) in vivo is Y181C, but substitutions at positions 103, 106, 108, 181, 188 and 190 have been also observed [33,34].…”

Biological mechanisms of vertical human immunodeficiency virus (HIV‐1) transmission

“…High-level resistance to NVP results from single nucleotide mutations at any of the reverse transcriptase codons 103,106,181,188,190 and 230 while mutations at codons 100, 101, 108 and 179 are associated with lower levels of resistance [171,172]. The mutations K103N and Y181C, which independently cause high levels of resistance, are the most common mutations that arise following NVP monotherapy [173]. These resistance mutations emerge quickly due to the high error rate of reverse transcription in the presence of selective pressure provided by the long half-life of NVP [173].…”

“…The mutations K103N and Y181C, which independently cause high levels of resistance, are the most common mutations that arise following NVP monotherapy [173]. These resistance mutations emerge quickly due to the high error rate of reverse transcription in the presence of selective pressure provided by the long half-life of NVP [173].…”

HIV genetic variation: Life at the edge

“…In the case of nevirapine, an anti-HIV-1 reverse transcriptase drug, resistance involving a single substitution emerged within days in vivo. 21 In such cases the resistant variant was probably present within the pre-treatment viral quasispecies. For full AZT resistance five substitutions are necessary.…”