       Document 0202
 DOCN  M9440202
 TI    Nevirapine resistance mutations of human immunodeficiency virus type 1
       selected during therapy.
 DT    9404
 AU    Richman DD; Havlir D; Corbeil J; Looney D; Ignacio C; Spector SA;
       Sullivan J; Cheeseman S; Barringer K; Pauletti D; et al; Department of
       Pathology, University of California, San Diego; 92093-0679.
 SO    J Virol. 1994 Mar;68(3):1660-6. Unique Identifier : AIDSLINE
       MED/94149857
 AB    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.
 DE    Antiviral Agents/*PHARMACOLOGY/THERAPEUTIC USE  Base Sequence  Drug
       Resistance, Microbial/GENETICS  Drug Therapy, Combination  Genotype
       Human  HIV Core Protein p24/BLOOD  HIV Infections/*DRUG THERAPY
       HIV-1/*GENETICS  Leukocyte Count  Molecular Sequence Data  *Mutagenesis
       Phenotype  Pyridines/*PHARMACOLOGY/THERAPEUTIC USE  Reverse
       Transcriptase/ANTAGONISTS & INHIB/*GENETICS  RNA, Viral/BLOOD
       *Selection (Genetics)  Support, Non-U.S. Gov't  Support, U.S. Gov't,
       Non-P.H.S.  Support, U.S. Gov't, P.H.S.  Time Factors  T4
       Lymphocytes/CYTOLOGY  Zidovudine/PHARMACOLOGY/THERAPEUTIC USE  JOURNAL
       ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

