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J Virol, June 1998, p. 5154-5164, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Genotypic Changes in Human Immunodeficiency Virus
Type 1 Associated with Loss of Suppression of Plasma Viral RNA Levels
in Subjects Treated with Ritonavir (Norvir) Monotherapy
P. Scott
Eastman,1,*
John
Mittler,2
Reed
Kelso,1
Chris
Gee,1
Eric
Boyer,1
Janice
Kolberg,1
Mickey
Urdea,1
John M.
Leonard,3
Daniel W.
Norbeck,4
Hongmei
Mo,5 and
Martin
Markowitz5
Chiron Corporation, Emeryville, California
946081;
Theoretical Biology and
Biophysics and Center for Nonlinear Studies, Los Alamos National
Laboratory, Los Alamos, New Mexico 875452;
Pharmaceutical Products Division3 and
Anti-Infective Research,4 Abbott
Laboratories, Abbott Park, Illinois 60064; and
Aaron Diamond
AIDS Research Center, New York University School of Medicine, New York,
New York 100165
Received 10 March 1997/Accepted 18 February 1998
Ten subjects received 600 to 1,200 mg of the human immunodeficiency
virus type 1 (HIV-1) protease inhibitor ritonavir per day. Following 2 weeks of therapy, plasma HIV RNA levels decreased by a mean of 1.57 (range, 0.89 to 1.96) log units. With continued therapy, HIV RNA levels
began to rise in eight subjects. The initial rise in plasma RNA levels
was temporally associated with the development and quantitative
increase in the V82 resistance mutation. Doubling times of the V82A
mutant virus were estimated to be 2.4 to 4.8 days. An L63P/A mutation
was commonly present at baseline even in subjects with a durable
virologic response. The concomitant acquisition of an L63P/A mutation
with the V82A/F mutation at the time when plasma RNA levels rebounded
suggests a role for the L63P/A mutation in improving the fitness of the
V82A/F mutation. Subsequent additional genotypic changes at codons 54 and 84 were often associated with further increases in plasma RNA
levels. Ongoing viral replication in the presence of drugs resulted in the appearance of additional genotypic changes, including the L90M
saquinavir resistance mutation, and decreased phenotypic susceptibility. The relative fitness of the protease V82A ritonavir resistance mutation and reverse transcriptase T215Y/F zidovudine resistance mutation following drug withdrawal were estimated to be 96 to 98% that of the wild type. Durability of the virologic response was
associated with plasma RNA levels at the nadir. A virologic response
beyond 60 days was not observed unless plasma HIV RNA levels were
suppressed below 2,000 copies/ml, consistent with estimates from V82A
doubling times for selection of a single resistance mutation to
dominate the replicating population.
*
Corresponding author. Mailing address: Chiron
Corporation, 4560 Horton St., Emeryville, CA 94608. Phone: (510)
601-3048. Fax: (510) 655-7733. E-mail address:
scott_eastman{at}cc.chiron.com.
J Virol, June 1998, p. 5154-5164, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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