Library Volume 1, Issue 3: Resistance Reporter©
from the HIV Drug Resistance Workshop 2007
XVI International HIV Drug Resistance Workshop, June 12-16, 2007
This important conference focuses on topics related to HIV drug
resistance, and the organizers traditionally only allow a select number
of attendees (~250). But of course, members of Resistance Reporter©'s
highly respected
editorial board were there; we selected the 6
scientifically-important presentations that would best support your
clinical practice. These selections have been grouped into three
sections that provide clinically-relevant information related to a
specific topic. The selections and summaries we have provided are of
truly noteworthy research; hot links to the abstracts and suggestions
for related reading makes broadening your existing knowledge on a
complex topic logical and easy.
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Section 1: Select presentations related to resistance to
integrase inhibitors
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Section 2: Select presentations related to resistance to CCR5
inhibitors
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Section 3: Select presentations related to resistance to TMC125
Select presentations related to resistance
to integrase inhibitors
Abstract
#8, Hazuda DJ
The HIV integrase inhibitor raltegravir,
formerly known as MK-0518, is quite potent in treatment-experienced
patients. Raltegravir produced HIV-1 RNA levels below 400 copies/mL at
week 24 in ~70% of triple-class-experienced patients in combination with
optimized background therapy in a phase II trial, compared with a 16%
response rate for patients on placebo plus optimized background therapy
. To identify mutations that may confer resistance to raltegravir, viral
isolates obtained from 38 raltegravir-treated patients who experienced
virologic failure were analyzed. Integrase mutations were found in 35
individuals and fell into two genetic pathways. The N155H mutation
reduced viral susceptibility to raltegravir by 10-fold, while the Q148
H/R/K did so by 25 fold; addition of secondary mutations L74M, E92Q,
G163R to N155H or E138K, G140S/A to Q148H/R/K resulted in high level
resistance. For example, the addition of G140S to Q148H or the addition
of E138A + G140A to Q148K increased viral resistance to raltegravir over
500-fold. While certain secondary mutations appeared to moderate
replication defects, all resulted in increased resistance suggesting
that N155H and Q148H/R/K may confer incomplete resistance in isolation.
Viral variants containing the N155H or Q148H/R/K mutations were
cross-resistant to several different integrase inhibitors, consistent
with a common mechanism of action among these agents.
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Abstract
#9, McColl DJ
Viral isolates were obtained from 30 very
highly treatment-experienced patients who received elvitegravir 250
mg/day and who experienced treatment failure during the GS-US-183-0105
trial. The baseline 50% inhibitory concentration (IC50) for the isolates
analyzed ranged from 0.91- to 2.53-fold compared to the assay control
virus. The most common integrase mutations that emerged during
elvitegravir treatment in 28 patients with baseline and on-treatment
genotype data included E92Q (in 39%), E138K (in 39%), Q148R/K/H (in
39%), N155H (in 39%), S147G (in 32%), and T66I/A/K (in 18%)—many of
which were previously identified as raltegravir resistance mutations
(see Abstract #8). Indeed, viral samples from patients who experienced
elvitegravir virologic failure showed a mean fold change to elvitegravir
greater than 151-fold (range: 1.02-301) as well as a mean fold change to
raltegravir greater than 28-fold (range: 0.78-256+), thereby providing
evidence for cross-resistance between these two agents. The replication
capacity of the viral isolates declined from a median of 108% at
baseline to 54% at the time of virologic failure (P≤.005).
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RELATED ARTICLES:
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Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and efficacy of
the HIV-1 integrase inhibitor raltegravir (MK-0518) in
treatment-experienced patients with multidrug-resistant virus: a
phase II randomized controlled trial. Lancet.
2007;369(9569):1261-1269.
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O'Neal R. MK-0518 and GS-9137: two promising integrase inhibitors in
the pipeline. BETA. 2006;18(4):13-16.
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DeJesus E, Berger D, Markowitz M, et al. Antiviral activity,
pharmacokinetics, and dose response of the HIV-1 integrase inhibitor
GS-9137 (JTK-303) in treatment-naive and treatment-experienced
patients. J Acquir Immune Defic Syndr. 2006;43(1):1-5.
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Markowitz M, Morales-Ramirez JO, et al.
Antiretroviral activity, pharmacokinetics, and tolerability of
MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy
for 10 days in treatment-naive HIV-1-infected individuals. J Acquir
Immune Defic Syndr. 2006 Dec 15;43(5):509-15
Select presentations related to resistance
to CCR5 inhibitors
CXCR4-Using Virus Detected in Patients Receiving Maraviroc in the Phase
III Studies MOTIVATE 1 and 2 Originates From a Pre-Existing Minority of
CXCR4-Using Virus
Abstract
#56, Lewis M
The CCR5 antagonist maraviroc has
demonstrated impressive activity in combination with optimized
background therapy in the MOTIVATE 1 and 2 phase III trials conducted in
treatment-experienced patients. Although only patients with CCR5-tropic
virus, determined at screening, were included in the MOTIVATE studies,
CXCR4-using virus emerged in some patients during maraviroc treatment.
Extensive phenotype testing and env gene sequencing of 240 clones
obtained at baseline and during treatment from 20 patients (16 on
maraviroc, 4 on placebo) revealed that CXCR4-using virus that emerged
during maraviroc treatment was already present at baseline in 14 of the
patients. Ten patients harbored CXCR4-using virus at baseline at a low
frequency (1%-6%), whereas 4 patients harbored a higher proportion of
CXCR4-using virus at baseline (> 10%). For the other 6 patients, the
CXCR4-using clones identified during treatment appeared to be
phylogenetically distinct from the baseline clones and the CCR5-using
clones obtained during treatment, indicating a separate ancestral origin
and not a shift in viral tropism. Consistent with this view, the
CXCR4-using clones contained between 7 and 17 amino acid changes in the
35-amino acid V3 loop, which plays an important role in coreceptor
recognition, further suggesting that a shift in viral tropism did not
occur through mutational evolution. Patients on maraviroc demonstrated
an almost complete loss of CCR5-using virus during treatment—a
phenomenon that may have enabled CXCR4-using virus present at baseline
to emerge.
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Abstract
#10, Mori J
In another analysis of MOTIVATE patients,
baseline and on-treatment HIV samples from individuals with CCR5-using
virus in whom maraviroc failed were assessed to identify phenotypic and
genotypic markers of maraviroc resistance. Out of these analyses, only a
reduced maximal percentage inhibition (MPI) emerged as a phenotypic
marker of maraviroc resistance in vivo; differences in the IC50 fold
change between baseline samples and on-treatment samples and between any
samples and the reference virus were not predictive for maraviroc
resistance. None of the 37 [38] viral clones assessed at baseline or the
25 clones assessed on treatment for patients on placebo had an MPI below
95%, whereas MPI values below this level were observed for 6 of 15 [4 of
12] patients who failed with maraviroc treatment. Further investigation
of on-treatment clones from these 6 patients revealed several amino acid
changes in the V3 loop from baseline that were important in conferring
maraviroc resistance; no cross-resistance to enfuvirtide was observed.
These amino acid changes were different from patient to patient,
reflecting the heterogeneity of the gp160 sequence.
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Abstract
#13, Tsibris AMN
To better understand the in vivo emergence
of resistance to the CCR5 inhibitor vicriviroc, Tsibris and colleagues
assessed viral samples from 8 patients who experienced virologic failure
at 16 weeks of vicriviroc treatment during the phase IIb ACTG A5211
trial. No consistent increase in the IC50 was found in patient samples
throughout 24 weeks of treatment. The largest IC50 change observed in
comparison with a control strain was 2.83-fold. Sequencing of the env
gene identified amino acid changes in the V3 loop that emerged after
virologic failure, but not before, in 4 individuals randomized to
receive vicriviroc at 5 mg or 10 mg daily. No such changes were found in
2 individuals assigned to placebo or in 2 individuals assigned to
vicriviroc 15 mg. These amino acid changes differed between individuals.
Clonal analysis of another patient assigned to vicriviroc 10 mg who
demonstrated a progressive increase in phenotypic resistance to
vicriviroc identified the emergence of multiple changes in the V3 loop.
These recombinant viruses were exclusively R5. Analysis of a sample from
this patient obtained 5 months after vicriviroc discontinuation showed a
return toward genotypically wild-type, vicriviroc-sensitive, R5-tropic
only virus, suggesting that wild-type virus has a fitness advantage over
vircriviroc-resistant virus.
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RELATED ARTICLES:
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Melby T. HIV Coreceptor Use in Heavily Treatment-Experienced Patients:
Does It Take Two to Tangle? Clin Infect Dis. 2007;44(4):596-598.
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Zuger A. Who Will Benefit From CCR5 Inhibitors? More advanced disease is
correlated with a higher probability of mixed viral populations or
dual-tropic virus. AIDS Clinical Care. March 12, 2007.
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Westby M, Smith-Burchnell C, Mori J, et al. Reduced Maximal Inhibition
in Phenotypic Susceptibility Assays Indicates That Viral Strains
Resistant to the CCR5 Antagonist Maraviroc Utilize Inhibitor-Bound
Receptor for Entry. J Virol. 2007;81(5):2359-2371.
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Westby M, Lewis M, Whitcomb J, et al. Emergence of CXCR4-Using Human
Immunodeficiency Virus Type 1 (HIV-1) Variants in a Minority of
HIV-1-Infected Patients Following Treatment with the CCR5 Antagonist
Maraviroc Is from a Pretreatment CXCR4-Using Virus Reservoir. J Virol.
2006;80(10):4909-4920.
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Gulick RM, Su Z, Flexner C, et al. Phase 2 Study of the Safety and
Efficacy of Vicriviroc, a CCR5 Inhibitor, in HIV-1-Infected,
Treatment-Experienced Patients: AIDS Clinical Trials Group 5211. J
Infect Dis. 2007;196(2):304-312.
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Strizki J et al. Discovery and Characterization of Vicriviroc (SCH
417690), a CCR5 Antagonist with Potent Activity against Human
Immunodeficiency Virus Type 1. Antimicrobial Agents and Chemotherapy
49(12): 4911-4919. December 2005.
Select presentations related to resistance
to TMC125
Abstract
#32, Vingerhoets J
Etravirine is purported to have activity
against NNRTI-resistant HIV and a high genetic barrier to resistance.
This study assessed the effects of genotype and baseline phenotype on
the 24-week virologic response to etravirine among treatment-experienced
patients participating in the randomized DUET-1 and DUET-2 trials. None
of the patients included in the analysis received enfuvirtide as a new
drug in their optimized background regimen and patients who discontinued
treatment for reasons other than virological failure were also excluded.
Forty-four NNRTI resistance-associated mutations were studied in
patients who had a suboptimal virologic response to treatment; only
those present in 5 or more patients at baseline (n=26) were included in
the final analysis. Thirteen mutations were associated with a decreased
virologic response to etravirine: V90I, A98G, L100I, K101E/P, V106I,
V179D/F, Y181C/I/V, and G190A/S. Many of these mutations occurred in
conjunction with other NNRTI-associated mutations. Y181V, G190S, and
V179F had the strongest effect on virologic response, but these
mutations were present in fewer than 5% of patients. The number of
etravirine-associated mutations present at baseline was a very strong
predictor of virologic response (P=.0008), and the poorest virologic
response to etravirine was observed in patients with 3 or more
etravirine-associated mutations at baseline.
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RELATED ARTICLES:
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