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M9480646.TXT
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1994-08-20
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Document 0646
DOCN M9480646
TI Quasispecies dynamics and the emergence of drug resistance during
zidovudine therapy of HIV infection.
DT 9410
AU Frost SD; McLean AR; Department of Zoology, University of Oxford, U.K.
SO AIDS. 1994 Mar;8(3):323-32. Unique Identifier : AIDSLINE MED/94304552
AB OBJECTIVE: To investigate the roles of mutation, competition and
population dynamics in the emergence of drug resistant mutants during
zidovudine therapy. DESIGN: A mathematical model of the population
dynamics of the viral quasispecies during zidovudine therapy was
investigated. METHODS: The model was used to simulate changes in the
numbers of uninfected and infected cells and the composition of the
viral quasispecies in the years following initiation of therapy.
Resulting scenarios in asymptomatic and AIDS patients were compared. The
model was also used to investigate the efficacy of a treatment regimen
involving alternating zidovudine and dideoxyinosine therapy. RESULTS:
The behaviour of the model can be divided into three stages. Before
therapy, mutation maintains a small pool of resistant mutants,
outcompeted to very low levels by sensitive strains. When therapy begins
there is a dramatic fall in the total viral load and resistant strains
suddenly have the competitive advantage. Thus, it is resistant strains
that infect the rising number of uninfected CD4+ cells. During this
second stage the rapid effects of population dynamics swamp any effects
of mutation between strains. When the populations of infected and
uninfected cells approach their treatment equilibrium levels, mutation
again becomes important in the slow generation of highly resistant
strains. CONCLUSIONS: The short-term reduction in viral replication at
the initiation of therapy generates a pool of uninfected cells which
cause the eventual increase in viral burden. This increase is associated
with (but not caused by) a rise in frequency of resistant strains which
are at a competitive advantage in the presence of the drug. When therapy
is ceased, reversion of resistance is slow as resistant strains are
nearly as fit as sensitive strains in the absence of drug.
DE Didanosine/ADMINISTRATION & DOSAGE/THERAPEUTIC USE Drug Resistance,
Microbial/GENETICS Drug Therapy, Combination Genes, pol Human
HIV/*DRUG EFFECTS/GENETICS/PHYSIOLOGY HIV Infections/BLOOD/*DRUG
THERAPY/MICROBIOLOGY Leukocyte Count Models, Biological Mutation
Population Dynamics Species Specificity Support, Non-U.S. Gov't T4
Lymphocytes Virus Replication/DRUG EFFECTS Zidovudine/ADMINISTRATION &
DOSAGE/*THERAPEUTIC USE JOURNAL ARTICLE
SOURCE: National Library of Medicine. NOTICE: This material may be
protected by Copyright Law (Title 17, U.S.Code).