Antiviral Therapy 2012; 17:12271231 (doi: 10.

3851/IMP2414)

Commentary
Targeting chronic central nervous system HIV
infection
Richard W Price1*, Ronald Swanstrom 2
Department of Neurology, University of California San Francisco, San Francisco General Hospital, San Francisco, CA, USA
UNC Center For AIDS Research, University of North Carolina at Chapel Hill, Lineberger Cancer Center, Chapel Hill, NC, USA

1
2

*Corresponding author e-mail: rwprice@sfgh.ucsf.edu

Central nervous system (CNS) HIV infection is a nearly

universal facet of systemic infection. Although antiretroviral therapy is generally effective in suppressing
this infection and reducing its severe complications,
reports of continued neurological abnormalities have
questioned whether treatment developed for systemic
efficacy is optimized for CNS infection. Shikuma et al.

report that a monocyte efficacy score based on cell

culture studies and applied to antiretroviral drugs correlated with neuropsychological performance in a previously reported cohort. Although there are important
questions regarding the theoretical underpinnings of
both this score and its application, the findings present
a novel slant on therapy.

Background: CNS antiretroviral therapy

The past few years have witnessed heightened interest in
central nervous system (CNS) HIV-1 infection, its longterm consequences and, in particular, its effective treatment. This is not a new issue. It has long been evident
that CNS infection or as more commonly documented,
the presence of virus in cerebrospinal fluid (CSF) is
a nearly universal facet of systemic infection that
begins shortly after initial virus exposure and continues through the course of untreated systemic infection
[13]. Although most often clinically silent and seemingly innocent despite local inflammatory reactions, it
can evolve in some patients to frank HIV encephalitis
presenting clinically as HIV-associated dementia (HAD)
with synaptic and dendritic alterations and neuronal
loss [4], most often in the context of advanced systemic
infection and immunosuppression [5]. The effective
treatment and prevention of this severe end point has
long been an important objective of clinical research,
and the introduction of suppressive antiretroviral therapy (ART) has generally been very successful in both
arresting established disease and reducing the incidence
of HAD [6,7].
Recent attention to CNS infection has been provoked
by a number of observations and potential treatment
issues, including reports of a high prevalence of neuropsychological test impairment in treated patients [8],
potential interactions of HIV-related brain injury with
brain aging as patients survive longer with effective
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therapy [9], pharmacological limitations in treating

compartmentalized CNS infection as a result of the
bloodbrain and bloodCSF barriers that restrict antiviral drug exposure [10], reports of symptomatic and
asymptomatic CNS (or CSF) viral escape in treated
patients [11,12], the potential for CNS infection to
serve as a viral reservoir that may be a source for virological failure and limit viral eradication [13,14], and
the possibility that antiretroviral drugs may have CNS
toxicity [15].
These considerations have led to more careful scrutiny of the CNS effects of therapy and, in particular, to
drug combinations that might be more effective in suppressing CNS infection and its consequences [10]. This
effort has centred principally on the capacity of different drugs to reach CNS targets. Prominent in these
efforts has been the development of a CNS penetration
effectiveness (CPE) score by Letendre et al. [16]. This
defines an aggregate score for a drug regimen based on
the sum of a three-level scale (0, 0.5 and 1) [16], or in
its more recent iteration, a four-level scale (14) [17]
for each drug based on available data mainly on CSF
pharmacokinetics, but where available also on measures of drug effect (mostly on CSF HIV RNA concentrations). The utility of this aggregate score in predicting treatment response has been supported by some
studies, although not by others [1721]. Importantly,
most of these studies involve observational cohorts
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RW Price & R Swanstrom

or retrospective analysis of trials structured for other

purposes rather than randomized trials designed specifically to address CNS drug efficacy.
Whatever the precision and utility of this simplified
score, its rationale is clear it aims to better treat infection within the CNS and, more precisely, the compartmentalized CNS infection that is genetically distinct
from the systemic infection measured in plasma [22].
Efforts at special CNS drug targeting assume that current antiviral regimens, which have been developed and
refined on the basis of systemic efficacy in suppressing
plasma virus and sustaining blood CD4+ T-cell counts,
are not optimized for preventing or treating CNS infection. Without drug penetration, it is inferred that CNS
infection may persist and continue to cause CNS injury
despite systemic control. In most patients there is little evidence for this, although there are clear exceptions. Notably, Canestri et al. [11] reported a group of
11 patients with new CNS disease despite suppression
of plasma virus to near or below the clinical detection
level who had higher HIV RNA concentrations in CSF
than in plasma. These patients improved clinically after
treatment was modified taking into account CSF viral
genotypic resistance and CNS drug entry. Although
additional reports have documented similar cases
[23], this neuro-symptomatic CSF escape nonetheless
appears to be rare. The Canestri et al. [11] cases were
gathered over a 5-year period from clinics that had followed approximately 6,000 HIV-infected patients per
year. A second type of CSF escape was documented
by Edn et al. [12] in a retrospective series reporting
low levels of CSF HIV RNA in 7 of 69 neurologically asymptomatic or stable patients with suppressed
plasma virus. The clinical significance of this more common CSF escape is not yet clear: whether innocent and
equivalent to plasma blips or indicative of persistent
compartmentalized CNS infection with eventual neuropathogenic potential is an important question that
needs to be addressed in the current setting of suppressive therapy. This study also showed no relationship
between CSF escape and CPE score. Mild elevation of
CSF neopterin, a marker of macrophage activation, in
the escaped group suggests that there was an active host
immunological response in these subjects.
How do these virological observations relate to
the more common issue of neurological symptoms or
neuropsychological test impairment in seemingly welltreated patients? This relationship is to a large extent
uncertain. Many factors can contribute to test impairment, beginning with normal variation in performance
that assures 16% of individuals will be impaired, and
a larger number may be so classified as the number of
tests expands [24]. Confounding CNS diseases, drug use,
depression and the like are also important contributors
to clinical symptoms and test impairment [20]. Where
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HIV infection appears to be the only evident cause, the

critical unanswered question is whether the underlying
brain injury was sustained before treatment initiation
resulting in static residual damage, or whether the neuropathological process actually continues despite systemically suppressive treatment. If the former, then the
remedy is earlier initiation of treatment, but if injury
continues despite plasma viral suppression additional
treatment strategies are needed.

Treating monocyte infection

In this issue of Antiviral Therapy, Shikuma et al. [25]
outline a different approach to treating CNS infection
and preventing CNS injury, one that proposes to target
HIV replication in cells of the monocyte-macrophage
lineage. This uses a monocyte efficacy (ME) score
for different drugs derived from cell culture studies,
reviewed by their co-authors Gavegnano and Schinazi
[26], to predict CNS treatment effect. They report that
this ME score predicted aggregate test performance
(NPZ8 score) in a previously reported cohort, whereas
the CPE score did not.
This approach targets a different pathogenetic
schema than the CPE score. Rather than drug accessibility to CNS infection, it focuses on HIV replication
in monocytes and macrophages outside of the CNS.
It is predicated on the hypothesis that infected monocytes may be relatively impervious to some standard
therapies and may continue to seed the brain despite
treatment that suppresses plasma virus. After entering the CNS, these infected cells differentiate into
macrophages where they assume a pathogenic role.
However, there is little evidence that such a cycle of
monocyteCNS macrophage entry and infection, in
fact, takes place in treated patients. In this hypothetical cycle, when are these cells initially infected and
in what ontogenetic state? Is it as monocyte progenitors, as circulating monocytes as the authors seem
to favour, or as macrophages within the brain? The
authors cite their own work [27] and, in fact, correlate
detection of HIV DNA in peripheral blood mononuclear cells (PBMCs) with lower ME score [25]. However, circulating monocytes express only low levels of
CD4 [28], and it is generally accepted that monocytes
are difficult to infect prior to differentiation into macrophages [2931]. Although CNS macrophages are
infected in overt HIV encephalitis, it is not clear that
they are already infected when they enter the CNS
rather than acquiring and propagating infection in situ
in the absence of drug therapy. In one recent report
using sensitive methods the authors failed to find viral
DNA in the blood monocyte population [32], while
in another report viral DNA was rare and markedly
lower than in CD4+ T-cells [33]; similar results have
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Treating CNS HIV infection

Table 1. Comparison of antiretroviral therapy regimen scores

Initial therapy
recommendations

NRTI1

NRTI2

Drug class

DHHS preferred
DHHS alternative

DHHS acceptable

TDF
ABC
ABC
ZDV
ZDV
ABC
TDF
ZDV
ABC
TDF

FTC
EFV

7
3TC
EFV

8
3TC FPV/r 8
3TC
NVP

10
3TC EFV
9
3TC NVP
9
FTC NVP
8
3TC SQV/r 7
3TC SQV/r 6
FTC SQV/r 5

NNRTI

PI

CPE 2010

Monocyte
efficacy score
163
153
153
120
200
73
83
120
73
83

ABC, abacavir; CPE, central nervous system penetration effectiveness; EFV, efavirenz; FPV/r, ritonavir-boosted fosamprenavir; FTC, emtricitabine; NNRTI, non-nucleoside
reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; SQV/r, ritonavir-boosted saquinavir; TDF, tenofovir
disoproxil fumarate; ZDV, zidovudine; 3TC, lamivudine.

also been seen but not reported by others (R Koup,

personal communication). These types of studies crucially rely on the quality of the cell sorting step, and it
is essential to carefully define the level of contaminating T-cells in the sorted monocyte pool. Finally, in our
own work we noted that the presence of macrophagetropic HIV in the CSF/CNS did not predict the presence of virus with this entry phenotype in the blood
[34]. Thus, although CNS macrophages are key cells
in the pathogenesis of overt HIV encephalitis, evidence
that infected blood monocytes play a role in evading
systemic antiviral therapy and seeding the CNS in the
face of treatment has little direct support.
Additionally, the applicability of the in vitro system
used to derive the monocyte score requires scrutiny. This
score is based on a cell culture system in which donor
primary monocytes are first allowed to differentiate into
macrophages before undergoing what they term acute
infection, in which antiviral drugs are added to the system before viral inoculation in order to inhibit the initial
cycle of replication. The ME score is the reciprocal of the
median effective concentration (1,000) in this system.
It does not otherwise directly integrate human dosing
or in vivo levels achieved for each drug. Because of the
differentiation of these cells in culture, the system likely
better tests susceptibility of macrophages rather than
monocytes. Moreover, because of differences in donor
cell properties, in vivo tissue-specific macrophage variation and viral isolate tropism, the applicability of this
score to patient populations cannot be taken for granted.
To illustrate some of the practical issues, Table 1
compares CPE and ME scores for regimens included in
the current DHHS Guidelines as initial therapy [35] for
which monocyte scores can be calculated from the data
presented by Shikuma et al. [25]. Because many of the
drugs used to treat their cohort are no longer commonly
used and data for many of the contemporary drugs are
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not available, this list is small and difficult to apply

to current therapies. However, it shows that the commonly used combination of tenofovir disoproxil fumarate/emtricitabine/efavirenz and the alternative regimens using abacavir/lamivudine with either efavirenz
or fosamprenavir/ritonavir have ME scores above the
means of the neurologically normal or asymptomatic
abnormal test groups reported by Shikuma et al. [25].
The table also shows that conflicts between CPE and
ME scores exist in some regimens, for example with the
high CPE and low ME score of abacavir/lamivudine/
nevirapine. More generally, if the ME score predicts
effectiveness at suppressing a component of systemic
infection, then one may ask why it would not also predict higher systemic efficacy. If monocytemacrophage
infection can select for drug resistance, one might
expect spread of resistance to other cell types including
CD4+ T-lymphocytes.
The authors discuss combining their score with some
adaptation of the CPE to take into account both brain
exposure and macrophage exposure to account for
more direct treatment of infected brain macrophages,
although this is not included in the presented analysis.
As perhaps implied by the comparisons in Table 1, this
might involve compromise of one or more treatment
properties in designing such regimens.

Evaluating central nervous system drug

efficacy
While one may question some of the scientific underpinnings of the ME score and the authors view that
the results support the group of underlying hypotheses,
it is still important to take into account the empirical
evidence that the ME score correlated with the neuropsychological test outcome, even if as a step in refining both these hypotheses and the score. The authors
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RW Price & R Swanstrom

report a correlation of the ME score with neuropsychological test outcomes both as a normalized continuous
variable (the NPZ8 score) and by diagnostic categories
determined by score definitions and clinical information, although oddly many of the NPZ8 scores of the
subjects categorized as neuropsychologically abnormal and of mild cognitive motor disorder were within
the range of -1 to 1, considered normal in most studies [25]. Importantly, they also analyse outcomes in the
subset of patients with suppressed plasma viral loads,
in whom the confounding outcomes of the weaker systemic effects of some regimens and of drug resistance
are thereby reduced. Although the effect of the ME
scored is not profound, it is statistically significant.
The main study uses cross-sectional analysis of a
cohort and assumes that the antiviral regimen they had
been taking at study entry exerted a therapeutic or preventative effect on their neurological performance over
the duration of therapy, in this study a mean of 2.1 years.
The analysis does not take into account the patients
pretreatment status. Because the treatments were prescribed by their care providers, the individual drugs
and their combinations were varied and, of course, not
randomized. This type of observational cohort makes
it difficult to discern the effect of an individual drug
or combination, and underscores the attractiveness of
an aggregate score such as the CPE or ME score that
attempts to represent a shared, though variable drug
property across this range of regimens. By contrast,
such scores fail to take into account many of the other
properties of the regimen that contribute to systemic
and likely CNS efficacy and that have been evaluated
over the course of an extensive body of clinical trials
and other studies. In observational studies such as this
one, other important clinical factors may contribute to
drug selection, and need to be taken into account in
the analysis [36]. Hence the application of either CPE
or ME scores needs to be tempered by the broader picture of systemic drug experience. Unfortunately, this
study did not measure CSF HIV RNA levels, so this
more direct assessment of the effect on CNS infection
is unknown.

infection a helpful step in this direction? Will focus on

treating this component of infection attenuate the continued CNS morbidity beyond that conferred by early
treatment initiation, more effective systemic infection
control and reduced immune activation?
The contribution of Shikuma et al. [25] suggests
one approach, albeit limited by questions regarding
the underlying hypothetical framework. What next
then? As can be seen from Table1, the available data
cannot readily be used to judge contemporary preferred treatments, so this hypothesis needs to be supported by broader and more robust cell culture data
using consistent methods as a basis for this score. The
resultant predictive value of the ME score will need to
be examined in other cohorts both cross-sectionally as
in this initial study, but also using a prospective longitudinal design. While this has generally proved difficult in purely neurologically-directed trials, studies
that piggy-back on prospective randomized clinical
trials where regimens have different ME (and CPE)
scores should be considered. End points for such studies should include not only neuropsychological test
outcomes but biological measures including CSF HIV
RNA (viral load, genetic compartmentalization and
macrophage entry phenotype) and markers of macrophages involvement such as the activation marker
neopterin, or the chemokine CCL2/MCP-1 [37].
Using these combined strategies, it should be possible
to further test this score and reflect on the underlying
theoretical framework.

Acknowledgements
The authors work in this area is funded by an NIH
grant MH094177 from the National Institute of Mental Health.

Disclosure statement
RWP has received research grant support from Merck
and Co., and an honorarium from Abbott Laboratories.
RS declares no competing interests.

Conclusions

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Accepted 23 May 2012; published online 28 September 2012

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