Download Is the Glass Three-Quarters Full or One-Quarter

E D I T O R I A L C O M M E N TA R Y
Is the Glass Three-Quarters Full or One-Quarter Empty?
Justin C. McArthur1 and Scott L. Letendre2
1
Johns Hopkins University, Baltimore, Maryland; 2University of California, San Diego
(See the article by Spudich et al., on pages 1686–96.)
The neurological manifestations of HIV
infection continue to be a major source
of morbidity and mortality, despite the advances in highly active antiretroviral therapy (ART) during the past decade. The
annual incidence of HIV dementia before
ART was ∼7% in patients with AIDS [1]
but has decreased by 50% since the introduction of ART [2]. Viral invasion of the
central nervous system (CNS) occurs as
an extremely early event after HIV infection [3, 4], yet we do not know whether
latency is established at this early point;
additionally, in general, productive infection is uncommon until after the development of immunosuppression [5]. Once
in the CNS [6], HIV establishes a chronic infection that predominantly involves
monocytes, perivascular macrophages, microglial cells, and, to some extent, a restricted infection of astrocytes [7, 8]. Since
the earliest years of the HIV epidemic,
there has been great interest in studying
cerebrospinal fluid (CSF) in HIV infection, because this compartment represents
a “window” into HIV replication, treatReceived 21 August 2006; accepted 28 August 2006;
electronically published 3 November 2006.
Potential conflicts of interest: none reported.
Financial support: National Institutes of Health (grants
NS44807 and MH075673 to J.C.M. and AI27670, MH58076,
and MH62512 to S.L.).
Reprints or correspondence: Dr. Justin C. McArthur, Johns
Hopkins Hospital, Meyer 6-109, 600 N. Wolfe St., Baltimore,
MD 21287-7609 ([email protected]).
The Journal of Infectious Diseases 2006;194:1628–31
2006 by the Infectious Diseases Society of America. All
rights reserved.
0022-1899/2006/19412-0002$15.00
ment response, and damage in brain
parenchyma.
The study by Spudich et al. [9] in this
issue of the Journal of Infectious Diseases
provides new information about the virological responses to ART in the CSF. It
represents a cross-sectional analysis of 139
HIV-positive subjects categorized as having therapeutic success or failure on the
basis of their virological response to ART.
The estimated blood-brain barrier penetration of antiretroviral regimens was categorized using 2 methods, including one
used in an ongoing National Institutes of
Health–funded study of the effects of antiretroviral therapy on CNS HIV infection—the CNS HIV Antiretroviral Effects
Research (CHARTER) study. The primary
outcome measure was CSF HIV RNA levels below the lower limit of quantification
of 2.5 copies/mL, which was achieved in
72% of subjects with successful therapy.
Among subjects with failed therapy, CSF
HIV RNA levels were much lower than in
those who received no antiretrovirals,
which is consistent with prior reports [10,
11]. Taken together, the results demonstrate that ART suppresses HIV in CSF of
a larger proportion of ART-treated subjects than it does in plasma. The authors
note that this “disproportionate” treatment effect on the CNS compartment may
be due to reduced T cell activation and
trafficking and stands in contrast to previous pessimistic predictions of compartmentalized infection and the limited tissue
penetration of antiretrovirals. Further-
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more, the authors observed a relatively
small number of cases of CNS escape (i.e.,
HIV RNA levels much greater in CSF than
in plasma), and this did not appear to have
clinical consequences.
Along with considerable clinical implications, these findings have important
limitations. One potential limitation is the
study’s cross-sectional design. The ongoing study will generate important longitudinal observations, but the present analyses do not adjust for 2 key, time-based
measures: duration of the current regimen
[12] and duration of treatment failure
[13]. For example, were HIV RNA levels
12.5 copies/mL associated with shorter
durations of therapy? If they were, then
the 28% prevalence of detectable HIV
RNA in CSF in subjects with successful
therapy may simply have been due to sampling. However, if they were not, then this
result suggests that a substantial minority
of subjects with successful therapy may
have ongoing, low-level HIV replication
in the CNS—a finding that may have
important clinical implications. Another
substantial limitation, which is acknowledged by the authors, is the low prevalence
of individuals with HIV-associated cognitive impairment or advanced immunosuppression. In fact there were only 3
individuals with AIDS dementia complex
among subjects with successful therapy,
and they had mild stage 1, static disease.
Because the predominant cellular source
of HIV probably differs between individuals who have earlier stage HIV disease
Table 1. Examples of cerebrospinal fluid (CSF) markers that have either associative or predictive value in HIV-associated cognitive disorders.
Marker
Role
Reference
CSF
Fractalkine
sFas
Associative
Associative
[6]
[7]
Protein carbonyl
Sphingolipid products
Associated with mild dementia
Associated with mild dementia
[8]
[10]
Associative
Predictive
[11]
[12]
Blood
4348-kDa protein in cultured blood monocytes
MCP-1 polymorphisms
NOTE. Associative marker, correlates cross-sectionally; MCP, macrophage chemoattractant protein; predictive marker, longitudinal prediction [3]; sFas, soluble Fas.
and normal cognition (trafficking T lymphocytes) and those who have AIDS or
active or progressive dementia (trafficking
tissue macrophages and microglia), the effectiveness of ART in the CNS probably
differs substantially among these individuals. The findings from the largely dementia-free study population at the University of California, San Francisco (UCSF)
primarily generalize to the first group, who
are at a low risk for the neurocognitive
complications of HIV infection. A third
important limitation was the analysis of
ART penetration. The authors used 2 different approaches to estimate regimen
penetration but related scores to group
membership, not to HIV RNA levels in
CSF. Penetration scores did not differ
between groups but were much higher
(mean, ∼2.8) than those in a recent analysis of the CHARTER cohort (mean, 1.2)
[14]. Because important differences in the
stage of disease, the prevalence of cognitive
impairment, and antiretroviral regimens
appear to exist between the UCSF and the
CHARTER cohorts, the findings should
not necessarily be viewed as contradictory.
Finally, with respect to the relationship between results of resistance analyses in CSF
and plasma, the assay could only be performed for 13 subjects because of the assay
requirements of an HIV RNA level of 1500
copies/mL.
The findings of the study by Spudich et
al. raise several questions. First, does the
pathogenesis of HIV-associated neurocognitive impairment differ in untreated and
treated populations? In the study, 28% of
subjects with successful treatment had
measurable HIV RNA in CSF. If the CNS
is relatively more susceptible to the pathogenic effects of HIV than are other organ
systems, this observation may explain the
continuing high prevalence of cognitive
impairment in treated populations.
Second, do clinically useful surrogate
markers for HIV-associated brain injury
exist at present? The measurement of HIV
RNA levels in CSF was originally a derivative of the use of HIV RNA levels in
plasma to monitor the state and progression of HIV disease and responses to
antiretroviral therapy [15]. Although the
HIV RNA level in plasma is arguably one
of the best-validated surrogate markers
ever developed, levels in CSF have not
had a comparable translation into clinical
practice, despite their promise having been
demonstrated during the pre-ART era
[16]. Two reasons for this are that the predominant source of HIV RNA in CSF
shifts as HIV infection evolves and that
the diagnostic utility of HIV RNA levels
in CSF wanes in treated populations. Early
during infection, when there is typically
CSF pleocytosis, the source of virus in the
CSF may be transitory and supplied by
the constant traffic of infected cells from
the blood to the CSF. As infection progresses and the early CSF pleocytosis
abates, the source of CNS virus becomes
autonomous and is sustained from sources
within the CNS itself [17–19]. Evidence
for this comes from studies of the response
to ART; the rate of HIV decrease in the
CSF is slower than in plasma in individuals
with AIDS- or HIV-associated dementia,
which is consistent with a longer-lived
source of replication, such as brain macrophages [19, 20]. Because effective, and
even ineffective, ART can reduce HIV
RNA levels in CSF, this measurement has
had limited diagnostic sensitivity or specificity [1, 16] in large contemporary cohort studies that have included substantial
proportions of treated individuals [21]. It
may have value in select clinical settings,
such as identifying CNS escape [6] or assessing the efficacy of a new antiretroviral
regimen in treating established dementia.
Elevations in a diverse range of immunological markers within the CSF were
identified well before introduction of assays for HIV RNA (table 1), and several
have been consistently shown to be higher
in patients with HIV-associated dementia
and to correlate with its severity. Most of
these were documented in individuals not
treated with ART, and recent studies during the ART era have suggested that these
immune activation markers are attenuated
[22]. The markers that have been studied
most extensively are b2-microglobulin,
neopterin, quinolinic acid, and macrophage chemoattractant protein (MCP)–1
[23, 24], but other “footprints” of immunological or other host responses have
been reported [25, 26]. None of these has
entered mainstream clinical practice with
regard to the diagnosis of HIV-associated
dementia. The nonspecificity of elevated
EDITORIAL COMMENTARY • JID 2006:194 (15 December) • 1629
immune markers has discouraged clinical
application for the individual patient. One
marker that has consistently shown promise is the b-chemokine MCP-1. The ratio
of plasma:CSF MCP-1 may be a predictive marker of subsequent AIDS dementia
complex or simian immunodeficiency virus encephalitis [27, 28].
Third, what is the clinical significance
of antiretroviral resistance mutations in
CSF? Recent studies from the CHARTER
cohort have suggested that there are differences in the patterns of antiretroviral
resistance mutations between plasma and
CSF. Up to one-third of samples were discordant, with no discernible influence of
antiretroviral regimen choice (J. Wong, unpublished data). By contrast, cases of clinically obvious CNS escape [29] have been
few. This apparent inconsistency raises the
question: will treatment failure due to resistant strains of HIV generated within the
CNS appear clinically as only primary
CNS escape, or will it be clinically indistinguishable from treatment failure due to
resistance generated in other tissues? The
evidence to date supports the latter alternative. It then follows that better control
of HIV in the brain and other protected
compartments may result in more treatment successes.
Fourth, do the benefits (CD4+ T cell
maintenance, neuroprotection) of continuing a failing ART regimen outweigh
the risks (e.g., drug toxicity and an increasing generation of resistant mutants)
in individuals with no treatment options?
The answer to this complex question will
likely depend on highly variable clinical
circumstances and should be addressed in
subsequent treatment guidelines.
Given the continued impact of HIVassociated cognitive dysfunction across the
world and the evolving nature of neurological damage [30], we argue that it is
ever more important to study the CSF in
the context of HIV infection. We need
the equivalent of the excellent surrogate
marker plasma viral load to apply to the
diagnosis, staging, and treatment of HIVassociated dementia.
Acknowledgments
We thank Ron Ellis, Christina Marra, David
Simpson, and our colleagues in the CHARTER
study for the helpful comments and suggestions.
12.
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