236 • CID 2005:41 (15 July) • HIV/AIDS
H I V / A I D SM A J O R A R T I C L E
Antiviral Activity of Lamivudine in Salvage Therapy
for Multidrug-Resistant HIV-1 Infection
Thomas B. Campbell,1Nancy S. Shulman,2Steven C. Johnson,1Andrew R. Zolopa,2Russell K. Young,1
Lane Bushman,3Courtney V. Fletcher,3E. Randall Lanier,4Thomas C. Merigan,2and Daniel R. Kuritzkes5
Division of Infectious Diseases, Departments of
Research Triangle Park, North Carolina; and
Harvard Medical School, Boston, Massachusetts
2Clinical Pharmacy, University of Colorado Health Sciences Center, Denver,
4Department of Clinical Virology, GlaxoSmithKline,
5Section of Retroviral Therapeutics, Brigham and Women’s Hospital and Division of AIDS,
3Division of Infectious Disease, Stanford Medical School, Stanford, California;
multidrug-resistant human immunodeficiency virus type 1 (HIV-1). Available data suggest that lamivudine con-
tributes to partial viral suppression, despite the presence of M184V mutationsandhigh-levelphenotypiclamivudine
Selective lamivudine withdrawal was studied in 6 subjects who had incomplete viral suppression
during antiretroviral treatment for multidrug-resistant HIV-1 infection.
Plasma levels of HIV-1 RNA increased to 0.5 log10copies/mL above baseline 6 weeks after the
withdrawal of lamivudine treatment (), even though reversion of lamivudine resistancewasnotyetdetected.P p .04
Early increases in plasma levels of HIV-1 RNA after lamivudine withdrawal were associated with the presence of
the T215Y/F mutation and broad phenotypic resistance to nucleoside reverse-transcriptase inhibitors at baseline.
Genotypic and phenotypic reversion of lamivudine resistance was detected in 4 subjects 8–14weeksafterwithdrawal
of lamivudine therapy. The duration of lamivudine withdrawal ranged from 8 to 22 weeks; all subjects resumed
lamivudine treatment. Plasma levels of HIV-1 RNA were 0.6 log10copies/mL above baseline (
lamivudine therapy was resumed. After the resumption of lamivudine treatment, plasma HIV RNA levelsdecreased
to baseline levels in 3 subjects but remained elevated in 3 subjects who had evolution of increased antiretroviral
drug resistance during the period of lamivudine withdrawal. Safety concerns raised by this latter finding led to
permanent closure of the study.
In select cases of multidrug-resistant HIV-1 infection, lamivudine contributes to suppression of
HIV-1 replication, despite the presence of M184V mutations and lamivudine resistance.
Maximum suppression of virus replication is often not achievable for persons infected with
) whenP p .03
Treatment options for persons infectedwithmultidrug-
resistant HIV-1 are limited, and, in many cases, sup-
pression of plasma levels of HIV-1 RNA to less than
detectable levels is not possible. However, the accu-
mulation of drug-resistance mutations in reverse tran-
scriptase (RT) and protease (PR) is sometimes associ-
ated with plasma HIV-1 RNA levels that are less than
pretreatment levels. In addition, antiretroviral drugs
may have partial activity, even in the presence of sub-
stantial resistance. Although complete viralsuppression
Received 29 November 2004; accepted 3 March 2005; electronically published
7 June 2005.
Reprints or correspondence: Dr.ThomasCampbell,CampusBoxB-168,University
of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262
Clinical Infectious Diseases 2005;41:236–42
? 2005 by the Infectious Diseases Society of America. All rights reserved.
may not be achievable in such patients, maintenance
of even partial viral suppression provides a clinicalben-
High-level lamivudine resistance is conferred bymu-
tations at RT codon 184 that produce a M184V or
M184I substitution in the conserved YMDD motif of
the RT polymerase domain . Despite the rapid ap-
pearance of the 184V mutation duringlamivudinether-
apy, plasma HIV-1 RNA levels remain partially sup-
pressed when lamivudine therapy is continued [3–5].
Withdrawal of lamivudine monotherapy or discontin-
uation of treatment with multidrug regimens that in-
clude lamivudine in persons infected with HIV-1 with
the 184V mutation is associated with increased plasma
levels of HIV-1 RNA and reversion to wild-type 184M
virus [6–8]. Explanations for the apparent paradox be-
tween the development of high-level lamivudine resis-
tance and continued partial suppression of HIV-1 rep-
by guest on November 26, 2015
242 • CID 2005:41 (15 July) • HIV/AIDS
Virologic, Roche Pharmaceuticals, Abbott, and Gilead. E.R.L. is an em-
ployee of GlaxoSmithKline. T.C.M. is a consultant for Quest Diagnostics.
D.R.K. is a consultant for and has received honoraria and research grant
support from GlaxoSmithKline. S.C.J. has received research funding from
Bayer Corporation and Bristol-Myers Squibb Company and is a consultant
for AstraZeneca and Aventis Pharmaceuticals. A.R.Z. has received research
funding from Bristol-Myers Squibb, Abbott, and Johnson & Johnson; is a
consultant for Bristol-Myers Squibb; and is a scientific advisor for Bristol-
Myers Squibb, Gilead, Virologic, and Roche Diagnostics. R.K.Y., L.B., and
C.V.F.: no conflicts.
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