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Assessment of JC virus DNA in blood and urine from natalizumab-treated patients.

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RAPID COMMUNICATION
Assessment of JC Virus DNA
in Blood and Urine from
Natalizumab-Treated Patients
Richard A. Rudick, MD,1 Paul W. O’Connor, MD,2 Chris H. Polman, MD,3
Andrew D. Goodman, MD,4 Soma S. Ray, PhD,5 Nancy M. Griffith, PhD,5
Stephanie A. Jurgensen, BS, MPH,5 Leonid Gorelik, PhD,5 Fiona Forrestal, MSc,5
Alfred W. Sandrock, MD, PhD,5 and Susan E. Goelz, PhD5
Objective: Analyses were conducted to determine the clinical utility of measuring JC virus (JCV) DNA in blood or
urine of natalizumab-treated multiple sclerosis (MS) patients to predict the risk of progressive multifocal
leukoencephalopathy (PML).
Methods: A total of 12,850 blood and urine samples from nearly 1,400 patients participating in natalizumab clinical trials
were tested for JCV DNA using a commercially available quantitative polymerase chain reaction (qPCR) assay. A subset
of these samples was also tested using a more sensitive qPCR assay developed at the National Institutes of Health (NIH).
Results: At the time natalizumab dosing was suspended, JCV DNA was detected in plasma by the commercial assay
in 4 of 1,397 (0.3%) patients; the NIH assay confirmed these positive samples and detected JCV DNA in an
additional 2 of 205 (1%) patients who tested negative with the commercial assay. None of these 6 JCV DNA positive
patients developed PML. In a 48-week study testing the safety of natalizumab redosing, JCV DNA was detected in
plasma of 6 of 1,094 (0.3%) patients, none of whom developed PML. Urine at baseline and week 48 was assessed in
224 patients; 58 (26%) were positive at baseline, and 55 (25%) were positive after 48 weeks of natalizumab,
treatment. JCV DNA was not detected in peripheral blood mononuclear cells from any of these 1,094 patients
before or after natalizumab treatment. In 5 patients who developed PML, JCV DNA was not detected in blood at
any time point before symptoms first occurred.
Interpretation: Measuring JCV DNA in blood or urine with currently available methods is unlikely to be useful for
predicting PML risk in natalizumab-treated MS patients.
ANN NEUROL 2010;68:304–310
N
atalizumab, a monoclonal antibody directed against
a-4 integrin, is approved for the treatment of
relapsing-remitting multiple sclerosis (MS). As of June
2010, natalizumab had been prescribed to >71,400 individuals. On rare occasions, natalizumab is associated with
progressive multifocal leukoencephalopathy (PML), a
demyelinating disease of the central nervous system that
occurs in immune-compromised individuals1 and is
caused by the JC virus (JCV).2,3 JCV is among the most
prevalent viruses in the human population.4 JCV replicates asymptomatically in the kidney; 20 to 50% of
healthy individuals shed JCV into the urine at any given
time.5–7 Although JCV found in brains of PML patients
exhibits alterations in the regulatory region and the
major coat protein, the role of these alterations in PML
pathogenesis remains unknown.
Because of the widespread use of natalizumab and the
often devastating consequences of PML, there is a compelling need for methods to identify patients at higher risk of
PML. Previously published studies have reported conflicting
information on the effect of natalizumab on JCV DNA
presence in bodily fluids. Chen et al8 reported that JCV
DNA increased in plasma, peripheral blood mononuclear
cells (PBMCs) and urine after 12 to 18 months of
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22107
Received Mar 19, 2010, and in revised form May 6, 0000. Accepted for publication May 28, 2010.
Address correspondence to Dr Rudick, Department of Neurology, Mellen Center for Multiple Sclerosis Treatment and Research,
the Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195. E-mail: rudickr@ccf.org
From the 1Cleveland Clinic Foundation, Cleveland, OH; 2St. Michael’s Hospital, Toronto, Ontario, Canada; 3VU Medical Center, Free University Hospital,
Amsterdam, the Netherlands; 4University of Rochester Medical Center, Rochester, NY; 5Biogen Idec, Inc., Cambridge, MA.
Additional supporting information can be found in the online version of this article.
C 2010 American Neurological Association
304 V
Rudick et al: JCV and Natalizumab
TABLE 1: Sources of Patients, Samples, and JCV DNA Assay Methodologies
Study
1
2
3
Samples
Natalizumab
Exposure
Patients,
No.
Type
Number
Assay
Comment
DSSA
Mean, 22 months;
median, 30 months;
range, 1–41 months*
1,397
205
Plasma
Plasma
1,397
205
ViraCor
NIH
All subjects.
Randomly selected
from patients who
tested negative with
ViraCor assay.
AFFIRM,
SENTINEL,
BIIB 1808
Mean, 22 months;
range, 1–41
months
6
Serum
73
NIH
Stored samples
from patients
testing positive
in DSSA.
STRATA
up to 48 weeks
1,094
224
Plasma
PBMCs
Urine
6,614
4,066
448
ViraCor
ViraCor
ViraCor
Samples obtained
at intervals over
48 weeks.
2
Serum
22
NIH
3
Plasma
15
ViraCor
PBMCs
12
ViraCor
Urine
11
ViraCor
Stored samples from
SENTINEL study.
Samples collected
during STRATA.
Samples collected
during STRATA.
Samples collected
during STRATA.
Source
PML patients
2–4 years
JCV ¼ JC virus; DSSA ¼ Dose Suspension Safety Assessment; NIH ¼ National Institutes of Health; AFFIRM ¼ Natalizumab
Safety and Efficacy in Relapsing Remitting Multiple Sclerosis11; SENTINEL ¼ Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis12; BIIB 1808 ¼ Open-Label Safety Extension
Study; STRATA ¼ Safety of TYSABRI Redosing and Treatment; PBMC ¼ peripheral blood mononuclear cell; PML ¼ progressive multifocal leukoencephalopathy.
*Mean, median, and range of exposure applies to 1,305 natalizumab-treated patients; 92 patients were natalizumab naı̈ve.
natalizumab treatment, and Sadiq et al9 reported the
appearance of JCV DNA in plasma in 1 of 93 patients,
and in cerebrospinal fluid of 2 of 93 patients after starting
natalizumab treatment. None of the patients in these studies developed PML. Conversely, Jilek et al10 did not show
increased occurrence of JCV DNA in plasma, PBMCs, or
urine in 24 patients treated with natalizumab for 18
months. To more thoroughly assess the clinical utility of
measuring JCV DNA in blood or urine of natalizumabtreated MS patients to predict risk for PML, we measured
JCV DNA in a large number of patients in natalizumab
clinical studies. The study addressed 2 questions:
• Does treatment with natalizumab alter the presence of
JCV in blood or urine?
• Does the presence or absence of JCV in the blood or
urine provide any indication of risk for PML?
Subjects and Methods
Protocols and Sources of Material
The current analysis was comprised of 3 separate studies, as presented in Table 1. The purpose of Study 1 was to assess the fre-
September, 2010
quency of JCV DNA in a large group of MS patients participating
in a safety study at the time natalizumab clinical use was suspended
(the Dose Suspension Safety Assessment, DSSA). Stored samples
from natalizumab pivotal trials (AFFIRM,11 SENTINEL12) were
analyzed for all patients who tested positive in the DSSA study.
The purpose of Study 2 was to assess whether 48 weeks of natalizumab treatment increased the occurrence of JCV DNA in plasma,
PBMCs, or urine in the Safety of Natalizumab Redosing
(STRATA) Study. Finally, the purpose of Study 3 was to assess
whether JCV DNA could be detected in stored serum or plasma
samples of patients prior to developing natalizumab-associated PML.
STUDY 1. Following natalizumab suspension in February
2005, all clinical trial participants were assessed for PML symptoms.13 Plasma samples from 1,397 patients in this study were
assayed for JCV DNA using the ViraCor quantitative polymerase chain reaction (qPCR) assay described below. In addition,
205 samples that tested negative with the ViraCor assay were
retested at the National Institutes of Health (NIH) using a
more sensitive assay described below. Seventy-three serially
collected, stored serum samples from the AFFIRM11 and
SENTINEL12 pivotal trials were analyzed using the NIH assay
for all 6 subjects who tested positive in the DSSA study by either the ViraCor or NIH assay.
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ANNALS
of Neurology
STUDY 2. STRATA was an open-label, single-arm, multinational study of patients who previously completed either the
AFFIRM,11 SENTINEL,12 GLANCE,14 or STARS (Study of
TYSABRI Against Rebif in relapsing multiple Sclerosis) studies.
The purpose of STRATA was to evaluate the safety of natalizumab redosing. A pre-specified objective of the STRATA study
was to determine whether serial blood testing can be used to
predict PML. Plasma, PBMCs, and urine samples were collected at least every 12 weeks for the 48-week study, and during
the last study visit in patients who prematurely withdrew from
the study. Samples were tested to determine the frequency of
JCV DNA detection and to assess the association of viremia
and uremia with PML in a natalizumab-treated population.
A total of 1,094 patients enrolled in STRATA. Due to
the suspension of natalizumab, all of these subjects had at least
1 year of natalizumab treatment interruption (range, 57–157
weeks) from the time of DSSA to the start of STRATA. At
entry into STRATA, mean age was 41.4 years, 69% were
female, and the median number of years since diagnosis of MS
was 8 (range, 4–34). JCV DNA was analyzed in >6,000
plasma samples and >4,000 PBMC samples from 1,094
patients, and in >400 urine samples from 224 patients using
the ViraCor assay.
STUDY 3 (PML CASES). Stored serum or plasma samples
were available from a total of 5 patients prior to their developing natalizumab-associated PML. Twenty-two serum samples
were available from 2 PML patients from the SENTINEL12
study, and were tested using the NIH assay. Fifteen plasma
samples, 12 PBMC samples, and 11 urine samples were available from 3 PML patients from STRATA, and were tested
using the ViraCor assay.
Sample Processing and Assays
Plasma, serum, and urine were collected and aliquoted into
cryovials. All samples were frozen at 20 to 70 C, shipped
frozen, and stored at a central laboratory. PBMCs from buffy
coats were obtained from whole blood drawn into acid citrate
dextrose solution A (ACDA) tubes and shipped at ambient
temperature to a central laboratory as described in detail in
Supplement A.
Real-Time qPCR Assays
Details of real-time qPCR assays are provided in Supplement A.
COMMERCIAL (ViraCor) ASSAY. JCV DNA was assessed
in all plasma samples by qPCR using a fully validated Clinical
Laboratory Improvement Amendments-certified commercial
assay (ViraCor Laboratories, Lee’s Summit, MO). In a validation performed retrospectively, the quantifiable range of the
assay (limit of quantitation, LOQ) was 500 5 107 copies/
ml. The lower limit of detection (LOD) for the assay was 50
copies/ml, albeit the variance of detection at this level was
>40%. This assay was independently assessed by Quality Control of Molecular Diagnostics (Glasgow, Scotland) for the JCV
306
detection assay (JCBKDNA07) as a part of an international
effort to standardize JCV qPCR assays.
NIH ASSAY. As a supplement to the data generated using
the ViraCor assay, a subset of samples from the DSSA and
stored serum samples from selected patients were independently
analyzed at the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke
at the NIH, using a manual, ultrasensitive assay.15 The LOQ
for this system of JCV detection was from 45 to 4.5 108
copies/ml, with an LOD of 10 copies/ml. Samples are classified
as not detected, positive (detected), and not confirmed. Samples
classified as not confirmed had detectable JCV DNA in 1 of
the duplicate wells, but both wells were negative on retest.
Results
Study 1
JCV DNA was analyzed in plasma samples from 1,397
MS patients (1,305 previously natalizumab-treated and
92 natalizumab-naive) from the DSSA using the ViraCor
assay (Table 2). Mean exposure for the natalizumabtreated patients was 22 months (median, 30 months;
range, 1–41 months, with 742 patients having >24
months of treatment). JCV DNA was detected in 4 of
1,397 plasma samples (0.3%) using the ViraCor assay,
and each of these results were confirmed by the NIH
assay (Fig 1). Using the more sensitive NIH assay to retest
205 samples that had tested negative with the ViraCor
assay, an additional 2 JCV DNA-positive samples were
identified. Importantly, none of these 6 patients who had
JCV DNA-positive plasma samples developed PML.
Among the 6 patients who had JCV DNA-positive
plasma samples, 3 were natalizumab-naive, and exposure
in the other 3 ranged from 8 to 35 months. Hence, 3% (3
of 92) of natalizumab-naive patients were positive for JCV
DNA in plasma, compared with 0.2% (3 of 1,305) of
natalizumab-treated patients. To further characterize these
6 viremic patients, 73 samples that had been serially collected prior to their entry into the DSSA were tested for
JCV DNA with the NIH assay (see Fig 1). Two patients
(MS3, MS5) had no detectable JCV DNA, 1 patient
(MS6) had a result at doses 15 and 30 that were not confirmed (JCV DNA was not detected upon retesting), and
3 patients (MS1, MS2, MS4) had multiple (13 of 37)
JCV DNA-positive samples. Of particular note, patient
MS4 had multiple JCV DNA-positive samples despite
being natalizumab-naive. In addition, patient MS2, who
was the only patient who was persistently viremic over
nearly a 3-year period (which included 2 years of placebo
treatment), was screened for participation in STRATA and
still exhibited viremia after a treatment gap of >1 year.
This patient did not participate in STRATA, and did not
develop PML.
Volume 68, No. 3
Rudick et al: JCV and Natalizumab
TABLE 2: JCV DNA Sample Testing Results
Study
Source
Sample
Type
Results (positive
results per number of
samples tested)
Comments
1
DSSA
Plasma
4 of 1,397 (0.3%) positive
Plasma
2 of 205 (1%) positive
AFFIRM,
SENTINEL,
BIIB 1808
Serum
14 of 73 (19%) positive
1 of 4 previously treated
with natalizumab.
2 of 2 previously treated
with natalizumab.
Most (10 of 14) positive
results were from a single,
persistently viremic placebo
patient. See Figure 1.
STRATA
Plasma
1 of 1,078 (0.1%)
positive at baseline;
2 of 675 (0.3%)
positive at 48 weeks
All patients negative,
at all time points
58 of 224 (26%)
positive at baseline;
55 of 224 (25%)
positive at 48 weeks
See Supplement A, Table 2.
Serum and
plasma
All 5 patients negative,
at all time points
PBMCs
All 3 STRATA patients
negative at all time points
2 of 3 STRATA
patients tested positive
22 samples from
2 patients from SENTINEL
study. 15 samples from
3 patients from STRATA
study. See Figure 2.
See Results.
2
PBMCs
Urine
3
PML patients
Urine
See Supplement A, Table 2.
See Supplement A, Table 2.
See Results.
JCV ¼ JC virus; DSSA ¼ Dose Suspension Safety Assessment; AFFIRM ¼ Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis11; SENTINEL ¼ Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients
with Relapsing Remitting Multiple Sclerosis12; BIIB 1808 ¼ Open-Label Safety Extension Study; STRATA ¼ Safety of TYSABRI
Redosing and Treatment; PBMC ¼ peripheral blood mononuclear cell; PML ¼ progressive multifocal leukoencephalopathy.
Study 2
Plasma, PBMC, and urine samples were prospectively collected from 1,094 patients in the STRATA study to assess
whether the detection of JCV DNA changed after natalizumab treatment. Using the ViraCor assay to test >6,000
plasma samples, only 7 samples from 6 patients were positive for JCV DNA, and none of these patients developed
PML (see Supplement A, Table S2). At study entry, at least
1 year after the last natalizumab infusion, 1 of 1,078
(0.1%) subjects had detectable JCV DNA in plasma. Of
the 675 patients who were tested after 48 weeks of natalizumab dosing, 2 (0.3%) were positive. Five patients had
JCV DNA detected at a single time point, and four of
these subjects were negative in subsequent samples (there
was no sample available from the fifth subject). JCV DNA
was detected in samples from a 6th patient at weeks 24 and
September, 2010
36, but was not detected in a sample obtained 1 month
later. The range of JCV DNA concentrations measured in
plasma was 100 to 81,041 copies/ml (mean, 13,633 copies/ml; median, 200 copies/ml).
JCV DNA was assessed in 4,066 PBMC samples
that were obtained from 1,094 STRATA subjects using
the ViraCor assay, and was not detected in any of the
samples tested, including samples obtained from 695
subjects at the end of the 48-week study.
Urine samples from 250 randomly selected patients
in STRATA were analyzed using the ViraCor assay; 224
patients had samples available at both the baseline and
the 48-week assessments. The percentage of urine samples positive for JCV DNA was 26% (58 of 224) at baseline (ie, off natalizumab) and 25% (55 of 224) after 48
weeks of natalizumab treatment.
307
ANNALS
of Neurology
FIGURE 1: Longitudinal testing of samples from patients positive for JC virus (JCV) DNA in plasma in the Dose Suspension Safety
Assessment (DSSA). There was no appreciable treatment gap for any of these subjects between the last study visit and the DSSA,
whereas there was a >20-month treatment interruption between the DSSA and the start of STRATA. Not detected 5 no JCV DNA
was detected in duplicate samples tested; Not confirmed 5 JCV DNA detected in 1 of 2 duplicate samples, but JCV DNA not
detected in a second set of duplicate samples; Positive 5 detected in duplicate samples; Gray backshading 5 samples collected
during natalizumab treatment; *Follow-up visit at week 128; #28 doses. NIH 5 National Institutes of Health.
PML Patients
Two patients from the SENTINEL12 study developed
PML (Fig 2). A total of 22 pre-PML samples from these
2 patients were tested for JCV DNA using the NIH
assay. In 1 patient (SENTINEL case 1) who developed
PML after 37 infusions of natalizumab, 12 pre-PML
samples that were collected over 30 months were tested.
None of these samples were positive for JCV DNA,
including the last sample, which had been collected 3
months before PML diagnosis. In the other patient
(SENTINEL case 2) who developed PML, 10 pre-PML
samples that were collected over 2 years were tested and
none were positive for JCV DNA, including the last
sample that had been collected approximately 3 months
before diagnosis.
Three cases of PML occurred in patients from the
STRATA study after 33, 34, and 44 doses of natalizumab. JCV DNA was not detected in plasma or PBMC
samples taken at least every 12 weeks throughout the 48week study period in any of these patients; however, it
should be noted that collection of these samples preceded
the onset of PML symptoms by at least 20 months. The
urine of 2 of these 3 patients was positive for JCV DNA
at baseline (700 copies/ml in the first patient, 7,576 copies/ml in the second) and throughout the study (41,168
copies/ml in the first patient at week 24, 1,044 copies/
308
ml in the second patient at week 48). JCV DNA was not
detected in urine at any time point in the third patient.
Discussion
We measured the presence of JCV DNA in blood and
urine to determine if it could be useful in predicting PML
risk in natalizumab-treated MS patients. Using qPCR
methodology, the data reported here indicate the following: (1) JCV viremia was rare; (2) treatment with natalizumab was not associated with an increased prevalence of
JCV viremia at the time points that samples were taken;
(3) presence of JCV DNA in the blood was not associated
with the development of PML; and (4) patients who
developed natalizumab-related PML tested negative in
blood and PBMCs prior to onset of symptoms.
Using a standard commercial (ViraCor) assay in a
cross-sectional analysis of nearly 1,400 patients from
natalizumab trials (including >1,300 patients who had
been treated with natalizumab for an average of 2 years),
the incidence of JCV-positive plasma or serum was found
to be <1%, which is similar to rates reported in healthy
individuals.5,16 In this study, the ViraCor assay identified
4 patients who were JCV DNA positive in plasma. A
more sensitive qPCR assay performed at the NIH (limit
of detection ¼ 10 copies/ml) confirmed these 4 samples
Volume 68, No. 3
Rudick et al: JCV and Natalizumab
FIGURE 2: JC virus (JCV) DNA load (copies/ml) in serum (top) and plasma (bottom) samples collected prior to progressive
multifocal leukoencephalopathy (PML) diagnosis in natalizumab-treated PML patients. Not detected 5 no JCV DNA was detected
in duplicate samples tested; Not confirmed 5 JCV DNA detected in 1 of 2 duplicate samples, but JCV DNA not detected in a
second set of duplicate samples; Positive 5 JCV DNA detected in duplicate samples. MRI 5 magnetic resonance imaging.
as positive and identified an additional 2 positive samples
from a randomly selected subset of 205 who tested negative using the ViraCor assay. This suggests that the ViraCor assay had a false-negative rate of about 1% compared with the NIH assay. Importantly, none of these
DNA-positive patients developed PML.
Similar results were obtained from the STRATA
study. JCV DNA was tested in >6,000 plasma samples
from >1,000 patients, and only 7 samples from 6
patients were positive. None of these patients developed
PML. PBMC samples from >1,000 STRATA patients
were also assayed. More than 600 of these patients were
treated with natalizumab for 48 weeks. All PBMC samples (>4,000) tested negative for JCV DNA. There was
also no suggestion of increased JCV shedding from kidney associated with natalizumab treatment in that the percentage of patients shedding JCV in urine was similar to
the incidence observed in healthy individuals5–7 and did
not increase during 48 weeks of natalizumab treatment.
In fact, some patients who had JCV DNA detected in
urine at baseline had no JCV DNA detected in urine after
48 weeks of natalizumab treatment.
The prevalence of JCV DNA in blood and urine of
natalizumab-treated patients reported here is consistent with
several other reports from smaller numbers of patients that
did not find increased JCV DNA in plasma, PBMCs, or
urine after 15 to 30 months of natalizumab therapy.17 HowSeptember, 2010
ever, our data contrast with recent reports by Chen et al8 and
Sadiq et al.9 Chen et al.8 detected JCV DNA in urine from
64% of 19 patients treated with natalizumab for 12 months,
and observed increased JCV DNA in plasma and PBMCs
following treatment for 18 months. Possible explanations
for the discrepant findings reported by Chen et al8 and Sadiq
et al9 include differences in assay methodologies, sample
handling (particularly in samples with low DNA copy numbers), and chance occurrence in a small cohort.
Five patients from the studies reported here developed natalizumab-associated PML. In the 3 PML patients
from the STRATA12 study, JCV DNA was not detected
in any available plasma or PBMC samples, at any time
point, prior to the onset of PML symptoms. Interpretation of this result is complicated because blood collection
only occurred during the initial year, whereas PML did
not develop until the third or fourth year of treatment.
However, sampling was more complete in the 2 PML
patients from the SENTINEL12 study. Using the more
sensitive NIH assay, JCV DNA was not confirmed at various time points prior to the onset of PML (detected in 1
of 2 duplicate samples, but not detected in a retest of
duplicate samples), and was only detected after the onset
of PML.
Results from this study do not support routine
clinical testing for JCV DNA in blood or urine to stratify patients for PML risk for several reasons. First, the
309
ANNALS
of Neurology
likelihood of detecting JCV DNA in blood was no
higher in natalizumab-treated MS patients than in natalizumab-naive MS patients. Second, the frequency of JCV
DNA-positive plasma or serum samples was extremely
low and was not associated with development of PML.
JCV DNA was not detected in any of the blood samples
that were analyzed from the 3 patients who developed
PML in STRATA, or in the 3 original PML cases from
SENTINEL. Conversely, none of the patients who tested
positive for JCV DNA in blood has subsequently developed PML. Third, because the frequency of PML is
approximately 0.1%, and the frequency of JCV DNA in
urine is approximately 25%, the predictive value of a
positive urine test is extremely low. Further, the predictive value of a negative test is poor, in that 1 of 3 cases
who developed PML was urinary JCV DNA negative at
all time points tested. Therefore, in aggregate these data
do not support the use of JCV DNA testing in blood or
urine to predict PML risk, given currently available
methodologies.
Despite the lack of clinical utility for JCV DNA
testing to stratify patients for PML risk, further research
is urgently needed to understand the pathogenesis of
natalizumab-associated PML, and to develop clinical
assays that can be used to determine individual risk for
PML prior to and during treatment. It seems likely that
the pathogenesis of PML includes transient viremia, but
further research and assay development will be required
to achieve adequate sensitivity and specificity to support
clinical decision making.
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Acknowledgment
The data contained in this report were derived from the
NIH Laboratory of Molecular Medicine and Neuroscience and were shared with Biogen Idec under a collaborative agreement. We thank B. Aschenbach for his
assistance in preparing the manuscript.
Potential Conflicts of Interest
R. Rudick, P. O’Connor, C. Polman, and A. Goodman
have received consulting fees from Biogen Idec. All other
authors are employees of Biogen Idec.
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patients, dna, urine, virus, natalizumab, assessment, treated, blood
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