Seminar

Syphilis
Rosanna W Peeling, David Mabey, Xiang-Sheng Chen, Patricia J Garcia

Lancet 2023; 402: 336–46 Syphilis is a sexually and vertically transmitted bacterial infection caused by the bacterium Treponema pallidum. Its
London School of Hygiene & prevalence is high in low-income and middle-income countries, and its incidence has increased in high-income
Tropical Medicine, London, UK countries in the last few decades among men who have sex with men. Syphilis is a major cause of adverse pregnancy
(Prof R W Peeling PhD,
outcomes in low-income and middle-income countries. Clinical features include a primary chancre at the point of
D Mabey MD); University of
Manitoba, Winnipeg, MB, inoculation, followed weeks later by the rash of secondary syphilis, a latent period, and in some cases, involvement of
Canada (Prof R W Peeling); the eyes, CNS, and cardiovascular systems. It is diagnosed serologically. A single intramuscular dose of long-acting
Institute of Dermatology, benzathine penicillin is recommended for people who have had syphilis for less than 1 year and longer courses for
Chinese Academy of Medical
people with late latent syphilis. Control strategies include screening and treatment of all pregnant women, and
Sciences and Peking Union
Medical College, Nanjing, China targeted interventions for groups at high risk. Vaccine development, research on antibiotic prophylaxis, and digital
(Prof X S Chen MD); National messaging as prevention strategies are ongoing.
Center for STD Control,
Nanjing, China (Prof X S Chen);
Center for Global Health,
Introduction vaccine development and the WHO and UNAIDS goal of
Southern Medical University, Syphilis is a sexually and vertically transmitted bacterial global elimination of mother-to-child transmission of
Guangzhou, China infection caused by Treponema pallidum. It was HIV.
(Prof X S Chen); School of Public first described in Europe in the early 16th century,
Health, Universidad Peruana
Cayetano Heredia, Lima, Peru
leading to the suggestion that it was brought back from Epidemiology
(P J Garcia, MD); University of North America by Columbus and his crew, but According to the most recent estimate by WHO, there
Washington, Seattle, WA, USA contemporary evidence suggests that it is more likely to were approximately 17·7 million adults aged between
(P J Garcia) have been imported from Africa through contact with 15 years and 49 years with syphilis globally in 2012, and
Correspondence to: cases of yaws, as originally suggested by an estimated 6·3 million new cases in 2016.5,6 The
Prof Rosanna W Peeling, Clinical
Thomas Sydenham in 1679.1 T pallidum is also the cause estimated prevalence and incidence varied substantially
Research Department, London
School of Hygiene & Tropical of the non-venereal treponematoses yaws, pinta and by region and country, with the highest prevalence in
Medicine, London WC1E 7HT, UK bejel (endemic syphilis), which are spread by skin-to- Africa, and more than 60% of new patient diagnoses
rosanna.peeling@lshtm.ac.uk skin contact, mainly between children living in warm occurring in LMICs. High-income countries have a low
climates. Although these infections are caused by syphilis prevalence among heterosexual men and women,
different sub-species, these four sub-species are but they are witnessing a resurgence among men who
morphologically and antigenically indistinguishable, have sex with men (MSM). This resurgence is closely
they share more than 99·8% DNA sequence homology,2 associated with HIV infection and high-risk sexual
and the diseases they cause are clinically similar. This behaviours.7 Some studies have observed some degree of
supports the unitarian hypothesis, which states that the risk compensation for syphilis after the implementation
only difference between syphilis and the non-venereal of pre-exposure prophylaxis (PrEP) for HIV among
treponematoses is the route of transmission.3 populations at high risk, particularly in MSM.8,9 This risk
Syphilis can be diagnosed at the point of care (POC) by compensation signals the potential for future increases in
rapid lateral flow antibody test and effectively treated syphilis cases along with expansion of the PrEP, if no
with a single dose of long-acting penicillin; yet it remains interventions occur.10
a major cause of adverse pregnancy outcomes in many In the USA the incidence of primary and secondary
low-income and middle-income countries (LMICs), and syphilis among MSM (229 cases per 100 000 people) was
its incidence has increased in high-income countries in 243 times the rate for women (0·94 cases
the last few decades. Syphilis has been described as the per 100 000 people) in 2013, and 214 times the rate for
great imitator because of its many and varied clinical heterosexual men (1·07 cases per 100 000 people);11 but
manifestations.4 In this Seminar we describe the the reported rate of primary and secondary syphilis
epidemiology, clinical features, diagnosis, and among women doubled between 2014 and 2018, an
management of syphilis, and we assess progress towards increase strongly associated with injecting drug use.12
The number of patients diagnosed with congenital
syphilis increased four times between 2013 and 2018.13 In
Search strategy and selection criteria Canada, most provinces and territories reported increases
We searched PubMed to identify peer-reviewed articles in their infectious syphilis rates between 2014 and 2018
published in English between Jan 1, 2010, and Feb 28, 2021, with the highest being 261 cases per 100 000 people.14
using the terms “syphilis”, “syphilis epidemiology”, and In 2012, syphilis rates in men were 18 times higher than
“syphilis treatment”. We also referred to older literature on in women, with the highest rates observed in the age
the management and clinical presentations of the disease groups 25–29 years and 30–39 years. However, over the
written in the pre-penicillin era. past 5 years, infection rates have substantially increased
in women of reproductive age.15 Preliminary data indicate

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a reduction in the male-to-female ratio of new syphilis

infections from eight males to one female in 2017, to
four males to one female in 2018, with the rate of
congenital syphilis in Canada in 2018, at its highest in the
last 25 years.14 In Europe an increase in syphilis incidence
has been reported since 2010 and this trend appears to be
accelerating, especially among MSM. Outbreaks in
heterosexual populations have also been reported, with
an increase in congenital syphilis cases.16
In LMICs, spread of syphilis among heterosexual
relationships has declined in the general population in
recent years,17 but prevalence remains high in sub-
populations at high risk such as female sex workers
(FSWs) and their male clients. A 2016 study of female sex
Figure 1: Primary chancre with desquamating palmar rash of secondary
workers in Johannesburg, South Africa, found that syphilis
21% of participating women had serological evidence of
past or current syphilis, and 3% had an active infection.18
In China, syphilis incidence and prevalence remains low
in the general population, but there is up to 5% prevalence
of syphilis among FSWs and 3% in their male clients.19–21
In 2016 the prevalence of syphilis in pregnant women
was estimated to be 0·69% globally with marked regional
differences, from 0·10% in the European region to 1·52%
in the African region.22 Worldwide syphilis in pregnancy
was estimated to have caused 397 000 adverse birth
outcomes in 2012 and 355  000 in 2016, including
143 000 early fetal deaths or stillbirths, and 61 000 neonatal
deaths.23 The decrease in adverse birth outcomes due to
syphilis between 2012 and 2016 is believed to reflect Figure 2: Papular palmar rash of secondary syphilis
increased access to syphilis screening and treatment at
antenatal clinics. However, 57% of the adverse birth syphilis present between 3 weeks and 8 weeks after the
outcomes in 2016 were estimated to have been in women initial appearance of the primary chancre.
who had attended an antenatal clinic for HIV screening The rash of secondary syphilis can be macular or
but were not screened for syphilis, representing a missed papular, is often desquamating, typically affects the palms
opportunity.23 and soles, and does not itch (figure 2). Other common
signs include oral ulceration or mucous patches,
Clinical presentation, signs, and symptoms generalised lymphadenopathy, and in moist areas such as
After an incubation period of 10–70 days (median 21 days) the axillae and perineum, soft, raised wart-like lesions
a primary chancre develops at the site of inoculation known as condylomata lata (figure 3). Fever, hepatitis, and
(figure 1).7,24 The chancre is typically a painless, single, nephritis might also be seen in secondary syphilis.
non-tender, indurated ulcer, with a raised edge and a Lumbar puncture is not routinely recommended in
clean base. The primary presentation of syphilis has also patients who are HIV negative, but can reveal
been described with two or more painful ulcers,25,26 but it cerebrospinal fluid (CSF) abnormalities. On serum
might be accompanied by regional lymphadenopathy, testing, raised protein and cell counts are commonly seen
which is also typically painless and non-tender. None of in the blood of patients with secondary syphilis and these
the known characteristics of the chancre are sufficiently can be accompanied by meningeal symptoms. The
specific and, in fact, the differential diagnosis of syphilis significance of these findings and the need for treatment
has to be included in the face of any mucosal ulceration in patients with no clinical evidence of neurological
or erosion. Since the chancre is usually painless and, in involvement remains unclear and continues to be an area
women, is often on the cervix, the patient might be of controversy. The significance of positive syphilis
unaware of it. serology on CSF samples is difficult to assess due to the
The differential diagnosis of primary syphilis includes passive transfer of antibodies from blood through the
genital herpes simplex, lymphogranuloma venereum, blood–brain barrier. Ocular involvement can also be seen
Behçet’s disease, and less common sexually transmitted in secondary syphilis, most commonly posterior uveitis or
diseases (STDs) such as chancroid and granuloma panuveitis, which can lead to blindness unless promptly
inguinale. The primary chancre usually resolves treated.27 It has been suggested that ocular and CNS
spontaneously over several weeks. The signs of secondary involvement is more common in patients with HIV.28

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Cardiovascular lesions include aortitis, aortic aneurysm,

aortic valve disease, and coronary ostial occlusion.
Involvement of the CNS can occur at any time in the
course of syphilis. Mild meningeal symptoms are not
uncommon in secondary syphilis, and can resolve
without treatment.30 Meningovascular syphilis, due to
inflammation of small arteries in the brain or spinal
cord, presents typically as a stroke 5–10 years after
infection. Later neurological manifestations include
tabes dorsalis, due to involvement of the posterior
columns of the spinal cord, and general paresis, a form
of progressive dementia sometimes with psychotic
features. These late manifestations were commonly seen
in the pre-antibiotic era but are now rare.
Children born to women with untreated syphilis are at
risk of congenital syphilis, acquired in utero. The risk is
Figure 3: Condylomata lata of secondary syphilis highest in babies born to women with primary, secondary,
or early latent syphilis. In the absence of treatment, a
study in Tanzania showed that 25% of women with latent
syphilis (and rapid plasma reagin [RPR] titres of 1:8 or
higher), will deliver a stillborn baby, and 33% of women
with untreated syphilis will deliver a low-birthweight
baby.31 Signs of syphilis in the neonate include a
generalised, bullous rash (figure 4), anaemia, jaundice,
and hepatosplenomegaly. Infants with congenital
syphilis can appear healthy at birth and present in the
first few months of life with failure to thrive, a
desquamating rash that usually affects the palms and
soles (figure 5), persistent nasal discharge, anaemia, and
hepatosplenomegaly. Bone involvement (osteitis or
Figure 4: Bullous rash in a neonate with congenital syphilis periostitis) is common and can cause pseudoparalysis of
a limb due to pain, but it is not always clinically apparent.
Older children can present with late complications,
including deafness, interstitial keratitis, and
abnormalities of the bones and teeth (figure 6).

Pathophysiology
Syphilis is caused by the spirochaete Treponema pallidum
(order Spirochaetales), a long, thin, slowly growing spiral
shaped bacterium that, until recently, could not be
cultured in vitro, but can now be cultured in rabbit tissue
Figure 5: Macular, desquamating rash in a baby with congenital syphilis cells.32 Transmission occurs during sexual contact with
an actively infected partner. Spirochaetes directly
The lesions of secondary syphilis generally resolve penetrate mucous membranes or they enter through
within a few weeks in the absence of treatment, although abrasions in skin. To establish infection, T pallidum must
studies from the pre-antibiotic era suggest that syphilis adhere to epithelial cells and extracellular matrix
relapses in about 25% of patients, usually within the components. Once below the epithelium, organisms
first year.29 The disease then enters the latent stage, with multiply locally at the site of the primary chancre and
no symptoms or signs, but the patient is at risk of later disseminate through lymphatics and bloodstream
developing tertiary syphilis in the future. Studies from giving rise to the lesions of secondary syphilis.33
the pre-antibiotic era suggest that, in the absence of Although a local inflammatory response to T pallidum
treatment, approximately a third of patients will develop causes the clinical manifestations of syphilis, the
tertiary syphilis. The lesions of tertiary syphilis fall into mechanisms that cause tissue damage and the host
three categories: gummatous, cardiovascular, or defenses that eventually gain a measure of control over
neurosyphilis. A gumma is a painless, punched-out ulcer the bacterium are poorly defined. Perivascular infiltrates
with little or no inflammatory reaction, usually affecting composed of lymphocytes, histiocytes, and plasma cells,
the skin, but occasionally involving bones or viscera. accompanied by endothelial cell swelling and proliferation

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are histological hallmarks of syphilis, regardless of site or

disease stage. Endothelial swelling and proliferation can
progress to frank endarteritis obliterans, leading to
occlusion of arteries and severe clinical manifestations,
such as the stroke syndromes of meningovascular
syphilis.
T pallidum has an abundance of lipoproteins that are
predominantly located below its cytoplasmic surface. This
feature enables the spirochaete to avoid triggering host
innate immune mechanisms, facilitating local replication
and early dissemination. The low surface antigenicity of
T pallidum promotes evasion of adaptive immune
responses, facilitating persistence, and earning T pallidum
its recognition as the “stealth pathogen”.33,34

Diagnosis Figure 6: Notched incisors of Hutchinson’s teeth in a child with congenital

T pallidum can be detected in the lesions of primary and syphilis
secondary syphilis. Traditionally this diagnosis was done
by dark field microscopy, which requires a dark field hepatitis C, or leprosy. False negative results can occur
microscope condenser and a skilled microscopist, and is when there is an excess of antibody, a phenomenon
no longer widely used. Nucleic acid amplification tests known as the prozone effect. This can be resolved if
have been used to detect the DNA of the spirochaete in serum samples are tested in 2 or 3 dilutions. Titres
skin, mucosal, oral or rectal lesions.35,36 These tests for generally decline after treatment and become non-reactive
early syphilis could play an important role in controlling within 12 months. However, about 10% of individuals
the syphilis epidemic. A study in 2019 has shown that the with syphilis have a persistently reactive NTT even after
combination of antibody and nucleic acid amplification effective treatment (the so-called serofast state).39
testing in a population that is at high risk from the Treponemal tests detect antibodies to T pallidum
disease (ie, MSM) can increase the sensitivity of syphilis proteins and are highly specific, although they do not
screening.37 There is also the potential to use nucleic distinguish between syphilis and the non-venereal
amplification tests in neonates with congenital syphilis. treponematoses. As treponemal antibodies usually
However, they are not recommended for use with blood persist for life, they cannot be used to distinguish
or CSF as few organisms are present. These nucleic acid between active, past, or previously treated infection, or as
amplification tests require technical expertise and a test of cure. Treponemal tests include the fluorescent
laboratory equipment, have not been thoroughly treponemal antibody absorbed (FTA-ABS) test, the
clinically validated, and are not widely available. T pallidum particle agglutination (TPPA) and T pallidum
Antibodies to T pallidum are detectable 10–15 days after haemagglutination (TPHA) assays, and a number of
the appearance of the primary chancre, and syphilis is commercially available enzyme immunoassays.
usually diagnosed serologically.38 There are two categories Treponemal tests have traditionally been used as
of serological tests for syphilis, one that detects non- confirmatory assays following a positive NTT result but,
treponemal antibodies and the other that detects since treponemal enzyme immunoassays and rapid tests
treponemal antibodies. became available, a reverse testing algorithm has been
Non-treponemal tests (NTTs) include rapid plasma adopted in some countries. In this algorithm, patients
reagin (RPR), the Venereal Disease Research Laboratory are first screened using a treponemal test, and those who
(VDRL), and the toluidine red unheated serum test test positive then have an NTT to distinguish between
(TRUST). They use antigens synthesised from lecithin, active and previously treated syphilis.40
cholesterol, and cardiolipin to detect Rapid, serological tests that can be performed at the
IgG and IgM antibodies produced in response to point-of-care (POC) and meet the ASSURED criteria (they
T pallidum infection by agglutination of antigen-coated are affordable, sensitive, specific, user friendly, rapid and
particles. NTTs can be performed as qualitative assays for robust, equipment-free, and deliverable) are now available
screening or as quantitative assays, using doubling for syphilis.41 These are lateral flow assays, which only
dilutions to determine titre, to help stage infection and require one drop of blood obtained from a finger prick
assess the response to treatment. Low titre (1:2 or 1:4) and can give a result in 15 min, enabling immediate
biological false positive NTT results, with a negative treatment of those who test positive. Systematic reviews of
treponemal test, occur in about 2−5% of the population. commercially available rapid treponemal tests showed
As the antigen is not specific for T pallidum, false positive that these tests have sensitivities of 76–86% and
results can be due to acute febrile illnesses, pregnancy, or specificities of 96–99% compared with laboratory
chronic conditions such as autoimmune diseases, reference assays such as TPPA.42,43 Studies to implement

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screening programmes.54,55 These rapid POC tests not

HIV–syphilis dual rapid diagnostic tests only make testing accessible for syphilis diagnosis in
general, but also play an important role in reducing
adverse pregnancy outcomes and moving towards the
Syphilis HIV global elimination of congenital syphilis by ensuring that
all pregnant women are screened and treated at their first
visit to the antenatal clinic.23
Patients with neurological symptoms or signs should
Positive Negative Negative Positive
have a lumbar puncture. Since there is no standard test for
the diagnosis of neurosyphilis, a combination of laboratory
Treat Refer for confirmatory tests and clinical signs and symptoms is used.56–58 A reactive
testing
CSF VDRL test is highly predictive of neurosyphilis, but
less than 80% sensitive. More than five white cells
Figure 7: Syphilis testing and treatment algorithm for prenatal screening50 per mm³ of CSF (or >20 cells per mm³ in patients with
Pregnant women who have tested positive and received treatment during a
previous pregnancy should be considered for re-treatment on receiving a
HIV who are not receiving antiretroviral therapy) is a
positive syphilis test result in subsequent pregnancies. sensitive but not a specific marker for neurosyphilis.
CSF protein concentrations can be elevated in patients
with neurosyphilis, but this finding has low sensitivity and
HIV–syphilis dual rapid diagnostic tests
specificity. In low-resource settings where syphilis and
HIV are prevalent, rapid and simple tests should be
integrated with less invasive and more acceptable
approaches of specimen collection. Studies in people with
Syphilis HIV and without HIV have shown that patients with a serum
RPR titre greater than or equal to ≥1/32 or a peripheral
blood CD4 count less than 350 cells per mL, or both, were
Treat if no previous treatment Positive Negative Negative Positive significantly more likely to have neurosyphilis, indicating
use of criteria based on these tests could improve the
ability and efficiency to identify asymptomatic
Non-treponemal tests Refer for confirmatory
testing neurosyphilis.59
The diagnosis of congenital syphilis can be difficult
since maternal IgG antibodies cross the placenta,
complicating the interpretation of reactive serological
Positive Negative tests in neonates. Treatment decisions must be made on
the basis of the identification of syphilis in the mother,
Treat adequacy of maternal treatment, presence of clinical,
laboratory, or radiographic evidence of syphilis in the
Figure 8: Syphilis testing and treatment algorithm for populations at high risk50 neonate, and comparison of maternal (at delivery) and
neonatal NTT titres.40
these tests show that they can be catalysts for health-
system strengthening as well as saving newborn lives.44,45 Management
A rapid POC test that detects both treponemal and non- Penicillin remains the treatment of choice for syphilis,
treponemal antibodies, and can therefore distinguish and resistance to penicillin has never been reported in
between active, previous, and treated infection, has been T pallidum. There was a worldwide shortage of benzathine
evaluated in several settings and found to be both penicillin which has been resolved.60–62 For treatment of
sensitive and specific.46–48 Although the sensitivity of the early syphilis WHO, the US Centers for Disease Control
non-treponemal component is lower in samples with a and Prevention (CDC), and European guidelines
low (<1:8) RPR titre.46,47,48 recommend a single dose of intramuscular benzathine
Dual HIV–syphilis (treponemal) rapid tests are also penicillin, or intramuscular procaine penicillin daily for
available and can be used to expand screening in prenatal 10 days. Since T pallidum divides more slowly than most
and high-risk populations.49 WHO has published bacteria, it is necessary to maintain penicillin
algorithms on how to use them in high-prevalence and concentrations in the blood above the minimum
low-prevalence settings (figure 7 and 8).50 A systematic inhibitory concentration for at least 10 days. The
review showed that they have satisfactory performance CDC treatment guidelines are shown in the table.40
and three tests have been pre-qualified by WHO.51–53 The Although a single dose of benzathine penicillin G is
use of a single specimen to screen for both HIV and effective in most cases of early syphilis, some experts
syphilis in prenatal and populations at high risk is more recommend that primary, secondary, and early latent
efficient and cost saving compared with separate cases be treated with two doses of benzathine penicillin G

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2·4 million units 1 week apart, particularly in pregnant courses given for early syphilis. Similarly, for those with
women. This recommendation is due to difficulty in late syphilis who cannot be treated with penicillin, longer
accurately staging cases of syphilis and physiological schedules of doxycycline are recommended, followed up
changes in pregnancy that can alter the pharmacokinetics with repeat NTT serology (table).
of penicillin and reduce plasma penicillin levels.63 Soon CNS involvement can occur at any stage of syphilis but,
after the onset of treatment, around 30% of patients will in the absence of clinical evidence of ocular or
experience a Jarisch-Herxheimer reaction, with fever, neurological symptoms or signs, there is no need for
rigors, myalgia, and arthralgia. This is more common in more intensive treatment. Patients with neurosyphilis, or
patients with secondary syphilis, and usually resolves with ophthalmic or auditory abnormalities should be
within 24 h. Patients with a Jarisch-Herxheimer reaction treated with high-dose aqueous crystalline, or daily
can be treated with antipyretics. intramuscular procaine penicillin plus probenecid for
Patients who are allergic to penicillin should be treated 10–14 days (table).
with doxycycline or ceftriaxone (unless penicillin allergy Patients who are HIV positive with early syphilis are
was severe or a type 1 IgE-mediated hypersensitivity more likely to have CSF abnormalities than those who
reaction, given the small risk of cross-reactivity with are HIV negative.39,70 Since the single dose of benzathine
cephalosporins) or treated with penicillin following penicillin recommended for treatment of early syphilis
desensitisation. A single oral dose of azithromycin 2 g does not reliably lead to a treponemacidal level in
was shown to be equivalent to benzathine penicillin in the CSF, it has been suggested that patients with HIV
the treatment of early syphilis in two trials in Africa,64,65 and early syphilis should receive more intensive
but strains of T pallidum with mutations conferring treatment. A randomised controlled trial compared the
resistance to azithromycin and other macrolides are now outcomes of treatment for early syphilis between patients
common worldwide and macrolides are no longer who received a single injection of benzathine penicillin
recommended, except in situations in which alternative and patients who received enhanced therapy comprising
treatments cannot be given and close follow-up can be benzathine penicillin, amoxicillin, and probenecid. 101 of
guaranteed.66–69 the 541 patients enrolled were HIV positive. There was
Patients with late latent syphilis (>1 year post-infection) no significant difference in clinical outcome between
should receive longer courses of treatment with patients receiving standard or enhanced treatment.39
benzathine penicillin or procaine penicillin than the However, people with HIV responded less well

Treatment option 1 Treatment option 2 Treatment option 3

Primary and secondary syphilis in non- Penicillin G benzathine, 2·4 million units in a single Doxycycline, 100 mg orally twice a day for Ceftriaxone, 1 g daily, intramuscular or
pregnant adults, including adults with intramuscular dose 14 days intravenous, for 10–14 days
HIV
Early latent syphilis in non-pregnant Penicillin G benzathine, 2·4 million units in a single Doxycycline, 100 mg orally twice a day for ··
adults, including adults with HIV intramuscular dose 28 days
Late latent syphilis in non-pregnant Penicillin G benzathine, 7·2 million units total, Doxycycline, 100 mg orally twice a day for ··
adults, including adults with HIV administered in 3 intramuscular doses of 28 days
2·4 million units each at 1-week intervals
Late syphilis (gummas and Penicillin G benzathine, 7·2 million units total, ·· ··
cardiovascular manifestations) but not administered in 3 intramuscular doses of
neurosyphilis 2·4 million units each at 1-week intervals
Neurosyphilis and ocular syphilis Aqueous crystalline penicillin G, Penicillin G procaine, 2·4 million units in a single ..
18–24 million units per day, administered in intramuscular dose daily, plus probenecid,
INTRAVENOUS doses of 3–4 million units every 4 h 500 mg administered orally four times per day,
or as a continuous infusion, for 10–14 days both for 10–14 days
Primary and secondary syphilis in Penicillin G benzathine, 2·4 million units in a single ·· ··
pregnancy intramuscular dose
Early latent syphilis in pregnancy Penicillin G benzathine, 2·4 million units in a single ·· ··
intramuscular dose
Late latent syphilis in pregnancy Penicillin G benzathine, 7·2 million units total, ·· ··
administered in 3 intramuscular doses of
2·4 million units each at 1-week intervals
Congenital syphilis Aqueous crystalline penicillin G Procaine penicillin G 50 000 units/kg per dose ..
100 000–150 000 units/kg per day, administered as intramuscular in a single daily dose for 10 days
50 000 units/kg per dose intravenous every 12 h
during the first 7 days of life and every 8 h
thereafter for a total of 10 days

Table: Centers for Disease Control and Prevention Syphilis Treatment Guidelines40

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serologically and, due to loss of patients during follow- promotion should be encouraged. Control programmes
up, the study was underpowered to detect a clinical worldwide have known since the 1930s that testing is a
difference. Given the inconclusive results of this and critical component of syphilis control. Premarital syphilis
other studies, many clinicians continue to offer enhanced testing used to be mandatory, as was prenatal screening,
therapy to patients with both HIV and early syphilis. and on entry into military service, certain businesses,
Since it is not possible to confirm or exclude the and educational institutions. With the decline in syphilis,
presence of viable T pallidum after treatment the efficacy all these testing requirements ceased except for screening
of treatment for syphilis is measured indirectly, using and treatment of pregnant women, which remains
serology. Cure is usually defined as reversion to negative, recommended in almost every country.
or a four-fold drop in titre of an NTT such as the RPR or With most pregnant women accessing antenatal care
VDRL.7 However, few patients remain seropositive, or do and the availability of reliable rapid POC tests, prenatal
not attain this reduction threshold, despite almost syphilis screening should be feasible, even for populations
certainly having been cured and with no evidence of in LMICs that do not have access to laboratory testing.
progressive disease—the so-called serofast state.39 The In 2015, Cuba became the first country to be validated for
management of these patients depends on taking a the elimination of mother-to-child transmission of HIV
detailed sexual history to exclude the possibility of and syphilis (eMTCT).73 Since then, 15 other countries,
reinfection, which can be challenging. The serofast state is Anguilla, Antigua, Armenia (HIV only), Barbuda, Belarus,
more commonly seen in patients with late syphilis and Bermuda, Cayman Islands, Malaysia, Maldives, Moldova
low RPR titres, and in HIV-positive patients who are not (syphilis only), Montserrat, Oman, Saint Kitts and Nevis,
on antiretroviral treatment.39 Since few data are available Sri Lanka, and Thailand have achieved eMTCT.73 The
on long-term clinical outcomes for patients in a serofast important lesson here is that countries do not need to have
state, CDC guidelines recommend continuing clinical high incomes to achieve dual eMTCT. What it takes is
follow-up, and retreatment if follow-up cannot be political will, a well-functioning health-care system in
ensured.40 which no one is left behind in provision of prenatal testing
A study in Tanzania showed that adverse pregnancy and timely treatment, and follow-up of sexual partners for
outcomes due to syphilis can be prevented with a single testing and treatment. In the Western Pacific Region of
dose of benzathine penicillin given before 28 weeks’ WHO, member states endorsed the Asia Pacific Regional
gestation.71 In that setting, in which 5–6% of pregnant Framework for Triple Elimination of Mother-to-Child
women had syphilis, this was one of the most cost-effective Transmission of HIV, Hepatitis B and Syphilis 2018–2030.74
interventions available in terms of cost per disability- However, the opportunities for prevention of congenital
adjusted life-year saved.72 Pregnant women who test syphilis with timely syphilis diagnosis and treatment of
positive using a rapid syphilis (treponemal) test should be pregnant women and their partners with syphilis, are still
given a dose of benzathine penicillin without waiting for a missed by many settings in either LMICs or high-income
confirmatory test for active infection, as the confirmatory countries.
test often has to be sent to a laboratory and women might Screening programmes for groups at high risk, and
fail to return for their follow-up appointments. Long-acting notification and treatment of sexual partners of patients
penicillin is the only antibiotic known to be effective in with syphilis are also recommended. Most cases of syphilis
preventing adverse pregnancy outcomes due to syphilis.60 in high-income countries are in MSM, among whom HIV
Since doxycycline is contraindicated in pregnancy, and co-infection is common. Adopting the dual HIV–syphilis
macrolides such as azithromycin and erythromycin do not rapid screening test for MSM would be useful. Regular
cross the placenta, there are few alternatives to penicillin screening of patients with HIV, and those using pre-
for the treatment of pregnant women with syphilis who exposure prophylaxis against HIV, is a high priority. China
are allergic to penicillin. WHO and CDC recommend has implemented effective national syphilis control
desensitisation and treatment with penicillin for those programmes targeting both groups at high risk and
who are allergic to penicillin or, alternatively, treatment pregnant women through cross-cutting strategies focusing
with ceftriaxone.40 on Three Screenings Linked to One Standardized Care
Infants with confirmed congenital syphilis, and infants (3 × 1 Screening Linked to Standardised Care), in addition
born to mothers with syphilis who are asymptomatic but to continuously promoting sustained behaviour change
whose mothers were not treated with a recommended and condom promotion which is integrated into HIV
penicillin-containing regimen more than 30 days before prevention.75,76
delivery, should be treated with aqueous benzyl penicillin Increasingly, more tools and options have been developed
intravenously or intramuscular procaine penicillin daily to improve syphilis messaging and testing in populations
for 10 days (see table). at high risk. The success of self-testing and using dried
blood spots to increase access to HIV testing might
Control and prevention translate into similar programmes for syphilis or into
As for other sexually transmitted infections, primary integrated HIV and syphilis programmes.77–80 Different
prevention through health education and condom models of provision or distribution of self-testing have been

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reported.81,82 The use of a social entrepreneurship model or months are completely protected from symptomatic
monetary incentives to promote self-testing in China was reinfection with the same isolate, and can be protected
successful at increasing uptake of testing and access to care from symptomatic infection with a different
for people with HIV and syphilis.83,84 In addition, a study in (heterologous) isolate.93 Vaccination of rabbits with
South Africa indicated that allocation of a gift (a US$5 food gamma-irradiated T pallidum provides complete
voucher for families) to a family could significantly increase protection against homologous infection,94 and a subunit
the probability of family members consenting to home- vaccine has been shown to reduce the bacterial organ-
based HIV testing in the same year by 25 percentage load following T pallidum challenge.95 That protective
points.85 immunity is conferred by previous infection with
Innovative approaches for populations at high risk are T pallidum in humans was first noted almost 200 years
being piloted, with social network strategies and ago by Abraham Colles, who reported that chancres of the
technologies used to promote the uptake of testing. A nipple were commonly seen in women who breastfed
randomised controlled trial aimed at promoting the uptake infants with congenital syphilis who were not their own,
of syphilis testing by recruiting participants from an but they were not seen in breastfeeding mothers of such
MSM-oriented mobile social app is ongoing.86 Participants infants.96 Protective immunity has been confirmed in a
are randomised to one of three groups: (1) the control recent study that showed that previous syphilis attenuates
group in which participants are provided information the clinical and laboratory manifestations of T pallidum
about local STD services and encouraged to take up free infection.97
syphilis testing at their local testing or counselling clinic; The incidence of congenital syphilis decreased worldwide
(2) a standard self-test group in which participants can between 2012 and 2016 although maternal prevalence was
request syphilis self-tests online and packages are sent by stable,22 suggesting that the reduction was due to increased
mail, along with text message reminders for testing; access to antenatal screening and treatment. Achieving
(3) a lottery incentivised self-testing group in which global elimination, however, will require further
participants are provided with the interventions in both the improvements in access to screening and treatment of
control group and the standard syphilis self-testing group. early antenatal syphilis, improving partner management,
In addition, participants who confirm that they have tested and reducing syphilis prevalence in the general population
for syphilis during the trial period either through self- by expanding testing, treatment, and partner referral,
testing or facility-testing will be entered into a lottery draw. which could be difficult to achieve due to the impact of the
The primary outcome is the proportion of participants who COVID-19 pandemic on health-care seeking and provision.
tested for syphilis in the past 3 months. The use of the Only through effective control of the infection among
internet and text messaging to remind those at high risk of populations at high risk such as MSM, female sex workers,
testing and to notify partners of syphilis cases has been and their clients can the elimination of mother-to-child
shown to be effective in increasing the detection of early transmission of syphilis be made sustainable. The
syphilis in asymptomatic individuals before progression to diagnosis of congenital syphilis has been difficult as
secondary syphilis.87–90 IgM tests are not sufficiently sensitive, especially in infants
For clinic-based settings, a systematic review comparing who are asymptomatic. Recent studies on an IgA antibody
the cost and effectiveness of different interventions to test to diagnose active syphilis also have potential as a
improve STD screening or rescreening in clinic-based diagnostic test for congenital syphilis since IgA does not
settings published between 2000 and 2014 showed that cross the placenta.98 Facing the increase of congenital
low-cost interventions such as strategic placement or syphilis cases in high-income countries, further studies on
automated collection of specimens and electronic health innovative strategies including the use of POC testing in
records were effective and low cost.91 Patient reminders for these countries are needed.
screening or rescreening using text, telephone, or Research into the prevention of syphilis transmission
postcards were highly or moderately effective at low or in populations at high risk are ongoing, with particular
moderate cost. Having dedicated clinic staff to promote concern over the syndemics of HIV, hepatitis C, and
and carry out testing was effective but came at a high cost. syphilis.99,100 Preliminary results from an open-label trial
In this digital age, electronic readers for rapid tests can in France showed that antibiotic prophylaxis with a single
prevent subjective reading of the rapid test results, and the dose of doxycycline 200 mg was effective in reducing the
digitised data can be transmitted automatically to a central incidence of both chlamydia and syphilis in people
database for real-time surveillance.92 taking PrEP.101 Although these early results are
promising, concerns about its sustainability, potential
Outlook and future research impact on antibiotic resistance, and possible rebound in
A vaccine against syphilis is a high priority and there is infections following the conclusion of the study need to
evidence that previous infection and vaccination can give be addressed.102
rise to protective immunity against T pallidum. Studies in Looking into the future, a better understanding of
the rabbit model showed (likely in the 1950s) that syphilis transmission, including estimates of trans­
untreated animals infected with T pallidum for 3 or more missibility for primary and secondary syphilis, and the

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extent and duration of infectiousness in latent syphilis is 15 Public Health Agency of Canada. Syphilis in Canada, technical
needed. Accurate tests to aid in the diagnosis of congenital report on epidemiological trends, determinants and interventions.
Centre for Communicable Diseases and Infection Control,
syphilis, reinfection, and a test of cure would be useful. Infectious Disease Prevention and Control Branch. Public Health
Research to elucidate host immune responses to infection, Agency of Canada, 2020.
especially the serofast state, and how treatment at varying 16 European Centre for Disease Prevention and Control. Syphilis
and congenital syphilis in Europe –A review of epidemiological
stages of infection modifies the risk of re-infection could trends (2007–2018) and options for response. Stockholm: ECDC,
translate into better patient management. Ultimately, 2019.
research on disease-prevention methods including 17 Bisseye C, Eko Mba JM, Ntsame Ndong JM, et al. Decline in the
seroprevalence of syphilis markers among first-time blood donors
antibiotic prophylaxis, and how best to incentivise healthy in Libreville (Gabon) between 2004 and 2016. BMC Public Health
sexual behaviours in people at risk from syphilis, offer the 2019; 19: 167.
best hope in control and elimination of this silent 18 Black V, Williams BG, Maseko V, Radebe F, Rees HV, Lewis DA.
Field evaluation of standard diagnostics’ Bioline HIV/syphilis duo
epidemic. test among female sex workers in Johannesburg, South Africa.
Contributors Sex Transm Infect 2016; 92: 495–98.
RWP and DM conceived the paper and all authors contributed to the 19 Tao Y, Chen MY, Tucker JD, et al. A nationwide spatiotemporal
writing and finalisation of the manuscript. analysis of syphilis over 21 years and implications for prevention
and control in China. Clin Infect Dis 2020; 70: 136–39.
Declaration of interests 20 McLaughlin MM, Chow EP, Wang C, et al. Sexually transmitted
We declare no competing interests. infections among heterosexual male clients of female sex workers
Acknowledgments in China: a systematic review and meta-analysis. PLoS One 2013;
8: e71394.
For photo credits, we gratefully acknowledge: 1) photos for the first
4 figures provided by Prof David Mabey; 2) Figures 5 and 6 provided to us 21 Su S, Chow EPF, Muessig KE, et al. Sustained high prevalence of
viral hepatitis and sexually transmissible infections among female
by Dr. Ming-Zhi Wu from the Suzhou Fifth People’s Hospital, Suzhou,
sex workers in China: a systematic review and meta-analysis.
China. Patient consent obtained (or parental consent) for each photo. BMC Infect Dis 2015; 16: 16.
References 22 Korenromp EL, Rowley J, Alonso M, et al. Global burden of maternal
1 Sydenham T. Epistle II: Venereal disease. London: The Sydenham and congenital syphilis and associated adverse birth outcomes-
Society, 1679. estimates for 2016 and progress since 2012. PLoS One 2019;
2 Cejková D, Zobaníková M, Chen L, et al. Whole genome sequences 14: e0211720.
of three Treponema pallidum ssp. pertenue strains: yaws and syphilis 23 Storey A, Seghers F, Pyne-Mercier L, Peeling RW, Owiredu MN,
treponemes differ in less than 0.2% of the genome sequence. Taylor MM. Syphilis diagnosis and treatment during antenatal care:
PLoS Negl Trop Dis 2012; 6: e1471. the potential catalytic impact of the dual HIV and syphilis rapid
3 Hudson EH. A unitarian view of treponematosis. Am J Trop Med Hyg diagnostic test. Lancet Glob Health 2019; 7: e1006–08.
1946; 26: 135–39. 24 Ho EL, Lukehart SA. Syphilis: using modern approaches to
4 Peeling RW, Hook EW 3rd. The pathogenesis of syphilis: the great understand an old disease. J Clin Invest 2011; 121: 4584–92.
mimicker, revisited. J Pathol 2006; 208: 224–32. 25 Towns JM, Leslie DE, Denham I, Azzato F, Fairley CK, Chen M.
5 WHO. Web Annex 1. Key data at a glance. In: Global progress Painful and multiple anogenital lesions are common in men with
report on HIV, viral hepatitis and sexually transmitted infections, Treponema pallidum PCR-positive primary syphilis without herpes
2021. Accountability for the global health sector strategies simplex virus coinfection: a cross-sectional clinic-based study.
2016–2021: actions for impact. Geneva: World Health Organization, Sex Transm Infect 2016; 92: 110–15.
2021. http://apps.who.int/iris/bitstream/handle/10665/342808/ 26 Chapel TA. The variability of syphilitic chancres. Sex Transm Dis
9789240030985-eng.pdf (accessed Sept 17, 2022). 1978; 5: 68–70.
6 Rowley J, Vander Hoorn S, Korenromp E, et al. Chlamydia, 27 Gu X, Gao Y, Yan Y, et al. The importance of proper and prompt
gonorrhoea, trichomoniasis and syphilis: global prevalence and treatment of ocular syphilis: a lesson from permanent vision loss in
incidence estimates, 2016. Bull World Health Organ 2019; 52 eyes. J Eur Acad Dermatol Venereol 2020; 34: 1569–78.
97: 548–62. 28 Mathew D, Smit D. Clinical and laboratory characteristics of ocular
7 Ghanem KG, Ram S, Rice PA. The modern epidemic of syphilis. syphilis and neurosyphilis among individuals with and without
N Engl J Med 2020; 382: 845–54. HIV infection. Br J Ophthalmol 2021; 107: 70–74.
8 Traeger MW, Cornelisse VJ, Asselin J, et al. Association of HIV 29 Gjestland T. The Oslo study of untreated syphilis: an epidemiologic
preexposure prophylaxis with incidence of sexually transmitted investigation of the natural course of syphilitic infection based on a
infections among individuals at high risk of HIV infection. JAMA restudy of the Boeck-Bruusgaard material. J Chronic Dis 1955;
2019; 321: 1380–90. 2: 311–44.
9 Azarnoosh M, Johansen IS, Martin-Iguacel R. Incidence of sexually 30 Lukehart SA, Hook EW 3rd, Baker-Zander SA, Collier AC,
transmitted infections after initiating HIV pre-exposure prophylaxis Critchlow CW, Handsfield HH. Invasion of the central nervous
among MSM in southern Denmark. Am J Men Health 2021; system by Treponema pallidum: implications for diagnosis and
15: 15579883211018917. treatment. Ann Intern Med 1988; 109: 855–62.
10 Ong JJ, Fu H, Baggaley RC, et al. Missed opportunities for sexually 31 Watson-Jones D, Changalucha J, Gumodoka B, et al. Syphilis and
transmitted infections testing for HIV pre-exposure prophylaxis pregnancy outcomes in Tanzania. I. Impact of maternal syphilis on
users: a systematic review. J Int AIDS Soc 2021; 24: e25673. outcome of pregnancy in Mwanza region, Tanzania. J Infect Dis
11 Peterman TA, Su J, Bernstein KT, Weinstock H. Syphilis in the United 2002; 186: 940–47.
States: on the rise? Expert Rev Anti Infect Ther 2015; 13: 161–68. 32 Edmondson DG, Hu B, Norris SJ. Long-term in vitro culture of the
12 Kidd SE, Grey JA, Torrone EA, Weinstock HS. Increased syphilis spirochete Treponema pallidum subsp. pallidum. MBio
methamphetamine, injection drug, and heroin use among women 2018; 9: e01153–18.
and heterosexual men with primary and secondary syphilis — 33 Radolf JD, Deka RK, Anand A, Šmajs D, Norgard MV, Yang XF.
United States, 2013–2017. MMWR Morb Mortal Wkly Rep 2019; Treponema pallidum, the syphilis spirochete: making a living as a
68: 144–48. stealth pathogen. Nat Rev Microbiol 2016; 14: 744–59.
13 Kimball A, Torrone E, Miele K, et al. Missed opportunities for 34 Peeling RW, Mabey D, Kamb ML, Chen XS, Radolf JD,
prevention of congenital syphilis - United States, 2018. Benzaken AS. Syphilis. Nat Rev Dis Primers 2017; 3: 17073.
MMWR Morb Mortal Wkly Rep 2020; 69: 661–65. 35 Gayet-Ageron A, Lautenschlager S, Ninet B, Perneger TV,
14 Choudhri Y, Miller J, Sandhu J, Leon A, Aho J. Infectious and Combescure C. Sensitivity, specificity and likelihood ratios of PCR
congenital syphilis in Canada, 2010-2015. Can Commun Dis Rep in the diagnosis of syphilis: a systematic review and meta-analysis.
2018; 44: 43–48. Sex Transm Infect 2013; 89: 251–56.

344 www.thelancet.com Vol 402 July 22, 2023

 Seminar

36 Getman D, Lin M, Barakat N, et al. Analytical performance 58 Landry T, Smyczek P, Cooper R, et al. Retrospective review of
characteristics of a new transcription-mediated amplification assay tertiary and neurosyphilis cases in Alberta, 1973–2017. BMJ Open
for Treponema pallidum. J Clin Microbiol 2021; 59: e0051121. 2019; 9: e025995.
37 Golden M, O’Donnell M, Lukehart S, et al. Treponema pallidum 59 Chen XS. Rapid diagnostic tests for neurosyphilis. Lancet Infect Dis
nucleic acid amplification testing to augment syphilis screening 2013; 13: 918–19.
among men who have sex with men. J Clin Microbiol 2019; 60 WHO. Shortages of benzathine penicillin. How big is the problem?
57: e00572–19. And why it matters. https://www.who.int/news/item/26-12-2017-
38 Unemo M, Ballard R, Ison C, Lewis D, Ndowa F, Peeling R, eds. shortages-of-benzathine-penicillin.-how-big-is-the-problem-and-
Laboratory diagnosis of sexually transmitted infections, including why-it-matters (accessed July 3, 2023).
human immunodeficiency virus. Geneva: World Health 61 Rocha AFB, Araújo MAL, Taylor MM, Kara EO, Broutet NJN.
Organization, 2013. Treatment administered to newborns with congenital syphilis
39 Seña AC, Zhang XH, Li T, et al. A systematic review of syphilis during a penicillin shortage in 2015, Fortaleza, Brazil. BMC Pediatr
serological treatment outcomes in HIV-infected and HIV-uninfected 2021; 21: 166.
persons: rethinking the significance of serological non-responsiveness 62 Nurse-Findlay S, Taylor MM, Savage M, et al. Shortages of
and the serofast state after therapy. BMC Infect Dis 2015; 15: 479. benzathine penicillin for prevention of mother-to-child
40 US Centers for Disease Control and Prevention. Syphilis, Sexually transmission of syphilis: an evaluation from multi-country surveys
Transmitted Diseases Treatment Guidelines, 2015. https://www. and stakeholder interviews. PLoS Med 2017; 14: e1002473.
cdc.gov/std/treatment-guidelines/syphilis.htm 63 Canadian Guidelines. Syphilis treatment and follow-up. 2020.
(accessed July 3, 2023). https://www.canada.ca/en/public-health/services/infectious-
41 Peeling RW, Holmes KK, Mabey D, Ronald A. Rapid tests for STIs: diseases/sexual-health-sexually-transmitted-infections/canadian-
the way forward. Sex Transm Infect 2006; 82: v1–6. guidelines/syphilis/treatment-follow-up.html
42 Tucker JD, Bu J, Brown LB, Yin YP, Chen XS, Cohen MS. (accessed Aug 8, 2021).
Accelerating worldwide syphilis screening through rapid testing: 64 Riedner G, Rusizoka M, Todd J, et al. Single-dose azithromycin
a systematic review. Lancet Infect Dis 2010; 10: 381–86. versus penicillin G benzathine for the treatment of early syphilis.
43 Jafari Y, Peeling RW, Shivkumar S, Claessens C, Joseph L, Pai NP. N Engl J Med 2005; 353: 1236–44.
Are Treponema pallidum specific rapid and point-of-care tests for 65 Hook EW 3rd, Behets F, Van Damme K, et al. A phase III
syphilis accurate enough for screening in resource limited settings? equivalence trial of azithromycin versus benzathine penicillin for
Evidence from a meta-analysis. PLoS One 2013; 8: e54695. treatment of early syphilis. J Infect Dis 2010; 201: 1729–35.
44 Mabey DC, Sollis KA, Kelly HA, et al. Point-of-care tests to 66 Chen X-S, Yin YP, Wei WH, et al. High prevalence of azithromycin
strengthen health systems and save newborn lives: the case of resistance to Treponema pallidum in geographically different areas in
syphilis. PLoS Med 2012; 9: e1001233. China. Clin Microbiol Infect 2013; 19: 975–79.
45 García PJ, Cárcamo CP, Chiappe M, et al. Rapid syphilis tests as 67 Read P, Jeoffreys N, Tagg K, Guy RJ, Gilbert GL, Donovan B.
catalysts for health systems strengthening: a case study from Peru. Azithromycin-resistant syphilis-causing strains in Sydney,
PLoS One 2013; 8: e66905. Australia: prevalence and risk factors. J Clin Microbiol 2014;
46 Yin YP, Chen XS, Wei WH, et al. A dual point-of-care test shows 52: 2776–81.
good performance in simultaneously detecting nontreponemal and 68 Beale MA, Marks M, Sahi SK, et al. Genomic epidemiology of
treponemal antibodies in patients with syphilis: a multisite syphilis reveals independent emergence of macrolide resistance
evaluation study in China. Clin Infect Dis 2013; 56: 659–65. across multiple circulating lineages. Nat Commun 2019; 10: 3255.
47 Causer LM, Kaldor JM, Conway DP, et al. An evaluation of a novel 69 Tuddenham S, Ghanem KG. Emerging trends and persistent
dual treponemal/nontreponemal point-of-care test for syphilis as a challenges in the management of adult syphilis. BMC Infect Dis
tool to distinguish active from past treated infection. Clin Infect Dis 2015; 15: 351.
2015; 61: 184–91. 70 Rolfs RT, Joesoef MR, Hendershot EF, et al. A randomized trial of
48 Marks M, Yin YP, Chen XS, et al. Metaanalysis of the performance enhanced therapy for early syphilis in patients with and without
of a combined treponemal and nontreponemal rapid diagnostic test human immunodeficiency virus infection. N Engl J Med 1997;
for syphilis and yaws. Clin Infect Dis 2016; 63: 627–33. 337: 307–14.
49 Taylor MM, Peeling RW, Toskin I, Ghinidelli M. Role of dual HIV/ 71 Watson-Jones D, Gumodoka B, Weiss H, et al. Syphilis in
syphilis test kits in expanding syphilis screening. Sex Transm Infect pregnancy in Tanzania. II. The effectiveness of antenatal syphilis
2017; 93: 458–59. screening and single-dose benzathine penicillin treatment for the
50 WHO. WHO information note on the use of dual HIV/syphilis prevention of adverse pregnancy outcomes. J Infect Dis 2002;
rapid diagnostic tests (RDT). Geneva: World Health Organization, 186: 948–57.
2017. 72 Terris-Prestholt F, Watson-Jones D, Mugeye K, et al. Is antenatal
51 Gliddon HD, Peeling RW, Kamb ML, Toskin I, Wi TE, Taylor MM. syphilis screening still cost effective in sub-Saharan Africa.
A systematic review and meta-analysis of studies evaluating the Sex Transm Infect 2003; 79: 375–81.
performance and operational characteristics of dual point-of-care 73 WHO. Triple elimination initiative of mother-to-child transmission
tests for HIV and syphilis. Sex Transm Infect 2017; 93: S3–15. of HIV, syphilis and hepatitis B. https://www.who.int/initiatives/
52 Holden J, Goheen J, Jett-Goheen M, Barnes M, Hsieh YH, triple-elimination-initiative-of-mother-to-child-transmission-of-hiv-
Gaydos CA. An evaluation of the SD Bioline HIV/syphilis duo test. syphilis-and-hepatitis-b (accessed July 3, 2023).
Int J STD AIDS 2018; 29: 57–62. 74 WHO Asia Pacific Region. The triple elimination of mother-to-child
53 WHO. Pre-qualified HIV syphilis combo tests. https://extranet. transmission of HIV, hepatitis B and syphilis in Asia and the
who.int/pqweb/sites/default/files/documents/230607_prequalified_ Pacific, 2018–2030.
IVD_product_list.pdf (accessed July 3, 2023). 75 Chen XS. Challenges in responses to syphilis epidemic.
54 Bristow CC, Larson E, Anderson LJ, Klausner JD. Cost-effectiveness Lancet Infect Dis 2017; 17: 793–94.
of HIV and syphilis antenatal screening: a modelling study. 76 Chen XS. Turning off the tap: sustaining elimination of congenital
Sex Transm Infect 2016; 92: 340–46. syphilis through the programme targeting high-risk groups.
55 Rodriguez PJ, Roberts DA, Meisner J, et al. Cost-effectiveness of J Glob Health 2019; 9: 020312.
dual maternal HIV and syphilis testing strategies in high and low 77 WHO. Guidelines on HIV self-testing and partner notification.
HIV prevalence countries: a modelling study. Lancet Glob Health December 2016. http://apps.who.int/iris/bitstre
2021; 9: e61–71. am/10665/251655/1/9789241549868-486eng.pdf?ua=1 (accessed July
56 Mercurio L, Taylor LE, Jarman AF. Neurosyphilis: old disease, new 3, 2023).
implications for emergency physicians. Clin Pract Cases Emerg Med 78 Johnson CC, Kennedy C, Fonner V, et al. Examining the effects of
2019; 4: 46–50. HIV self-testing compared to standard HIV testing services:
57 Lu Y, Ke W, Yang L, et al. Clinical prediction and diagnosis of a systematic review and meta-analysis. J Int AIDS Soc 2017; 20: 21594.
neurosyphilis in HIV-negative patients: a case-control study. 79 Qin Y, Han L, Babbitt A, et al. Experiences using and organizing
BMC Infect Dis 2019; 19: 1017. HIV self-testing. AIDS 2018; 32: 371–81.

www.thelancet.com Vol 402 July 22, 2023 345

 Seminar

80 van Loo IHM, Dukers-Muijrers NHTM, Heuts R, 92 Wedderburn CJ, Murtagh M, Toskin I, Peeling RW. Using electronic
van der Sande MAB, Hoebe CJPA. Screening for HIV, hepatitis B readers to monitor progress toward elimination of mother-to-child
and syphilis on dried blood spots: a promising method to better transmission of HIV and syphilis: an opinion piece.
reach hidden high-risk populations with self-collected sampling. Int J Gynaecol Obstet 2015; 130: S81–83.
PLoS One 2017; 12: e0186722. 93 Turner TB, Hollander DH. Biology of the treponematoses. Geneva,
81 Bil JP, Prins M, Stolte IG, et al. Usage of purchased self-tests for Switzerland: World Health Organization, 1957.
HIV and sexually transmitted infections in Amsterdam, the 94 Miller JN. Immunity in experimental syphilis. VI. Successful
Netherlands: results of population-based and serial cross-sectional vaccination of rabbits with Treponema pallidum, Nichols strain,
studies among the general population and sexual risk groups. attenuated by -irradiation. J Immunol 1973; 110: 1206–15.
BMJ Open 2017; 7: e016609. 95 Lithgow KV, Hof R, Wetherell C, Phillips D, Houston S,
82 Wang C, Cheng W, Li C, et al. Syphilis self-testing: a nationwide Cameron CE. A defined syphilis vaccine candidate inhibits
pragmatic study among men who have sex with men in China. dissemination of Treponema pallidum subspecies pallidum.
Clin Infect Dis 2020; 70: 2178–86. Nat Commun 2017; 8: 14273.
83 Zhong F, Tang W, Cheng W, et al. Acceptability and feasibility of a 96 Colles A. Practical observations on the venereal disease, and on the
social entrepreneurship testing model to promote HIV self-testing use of mercury. London: Sherwood, Gilbert and Piper, 1837: 304.
and linkage to care among men who have sex with men. HIV Med 97 Marra CM, Maxwell CL, Sahi SK, Tantalo LC, Dunaway SB,
2017; 18: 376–82. Lukehart SA. Previous Syphilis Alters the Course of Subsequent
84 Zhang W, Luo H, Ma Y, et al. Monetary incentives for provision of Episodes of Syphilis. Clin Infect Dis 2020; 71: 1243–47.
syphilis screening, Yunnan, China. Bull World Health Organ 2017; 98 Pham MD, Wise A, Garcia ML, et al. Improving the coverage and
95: 657–62. accuracy of syphilis testing: The development of a novel rapid,
85 McGovern ME, Herbst K, Tanser F, et al. Do gifts increase consent point-of-care test for confirmatory testing of active syphilis infection
to home-based HIV testing? a difference-in-differences study in and its early evaluation in China and South Africa.
rural KwaZulu-Natal, South Africa. Int J Epidemiol 2016; 45: 2100–09. EClinicalMedicine 2020; 24: 100440.
86 Cheng W, Wang C, Tang W, et al. Promoting routine syphilis 99 Bolan RK, Beymer MR, Weiss RE, Flynn RP, Leibowitz AA,
screening among men who have sex with men in China: study Klausner JD. Doxycycline prophylaxis to reduce incident syphilis
protocol for a randomised controlled trial of syphilis self-testing and among HIV-infected men who have sex with men who continue to
lottery incentive. BMC Infect Dis 2020; 20: 455. engage in high-risk sex: a randomized, controlled pilot study.
87 Bissessor M, Fairley CK, Leslie D, Chen MY. Use of a computer Sex Transm Dis 2015; 42: 98–103.
alert increases detection of early, asymptomatic syphilis among 100 Azbel L, Polonsky M, Wegman M, et al. Intersecting epidemics of
higher-risk men who have sex with men. Clin Infect Dis 2011; HIV, HCV, and syphilis among soon-to-be released prisoners in
53: 57–58. Kyrgyzstan: Implications for prevention and treatment.
88 Bourne C, Knight V, Guy R, Wand H, Lu H, McNulty A. Short Int J Drug Policy 2016; 37: 9–20.
message service reminder intervention doubles sexually transmitted 101 Molina JM, Charreau I, Chidiac C, et al. Post-exposure prophylaxis
infection/HIV re-testing rates among men who have sex with men. with doxycycline to prevent sexually transmitted infections in men
Sex Transm Infect 2011; 87: 229–31. who have sex with men: an open-label randomised substudy of the
89 Zou H, Fairley CK, Guy R, et al. Automated, computer generated ANRS IPERGAY trial. Lancet Infect Dis 2018; 18: 308–17.
reminders and increased detection of gonorrhoea, chlamydia and 102 Grant JS, Stafylis C, Celum C, et al. Doxycycline prophylaxis for
syphilis in men who have sex with men. PLoS One 2013; 8: e61972. bacterial sexually transmitted infections. Clin Infect Dis 2020;
90 Taylor MM, Frasure-Williams J, Burnett P, Park IU. Interventions to 70: 1247–53.
Improve Sexually Transmitted Disease Screening in Clinic-Based
Settings. Sex Transm Dis 2016; 43: S28–41. Copyright © 2023 Elsevier Ltd. All rights reserved
91 Chow EPF, Callander D, Fairley CK, et al. Increased syphilis testing
of men who have sex with men: greater detection of asymptomatic
early syphilis and relative reduction in secondary syphilis.
Clin Infect Dis 2017; 65: 389–95.

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