Antiviral Chemistry & Chemotherapy 16:295–302
In vitro activity of SPD754, a new deoxycytidine
nucleoside reverse transcriptase inhibitor (NRTI),
against 215 HIV-1 isolates resistant to other NRTIs
Richard C. Bethell1*, Yolanda S. Lie2 and Neil T. Parkin2
1
Shire BioChem Inc., Ville St. Laurent, Québec, Canada. Presently: Boehringer Ingelheim (Canada) Ltd, Laval,
Québec, Canada
2
ViroLogic, Inc., South San Francisco, CA, USA
*Corresponding author: Tel: +1 450 682 4641 ext. 4332; Fax: +1 450 682 4642;
Email: rbethell@lav.boehringer-ingelheim.com
This work was presented in part at the 12th International HIV Drug Resistance Workshop, Cabo San Lucas,
Mexico, June 10–14 2003 (Abstract 3).
SPD754 (also known as AVX-754) is a deoxycytidine analogue nucleoside reverse transcriptase
inhibitor (NRTI) with antiretroviral activity against
HIV-1 and HIV-2 in vitro and against recombinant
viruses containing thymidine analogue mutations
(TAMs). In order to better establish the activity of
SPD754 against HIV-1 containing TAMs, twelve
panels of up to twenty clinical isolates with
defined TAM combinations were selected from
the ViroLogic database. Phenotypic viral susceptibility to SPD754 and five other NRTIs was tested
using the PhenoSense HIV assay and expressed as
median fold-change compared with a reference
strain. In total, 215 isolates were selected, representing four TAM patterns in both pathways by
which TAMs accumulate clinically. The presence of
five TAMs in the 41, 215 pathway, at codons 41,
67, 210, 215, and 219 of reverse transcriptase (RT),
produced a median 1.8-fold reduction in SPD754
susceptibility, compared with fold reductions to
zidovudine, lamivudine, abacavir, didanosine
and tenofovir of 438, 4.8, 4.5, 1.4 and 3.6, respectively. Five TAMs in the 67, 70, 219 pathway (at
codons 41, 67, 70, 215 and 219) reduced SPD754
susceptibility by a median 1.3-fold, compared
with fold reductions for the aforementioned
NRTIs of 108, 3.2, 3.0, 1.3 and 2.5, respectively.
M184V addition reduced SPD754 susceptibility by
1.8-fold in the presence or absence of TAMs.
SPD754 retains a substantial proportion of its
antiviral activity against HIV-1 containing
multiple TAMs, with or without the M184V mutation. These data suggest that SPD754 is a
promising new NRTI for the treatment of NRTIexperienced HIV-infected patients.
Keywords: Antiretroviral agents, antiviral drug
resistance, human immunodeficiency virus, HIV-1
reverse transcriptase, reverse transcriptase
inhibitors, SPD754
Introduction
Nucleoside reverse transcriptase inhibitors (NRTIs) are
the backbone of highly active antiretroviral therapy
(HAART) regimens recommended for the treatment of
patients with HIV infection (Dybul et al., 2002; Panel on
Clinical Practices for Treatment of HIV Infection, 2003).
HAART regimens have substantially reduced morbidity
and mortality associated with HIV disease (Palella et al.,
1998; Murphy et al., 2001). However, resistance to antiretrovirals, including NRTIs, is increasingly common and
is an important cause of virological treatment failure
(Deeks, 2004). A longitudinal study in France found that
78% of HIV samples collected from treated patients
©2005 International Medical Press 0956-3202
between 1997 and 2000 had mutations in the reverse
transcriptase (RT) genome conferring resistance to at
least one NRTI (Tamalet et al., 2003). A quarter of
isolates were genotypically resistant to all three major
antiretroviral classes, that is NRTIs, non-nucleoside
reverse transcriptase inhibitors and protease inhibitors.
Similar data have been reported from the United States
(Kagan et al., 2000; Richman et al., 2004). Primary infection with NRTI-resistant HIV is also of increasing
concern in some countries, including the United States
(Salomon et al., 2000; UK Collaborative Group, 2001;
Little et al., 2002).
295
R Bethell et al.
NRTIs share a common mechanism of action: following
intracellular activation to the triphosphate (TP) form, they
compete with endogenous phosphonated nucleotides for
binding to viral RT. RT incorporates NRTI-monophosphates into nascent DNA chains during replication,
causing chain termination. Resistance to NRTIs occurs
primarily via two mechanisms: increased rates of phosphorylysis of the incorporated NRTI-monophosphate and
improved specificity of the RT for the natural nucleoside
triphosphate relative to the triphosphorylated NRTI (de
Mendoza et al., 2002). Mutations at codons 41, 67, 70, 210,
215 and 219 of the RT genome – collectively known as
‘thymidine analogue mutations’ (TAMs) because of their
initial association with resistance to zidovudine and stavudine – act to increase the rate of phosphorylysis. HIV-1
acquires these mutations sequentially during NRTI treatment, and the accumulation of these mutations leads to
progressive decreases in susceptibility to all NRTIs
(Whitcomb et al., 2003). This accumulation occurs via two
pathways determined by the first TAM present at first
treatment failure, which is itself determined by the treatment regimen. One pathway originates through mutations
at codons 41 or 215 (predominantly 215Y ). After both of
these mutations have been selected, mutations at codons
210, 67 and 219 are accumulated sequentially. The other
pathway is characterized by the accumulation of three
mutations at codons 67, 70 and 219. Once these three
mutations have been selected, mutations at codons 215
(predominantly 215F) and 41 are accumulated sequentially
(Flandre et al., 2003, Marcelin et al., 2004).
Other mutations, such as the M184V mutation, alter the
structure of the NRTI binding site upon RT. Such mutations result in better discrimination between the nucleoside
triphosphate substrate and the NRTI-triphosphate, diminishing the probability of a chain termination event during
reverse transcription. M184V is rapidly selected during
lamivudine-containing HAART (Descamps et al., 2000;
Maguire et al., 2000) and causes high-level resistance to
lamivudine and reduced susceptibilty to didanosine,
zalcitabine and abacavir (Whitcomb et al., 2003). Because
of the large number of patients who received sequential
monotherapy or dual NRTI therapy with zidovudine or
stavudine and lamivudine prior to the introduction of triple
drug combination therapy, and the large numbers of
patients who take lamivudine with zidovudine or stavudine
in HAART regimens, many treatment-experienced
patients harbour viruses that contain both TAMs and the
M184V mutation.
SPD754 (also known as AVX-754, and formerly as
BCH-10618) is a novel deoxycytidine analogue NRTI in
clinical development. SPD754 is the (–)-enantiomer of
2′-deoxy-3′-oxa-4′-thiocytidine (dOTC or BCH-10652)
(de Muys et al., 1999; Taylor et al., 2000). SPD754 showed
296
good antiviral activity against HIV-1 isolates in vitro, both
alone and in combination with other NRTIs (De Muys et
al., 1999; Taylor et al., 2000), good antiviral activity against
viruses with a range of NRTI-resistant genotypes (De Muys
et al., 1999; Taylor et al., 2000), and a low potential for
cellular and mitochondrial toxicity (Bethell RC, de Rooj
ER, Smolders KGM, van Schijndel HB, Timmermans EC
& de Baar MP (2004) Comparison of the in vitro mitochondrial toxicity of SPD754 and HepG2 cells with nine
other nucleoside reverse transcriptase inhibitors. 44th
Interscience Conference on Antimicrobial Agents &
Chemotherapy. Washington DC, USA. 30 October–2
November 2004. Abstract H-207). SPD754 showed
promising efficacy in a Phase II study of antiretroviralnaive, HIV-infected patients (Cahn P, Lange J, Cassetti I,
Sawyer J, Zala C, Rolon M, Bologna R & Shiveley L (2003)
Anti-HIV-1 activity of SPD754, a new NRTI: results of a
10 day monotherapy study in treatment-naïve HIV
patients. 2nd International Aids Society Conference. Paris,
France, 13–16 July 2003. Abstract LB-15). In order to
further characterize the activity of SPD754 against clinical
isolates of HIV-1 containing TAMs and the M184V mutation, SPD754 has been tested against a large panel of HIV1 clinical isolates with defined genotypic profiles associated
with NRTI resistance.
Materials and methods
Compounds
SPD754 was synthesized at Shire Pharmaceuticals (Laval,
Quebec, Canada) as described previously (Mansour et al.,
1995). Zidovudine and didanosine were sourced from
Sigma Chemical (MO, USA), lamivudine from Roxanne
Labs (CT, USA), abacavir from GlaxoSmithKline (NC,
USA) and tenofovir from Gilead Sciences (CA, USA). The
structures of all the antiviral compounds used in the present
study are shown in Figure 1.
Viruses and cells
Studies were performed using a panel of HIV-1 strains
with specific TAM patterns based on the data on pathways
for the selection of TAMs from the studies of Marcelin
et al. (2004) and Flandre et al. (2003). TAMs were defined
as M41L, D67N, K70R, L210W, T215F or Y, and K219E,
H, N, Q, R. Panels of clinical HIV-1 isolates with these
genotypic patterns were then selected from the ViroLogic
library of genotyped clinical isolates. Ten to twenty samples
with each genotype were selected.
Mutations at codons 44 (E44A or D) and 118 were
allowed within groups. Samples with mixtures at codons
41, 67, 70, 184, 210, 215 and 219 were excluded. Viruses
containing insertions at codon 69 or the Q151M mutation
were excluded, as were those with other mutations not
©2005 International Medical Press
SPD754 versus NRTI-resistant HIV
Figure 1. Chemical structures of SPD754, lamivudine, tenofovir, zidovudine, abacavir and didanosine
NH2
NH2
NH2
N
N
O
N
N
N
S
S
HO
P
O
SPD754
N
O
HO
HO
HO
O
N
O
N
O
Tenofovir
Lamivudine
O
O
HN
HN
N
O
O
N
HO
N
N
N
N
N
NH2
HO
O
NH
N
HO
N3
Zidovudine
Abacavir
typically included among TAMs (for example K65R, L74I
or V, and V75A, M, S, or T). Repeat samples from the same
patient with different genotypes were included, but only
one isolate from any given patient within any genotypic
group was permitted. None of the viruses contained mutations known to confer resistance to either non-nucleoside
reverse transcriptase inhibitors or protease inhibitors.
The effect of the M184V mutation on the antiviral
activity of NRTIs was determined by constructing similar
panels of viruses. Six such panels measured the effect of the
presence of the M814V mutation on the NRTI sensitivity
of wild-type virus and viruses with mutations TAMs at
codons 41 and 215, or codons 67, 70 and 219.
In all tests, NRTI susceptibility in the clinical isolates was
compared with that of a reference virus (strain CNDO)
containing the RT (and protease) sequences of the NL4-3
HIV-1. Cells were cultured as previously described for the
automated PhenoSense HIV assay (Petropoulos et al., 2000).
Antiviral assay
Phenotypic viral susceptibility to the aforementioned
NRTIs was assessed using the PhenoSense HIV assay
(Petropoulos et al. 2000). The results were expressed as
Antiviral Chemistry & Chemotherapy 16.5
Didanosine
median fold-change in 50% inhibitory concentration (IC50)
in clinical isolates, as compared with the reference strain.
Statistical methods
Analysis of the effect of M184V mutation on viral susceptibility to NRTIs was performed using pair-wise comparisons and plotted as bivariate scattergrams with linear
regression lines for the whole dataset or for the groups
with or without M184V. Pair-wise regression analysis of
log-transformed median fold-changes in susceptibility was
undertaken to evaluate the level of cross resistance between
SPD754 and the other NRTIs tested.
Results
A total of 215 isolates were selected (Table 1). These
isolates exhibited eight genotypic patterns containing only
TAMs, four in each of the two TAM pathways. Consistent
with previous results (Marcelin et al., 2004), viruses in the
41, 215 pathway contained predominantly Y at codon 215,
whereas viruses in the 67, 70, 219 pathway contained
predominantly F. A further three panels contained viruses
with M184V together with mutations with no TAMs or
297
298
20
20
20
20
20
20
15
10
20
20
15
15
Wild type
Wild type+M184V
41, 215 path
41, 215
41, 215+M184V
41, 210, 215
41, 67, 210, 215
41, 67, 210, 215, 219
67, 70, 219 path
67, 70
67, 70, 219
67, 70, 219+M184V
67, 70, 215, 219
41, 67, 70, 215, 219
5
4
–
–
–
15
19
20
18
19
–
–
Y
10
11
–
–
–
0
1
0
2
1
–
–
F
33
27
–
–
–
100
95
100
90
95
–
–
%Y
Codon 215
1.3
(0.9–1.9)
1.4
(1.0–1.7)
1.8
(1.6–2.7)
1.0
(0.6–1.9)
1.0
(0.8–1.2)
1.8
(1.2–2.6)
1.7
(1.2–2.4)
1.4
(1.1–1.9)
2.1
(1.3–3.1)
1.2
(0.7–1.7)
1.6
(1.2–2.1)
0.9
(0.7–1.1)
IC50 FC*
(range)
SPD754
–
–
1.9
–
–
–
–
–
1.7
–
1.8
–
∆184†
0.6
–
∆184†
–
0.2
108
–
(13.0–827)
44
–
(4.2–404)
3.4
0.2
(1.5–12.0)
21
–
(2.9–326)
5.5
–
(2.5–10.0)
438.0
–
(7.2–1000)
271
–
(5.6–1000)
91
(11–852)
6.0
(0.6–15)
33.1
–
(4.1–246)
0.5
(0.3–1.0)
0.7
(0.2–1.3)
IC50 FC*
(range)
Zidovudine
–
∆184†
–
–
–
–
–
–
3.2
(1.7–5.1)
3.8
(1.9–9.8)
–
–
200
116.2
(200–200)
1.7
(1.0–3.8)
1.6
(1.2–2.8)
4.8
(2.2–7.6)
4.2
(2.7–6.4)
1.9
(1.3–4.4)
200
138.5
(200–200)
1.4
(0.9–2.7)
200
214.4
(138–200)
0.9
(0.7–1.1)
IC50 FC*
(range)
Lamivudine
3.0
(1.5–5.3)
2.3
(1.5–4.0)
3.1
(2.5–5.5)
1.5
(0.8–3.2)
1.2
(0.9–1.6)
4.5
(1.8–6.7)
3.3
(1.8–4.7)
2.5
(1.3–3.8)
4.5
(2.6–6.2)
1.7
(1.3–3.1)
2.7
(1.8–3.3)
0.9
(0.6–1.1)
IC50 FC*
(range)
Abacavir
–
–
2.1
–
–
–
–
–
2.6
–
3.1
–
∆184†
1.3
(0.9–1.7)
1.1
(1.0–1.6)
1.3
(1.1–1.8)
0.9
(0.6–1.3)
1.0
(0.8–1.1)
1.4
(1.1–2.0)
1.3
(1.0–1.8)
1.2
(0.9–1.7)
1.5
(1.0–1.9)
1.0
(0.9–1.4)
1.3
(1.0–1.6)
1.0
(0.7–1.1)
IC50 FC*
(range)
–
–
1.4
–
–
–
–
–
1.5
–
1.3
–
∆184†
Didanosine
2.5
(1.5–5.0)
2.0
(1.0–3.6)
0.9
(0.6–1.6)
1.8
(1.1–4.6)
1.2
(0.9–1.7)
3.6
(1.1–9.1)
3.0
(1.0–5.7)
2.6
(1.4–5.9)
1.0
(0.4–1.4)
2.2
(1.3–4.7)
0.5
(0.4–0.6)
0.8
(0.4–0.9)
IC50 FC*
(range)
–
–
0.5
–
–
–
–
–
0.4
–
0.7
–
∆184†
Tenofovir
*Median (range) of the individual fold change (FC) values of the 50% inhibitory concentration (IC50) for clinical isolates relative to the standard reference strain (NL4-3). Data shown are rounded
values from the raw data. Upper limit of assay =200-fold for lamivudine. †Median FC value of isolates containing M184V relative to the median FC value of isolates with the same genotype without
M184V.
n
Genotype
Table 1. Effect of thymidine analogue mutations (TAMs) in the 41, 215 and 67, 70, 219 pathways, in the presence and absence of M184V mutations,
on HIV-1 in vitro susceptibility to SPD754 and other nucleotide reverse transcriptase inhibitors.
R Bethell et al.
©2005 International Medical Press
SPD754 versus NRTI-resistant HIV
with TAMs at either codons 41 and 215, or 67, 70 and
219. A further panel contained viruses with no nucleosideassociated mutations (NAMs).
Effect of TAMs on the antiviral activity of
SPD754 and other NRTIs
Viruses with no NAMs had a median 0.9-fold change in
susceptibility to SPD754 (range 0.7–1.1) relative to the
reference strain. The median fold-changes for all the other
NRTIs against this panel of viruses were also close to 1.0.
Mutations at codons 41 and 215 conferred a median
33-fold change in susceptibility to zidovudine relative to
wild-type HIV-1. The sequential addition of mutations at
codons 210, 67 and 219 progressively reduced susceptibility
to zidovudine until a median 438-fold reduction was
observed in the presence of all five mutations (Table 1).
Mutations at codons 67 and 70 conferred a median
5.0-fold change in susceptibility to zidovudine. A progressive decrease in susceptibility occurred with the accumulation of further mutations at codons 210, 67 and 219 until a
median 108-fold reduction occurred in the presence of all
five mutations (Table 1).
In contrast, mutations at codons 41 and 215 produced a
limited 1.2-fold (range 0.7–1.7) reduction in susceptibility
to SPD754. The incremental effects of further TAMs in
this pathway reached a 1.8-fold reduction (range 1.2–2.6)
when all five were present (Table 1). Similar fold-changes
in susceptibility to didanosine were observed, while reductions in susceptibility to lamivudine, abacavir and tenofovir
in the presence of all five TAMs were 4.8 (range 2.2–7.6),
4.5 (range 1.8–6.7) and 3.6 (range 1.1–9.1), respectively.
These levels of resistance to didanosine, abacavir and tenofovir and lamivudine are consistent with the results of a
previous study (Whitcomb et al. 2003).
Mutations at codons 67 and 70 had no effect on susceptibility to SPD754 (median fold-change 1.0; range
0.8–1.2). Accumulation of additional TAMs within this
pathway resulted in minimal changes in SPD754 susceptibility, which reached 1.3-fold change (0.9–1.9) when all
five TAMs were present (Table 1). Again, similar changes
in viral susceptibility to didanosine were observed, while
fold reductions in susceptibility to lamivudine, abacavir and
tenofovir in the presence of all five TAMs were 3.2 (range
1.7–5.1), 3.0 (range 1.5–5.3) and 2.5 (range 1.5–5.0),
respectively.
Effect of M184V mutation on the antiviral
activity of SPD754 and other NRTIs
Susceptibility to NRTIs was assessed in the presence and
absence of the M184V mutation in wild-type HIV-1 and
isolates with mutations at codons 41 and 215, or 67, 70 and
219. As expected, the presence of the M184V mutation
reduced median viral susceptibility to lamivudine to such a
Antiviral Chemistry & Chemotherapy 16.5
large extent that the IC50 value could not be determined
on any virus containing this mutation, regardless of the
background genotype.
Pair-wise comparisons showed that M184V addition
was associated with an approximate 1.8-fold reduction in
susceptibility to SPD754 in all genotypes (Table 1). In
comparison, M184V reduced abacavir susceptibility 2.1 to
3.1-fold and didanosine susceptibility by 1.3 to 1.5-fold.
M184V slightly increased viral susceptibility to tenofovir,
and this effect appeared slightly greater in the groups of
viruses containing TAMs than in the group lacking TAMs
(2.1 and 2.3-fold increased susceptibility in the 67, 70, 219
and 41, 215 groups respectively, compared with 1.5-fold in
the viruses lacking TAMs).
Cross resistance between NRTIs
Pair-wise regression analyses for SPD754 indicated that, as
for all other NRTIs (Whitcomb et al., 2003), there is
significant cross resistance between SPD754 and the other
NRTIs tested (r2 approximately 0.5–0.75) as shown in
Figure 2. The extent of cross resistance with zidovudine
and tenofovir was only apparent when samples with or
without M184V were analysed separately, whereas correlations between SPD754 and abacavir or didanosine were
evident with or without splitting the samples by the presence of M184V. However, in both subgroups, the extent of
cross resistance was substantial. In addition, there was
significant cross resistance between SPD754 and lamivudine in samples lacking M184V (r2=0.70; data not shown).
Discussion
Previous studies have demonstrated that TAM accumulation progressively decreases HIV susceptibility to all
NRTIs (Whitcomb et al., 2003). While measurable in vitro
resistance does not always result in reduced clinical susceptibility, clinical ‘cut off ’ thresholds for resistance assigned
for various NRTIs indicate that clinically significant reductions in susceptibility to a number of NRTIs can occur in
isolates with sufficient numbers of TAMs (Whitcomb
et al., 2003).
Data from the present study confirm that TAMs incrementally increase resistance to all of the NRTIs tested in
the present study, namely zidovudine, lamivudine, abacavir,
didanosine, tenofovir and SPD754. SPD754, along with
didanosine, showed a decrease in susceptibility of <50% in
the presence of up to five TAMs. The presence of five
mutations at codons 41, 67, 210, 215, and 219 conferred a
median 1.8-fold reduction in susceptibility to SPD754.
Similarly the presence of TAMs at codons 41, 67, 70, 215
and 219 conferred a median 1.3-fold reduction in susceptibility to SPD754. Until studies are performed to determine
the clinically relevant threshold for SPD754, we cannot
299
R Bethell et al.
Figure 2. Scattergrams based on pair-wise regression analysis showing potential level of in vitro cross
resistance between SPD754 and: A) abacavir, B) didanosine, C) tenofovir and D) zidovudine.
A
B
10
r2=0.76
r2=0.64
Didanosine FC
Abacavir FC
10
1
0
1
SPD754 FC
0
r2=0.70
r2=0.64
1
0
10
C
0
1
SPD754 FC
10
D
10
1000
2
r =0.53
r2=0.50
r2=0.59
r2=0.50
Zidovudine FC
Tenofovir FC
100
1
0
0
1
SPD754 FC
10
1
0
10
0
1
SPD754 FC
10
Values for r 2 indicate correlation co-efficients for the groups defined by the absence (M184 wt) or presence of the M184V mutation.
determine whether or not these modest reductions in
susceptibility will impact virological response rates.
Nonetheless, the relatively low magnitude of the susceptibility reductions suggest that SPD754 will be useful in the
treatment of NRTI-experienced HIV-infected patients, in
whom cross resistance among NRTIs limits the available
options for salvage therapy (Deeks, 2004).
The structural basis of the very high level of resistance
to lamivudine conferred by the M184V and M184I
mutations has been attributed to steric interactions
between the branched side-chain of these amino acids and
thiomethylene group of lamivudine, which is very much
larger than the oxygen atom of the natural substrates of the
reverse transcriptase (Sarafianos et al., 1999). The very
300
much lower magnitude of the decrease in susceptibility to
SPD754 conferred by M184V is therefore likely to result
from the much smaller size of a single sulphur atom of
SPD754 when compared to the corresponding thiomethylene group of lamivudine, as is shown in Figure 1.
Whitcomb et al. (2003) have proposed that NRTIs can
be divided into two groups according to the effect of the
M184V mutation in vitro: susceptibility to ‘Group 1’ agents
(zidovudine, stavudine, tenofovir and adefovir) is increased
by M184V, while susceptibility to Group 2 agents (lamivudine, emtricitabine, didanosine, zalcitabine and abacavir) is
decreased (Whitcomb et al., 2003). The clinical relevance
of these in vitro observations will vary according to the
clinical cut off for individual agents. The effect of the
©2005 International Medical Press
SPD754 versus NRTI-resistant HIV
M184V mutation on SPD754 susceptibility was consistent
regardless of the background genotype: the mutation
produced a small (1.8-fold) decrease in susceptibility to
SPD754 in the presence of TAMs accumulated via either
pathway. Clearly, SPD754 belongs in the second category
of NRTIs, although its activity was affected less than
that of many other members. In common with previous
reports (Miller et al., 2003), M184V slightly increased viral
susceptibility to tenofovir in the present study.
M184V-positive HIV-1 mutants show reduced replicative fitness owing to enhanced fidelity and/or impaired
processivity in the RT enzyme (Back et al., 1996; Naeger
et al., 2001; Diallo et al., 2003). Furthermore, there was a
0.5 log10 reduction in viral load relative to baseline viral load
among patients who received lamivudine monotherapy and
in whom the M184V was rapidly selected (Kuritzkes et al.
1996). These observations have led some to propose that
lamivudine administration should be continued in patients
with the M184V mutation in order to maintain a reduced
replicative capacity. However, an NRTI with potent clinical
antiretroviral activity [Bethell RC & Collins P (2004)
Genotypic and phenotypic analysis of HIV-1 isolates from
patients after 10 days monotherapy with SPD754. 44th
Interscience Conference on Antimicrobial Agents and
Chemotherapy. Washington DC, USA. 30 October–2
November, 2004. Abstract H-206] and demonstrated virological activity against M184V-containing isolates, such as
SPD754, is likely to offer greater clinical benefit than can
be achieved by maintenance of a virus with reduced fitness.
Future studies will determine whether SPD754 maintains
the M184V mutation during therapy.
In conclusion, SPD754 is likely to show activity against
HIV-1 containing multiple TAMs, in the absence or presence of the M184V mutation. These data suggest that
SPD754 is a promising new NRTI for the treatment of
NRTI-experienced HIV-infected patients, and support its
investigation for this indication in large-scale clinical trials.
References
Back N, Nijhuis M, Keulen W, Boucher CA, Oude Essink BO, van
Kuilenburg AB, van Gennip AH & Berkhout B (1996) Reduced
replication of 3TC-resistant HIV-1 variants in primary cells due
to a processivity defect of the RT enzyme. EMBO Journal
15:4040–4049.
Deeks SG (2004) Treatment of antiretroviral-drug-resistant HIV-1
infection. Lancet 362:2002–2011.
De Mendoza C, Gallego O & Soriano V (2002) Mechanisms of
resistance to antiretroviral drugs: clinical implications. AIDS
Review 4:64–82.
De Muys J-M, Gourdeau H, Nguyen-Ba N, Taylor DL, Ahmed PS,
Mansour T, Locas C, Richard N, Wainberg M & Rando RF
(1999) Anti-human immunodeficiency virus type 1 activity, intracellular metabolism and pharmacokinetics evaluation of 2′-deoxy3′-oxa-4′-thiocytidine Antimicrobial Agents & Chemotherapy
43:1835–1844.
Antiviral Chemistry & Chemotherapy 16.5
Descamps D, Flandre P, Calvez V, Peytavin, G, Meiffredy V, Collin
G, Delaugerre C, Robert-Delmas S, Bazin B, Aboulker JP, Pialoux
G, Raffi F & Brun-Vezinet F (2000) Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial of
induction-maintenance therapy. Trilege (Agence Nationale de
Recherches sur le SIDA 072) Study Team. Journal of the American
Medical Association 283:205–211.
Diallo K, Gotte M & Wainberg MA (2003) Molecular impact of the
M184V mutation in human immunodeficiency virus type 1 reverse
transcriptase. Antimicrobial Agents & Chemotherapy 47:3377–3383.
Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK & Panel on
Clinical Practices for the Treatment of HIV (2002) Guidelines
for using antiretroviral agents among HIV-infected adults and
adolescents. Annals of Internal Medicine 137 (5 Pt 2):381–433.
Flandre P, Descamps D, Joly V, Meiffredy V, Tamalet C, Izopet J,
Aboulker JP & Brun-Vezinet F (2003) Predictive factors and
selection of thymidine analogue mutations by nucleoside reverse
transcriptase inhibitors according to initial regimen received.
Antiviral Therapy 8:65–72.
Kuritzkes DR, Quinn JB, Benoit SL, Shugarts DL, Griffin A,
Bakhtiari M, Poticha D, Eron JJ, Fallon MA & Rubin M (1996)
Drug resistance and virologic response in NUCA 3001, a randomized trial of lamivudine (3TC) versus zidovudine (ZDV) versus
ZDV plus 3TC in previously untreated patients. AIDS
10(9):975–981.
Kagan MA, Fenwick RF & Merigan TC (2000). Recent trends in
HIV-1 drug resistant genotypes in the patient population referred
to a clinical diagnostics reference laboratory. Antiviral Therapy 5
(Suppl. 3):125.
Little SJ, Holte S, Routy JP, Daar ES, Markowitz M, Collier AC,
Koup RA, Mellors JW, Connick E, Conway B, Kilby M, Wang L,
Whitcomb JM, Hellmann NS & Richman DD (2002)
Antiretroviral-drug resistance among patients recently infected
with HIV. New England Journal of Medicine 347:385–394.
Maguire M, Gartland M, Moore S, Hill A, Tisdale M, Harrigan R
& Kleim JP (2000) Absence of zidovudine resistance in antiretroviral-naive patients following zidovudine/lamivudine/protease
inhibitor combination therapy: virological evaluation of the
AVANTI 2 and AVANTI 3 studies. AIDS 14:1195–1201.
Mansour TS, Jin H, Wang W, Hooker EU, Ashman C, Cammack
N, Salomon H, Belmonte AR & Wainberg MA (1995) Antihuman immunodeficiency virus and anti-hepatitis B virus activities
and toxicities of the enantiomers of 2′-deoxy-3′-oxa-4′-thiocytidine and their 5′-fluoro analogues in vitro. Journal of Medicinal
Chemistry 38:1–4.
Marcelin AG, Delaugerre C, Wirden M, Viegas P, Simon A,
Katlama C & Calvez V (2004) Thymidine analogue reverse
transcriptase inhibitors resistance mutations profiles and association to other nucleoside reverse transcriptase inhibitors resistance
mutations observed in the context of virological failure. Journal of
Medical Virology 72:162–165.
Miller MD, Margot NA, McColl DJ, Wrin T, Coakley DF &
Cheng AK (2003) Characterization of resistance mutation patterns
emerging over 2 years during first-line antiretroviral treatment
with tenofovir df or stavudine in combination with lamivudine and
efavirenz. Antiviral Therapy 8:S151.
Murphy EL, Collier AC, Kalish LA, Assmann SF, Para MF,
Flanigan TP, Kumar PN, Mintz L, Wallach FR, Nemo GJ & Viral
Activation Transfusion Study Investigators. (2001) Highly active
antiretroviral therapy decreases mortality and morbidity in patients
with advanced HIV disease. Annals Internal Medicine 135:17–26.
Naeger LK, Margot NA & Miller MD (2001) Increased drug
susceptibility of HIV-1 reverse transcriptase mutants containing
M184V and zidovudine-associated mutations: analysis of enzyme
processivity, chain-terminator removal and viral replication.
Antiviral Therapy 6:115–126.
301
R Bethell et al.
Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J,
Satten GA, Aschman DJ & Holmberg SD (1998) Declining
morbidity and mortality among patients with advanced human
immunodeficiency virus infection. HIV Outpatient Study
Investigators. New England Journal of Medicine 338:853–860.
Sarafianos SG, Das K, Clark AD, Ding J, Boyer PL, Hughes SH &
Arnold E (1999) Lamivudine (3TC) resistance in HIV-1 reverse
transcriptase involves steric hindrance with beta-branched amino
acids Proceedings of the National Academy of Sciences USA
96:10027–10032.
Panel on Clinical Practices for Treatment of HIV Infection (2003)
Guidelines for the use of antiretroviral agents in HIV-1-infected adults
and adolescents. Bethesda: US National Institutes of Health.
Tamalet C, Fantini J, Tourres C & Yahi N (2003) Resistance of
HIV-1 to multiple antiretroviral drugs in France: a 6-year survey
(1997–2002) based on an analysis of over 7000 genotypes. AIDS
17:2383–2388.
Petropoulos CJ, Parkin NT, Limoli KL, Lie YS, Wrin T, Huang W,
Tian H, Smith D, Winslow GA, Capon DJ & Whitcomb JM
(2000) A novel phenotypic drug susceptibility assay for human
immunodeficiency virus type 1. Antimicrobial Agents &
Chemotherapy 44:920–8
Richman DD, Morton SC, Wrin T, Hellmann N, Berry S, Shapiro
MF & Bozzette SA (2004) The prevalence of antiretroviral drug
resistance in the United States. AIDS 18:1393–1401.
Salomon H, Wainberg MA, Brenner B, Quan Y, Rouleau D, Cote P,
LeBlanc R, Lefebvre E, Spira B, Tsoukas C, Sekaly RP, Conway
B, Mayers D & Routy JP (2000) Prevalence of HIV-1 resistant
to antiretroviral drugs in 81 individuals newly infected by sexual
contact or injecting drug use. Investigators of the Quebec Primary
Infection Study. AIDS 14(2):F17–23.
Taylor DL, Ahmed PS, Tyms SA, Wood LJ, Kelly LA, Chambers P,
Clarke J, Bedard J, Bowlin TL & Rando RF 2000 (2000) Drug
resistance and drug combination features of the human immunodeficiency virus inhibitor, BCH-10652 ((±)-2′-deoxy-3′-oxa-4′thiocytidine, dOTC). Antiviral Chemistry & Chemotherapy
11:291–301.
UK Collaborative Group on Monitoring the Transmission of HIV
Drug Resistance (2001) Analysis of prevalence of HIV-1 drug
resistance in primary infections in the United Kingdom. British
Medical Journal 322:1087–1088.
Whitcomb JM, Parkin NT, Chappey C, Hellmann NS &
Petropoulos CJ (2003) Broad nucleoside reverse transcriptase
inhibitor cross resistance in HIV –1 clinical isolates. Journal of
Infectious Diseases 188:992–1000.
Received 11 April 2005, accepted 15 June 2005
302
©2005 International Medical Press