| Authors: Ellis R, Gelman B, Letendre S, Clifford D, Marra C, McArthur J, McCutchan J,Simpson D, Grant I, and the CHARTER Group |
| Abstract:Background:
No
reliable
biomarker
exists
for
HIV
sensory
neuropathy
(SN),
a
condition
associated
with
pain
and
disability
that
persists
despite
virologic
suppression
among
individuals
who
are
aging
on
long-‐term
combination
antiretroviral
therapy
(CART).
Chronic
monocyte
activation,
particularly
involving
the
dorsal
root
ganglia
(DRG),
may
contribute
to
the
persistence
of
HIV-‐SN.
Since
soluble
CD14
(sCD14)
is
shed
by
activated
monocytes,
we
hypothesized
that
levels
of
sCD14
in
cerebrospinal
fluid
(CSF)
might
be
elevated
in
HIV-‐SN.
Methods:
We
selected
78
HIV+
virally
suppressed
(plasma
VL<50
c/mL)
individuals
who
had
CSF
sCD14
levels
measured
in
CHARTER,
a
multicenter
study
of
neurological
disease
and
CART.
HIV-‐SN
was
defined
by
two
or
more
of
the
following
neuropathy
signs:
bilateral
distal
lower
extremity
reduced
(or
absent)
vibration
or
sharp
sensation
or
ankle
reflexes.
Neuropathy
symptoms
were
bilateral,
distal
neuropathic
pain,
paresthesias
or
numbness.
To
evaluate
the
specificity
of
associations
with
sCD14,
we
also
analyzed
another
marker
of
inflammation,
soluble
TNF
receptor-‐type
2
(sTNFR2).
Both
sCD14
and
sTNFR2
were
measured
in
CSF
by
commercially
available
ELISA.
For
parametric
analysis,
biomarker
values
were
log10-‐transformed,
normalizing
their
distributions.
Results:
Subjects
were
86%
men,
44%
non-‐white,
mean
age
42
years
(range
22-‐61),
median
[IQR]
nadir
and
current
CD4
170
[50,
272]
and
535
[349,694].
Twenty-‐four
(32%)
had
HIV-‐SN,
including
14
with
neuropathic
pain.
Older
age
was
associated
with
higher
CSF
sCD14
levels
(r
=
0.31;
p=0.006).
CSF
sCD14
levels
were
higher
in
those
with
HIV-‐SN
(mean
(±SD)
log10
CSF
sCD14
5.2(0.18)
vs.
5.0(0.24);
p=0.007;
Cohen’s
d
=
0.71)
and
in
those
who
reported
neuropathic
pain
regardless
of
neuropathy
signs
(5.1(0.21)
vs
5.0(0.24);
p=0.04).
Statistical
adjustment
for
age
attenuated,
but
did
not
eliminate,
the
relationship
between
HIV-‐SN
and
sCD14,
which
remained
significant
after
adjusting
for
other
significant
correlates
of
SN,
including
d-‐drug
use
and
nadir
CD4.
By
comparison,
CSF
levels
of
sTNFR2
were
not
related
to
HIV-‐SN.
Conclusions:
Elevated
CSF
levels
of
sCD14,
but
not
sTNFR2,
in
aging
persons
with
HIV-‐SN
on
virally
suppressive
CART
may
reflect
persistent
monocyte
activation,
possibly
producing
injury
to
sensory
neurons
in
DRG. |