Document 0245
 DOCN  M95A0245
 TI    Development of HIV-1 resistance to (-)2'-deoxy-3'-thiacytidine in
       patients with AIDS or advanced AIDS-related complex.
 DT    9510
 AU    Wainberg MA; Salomon H; Gu Z; Montaner JS; Cooley TP; McCaffrey R; Ruedy
       J; Hirst HM; Cammack N; Cameron J; et al; McGill University AIDS Centre,
       Jewish General Hospital, Montreal,; Quebec, Canada.
 SO    AIDS. 1995 Apr;9(4):351-7. Unique Identifier : AIDSLINE MED/95314790
 AB    OBJECTIVE: To determine the rate of development of in vitro HIV
       resistance to (-)2'-deoxy-3'-thiacytidine (3TC) and relate the effect of
       dose to emergence of resistance. METHODS: HIV-infected men and
       non-pregnant women, aged > or = 18 years, with a CD4 count < or = 300 x
       10(6)/l cells were followed in a Phase I/II study, in which they were
       evaluated for tolerance to 3TC and effect of this agent with regard to
       viral susceptibility. Peripheral blood and plasma samples were collected
       at regular intervals for analysis. HIV was isolated using umbilical cord
       blood mononuclear cells as targets. These cells were also used in
       determinations of median inhibitory drug concentration. Specific
       amplification of the 184 mutation site, associated with HIV resistance
       to 3TC, was performed by polymerase chain reaction, using specific
       primer pairs, on DNA harvested from infected peripheral blood
       mononuclear cells (PBMC) of donors or, alternatively, on DNA that had
       been reverse transcribed from plasma-associated HIV RNA. RESULTS:
       Phenotypic resistance was detected in approximately one-third of
       individuals studied, who were followed between 8 and 56 weeks.
       Development of 3TC resistance occurred independently of dose, although
       time of first appearance of resistant HIV-1 variants appeared reduced at
       high 3TC doses. Amino-acid changes at codon 184 in HIV-1 reverse
       transcriptase were associated with, and preceded, the development of
       phenotypic 3TC resistance. Most commonly, a Met to Ile substitution
       appeared transiently before being superceded by a Val substitution at
       codon 184. CONCLUSIONS: In vitro resistance to 3TC developed in a high
       proportion of subjects who received prolonged monotherapy with this
       drug. The development of resistance to 3TC was associated with
       appearance of mutated viral forms and the disappearance of wild-type
       virus, with regard to codon 184, in both patient plasma and PBMC.
 DE    Acquired Immunodeficiency Syndrome/*DRUG THERAPY/VIROLOGY  Adolescence
       Adult  AIDS-Related Complex/*DRUG THERAPY/VIROLOGY  Base Sequence
       Comparative Study  Cytosine/*ANALOGS & DERIVATIVES/ADMINISTRATION &
       DOSAGE/  PHARMACOLOGY  Dose-Response Relationship, Drug  Drug
       Resistance, Microbial/GENETICS  DNA Primers/GENETICS  Female  Human
       HIV-1/*DRUG EFFECTS/GENETICS/ISOLATION & PURIF  In Vitro  Male
       Molecular Sequence Data  Mutation  Phenotype  Proviruses/DRUG
       EFFECTS/GENETICS  Reverse Transcriptase/ANTAGONISTS & INHIB  RNA,
       Viral/GENETICS  Support, Non-U.S. Gov't  Time Factors  CLINICAL TRIAL
       CLINICAL TRIAL, PHASE I  CLINICAL TRIAL, PHASE II  JOURNAL ARTICLE
       MULTICENTER STUDY

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