Comment

the deleterious immune activation associated with the

disease.2,4,6 A recent study by Murray and colleagues6
showed that chloroquine signicantly decreased
expression of CD38 (a marker of treatment failure
and progression to AIDS, which is associated with
immune activation induced by viral replication) on
CD8 T cells10 and induced downmodulation of Ki67 (a
marker associated with immune-activation-induced
lymphocyte mitosis) on memory T cells;11 in-vitro
and in-vivo anti-inammatory eects were in good
agreement. One reason behind this agreement is
suggested by a recent study of hydroxychloroquine,12
which showed that the drug accumulates at high
concentrations in lymphoid tissues of patients
infected with HIV. These reproducible in-vivo eects of
quionoline antimalarials could be used as, or added to,
new strategies for restricting the HIV reservoir, which are
aimed at counteracting the residual immune activation
during antiretroviral therapy (favouring sustained viral
replication in anatomic sanctuaries), and targeting
activation or proliferation of central and transitional
memory T cells harbouring silent copies of the HIV
proviral DNA (contributing to maintenance of the viruss
genome during treatment).11 Notwithstanding the poor
ecacy of chloroquine for inuenza prevention, the
results reported by Paton and colleagues1 will help to
address the process of drug repositioning for treatment
of infectious diseases.

Andrea Savarino
Department of Infectious, Parasitic and Immune-mediated
Diseases, Istituto Superiore di Sanit, Viale Regina Elena, 299,
00161 Rome, Italy
andrea.savarino@iss.it
I declare that I have no conicts of interest.
1

8
9

10

11

12

Paton NI, Lee L, Xu Y, et al. Chloroquine for inuenza prevention: a

randomised, double-blind, placebo controlled trial. Lancet Infect Dis 2011;
published online May 6. DOI:10.1016/S1473-3099(11)70065-2.
Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Eects of
chloroquine on viral infections: an old drug against todays diseases?
Lancet Infect Dis 2003; 3: 72227.
Keyaerts E, Li S, Vijgen L, et al. Antiviral activity of chloroquine against
human coronavirus OC43 infection in newborn mice.
Antimicrob Agents Chemother 2009; 53: 341621.
Sperber K, Louie M, Kraus T, et al. Hydroxychloroquine treatment of
patients with human immunodeciency virus type 1. Clin Ther 1995;
17: 62236.
Sperber K, Chiang G, Chen H, et al. Comparison of hydroxychloroquine with
zidovudine in asymptomatic patients infected with human
immunodeciency virus type 1. Clin Ther 1997; 19: 91323.
Murray SM, Down CM, Boulware DR, et al. Reduction of immune activation
with chloroquine therapy during chronic HIV infection. J Virol 2010;
84: 1208286.
Di Trani L, Savarino A, Campitelli L, et al. Dierent pH requirements are
associated with divergent inhibitory eects of chloroquine on human and
avian inuenza A viruses. Virol J 2007; 4: 39.
Vezmar M, Georges E. Reversal of MRP-mediated doxorubicin resistance
with quinoline-based drugs. Biochem Pharmacol 2000; 59: 124552.
Saladino R, Barontini M, Crucianelli M, Nencioni L, Sgarbanti R,
Palamara AT. Current advances in anti-inuenza therapy. Curr Med Chem
2010; 17: 210140.
Savarino A, Bottarel F, Malavasi F, Dianzani U. Role of CD38 in HIV-1
infection: an epiphenomenon of T-cell activation or an active player in
virus/host interactions? AIDS 2000; 14: 107989.
Chomont N, DaFonseca S, Vandergeeten C, Ancuta P, Skaly RP.
Maintenance of CD4+ T-cell memory and HIV persistence: keeping
memory, keeping HIV. Curr Opin HIV AIDS 2011; 6: 3036.
Aguirre-Cruz L, Torres KJ, Jung-Cook H, et al. Preferential concentration of
hydroxychloroquine in adenoid tissue of HIV-infected subjects.
AIDS Res Hum Retroviruses 2010; 26: 33942.

Syphilis, still a major cause of infant mortality

Published Online
June 16, 2011
DOI:10.1016/S14733099(11)70150-5
See Online/Articles
DOI:10.1016/S14733099(11)70104-9

654

In The Lancet Infectious Diseases today, Sarah Hawkes and

colleagues1 review the eect of interventions to increase
the coverage of screening and treatment for syphilis in
pregnancy on the uptake of testing and treatment, and
on adverse pregnancy outcomes averted. This study is a
timely reminder that syphilis has not disappeared, and
remains a major, although entirely preventable, cause of
death in newborn babies.
Syphilis is estimated to be responsible for almost
500 000 perinatal deaths per year in sub-Saharan Africa
alone.2 Many of these are stillbirths, which have been
largely ignored by the global-health community. They
are rarely counted, are not included in national statistics,
or in estimates of the global burden of disease, and are
not mentioned in the Millennium Development Goals

(MDGs). The Lancets Stillbirths Series is a welcome

attempt to redress the balance. Lawn and colleagues3
estimated that 265 million stillbirths occur annually,
98% of them in developing countries. In northern
Tanzania, 51% of stillbirths in women who had not
been screened for syphilis during pregnancy could
be attributed to syphilis after adjustment for other
possible causes.4
In live born infants, most deaths from syphilis occur in
the rst weeks of life. As many countries make progress
towards achieving MDG 4to reduce mortality by
two thirds in children younger than 5 yearsneonatal
mortality (in the rst 4 weeks of life) remains high, now
accounting for some 40% of the total mortality. Early
neonatal mortality (in the rst week of life) has been a
www.thelancet.com/infection Vol 11 September 2011

Comment

particularly intractable issue5 and could be improved by

screening and treatment of all pregnant women.
If all pregnant women were screened, and those who
tested positive were treated with one dose of benzathine
penicillin before 28 weeks gestation, no stillbirths
or neonatal deaths would be due to syphilis. This is
one of the most cost-eective health interventions.
In Tanzania, the cost was $144 per woman screened,
$20 per woman treated, and $1056 per disabilityadjusted life year (DALY) saved, if the stillbirths averted
were included in the calculation.6,7 Screening of pregnant
women for syphilis is recommended in nearly all
countries, but is not widely implemented. In Tanzania,
less than half of women attending antenatal clinics are
screened for syphilis, and less than two thirds of those
testing positive receive treatment.8
These gures are not unusual in sub-Saharan Africa,
where access to laboratory testing is often poor, especially
in rural areas.9 The rapid-plasma-reagin serological test
is cheap, and can give a result in 10 min; but it requires
electricity. Many rural health facilities cant oer this test.
In facilities where it is available, samples are usually tested
in batches, and many women do not come back for their
results. Several of the studies reviewed by Hawkes and
colleagues1 showed that oering a decentralised, sameday testing and treatment service increased the coverage
of screening and treatment. Simple, aordable pointof-care tests for syphilis have recently become available.
These tests do not need laboratory equipment or
refrigeration, and give a reliable result in 15 min, greatly
facilitating the provision of a same-day testing and
treatment strategy in even the most remote rural health
facilities.10 These tests can be done on the same drop of
blood as an HIV rapid test, oering an opportunity to
integrate prenatal screening for these two infections and
hence to reduce costs and to avoid the tragedy of babies
avoiding HIV infection only to die of syphilis.11
The perception among many public health experts,
programme managers, and policy makers that syphilis
has disappeared has probably been the greatest barrier to
prevent syphilis deaths in babies. If you dont test for it,
you dont nd it, which reinforces the impression that it is
no longer an issue. Conclusions from systematic reviews12,13
using the rigid criteria laid down by the Cochrane and Child
Epidemiology Research Group (CHERG) guidelines were
that no good evidence that the treatment of syphilis in
pregnant women improved pregnancy outcome existed,
www.thelancet.com/infection Vol 11 September 2011

since no randomised trials showed it to be benecial. This

is hardly surprising, since it would not be ethical to do such
trials when the evidence of benet from observational
studies is so overwhelmingly strong; but the real danger
is that these reviews could convince policy makers and
programme managers that ignoring syphilis is justied.
This systematic review1 will remind policy makers that
syphilis continues to kill many babies, and will show them
how this needless burden of disease can be reduced.
David Mabey and Rosanna W Peeling
Clinical Research Department, London School of Hygiene and
Tropical Medicine, London WC1E 7HT, UK (DM, RWP)
david.mabey@lshtm.ac.uk
We declare that we have no conicts of interest
1

2
3

5
6

9
10

11
12
13

Hawkes S, Matin N, Broutet N, Low N. Eectiveness of interventions

to improve screening for syphilis in pregnancy: a systematic review and
meta-analysis. Lancet Infect Dis 2011; published online June 16.
DOI:10.1016/S1473-3099(11)70104-9.
Schmid G. Economic and programmatic aspects of congenital syphilis
prevention. Bull World Health Organ 2004; 82: 40209.
Lawn JE, Blencowe H, Pattinson R, et al, Lancets Stillbirths Series steering
committee. Stillbirths: Where? When? Why? How to make the data count?
Lancet 2011; 377: 144863.
Watson-Jones D, Changalucha J, Gumodoka B, et al. Syphilis in pregnancy
in Tanzania. I. Impact of maternal syphilis on outcome of
pregnancy. J Infect Dis 2002; 186: 94047.
Lawn JE, Cousens S, Zupan J, for the Lancet Neonatal Survival Steering Team.
4 million neonatal deaths: When? Where? Why? Lancet 2005; 365: 891900
Watson-Jones D, Gumodoka B, et al. Syphilis in pregnancy in Tanzania. II.
The eectiveness of antenatal syphilis screening and single-dose
benzathine penicillin treatment for the prevention of adverse pregnancy
outcomes. J Infect Dis 2002; 186: 94857.
Terris-Prestholt F, Watson-Jones D, Mugeye K, et al. Is antenatal syphilis
screening still cost eective in sub-Saharan Africa. Sex Transm Infect 2003;
79: 37581.
Watson-Jones D, Oli M, Terris-Prestholt F, et al. Antenatal syphilis
screening in sub-Saharan Africa: lessons learned from Tanzania.
Trop Med Int Health 2005; 10: 93443.
Gloyd S, Chai S, Mercer MA. Antenatal syphilis in sub-Saharan Africa: missed
opportunities for mortality reduction. Health Policy Plan 2001; 16: 2934.
Mabey D, Peeling RW, Ballard R, et al. Prospective, multi-centre clinic-based
evaluation of four rapid diagnostic tests for syphilis. Sex Transm Infect
2006; 82 (suppl 5): v1316.
Peeling RW, Mabey D, Fitzgerald DW, Watson-Jones D. Avoiding HIV
and dying of syphilis. Lancet 2004; 364: 156166.
Walker GJ. Antibiotics for syphilis diagnosed during pregnancy.
Cochrane Database Syst Rev 2001; 3: CD001143.
Blencowe H, Cousens S, Kamb M, Berman S, Lawn JE. Lives saved tool
supplement detection and treatment of syphilis in pregnancy to reduce
syphilis related stillbirths and neonatal mortality. BMC Public Health 2011;
11 (suppl 3): S9.

Erratum
Paton NI, Lee L, Xu Y, et al. Chloroquine for inuenza prevention: a randomised,
double-blind, placebo controlled trial. Lancet Infect Dis 2011; published online
May 6. DOI:10.1016/S1473-3099(11)70065-2In this Article, a hyphen
was missing from an authors surname. Her correct name is Annelies
Wilder-Smith. This correction has been made to the online version as of
Aug 22, 2011, and to the printed Article.

655