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Antimicrobial Agents and Chemotherapy, June 2000, p. 1767-1768, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
LETTERS TO THE EDITOR
Response to Antiretroviral Therapy in a Patient with an
Uncommon Codon 69 Insertion in the Human Immunodeficiency Virus
Type 1 Reverse Transcriptase
 |
LETTER |
Therapy failure of antiretroviral drugs may occur due to many
factors, and one of the most important is drug resistance development (3). In the last few years, several authors have written
about the phenomenon of multiple nucleoside resistance (MDR), which confers simultaneous resistance to many nucleoside reverse
transcriptase inhibitors (NRTI) (2, 4). Different mechanisms
are involved in this event; one of these is the codon 69 insertion,
whose role continues to be controversial. Larder et al. (5)
hypothesized that this insertion could effect nucleoside resistance
particularly when combined with other mutated codons within the reverse
transcriptase, and Winters et al. (10) reported that this
insertion accounted for increases of up to 10-fold in the 50%
inhibitory concentrations (IC50) of most nucleosides except stavudine.
Here we report the case of a patient treated with various
antiretroviral drugs in whom we found a viral mutant with an unusual codon 69 reverse transcriptase insertion. A 37-year-old heterosexual woman began therapy with zidovudine (ZDV) in December 1994. After 8 months we changed ZDV to didanosine (ddI) due to a CD4+
cell decline. In July 1996 we measured the viral load for the first
time, which was very high (653,000 copies/ml; branched DNA), so we
began triple therapy with ZDV-zalcitabine (ddC)-saquinavir (SQV).
Three months later we again changed treatment due to a virological
failure (Fig. 1), and the patient then began
taking stavudine (d4T)-ddI-SQV. In November 1997, after a transient
virological response there was a viral-load rebound; therefore, we
started a double-protease-inhibitor regimen with ddI-ritonavir
(RTV)-SQV, because it was the only alternative regimen available.
Finally, after another virological failure and on the basis of a
resistance test performed, in September 1998 we introduced a new
treatment regimen: d4T-efavirenz (EFV)-nelfinavir (NFV). One month
later, the viral load decreased to an undetectable level, and the
situation has remained unchanged. Figure 1 shows CD4+ cell
counts and HIV-1 RNA modifications in relation to drug changes.
The patient was evaluated for drug resistance in March 1997 with both
genotypic and phenotypic analyses, conducted as previously reported
(6, 9). The results showed a genotypic profile for the
protease gene typical of multiple mutations linked to protease
inhibitor cross-resistance. Of note, the reverse transcriptase exhibited a resistance pattern that to our knowledge has been reported
only once before (5). The reverse transcriptase of our
patient (plasma RNA) showed mutations V106I and F214L and the T69S
insertion VG (GenBank accession number, AF186771); the amino acid
sequence from the culture supernatant showed a codon 210W mutation as
well. The phenotypic analysis, repeated in several experiments,
revealed a marked resistance to the protease inhibitors indinavir and
RTV (IC50 > 0.1 µM), to the NRTI ZDV (IC50 > 10 µM), ddI (IC50 > 1 µM), and lamivudine (IC50 = 1.169 µM). On the
other hand, a phenotypic susceptibility was evident for d4T
(IC50 = 0.052 µM) and the new protease inhibitor
tipranavir (IC50 = 0.191 µM).
This case offers additional evidence of newly described MDR insertions
in heavily pretreated HIV-1-infected subjects in the absence of optimal
viral suppression. Moreover, the finding of novel mutated codons can
account for the emergence of resistance in the presence of potentially
effective antiviral regimens, as described by Bloor et al.
(1), who pointed out the role of the E44D and V118I
mutations within the HIV-1 reverse transcriptase. As previously
reported (10), our patient experienced the beneficial effect
of d4T therapy, combined with EFV and NFV. Nevertheless, the potential
development of d4T phenotypic resistance should be taken into account
for NRTI-treated patients (7). Our report, as have others
(5, 8), emphasizes the importance of continued monitoring
for genotypic drug resistance in order to detect new mutations that can
impair the efficacy of combination therapies against HIV-1.
| |
FOOTNOTES |
*
Phone: 39-02-39042676 Fax:
39-02-3560805 E-mail: rusconi{at}mailserver.unimi.it
| |
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| | | | |
Paolo Bonfanti
Ivano Faggion
1st Division
of Infectious Diseases University of Milan Ospedale Luigi
Sacco 20157 Milan, Italy
|
| | | | |
Simona La Seta Catamancio
Michela Violin
Claudia Balotta
Stefano Rusconi*
Institute of Infectious and Tropical
Diseases University of Milan Ospedale Luigi Sacco via
G. B. Grassi 74 20157 Milan, Italy
|
Antimicrobial Agents and Chemotherapy, June 2000, p. 1767-1768, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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