Correspondence

AIDS
2009,
23:273–278


Nonsmoking and other cofactors for Kaposi’s sarcoma

The recent series of 28 cases of HIV-negative Kaposi’s
sarcoma in homo/bisexual men reported by Lanternier
et
al. [1], as well as the subsequent editorial comment
by Colman and Blackbourn [2], highlights the strong
contribution of cofactors to the development of this
malignancy. The primary cause of Kaposi’s sarcoma is
infection with Kaposi’s sarcoma associated herpesvirus
(KSHV, also known as human herpesvirus 8), but the vast
majority of KSHV-infected people do not develop
Kaposi’s sarcoma. We estimated that the annual incidence
of classic Kaposi’s sarcoma (cKS) is about 30/100 000
KSHV-seropositive Mediterranean men over 50 years of
age, or approximately 0.3% over 10 years [3]. In contrast,
the annual incidence of AIDS Kaposi’s sarcoma was about
3/100 in untreated HIV-infected KSHV-seropositive
homosexual men, or about 30% over 10 years [4]. This
illustrates that HIV is a very potent cofactor, increasing
the risk of Kaposi’s sarcoma by approximately 100-fold.

There must be cofactors for non-AIDS Kaposi’s sarcoma.
During 2002–2006, my colleagues and I conducted a
case–control study of cKS that encompassed the entire
island of Sicily. As in our previous case–control study of
cKS [5], the risk of cKS was three-fold lower among
KSHV-seropositive people who had ever smoked at least
one cigarette per week [6]. Moreover, the risk was even
lower (five-fold) among current smokers and intermediate
(two-fold) among former smokers. A significantly reduced
risk of AIDS Kaposi’s sarcoma with smoking was noted in
two cohorts of HIV-infected homosexual men in the
United States [7,8]. Neither Lanternier et
al.
[1] nor
Colman and Blackbourn [2] mention nonsmoking.

In a study by Lanternier et
al. [1], one of the 28 non-AIDS
Kaposi’s sarcoma (presumptively cKS) patients was noted
to have used corticosteroids for asthma. Systematically
collected data on medications would be helpful, as the risk
of cKS was increased more than two-fold with asthma in
our earlier study [5] and with corticosteroid use in both
studies [5,6].

Diabetes mellitus may also prove to be a cofactor. Four
(14%) of the 28 non-AIDS Kaposi’s sarcoma patients were
noted to have diabetes, although the expected prevalence
in this population is unknown [1]. The risk of cKS was
increased four-fold with diabetes in our recent study [6],
but this was not seen in the previous study [5].

Finally, inherited susceptibility surely contributes to the
development of Kaposi’s sarcoma among people who

have been infected with KSHV. In addition to HLA, as
mentioned by Colman and Blackbourn [2], other genes
that regulate innate immunity and cytokine balance could
be equally important [9,10].

Identification of cofactors can lead to useful interventions
to complement drugs directed against KSHV lytic
replication [11]. The ultimate goal is not cKS, because
the absolute risk is very low [3], but rather to reduce the
very serious morbidity and mortality from Kaposi’s
sarcoma in Africa [12,13]. Neither I nor anyone would
recommend smoking to reduce the risk of Kaposi’s
sarcoma. Instead, understanding the mechanism that
underlies this epidemiologic association could lead to an
effective prophylactic or treatment. Nicotine probably
will not fulfill this function [14]. Something else will.

James
J.
Goedert,
Infections
&
Immunoepidemiology
Branch,
National
Cancer
Institute,
Rockville,
Maryland,
USA.


Correspondence
to
James
J.
Goedert,
Infections
&
Immunoepidemiology
Branch,
National
Cancer
Institute,
Rockville,
MD
20852,
USA.
Tel:
+1
301
435
4724;
fax:
+1
301
402
0817;
e-mail:
goedertj@mail.nih.gov


Received:
2
October
2008;
revised:
22
October
2008;
accepted:
22
October
2008.


References

1.
Lanternier
F,
Lebbe´
C,
Schartz
N,
Farhi
D,
Marcelin
AG,
Ke´rob
D,
et
al.
Kaposi’s sarcoma in HIV-negative men having sex with
men. AIDS
2008;
22:1163–1168.
2.
Colman
R,
Blackbourn
DJ.
Risk factors in the development of
Kaposi’s sarcoma. AIDS
2008;
22:1629–1632.
3.
Vitale
F,
Briffa
DV,
Whitby
D,
Maida
I,
Grochowska
A,
Levin
A,
et
al.
Kaposi’s sarcoma herpes virus and Kaposi’s sarcoma in the
elderly populations of 3 Mediterranean islands. Int
J
Cancer
2001;
91:588–591.
4.
Engels
EA,
Biggar
RJ,
Marshall
VA,
Walters
MA,
Gamache
CJ,
Whitby
D,
et
al.
Detection and quantification of Kaposi’s sarcoma-
associated herpesvirus to predict AIDS-associated Kaposi’s
sarcoma. AIDS
2003;
17:1847–1851.
5.
Goedert
JJ,
Vitale
F,
Lauria
C,
Serraino
D,
Tamburini
M,
Montella
M,
et
al.
Risk factors for classical Kaposi’s sarcoma. J
Natl
Cancer
Inst
2002;
94:1712–1718.
6.
Anderson
LA,
Lauria
C,
Romano
N,
Brown
EE,
Whitby
D,
Graubard
BI,
et
al.
Risk factors for classical Kaposi sarcoma in
a population-based case–control study in Sicily. Cancer
Epidemiol
Biomarkers
Prev
2008;
17:1–9.
7.
Nawar
E,
Mbulaiteye
S,
Gallant
JE,
Wohl
DA,
Ardini
M,
Hendershot
T,
et
al.
Risk factors for Kaposi’s sarcoma among
HHV-8 seropositive homosexual men with AIDS. Int
J
Cancer
2005;
115:296–300.
ISSN 0269-9370 Q
2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.


274 AIDS 2009,
Vol
23
No
2


8.
Hoover
DR,
Black
C,
Jacobson
LP,
Martinez-Maza
O,
Seminara
D,
Saah
A,
et
al.
Epidemiologic analysis of Kaposi’s sarcoma as
an early and later AIDS outcome in homosexual men. Am
J
Epidemiol
1993;
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Brown
EE,
Fallin
D,
Goedert
JJ,
Chen
D,
Whitby
D,
Foster
CB,
et
al.
A common genetic variant in FCGR3A-V158F and risk of
Kaposi sarcoma herpesvirus infection and classic Kaposi sarcoma.
Cancer
Epidemiol
Biomarkers
Prev
2005;
14:633–637.


10.
Brown
EE,
Fallin
D,
Ruczinski
I,
Hutchinson
A,
Staats
B,
Vitale
F,
et
al.
Associations of classic Kaposi sarcoma with common
variants in genes that modulate host immunity. Cancer
Epidemiol
Biomarkers
Prev
2006;
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Martin
DF,
Kuppermann
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Wolitz
RA,
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AG,
Li
H,
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Engl
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Wabinga
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JW.
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J
Cancer
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Goedert
JJ,
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BM,
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Neve
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et
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Eur
Acad
Dermatol
Venerol
2008;
22:1101–1109.
DOI:10.1097/QAD.0b013e32831f4674


Efavirenz-induced osteomalacia

We report the case of a 45-year-old white woman who
presented with a 3-month history of generalized bone
pain and proximal myopathy. She was unable to climb
stairs or to get up from a chair without using her hands.
Her BMI was 19 kg/m2.

She received efavirenz, lamivudine and abacavir for HIV
infection. Her CD4 lymphocyte count was 150 cells/ml,
her HIV plasma viral load was undetectable. She was
treated with levetiracetam for epilepsy. Her last seizure
occurred 1 year previously and resulted in several rib
fractures. She had a history of chronic hepatitis C
infection. The hepatitis C virus (HCV) load was
560 000 copies/ml, aspartate transaminase 72 U/l (reference
<35), alanine transaminase 48 U/l (reference <34),
gamma glutamyl transferase 136U/l (reference 1–38).
She was an intravenous drug user but currently stable on
levomethadone substitution therapy (15 ml twice daily).

Her laboratory findings included a low phosphate at

0.4mmol/l (reference range 0.8–1.45), mild hypocalcaemia
at 2.0mmol/l (reference 2.2–2.7) and a raised
alkaline phosphatase at 393 U/l (reference <104). Serum
albumin was slightly low at 31g/l (reference 35–53), but
total protein was within normal range. Parathyroid
hormone was significantly elevated at 233.4 ng/l (reference
15–65), 25-hydroxycholecalciferol [25(OH) vitamin
D3] was less than 7ng/ml (reference 10–60), and
1,25-dihydroxycholecalciferol [1,25(OH)2 vitamin D3 or
calcitriol] was low at 10.7ng/l (reference 17–53). The
isoenzyme profile of the alkaline phosphatase showed a
raised bone fraction at 264 U/l (reference <60). Beta
crosslaps were elevated at 0.844 ng/ml (reference <0.6),
indicating increased bone resorption. Calcitonin, renal
function parameters and urinary calcium excretion were
within normal range but urinary phosphate excretion was
low at 6.9mmol/day (reference 25–64).
Bone scintigraphy revealed activity in the right iliac crest
and hip, several ribs, and bilaterally in some metatarsal

bones (Fig. 1). The findings on computed tomography
were in keeping with old rib fractures but did not show a
radiologic equivalent for the scintigraphic activity.

The combination of low-normal calcium, low phosphate,
raised alkaline phosphatase with raised bone isoenzyme,
raised parathyroid hormone and nondetectable 25(OH)
vitamin D3 is pathognomonic for osteomalacia. The
clinical presentation included severe proximal myopathy
and a waddling gait.

There was no evidence of coeliac disease or any other
malabsorption syndrome. Anticonvulsant medication
and other cytochrome P450 inducers, including rifabutin
and rifampicin, are associated with osteomalacia due to
induction of hepatic metabolism [1–3]. However, this
patient received levetiracetam, which is not metabolized
via the cytochrome P450 pathway [4].

We propose that the vitamin D deficiency was caused by
increased hepatic turnover due to CYP450 enzyme
induction by efavirenz. The patient experienced symptoms
of withdrawal from levomethadone when efavirenz
was commenced suggesting increased enzyme activity
[5].

Substitution of vitamin D3 and calcium did not result in
normal serological bone metabolism markers. After
changing the antiretroviral regimen from efavirenzboosted
to ritonavir-boosted saquinavir, the laboratory
parameters began to normalize. Three months later, the
patient was pain free and no longer showed any proximal
weakness. Calcium, phosphate, alkaline phosphatase,
parathyroid hormone and vitamin D3 levels were within
normal range.

Vitamin D3 (cholecalciferol) is metabolized by the
cytochrome P450 system. It is hydroxylated to 25(OH)
vitamin D3 by hepatic microsomal CYP2R1 [6]. 25(OH)
vitamin D3 is further hydroxylated in the kidneys by

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.


Correspondence 275


Fig. 1. Bone scintigraphy. Several
skeletal
lesions
show
radioactive
activity
immediately
and
3
h
after
injection.


1a-hydroxylase, into two dihydroxylated metabolites, the
main biologically active hormone 1,25(OH)2 vitamin D3
and 24R,25(OH)2 vitamin D3.

Enzymatic induction results in accelerated turnover of
vitamin D3 and 25-OH-D3 to more inactive compounds
and decreases the availability of 25(OH) vitamin D3, which
may lead to a lowered production of 1,25-(OH)2D3 by the
kidney. Additionally, drugs as rifampicin and phenobarbital
lead to the upregulation of 25-hydroxyvitamin D3-24hydroxylase
(CYP24) gene expression, a mitochondrial
enzyme responsible for inactivating vitamin D metabolites
[7].

To our knowledge, there is only one case report of
asymptomatic efavirenz-associated vitamin D deficiency
in an African patient that moved to Scandinavia [8].
Another dark-skinned HIV-infected individual was
reported to develop symptomatic osteomalacia on
therapy with rifabutin [3]. To our knowledge, this is
the first report of a white patient presenting with
symptomatic osteomalacia due to efavirenz-induced
vitamin D deficiency.

It is well known that efavirenz and other non-nucleoside
reverse transcriptase inhibitors can induce enzymes of the
cytochrome P450 system. However, vitamin D deficiency
is rarely recognized in patients receiving the drug, possibly
due to the unspecific symptoms of early osteomalacia.
We recommend a high level of suspicion in patients
complaining of pain or weakness. Regular measurements
of calcium, phosphate and alkaline phosphatase may help
diagnose the condition early.

Christian
Herzmann
and
Keikawus
Araste´h,
Vivantes
Auguste
Viktoria
Klinikum,
Department
of
Infectious
Diseases,
Berlin,
Germany.


Correspondence
to
Dr
Christian
Herzmann,
MD,
Vivantes
Auguste
Viktoria
Klinikum,
Department
of
Infectious
Diseases,
Rubensstr.
125,
12159
Berlin,
Germany.


Received:
3
October
2008;
accepted:
22
October
2008.


References

1.
Christiansen
C,
Rødbro
P,
Lund
M.
Incidence of anticonvulsant
osteomalacia and effect of vitamin D: controlled therapeutic
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Med
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Valsamis
HA,
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Bolland
MJ,
Grey
A,
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AM,
Thomas
MG.
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an HIV-infected man receiving rifabutin, a cytochrome P450
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Clin
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Antimicrob
2008;
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AIDS
2006;
20:1906–1907.
DOI:10.1097/QAD.0b013e32831f4685


Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.


276 AIDS 2009,
Vol
23
No
2


Which helminth coinfections really affect HIV disease progression?

The study by Walson et
al. [1] published in the recent issue
of AIDS
describes the results of the first randomized,
placebo-controlled trial to evaluate the impact of soil-

þ

transmitted helminth infection on CD4cell count and
viral load among HIV-1, geohelminth coinfected adults.
Walson et
al. [1] found that the elimination of Ascaris
infection is associated with a mean 109 cell/ml rise in

þ

CD4cell count (P
¼
0.003) and a 0.54 log10 reduction
in viral load (P
¼
0.09). Although these results lend
support to the hypothesis that helminthes may have a
direct impact on markers of HIV disease progression, the
study is worth evaluating further methodologically as the
interpretation of its results may have far-reaching
implications for public health policy and practice.

The study by Walson et
al. [1] contains multiple
ambiguities, beginning with its analytic plan. It is unclear
whether the authors compared the time-dependent

þ

trends in CD4cell counts and viral load between the
two study arms or whether they evaluated cross-sectional
differences in serial fashion. The difference between these
two methods is significant as a 0.54 log10 viral load decline
in the experimental arm is much less impressive if
there were a concurrent drop in viral load of similar
magnitude in the control arm. It would be helpful to have

þ

presented the mean CD4cell count and viral load for
each helminth species, before and after treatment, in both
arms. It is also unclear whether the authors accounted for
the inherent variability of HIV-1 RNA measures. This is
important when dealing with small viral load changes
(<1.0 log10), as viral setpoint differences in the order
of 0.3log10 occur via natural variation [2–4]. These
inherent fluctuations can affect statistical power calculations
and potentially cause a regression-to-the-mean
effect if not controlled for in the study’s design or analysis.

It is not only the variability of viral load measures that
could have affected the results, but also the absolute
values. At a level of 4.75 log10, the mean baseline viral
load of this study population is higher than other studies
[5–8]. A subgroup analysis from our own cohort
demonstrated that helminth elimination was associated
with a greater viral load decline among individuals with a
baseline viral load higher than 5.0 log10 [6]. Walson et
al.

[1] report that mean baseline viral load of the Ascarisinfected
participants was 0.21 log10 higher among experimental
participants compared with the controls. For all
other helminth species, viral loads were higher in controls
compared with the experimental arm. Thus, it may be
that the viral load decline was actually attributable to
higher baseline HIV RNA levels and not to the particular
helminth species.
In support of their findings, Walson et
al. [1] cite previous
studies that purportedly reported species-specific effects

þ

of helminth infection on HIV viral load and CD4cell

count. However, in our study among Zambian adults [6],
we reported that individuals with moderate to high
intensity infections experienced a nonsignificant trend of

0.12 log10 viral load reduction after intestinal helminth
clearance. These moderate-to-high intensity infections
just happened to occur among individuals infected with
Ascaris
and hookworm. When we assessed the impact of
each species on viral load (controlling for infection
intensity), we found no species-specific differences.
Walson et
al. [1] also claim that past studies were inherently
limited because they were not randomized. The assertion is
oversimplistic, as the validity of their results is diminished
by the post-hoc nature of their stratified analysis. Findings
that do not reflect an apriori
hypothesis are prone to
spuriousness. Multiple comparisons that are not planned
from study outset inevitably yield a significant association,
merely by chance alone. Such post-hoc analyses, therefore,
can only generate and not test hypotheses [9]. Walson et
al.’s

[1] a
posteriori
analysis, therefore, raises questions as to why
HIV was impacted by infection with Ascaris, but not by
hookworm or Trichuris.
The authors postulate that Ascaris
may have a greater
impact on HIV pathogenesis because it is the largest
geohelminth and, therefore, may stimulate host immunity
more than other species. There are problems with this
argument. First, there is no evidence that Ascaris
activates
host immunity more than other intestinal helminthes.
Second, it is not the larger size of the organism but the
greater intensity, invasiveness, and immunogenicity of the
infection that likely would cause a more robust activation
of host immunity [10]. It is possible that Ascaris
could
influence HIV immunology more than other helminthes
not because of its size or infectious load, but because
it may more intimately interact with gut-associated
lymphoid tissue implicated as integral to mechanisms of
HIV immunopathogenesis [11]. However, this might
apply to other geohelminthes as well.

Ultimately, the results of the current study suggest that the
story of HIV–helminth interactions is far from over.
Additional, well designed studies must be conducted to
more definitively address the issues raised, focusing not
just on helminth infections as a whole, but species-
specific effects as well.

Kayvon
Modjarrad,
Institute
for
Global
Health
and
the
Department
of
Medicine,
Division
of
Infectious
Diseases,
Vanderbilt
University,
Nashville,
Tennessee,
USA.


Correspondence
to
Kayvon
Modjarrad,
MD,
PhD,
Vanderbilt
University,
Institute
for
Global
Health,
2525
West
End
Avenue,
Suite
750,
Nashville,
TN
37203-1738,
USA.
E-mail:
kayvon.modjarrad@vanderbilt.edu


Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.


Correspondence 277

Received:
8
September
2008;
accepted:
24
October
2008.


References

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JL,
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PA,
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DOI:10.1097/QAD.0b013e32831fc692


Which helminth coinfections really affect HIV disease progression?

We appreciate the thoughtful comments by Modjarrad [1]
on our recent study, ‘Albendazole treatment of HIV-1
and helminth co-infection: a randomized, double-blind,
placebo-controlled trial’ [2]. Modjarrad [1] highlights
several important issues that merit clarification, specifically
concerning the analytical plan, merits of randomization,
and species-specific outcome evaluations.

As outlined in our paper, we conducted a traditional
randomized clinical trial. Individuals were enrolled at
baseline, randomized to the intervention or placebo,
and followed up at a prespecified standardized single
time-point. CD4 cell counts and HIV-1 RNA levels at
follow-up were compared between the two trial arms
(albendazole and placebo) after controlling for baseline
values. The mean initial CD4 cell counts and viral load by
species are provided in the table of the manuscript by
Walson et
al. [2]. This was not a cross-sectional observational
study, and the trial was designed with a single
follow-up time, so the methods of analysis mentioned by
Modjarrad [1] would not be applicable.

Modjarrad [1] erroneously suggests that the analyses were
conducted a
posteriori. As noted in the methods section of
our paper, the statistical analysis plan was determined
a
priori. The decision to include a modified intent-to-treat
analysis of follow-up CD4 cell counts and HIV-1 RNA
levels as well as the decision to stratify results by helminth
species were a-priori decisions. In fact, a post-hoc analysis
of changes in CD4 cell count and HIV-1 RNA between
the randomization arms suggests a significant benefit of

deworming on CD4 cell counts in all helminth-infected
individuals (decrease in CD4 cell count of 72 cells/mlin
the placebo arm compared with a decrease of 26 cells/ml
in the treatment arm; P
¼
0.043) as well as in the Ascaris
lumbricoides
infected cohort (decrease in CD4 cell count of
99 cells/ml in the placebo arm compared with an increase
of 9 cells/ml in the treatment arm; P
¼
0.005). Because we
had not elected a
priori
to include ‘change in CD4’ or
‘change in RNA’ as an outcome, we did not include these
findings in our paper and presented only data derived
from the a-priori statistical analysis plan.

Modjarrad [1] seems to confuse issues of randomized trial
design with analyses of multiple outcomes. It is important
to recognize the inherent superiority of the randomized
controlled trial over observational studies. Prior observational
studies of helminth infection in HIV-1 infected
individuals have been limited by potential confounding.
These studies have compared helminth-infected and
helminth-uninfected individuals or have included historical
controls. Significant differences exist at baseline in
rates of disease progression, immune activation, and
natural variation in the rate of CD4 cell count decline and
plasma HIV-1 RNA levels between these comparison
groups. The strength of the randomized controlled trial
study design is precisely that differences due to natural
variation are randomly distributed between the comparison
groups. If our analysis resulted in a type II error (not
finding an effect when one truly exists), this would most
likely be due to limitations in sample size (statistical power)
and not due to inherent differences between the groups.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.


278 AIDS 2009,
Vol
23
No
2


Finally, as we noted in our conclusions, we concur with
Modjarrad [1] that this study raises additional questions
concerning the species-specific nature of the effects
observed and that additional well designed randomized
trials should be conducted to answer these questions.

Judd
L.
Walsona,
Grace
John-Stewartb
and
Barbra
Richardsonc,
aDepartment
of
Medicine,
University
of
Washington
and
Centre
for
Clinical
Research,
Kenya
Medical
Research
Institute,
bDepartments
of
Medicine
and
Epidemiology,
and
cDepartment
of
Biostatistics,
University
of
Washington,
Seattle,
Washington,
USA.


Correspondence
to
Judd
L.
Walson,
University
of
Washington,
Seattle,
WA
98105,
USA.
E-mail:
walson@u.washington.edu


Received:
27
October
2008;
accepted:
27
October
2008.


References

1.
Modjarrad
K.
Which
helminth
coinfections
really
affect
HIV
disease
progression?
AIDS
2008;
22:000–000.
2.
Walson
JL,
Otieno
PA,
Mbuchi
M,
Richardson
BA,
Lohman-
Payne
B,
et
al.
Albendazole treatment of HIV-1 and helminth
co-infection: a randomized, double blind, placebo-controlled
trial. AIDS
2008;
22:1601–1609.
DOI:10.1097/QAD.0b013e32831fc6a5


Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.