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CORRESPONDENCE • CID 2010:50 (15 May) • 1425
1 5 M AY
Correspondence
Is It Time to Treat HIV Elite
Controllers with Combined
Antiretroviral Therapy?
To the Editor—I read with interest the
article by Sedaghat et al [1], who reported
long-term dynamics in human immuno-
deficiency virus (HIV) elite controllers.
Sedaghat and colleagues also observed an
elite controller with a progressive decrease
in the CD4 cell counts, who experienced
a marked decrease in immune activa-
tion that was not accompanied by the in-
crease in the CD4 cell count. The article
by Sedaghat and colleagues raises an in-
triguing issue regarding combined anti-
retroviral therapy (cART) in elite con-
trollers who experience progressive de-
creases in the CD4 cell count despite
having undetectable virus loads.
Although the estimated frequency of
elite controllers is !1% of persons with
chronic HIV infection [2], in an inter-
national study (the CASCADE study) of
recently HIV-infected patients [3], 10
(7%) of 145 persons with virologically
controlled HIV infection eventually ex-
perienced an AIDS-defining illness, and 5
(3.5%) experienced evidence of a pro-
gressive decrease in the CD4 T cell count
while plasma HIV RNA levels remained
undetectable, while not receivingcART.In
a more recent study, Hunt et al [4] ob-
served a proportion of elite controllers
among untreated patients who progressed
to AIDS—similar to the population from
the CASCADE study.
Moreover, Hatano et al [5] demon-
strated that the majority (98%) of elite
controllers have measurable plasma HIV
RNA levels, often at levels higher than
those observed in antiretroviral-treated
patients. It has also been demonstrated
that higher CD8 T cell activationlevelsare
associated with more rapid CD4 T cell
count decreases and clinical progression
among untreated patients [6]. In partic-
ular, elite controllers demonstrated ab-
normal levels of T cell activation despite
maintaining clinically undetectable levels
of viral replication along with higher CD8
T cell activation levels [4].
In December 2009, the Department of
HealthandHumanServiceshaspublished
up to date guidelines for HIV treatment
[7], and the panel members revised the
criteria when cART has to be started. The
panel recommends treatment of patients
with CD4 cell counts of 350–500 cells/
mm3, whereas for those with CD4 cell
counts 1500 cells/mm3, the panel favors
treatment as optional. In addition, the
panel states that cART may be theo-
retically beneficial for elite controllers,
although clinical data supporting treat-
ment for these patients are lacking.
I fully agree with Sedaghat et al [1] that
cART can reduce chronic immune acti-
vation and subsequently can block pro-
gressive decreases in the CD4 cell count,
which may lead to AIDS-defining illnesses
and to non–AIDS-defining illnesses—par-
ticularly in patients with CD4 cell counts
1350 cells/mm3. Thus, taken together,
clinical data and suggestions from the
panel members indicate that it may be
time for elite controllers with progressive
decreases in the CD4 cell count to be
treated with cART, and it is desirable to
design studies to test the efficacy of cART
inpreventingprogressionofHIVinfection
for elite controllers with progressive de-
creases in the CD4 cell count.
Acknowledgments
Potential conflicts of interest.
conflicts.
D.T.: no
Donato Torre
Section of Infectious Diseases,
General Hospital, Cittiglio (Varese), Italy
References
1. Sedaghat AR, Rastegar DA, O’Connell KA, Di-
noso JB, Wilke CO, Blankson JN. T cell dy-
namicsand the responsetoHAARTinacohort
of HIV-1-infected elite suppressors. Clin Infect
Dis 2009;49:1763–1766.
2. Walker BD. Elite control of HIV infection:
implications for vaccines and treatments. Top
HIV Med 2007;15:134–136.
3. Madec Y, Boufassa S, Porter K, Meyer L.
Spontaneous control of viral load and CD4
cell count progression among HIV-1 sero-
converters. AIDS 2005;19:2001–2007.
4. Hunt PW, Brenchley J, Sinclair E, et al. Re-
lationship between T cell activation and CD4
T cell count in HIV-seropositive individuals
with undetectable plasma HIV RNA levels in
the absence of therapy. J Infect Dis 2008;197:
126–133.
5. Hatano H, Delwart EL, Norris PJ, et al. Evi-
dence for persistence low-level viremia in in-
dividuals who control human immunodefi-
ciency virus in the absence of antiretroviral
therapy. J Virol 2009;83:329–335.
6. Liu Z, Cumberland WG, Hultin LE, Kaplan
AH, Detels E, Giorgi JV. CD8 T-lymphocyte
activation in HIV-1 disease reflects an aspectof
pathogenesisdistinctfromviralburdenandim-
munodeficiency. J Acquir Immune DeficSyndr
Hum Retrovirol 1998;18:332–340.
7. Panel on Antiretroviral Guidelines for Adults
and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-1 infected adults
and adolescents. Washington, DC: Depart-
ment of Health and Human Services, 1 De-
cember 2009. http://www.aidsinfo.nih.gov/
ContentFiles/AdultandadolescentGL.pdf. Ac-
cessed 13 January 2010.
Reprints or correspondence: Dr Donato Torre, Section of In-
fectious Diseases, General Hospital, Via Luvini 1, 21033 Cit-
tiglio (Varese), Italy (donatotorre@libero.it).
Clinical Infectious Diseases
? 2010 by the Infectious Diseases Society of America. All
rights reserved. 1058-4838/2010/5010-0016$15.00
DOI: 10.1086/652284
2010;50(10):1425
Reply to Torre
To the Editor—In his excellent assess-
ment of the recent literature and guide-
lines, Torre [1] asks whether it is time to
treat with combinationantiretroviralther-
apy (cART). To answer that question, it
may be best to take a step back and ask a
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1426 • CID 2010:50 (15 May) • CORRESPONDENCE
more fundamental question: what is the
rationalefortreatingelitesuppressorswith
cART in the first place? We know that
many of these patients are probably in-
fected with fully replication-competent
human immunodeficiency virus (HIV)–1
isolates [2, 3]. Furthermore,acomparison
of proviral and plasma HIV clones sug-
gests that viral evolution has occurred in
these patients, meaning that the virus has
tobereplicatingatlowlevels[4].Although
the majority of elite suppressors maintain
stable CD4+T cell counts, CD4+T cell
depletion has been reported in some elite
suppressors [5–8], all of whom have had
marked levels of immune activation. Im-
mune activation has been shown to be a
better correlate of HIV progression than
viremia in some studies [9, 10], and in
fact, Kaposi sarcoma has been reported in
an elitesuppressorwithrelativelyhighlev-
els of immune activation[7].Inourstudy,
we showed that treatment of an elite sup-
pressor with highly active antiretroviral
therapy (HAART) resulted in a marked
decline in immuneactivationeventhough
there was not a significant increase in
CD4+T cell count [8]. Thus, one could
argue that treatment with HAART will in-
hibit the low-level viral replication that is
probably responsible for the immune ac-
tivation in elite suppressors.
More patients will have to be studied
before we can determine whether this
strategy generally results in immune re-
constitution,buthowdowedefinesuccess
in cases in which CD4+T cell counts do
not rebound? Elite suppressors have viral
loads of !50 copies/mL at baseline, so us-
ing commercial viral load assays with cut-
off values of 50 copies/mL will be of little
help, and it is obviously challenging to
monitor these largely asymptomatic pa-
tients for other signs of clinical improve-
ment. The CD4+T cell count in our pa-
tient stabilized during HAART [8]; this
probably should be the minimum crite-
rion used in these cases. Finally,onecould
ask whether it makes sense to treat allelite
suppressors with HAART. Studies have
shown that, although these patients have
higher levels of immune activation than
uninfected subjects [6, 7], the majority
maintain stable CD4+T cell counts for
long periods of time [8, 11, 12]. Studies
comparing large cohorts of elite suppres-
sors and patients who are receiving
HAART will be needed to determine
whether subtle differences in morbidity
and mortality exist; ultimately, this will
guide the decision-making process. How-
ever, it should be noted that, although
manyelitesuppressorshavebeenclinically
stable for 120 years without therapy, no-
body has been taking HAART for that
long; thus, the long-term consequences of
this treatment remain unknown.
Acknowledgments
Financial support.
Health (R01 AI065960 to C.O.W. and R01
AI080328 to J.N.B.).
Potential conflicts of interest.
no conflicts.
National Institutes of
All authors:
Ahmad R. Sedaghat,1,aDarius A. Rastegar,1
Karen A. O’Connell,1Jason B. Dinoso,1
Claus O. Wilke,2and Joel N. Blankson1
1Department of Medicine, Johns Hopkins University
School of Medicine, Baltimore, Maryland;
and
for Computational Biology and Bioinformatics,
and Institute for Cell and Molecular Biology,
University of Texas at Austin, Austin, Texas
2Section of Integrative Biology, Center
References
1. TorreD.IsittimetotreatHIVelitecontrollers
with combined antiretroviral therapy [letter]?
Clin Infect Dis 2010;50(10):1425 (in this is-
sue).
2. Blankson JN, Bailey JR, Thayil S, et al. Iso-
lation and characterization of replication-
competent human immunodeficiency virus
type 1 from a subset of elite suppressors. J
Virol 2007;81(5):2508–2518.
3. Bailey JR, O’Connell K, Yang HC, et al. Trans-
mission of human immunodeficiency virus
type 1 from a patient who developed AIDS
to an elite suppressor. J Virol 2008;82(15):
7395–7410.
4. Bailey JR, Williams TM, Siliciano RF, Blank-
son JN. Maintenance of viral suppression
in HIV-1-infected HLA-B*57+ elite suppres-
sors despite CTL escape mutations. J Exp
Med 2006;203(5):1357–1369.
5. Greenough TC, Sullivan JL, Desrosiers RC.
Declining CD4 T-cell counts in a person in-
fected with nef-deleted HIV-1. N Engl J Med
1999;340(3):236–237.
6. Andrade A, Bailey JR, Xu J, et al. CD4+T cell
depletion in an untreated HIV type 1-infected
human leukocyteantigen-B*5801-positivepa-
tient with an undetectable viral load. Clin In-
fect Dis 2008;46(8):e78–e82.
7. Hunt PW, Brenchley J, Sinclair E, et al. Re-
lationshipbetweenTcellactivationandCD4+
T cell count in HIV-seropositive individuals
with undetectable plasma HIV RNA levels in
the absence of therapy. J Infect Dis 2008;
197(1):126–133.
8. SedaghatAR,RastegarDA,O’ConnellKA,Di-
noso JB, Wilke CO, Blankson JN. T cell dy-
namics and the response to HAART in a co-
hort of HIV-1-infected elite suppressors. Clin
Infect Dis 2009;49(11):1763–1766.
9. Giorgi JV, Hultin LE, McKeating JA, et al.
Shorter survival in advanced human immu-
nodeficiency virus type 1 infection is more
closely associated with T lymphocyte activa-
tion than with plasma virus burden or virus
chemokine coreceptor usage. J Infect Dis 1999;
179(4):859–870.
10. Sousa AE, CarneiroJ, Meier-SchellersheimM,
Grossman Z, Victorino RM. CD4 T cell de-
pletion is linked directlytoimmuneactivation
in the pathogenesis of HIV-1 and HIV-2 but
only indirectly to the viral load. J Immunol
2002;169(6):3400–3406.
11. Pereyra F, Palmer S, Miura T, et al. Persistent
low-level viremia in HIV-1 elite controllers
and relationship to immunologic parameters.
J Infect Dis 2009;200(6):984–990.
12. Okulicz JF, Marconi VC, Landrum ML, et al.
Clinical outcomes of elite controllers, vire-
mic controllers, and long-term nonprogres-
sors in the US department of defense HIVnat-
ural history study. J Infect Dis 2009;200(11):
1714–1723.
aPresent affiliation: Department of Otolaryngology, Massa-
chusetts Eye and Ear Infirmary, and Harvard Medical School,
Boston, Massachusetts
Reprints or correspondence: Dr Joel N. Blankson, Carnegie
346-ID, 600 N Wolfe St, Baltimore, MD 21287 (jblanks1
@jhmi.edu).
Clinical Infectious Diseases
? 2010 by the Infectious Diseases Society of America. All
rights reserved. 1058-4838/2010/5010-0017$15.00
DOI: 10.1086/652285
2010;50(10):1425–1426
Evaluation of Parvovirus
B19 Infection in Children
with Malignant
or Hematological Disorders
To the Editor—The potential benefit of
diagnostic screening for parvovirus B19
(B19) DNA by polymerase chain reaction
(PCR) was recently shown in children
with acute lymphoblastic leukemia (ALL),
because only 5% of the patients who had
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