Review
Syphilis and HIV: a dangerous combination
W A Lynn and S Lightman
HIV and syphilis affect similar patient groups and co-
infection is common. All patients presenting with syphilis
should be offered HIV testing and all HIV-positive patients
should be regularly screened for syphilis. Syphilis agent may
enhance the transmission of the other, probably through
increased incidence of genital ulcers. Detection and
treatment of syphilis can, therefore, help to reduce HIV
transmission. Syphilis may present with non-typical features
in the HIV-positive patient: there is a higher rate of
symptomless primary syphilis and proportionately more HIV-
positive patients present with secondary disease. Secondary
infection may be more aggressive and there is an increased
rate of early neurological and ophthalmic involvement.
Diagnosis is generally made with serology but the clinician
should be aware of the potential for false-negative serology
in both primary and, less commonly, in secondary syphilis.
All HIV-positive patients should be treated with a penicillin-
based regimen that is adequate for the treatment of
neurosyphilis. Relapse of infection is more likely in the
HIV-positive patient and careful follow-up is required.
Lancet Infect Dis 2004; 4: 456–66
Syphilis and HIV are both transmitted sexually and so it is
no surprise that a substantial number of people are infected
with both agents. HIV has several effects on the
presentation, diagnosis, disease progression, and therapy of
syphilis.1 Syphilis may increase the risk of HIV transmission
and acquisition by causing genital ulcers.2 Genital ulcer
disease is linked to increased risk of HIV infection and is
most commonly due to herpes simplex virus (HSV) in both
HIV positive and negative patients.3 Syphilis continues to
affect large numbers throughout much of the world and the
past 5 years has seen a number of outbreaks. HIV makes it
more likely for syphilis to present with non-typical features.4
Thus, it is important for medical practitioners to be aware of
how syphilis may present in patients with underlying HIV
infection and its implications for treatment and follow-up.
Controversy has surrounded the area of HIV and
syphilis co-infection. Some have argued that syphilis has a
different clinical presentation and is more aggressive in
people with HIV; others suggest there is little difference.
There are differences in the interpretation of serological tests
for syphilis in the HIV positive but how often does this
matter clinically? Finally, some recommend that all HIV-
positive patients should be treated as if they had
neurosyphilis regardless of the stage at which they present,
although the feared epidemic of neurological involvement
456
For personal use. Only reproduce with permission from The Lancet.
Syphilis and HIV
Complete Table of Contents
Subscription Information for
has not materialised. This article will try to answer some of
these questions by reviewing the epidemiology, diagnosis,
clinical features, and management of syphilis in people
infected with HIV. Congenital syphilis was reviewed in the
Lancet Infectious Diseases in 2002 and will not be discussed
here in detail.5
Epidemiology
WHO estimates that approximately 349 million people are
actively infected with a treatable sexually transmitted
disease.6 Of these, estimates from 1999 suggest an annual
rate for syphilis of approximately 12 million active
infections.6 Almost two-thirds of these cases are in sub-
Saharan Africa and south/southeast Asia. Recent outbreaks
have been reported from many countries on all
continents.7–10 In sub-Saharan Africa between 2 and 17% of
women test positive for syphilis in antenatal clinics and rates
of HIV co-infection are very high. In North America and
western Europe the incidence of syphilis is much lower at
less than 5/100 000 of the population or less.4,6 There was
steady decline in the incidence of syphilis in both Europe
and the USA during the second half of the last century,
leading to suggestions that endemic syphilis might even be
eradicated in these countries.4,11 The past few years, however,
have seen an upsurge in syphilis in Europe and isolated
outbreaks in North America.1,12,13 The reasons underlying
this reversal are complex but include migration of people
from high-prevalence countries, population mixing, changes
in risk behaviour including the use of the internet to meet
partners, use of recreational drugs, and a reduction in safe
sex practices in gay men.13
In the UK the incidence of syphilis fell dramatically
through the 1980s to less than 1/100 000 of the population.
A rise in syphilis incidence has been seen since 1996 with
most cases occurring in young men. Over the same time
period there has also been an increase in new HIV diagnoses
in the UK increasing the likelihood of HIV and syphilis co-
infection (figure 1). In 2002 syphilis rates for men in
England and Wales ranged from 0·5/100 000 in rural areas to
more than 2/100 000 in metropolitan districts with
particularly high rates in Brighton, Manchester, and
London.14,15 There has been a smaller but still significant rise
WAL is at the Institute of Ophthalmology, Moorfields Eye Hospital,
London, UK; and both authors are at the Department of Infectious
Diseases, Ealing Hospital, Southall, Middlesex, UK.
Correspondence: Dr W A Lynn, Infection and Immunity Unit, Ealing
Hospital, Southall, Middlesex UB1 3HW, UK. Tel +44 (0)208 967
5120; fax +44 (0)208 967 5677; email william.lynn@eht.nhs.uk
Infectious Diseases Vol 4 July 2004 http://infection.thelancet.com
 Syphilis and HIV
Review

in syphilis in women with by far the A

greatest number of cases reported 3500
Sex between men
from London. An enhanced syphilis Sex between men and women
3000
surveillance programme run by Injecting drug use

Number of diagnoses
the UK Health Protection Agency 2500 Blood/tissue
indicated that, in 2002, 57% of Mother to infant
2000 Other/undetermined
reported cases were from gay men, a
proportion of whom are co-infected 1500
with HIV.15,16 More detailed analysis
of the outbreak in Manchester 1000
highlighted unprotected oral sex
500
as a major risk factor for syphilis
transmission amongst gay men. 10
0
Many of these men followed safe sex 19 5
86
87

19 8
89
90

19 1
19 2
93
94

19 5
96
97
98
99
00

20 1
02
8

9
9

0
practices including the use of
19

19
19

19

19

19
19

19
19
19
20

20
condoms for anal intercourse but were Year of diagnosis
unaware that syphilis could be orally B
10
transmitted. <16
Rate per 100 000 population

9
The rate of HIV and syphilis co- 16–19
8 20–24
infection will vary depending on the
7 25–34
prevalence of both infections in 35–44
the community or the patient group 6
>45
being studied, along with individual 5
risk factors. Blocker and colleagues17 4
reviewed 30 studies that looked at HIV 3
rates in people with syphilis in the 2
USA. They reported an overall 1
median seroprevalence for HIV of 0
15·7% (27·5% in men and 12·4% in
95
96
97
98
99
00

01
02

95
96
97
98
99
00

01
02
women). This gave an odds ratio for
19
19
19
19
19
20

20
20

19
19
19
19
19
20

20
20
having HIV of 8·8 for men and 3·3 for Men Women
women presenting with syphilis.17
Furthermore, much higher rates of Figure 1. Number of new HIV-positive cases per year in the UK (A) and yearly syphilis rates by sex
HIV co-infection were detected in and age (B). Courtesy of the UK Health Protection Agency. 14

relation to specific risk factors, for

example intravenous drug use (22·5–70·6%) and gay sex Control (CDC) on the incidence of syphilis in 40 US states
(68–90%).17 In one Spanish study of 1161 HIV-positive over a 14-year period.21 There was a 90% reduction in
patients followed-up for 38 months the baseline syphilis syphilis cases between 1990 and 2000. Mathematical
seroprevalence was 13% and a further 4% acquired syphilis modelling suggested that AIDS-related mortality was
in follow-up.18 The German AIDS Study Group found 151 responsible for between one-third and half of this reduction.
cases of active syphilis in 11 368 HIV-positive patients Chesson and colleagues postulate that the decline in HIV
(1·33%).19 Of the 151 active cases 17·2% were primary mortality since the development of antiretroviral therapy,
syphilis, 36·4% secondary syphilis, 16·6% neurosyphilis, and coupled with continued high-risk sexual behaviour in HIV-
25·2% latent syphilis. These figures cannot be applied to all infected people22,23 may be responsible for recently reported
populations due to variation in underlying prevalence rates rises in syphilis transmission.
and risk factors but stress the high rates of co-infection and Syphilis, through genital ulcer disease, may increase
ongoing risk of disease acquisition. All patients presenting the risk of HIV transmission.2,24,25 For example, one
with a sexually transmitted infection should be offered HIV mathematical model has suggested that approximately 1000
testing and given advice on HIV prevention. Similarly all additional cases of heterosexual HIV transmission occur
people presenting with HIV should be screened for syphilis annually in the USA as a result of syphilis.26 Using syphilis
and re-screened regularly during follow-up. Reinfection and HIV co-infection data from black Americans in 2000,
with syphilis may occur and all patients should receive Chesson et al27 have calculated that 545 cases of HIV
advice on safe sexual practices. Current UK recommend- transmission were facilitated by syphilis in couples
ations are for annual serological testing for syphilis in all discordant for HIV. The additional health cost of the 545
HIV-infected people with consideration for more frequent potentially preventable HIV infections was estimated at
screening in the event of a local disease outbreak.20 US$113 million. These data come from the USA where the
The close interaction between HIV and syphilis prevalence of syphilis is much lower than in many countries
epidemiology is illustrated by Chesson and colleagues’ with a high burden of HIV infection. These data emphasise
analysis of available data from the US Centers for Disease the need to include the surveillance, prevention, and

Infectious Diseases Vol 4 July 2004 http://infection.thelancet.com 457

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 Review
Table 1. Sensitivity and specificity of serological tests in syphilis in HIV-negative people
Test Primary sensitivity (%)
Non-specific RPR 86
VDRL 80
Specific TPHA 80
MHA-TP 76
FTA-ABS 84
RPR=rapid plasma regain; VDRL=venereal disease research laboratory; TPHA=Treponema pallidum haemagluttination assay; MHA-TP=microhaemagluttination assay—
T pallidum, FTA-ABS=fluorescent treponemal antibody absorption test. Adapted from GR Kinghorn with permission.4
treatment of syphilis and other sexually transmitted
infections within HIV-control programmes. This is
particularly relevant to countries with a high prevalence of
syphilis, genital ulcer disease, and HIV.
Diagnosis
The key to syphilis recognition is a full examination by a
skilled medical practitioner familiar with the protean
manifestations of the infection. This examination should
include all of the skin and mouth as well as the genital
region. If syphilis is not suspected then the opportunity
for early diagnosis and treatment and public-health
intervention will be lost.
Serological diagnosis of active syphilis
The mainstay of diagnosis of syphilis in the non-HIV
infected adult is serology.4,28,29 Serological tests may be
negative in early primary syphilis and here direct
identification of the organism by dark field microscopy or
within tissue biopsies may confirm the clinical diagnosis.30
Serological investigations are divided into non-treponemal
antibody tests, such as the Venereal Diseases Research
Laboratory (VDRL) or the rapid plasma reagin (RPR), and
specific treponemal antibody tests (table 1).4,29 In general a
non-treponemal test plus a specific treponemal tests is used
for screening in both HIV-negative and positive people.20
Serological testing in the HIV-negative patient
In the HIV-negative patient, around 14% have negative
serology at presentation with primary syphilis but fewer than
1% will have negative tests with secondary disease.30 Without
therapy non-treponemal antibody titres peak during
secondary syphilis and then gradually decline, so that up to
20–25% of patients with untreated late latent syphilis may
have a negative non-treponemal antibody test. Specific
treponemal antibody, however, persists in almost all patients
with a sensitivity of 97–98% in late syphilis.4 After successful
antimicrobial therapy, non-treponemal serological tests
generally become negative within 1 year. However, a small
proportion of patients (fewer than 5%) have persistently
positive results despite effective therapy and are referred to
as “serofast”. By contrast, specific treponemal antibody tests
remain positive for life in almost all cases.
False positive non-treponemal antibody results are seen
in a range of conditions associated with phospholipid
antibody production including autoimmune diseases,
pregnancy, and several infectious agents including other
spirochaetal infections and HIV.31 False-positive non-
458
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Syphilis and HIV
Secondary sensitivity (%) Tertiary sensitivity (%) Specificity (%)
100 70 98
100 75 98
100 95 99
100 95 99
100 96 98
treponemal antibody titres are generally low, are not
persistent, and the patients have a negative specific
treponemal antibody test. False-negative non-treponemal
antibody tests are seen in approximately 2% of patients and
are due to the prozone effect where blocking antibodies or
very high antibody titres interfere with the assay.32 The
prozone effect is less common with newer tests but it is
important that all physicians testing patients for syphilis are
aware of the possibility of a false-negative test. The prozone
effect is easily avoided by testing diluted serum.
Serological testing in the HIV-positive patient
Case reports have identified potential differences in
serological testing for syphilis between HIV-negative and
HIV-positive patients although the clinical importance of
these differences remains unclear. These differences include
an increased rate of negative serological tests in both primary
and secondary syphilis,33,34 increased false-negative non-
treponemal antibody tests due to the prozone effect,35,36 high
rate of failure to clear non-treponemal antibody after
therapy (serofast),37 and seroreversion to negative of specific
treponemal antibody tests after therapy.38 The difference in
serological response in HIV-positive patients is not clearly
related to CD4 count but similar events have been reported
in non-HIV infected immunocompromised patients.32 False-
positive non-treponemal antibody tests are encountered
more frequently in the HIV-positive individual and may be
seen in up to 11% of cases.39 Reinfection with syphilis may
occur in HIV-negative or positive patients. It may be
difficult to distinguish on serological grounds between the
patient who is serofast after effective therapy, treatment
failure, and reinfection.40
Patients can present with the typical features of primary
or even secondary syphilis but have negative non-
treponemal and treponemal antibody results.33 Furthermore,
in the German study quoted earlier, of 151 HIV-positive
patients with syphilis, false-negative VDRL titres were seen
in 11 patients with non-primary syphilis (7·3%), and false-
positive specific treponemal antibody tests in 17 cases
(11·25%, Treponema pallidum haemagglutination in one
case and 19S-IgM-FTA-ABS-tests in 16).19 By contrast,
Gwanzura et al41 studied 709 serum samples from 580
patients in Zimbabwe using the RPR, VDRL, and T pallidum
haemagglutination. The prevalence of HIV in the cohort was
19·8% and 78 cases of active syphilis were detected. In
particular, the negative predictive value of combined
serology was greater than 99% with no difference between
the HIV-negative and positive patients.
Infectious Diseases Vol 4 July 2004 http://infection.thelancet.com
 Syphilis and HIV
Review

Thus, although individual case

reports identify patients presenting Primary
with manifestations of syphilis Secondary
with negative serology, there are Early latent
insufficient data to warrant an Late latent
alteration to using standard sero- Gummatous
logical tests for syphilis screening in Cardiovascular
HIV-positive patients.20 However, it is Meningeal
important that clinicians involved in Meningovascular
the care of people with HIV are aware General paralysis
that occasional patients may present Tabes dorsalis
with manifestations of syphilis and 0 6 12 2 4 6 8 10 20 30
have negative initial syphilis screening Months Years
tests. Such patients presenting Time from infection
with suspicious genital or other
lesions must have investigations Figure 2. Typical presentations of syphilis over time in the HIV-negative patient. Reproduced with
aimed at direct identification of the permission from G R Kinghorn. 4

organism—ie, dark-field microscopy

of material from lesions or by tissue biopsies.20 All patients A generalised macular rash with palmar-plantar involvement
should be referred to a clinic where such facilities are may also occur (figure 4)44 but other types may occur such
available and specialist expertise for the diagnosis and as lichenoid,45 papular, papulosquamous, ulcerated, and
management of syphilis is available. urticarial lesions with hair loss varying from alopecia46 to
involvement of the eyebrows and even total loss of body
Clinical manifestations of syphilis in the hair.47 Nodular and annular48 skin lesions over the face, back,
HIV-positive patient and limbs are reported as are large plaques on face, neck, and
Typically syphilis occurs in three phases—namely primary, upper extremities.49 Nodular skin lesions can be seen in
secondary, and tertiary disease. However, this is a gross secondary or tertiary syphilis and clinical and histological
oversimplification and the clinical presentation of syphilis is stages may overlap.48 Vesiculobullous skin lesions may occur
extremely variable over many years (figure 2).4 Several in congenital syphilis.50
differences have been reported in the manifestations of Due to the varied appearances of syphilis manifestations,
syphilis in HIV-positive patients. In particular there seems to and because several other diseases may cause similar
be a shift from presentation with primary to secondary appearances, biopsy is common and often establishes the
disease and more aggressive disease progression. diagnosis. Histologically a wide range of changes is seen.
Furthermore, HIV itself or opportunistic infections may Treponomes are seen in both the epidermis and dermis.51
confuse clinical and diagnostic findings. Plasma cells and lymphocytes (which can be CD4+
In the HIV-negative patient primary syphilis generally lymphocyte, CD8+ lymphocyte, or histiocytic in type)52 can
develops after an incubation period of 21 days with a be seen around blood vessels which may have marked
painless chancre at the site of inoculation. This pattern holds endothelial swelling and proliferation associated with
true for syphilis in the HIV-positive patient but primary increased levels of vascular endothelial derived growth
disease is more likely to be symptomless and HIV-positive factor.53 No correlation is seen between types of skin lesion
patients more often present with secondary or latent and VDRL titre. Nodular lesions may show sarcoid-like
infection. For example, the UK enhanced surveillance granulomata with lymphocytes, histiocytes, oeosinophils,
programme in London reported on the presentation of plasma cells, and multinucleated giant cells.54 In patients
syphilis in HIV-negative (n=215) and HIV-positive (n=311) with concomitant HIV infection, syphilis is only one of
men. Primary syphilis was diagnosed in 42% and 27% and many possible causes of skin rash. Although the skin lesions
secondary disease in 40% and 58% of HIV-negative and of syphilis may look similar in HIV-positive or HIV-negative
HIV-positive patients, respectively.15 It is important to patients, they may also look different. The rash may seem
recognise that with the relative increase in importance of atypical, resulting in the incorrect diagnosis of another
oral sex in transmission of syphilis the primary lesion may infection or malignancy.55–57 Biopsy is commonly needed to
not be in the genital area (figure 3). establish the diagnosis but the histological manifestations of
secondary syphilis are very variable even in the absence of
Cutaneous HIV.58 There may also be increased frequency of the lues
Skin lesions are a common manifestation of secondary maligna or the ulceronodular type42,59–62 and the disease
syphilis (72%)42 and may be the presenting feature. A course may be more aggressive.63–65 Co-pathologies such as
number of different types of skin lesions are recognised Kaposi’s sarcoma and other skin lesions may also occur.
together with lymphadenopathy, malaise, arthralgia, and With the possibility of falsely negative serology for syphilis in
fever. The most common type is of a diffuse maculopapular HIV infection, the diagnosis of syphilis as a cause of skin
rash which typically appears about 6 weeks after the primary lesions may be missed. Biopsy remains the key to making the
lesions and signifies haematogenous spread of T pallidum.43 diagnosis in these situations.33

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 Review
Figure 3. Healing syphilitic chancre in an HIV-positive homosexual man.
His only risk factor was unprotected receptive oral sex and he remained
undiagnosed for 6 weeks despite consulting his regular HIV-physician and
dentist. The diagnosis was only made when he finally presented with
fever, generalised lymphadenopathy, and the typical cutaneous changes
of secondary syphilis.
Bone and joint
Musculoskeletal manifestations can be associated with
congenital, secondary, and tertiary syphilis and can mimic a
wide range of rheumatic and systemic diseases with joint
involvement. Typically syphilitic arthritis is a chronic
symmetric polyarthritis. There are several causes of sexually
transmitted arthritis and arthralgia, inflammatory arthritis,
and neuropathic arthritis may occur during any stage of
congenital or acquired syphilis. Syphilitic synovitis responds
well to antibiotic therapy,66 but neuropathic lesions cannot
be treated effectively.67
Arthritis can also be the initial presentation of syphilis
with HIV infection and synovitis may occur in the presence
of marked CD4+ lymphocyte depletion. Difficulties occur in
diagnosis in HIV infection because of the negative syphilis
serology that can occur but also because of autoimmune
abnormalities that include positive rheumatoid factor,
nuclear antibody, and double-stranded DNA. The arthritis
responds well to treatment with penicillin even with HIV
infection.68
Clinically significant osteitis and osteomyelitis are rare
complications of primary or secondary syphilis in patients
who are and are not infected with HIV69 but bone pain is a
common feature of bone involvement70 and lytic lesions may
occur (figure 5).71 Osteitis of the skull has been reported as a
presenting feature of HIV infection70 as has ulnar osteitis
complicated by a pathological fracture, which responded to
high-dose intravenous penicillin G therapy and surgical
intervention.72
Central nervous system
Patients co-infected with syphilis and HIV present a
diagnostic and therapeutic challenge since both syphilis and
HIV infection can have neurological involvement, which can
be very variable.73,74 This makes the interpretation of
cerebrospinal fluid (CSF) analysis, on which the diagnosis of
neurosyphilis is based, particularly problematic.
Neurosyphilis may affect the brain, spinal cord, or
peripheral nerves. In HIV-negative patients, neurosyphilis
460
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Syphilis and HIV
can present in several ways. Neurological involvement may
occur in the early post-primary stage or after a gap of many
years (figure 2). In 10% of patients it is symptomless and the
peak incidence is 12–18 months post primary infection.
Meningeal involvement can occur with the patient
presenting with aseptic meningitis and acute symptoms such
as headache, neck stiffness, and photophobia. Cranial nerve
palsies, especially of the VII and VIII nerves, papilloedema,
and neuropsychiatric features or seizures can also
occur.73,75–78 Meninogovascular syphilis presents 4–7 years
after infection and symptoms occur because of vascular
ischaemia in the territory of the middle cerebral, basilar, or
spinal arteries. Hence patients may present with focal
neurological deficits such as hemiparesis, aphasia, or
seizures. The necrotising granulomatous gummas of late
syphilis within the central nervous system give rise to
symptoms and signs of space-occupying lesions. Rarely
parenchymatous involvement causes cognitive impairment,
psychiatric symptoms, and neurological signs affecting the
pupils and causing hypotonia of the face and limbs,
intention tremor, and hyper-reflexia.79
The increased prevalence of neurosyphilis in HIV
infection is shown in one study where incidence was 23·5%
in HIV-positive patients with untreated syphilis.80 This
prevalence contrasts with 10% in HIV-negative patients with
untreated syphilis.4 In HIV infection, neurosyphilis may be
symptomless but a range of presentations may also occur. All
types of neurosyphilis as described above are seen including
headache, hearing loss (which may be bilateral and severe),81
spastic paraparesis secondary to syphilitic meningomyelitis,82
medullary syndromes,83 stroke (which can be acute or sub-
acute involving the basal ganglia or middle cerebral
arteries),77,84 gait disturbances, and optic atrophy or pupillary
changes.85 Gummas may mimic the symptoms and signs of a
space-occupying intracranial lesion including meningioma
with headache and ataxia.77 Personality changes are the
commonest symptom of late syphilis with HIV infection and
are due to syphilitic vasculitis with lacunar infarcts. In
children with AIDS, syphilis may also contribute to the
neurological manifestations.86 Neurocognitive impairment is
common in HIV patients but is worse in those co-infected
with syphilis.87 Furthermore, co-infection with herpes
viruses, toxoplasmosis, cryptococci, progressive multifocal
leucoencephalopathy and other central nervous system
infections may complicate the clinical and diagnostic picture
in persons with underlying HIV.74,88
It is also suggested that HIV accelerates and changes the
clinical course of neurosyphilis89 and that co-infection with
HIV increases the incidence of the neurological
complications of syphilis.90 Aggressive neurosyphilis can
occur with either high or low CD4+ lymphocyte counts.91 In
one recent study a CD4 count of less than 350 indicated a
three-fold increased risk of neurological involvement in the
HIV-positive patient with syphilis.92 Neurospyhilis in the
context of HIV co-infection with HIV is more difficult to
diagnose because HIV infection itself is frequently associated
with a CSF pleocytosis.93 Significant differences were noted
in CSF measurements when HIV-positive patients were
compared with HIV-negative patients with syphilis,
Infectious Diseases Vol 4 July 2004 http://infection.thelancet.com
 Syphilis and HIV
Review

including a higher cell count, higher protein, and lower

glucose levels in the HIV-infected group.77 PCR has poor
sensitivity for the diagnosis of neurosyphilis in HIV and is
therefore not helpful in most patients where there is
diagnostic difficulty.94
Measurement of CSF antibodies to syphilis are generally
used to confirm neurological involvement. In HIV-negative
patients the presence of either non-treponemal or specific
treponemal antibodies in CSF indicates neurosyphilis.95 In
HIV-positive patients, however, the CSF VDRL may rarely
be negative despite neurosyphilis96 and when present CSF
treponemal antibodies commonly persist after therapy.97 The
CSF VDRL may rarely be negative in the HIV-negative
patient with neurosyphilis. Caution should also be used
when interpreting blood-contaminated CSF where a positive
serological result may come from the blood contamination.20
The problem of neurosyphilis in HIV-positive patients has
led some authorities to recommend lumbar puncture in all
HIV-positive patients irrespective of the stage of syphilis.98,99
An alternative strategy is to ensure that all HIV-positive
patients with syphilis receive a course of therapy that will
achieve treponemocidal concentrations of penicillin in both
serum and CSF.20 UK guidelines are that a full neurological
assessment should take place in all patients and a computed
tomography head scan and lumbar puncture are indicated
only if clinical abnormalities are found.20
Imaging may be of help in both diagnosis and
monitoring the effect of treatment. Computed tomography
scanning can show the presence of multifocal, low density
lesions with particular characteristics of infarction.100
Contrast-enhanced magnetic-resonance imaging (MRI) can
show the extent of involvement by neurosyphilis and may
show patchy contrast enhancement involving the basal
ganglia and middle cerebral artery territories or a mass
which may resolve on treatment.101 MRI is particularly useful
in diagnosing spinal cord involvement with syphilis.102,103
Retrospective studies of the treatment of neurosyphilis
in the presence of HIV infection suggest that for 23–60% of
HIV-infected patients current neurosyphilis therapy with
penicillin G does not work.37,97,104 However, the risk of
Figure 4. Involvement of the palm (A) and soles (B) with a lichenified scaly
neurological sequelae in HIV-infected patients with early rash due to secondary syphilis in an HIV-positive man presenting with
syphilis and abnormal CSF treated with penicillin is panretinitis. The rash had been present for several weeks and was
unknown.1 Standard treatment is with high-dose thought to be psoriasis by a rheumatologist who was seeing him for a
penicillin105,106 but there may be persistence.107 At least 3–4 “sero-negative” arthropathy.
weeks of treatment are recommended.108 Ceftriaxone has
excellent activity against T pallidum and has good central untreated patients that progress.112 Several different types
nervous system penetration. Case reports of effective use of of uveitis—anterior uveitis, posterior uveitis, and
ceftriaxone have been reported but data are limited and keratouveitis—are recognised. Patients with posterior uveitis
ceftriaxone is not licensed for use in neurosyphilis.109 may have vitritis, focal retinitis, chorioretinitis (figure 6),113,114
periphlebitis, retinal haemorrhages, papillitis,115 and
Ocular involvement exudative retinal detachments.116
The eyes and visual system can be affected in many different Many other signs of intraocular involvement may be
ways by syphilis but none of the signs are pathognemonic. seen including optic neuritis, neuroretinitis, and arterial
All structures of the eye may be affected110 but the and venous occlusion.117 Patients with neuroretinitis may
commonest manifestation is uveitis (intraocular notice painless fluctuating visual loss and floating spots,
inflammation). Uveitis can occur at all stages of syphilis which may be associated with retinitis, papillitis, vitritis,
including primary infection111 and may spontaneously and sometimes anterior uveitis. Isolated optic neuritis with
resolve but the relapse rate is high without treatment. It may unilateral visual loss may occur with signs of meningeal
also occur in tertiary syphilis affecting 2·5–5% of the 30% inflammation without any associated uveitis or retinal

Infectious Diseases Vol 4 July 2004 http://infection.thelancet.com 461

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 Review
Figure 5. Lytic lesion in the femur of the patient described in figure 4.
vasculitis.118 Paracentral scotomas and blind-spot
enlargement related to posterior pole lesions and papillitis
are the most common visual field defects. The orbit may
also be involved.119 Most patients recover well with
penicillin treatment but visual loss can occur from macular
oedema and retinal ischaemia from the endarteritis.120
However, not all ocular syphilis can be cured with
neurosyphilis regimens and many more will relapse with
less intense regimens.115
HIV infection itself can have many effects on the eye
and can cause uveitis as well as having associated infections,
malignancies and drugs that can cause uveitis.121 Severe
ocular manifestations and an accelerated natural course of
syphilis along with neurosyphilis may be associated with
HIV infection. Eye disease may be the presenting
Figure 6. Retinal photograph from an HIV-positive patient who presented with severe uveitis due to
syphilis. This picture after treatment of his syphilis shows healed chorioretinitis with a “salt and
pepper” appearance.
462
For personal use. Only reproduce with permission from The Lancet.
Syphilis and HIV
symptom/sign of co-infection with HIV.115,122 There are
differences in the uveitis seen in patients with syphilis co-
infected with HIV—the uveitis may be more severe in the
HIV-positive group123—panuveitis is more common than
isolated anterior uveitis,124 and a dense vitritis occurs
despite a low CD4+ lymphocyte count,125 but this usually
responds well to treatment.125 Papillitis, optic neuritis, and
retrobulbar optic neuritis126 may all be worse in HIV-
positive versus HIV-negative patients127 and there may be
concomitant central nervous system disease.
Syphilis serology may be negative when patients
present with inflamed eyes and co-infection with syphilis
and HIV. This may delay the diagnosis of syphilis128 since
none of these signs are specific for syphilis and if
investigations are negative, it is very likely that these
patients will be given systemic corticosteroids with severe
sequelae129 instead of disease resolution with penicillin.117
With penicillin treatment 67% of patients have improved
vision with reduced inflammatory signs in 92%130 but
relapses of ocular disease may also occur despite
treatment.123
Cardiovascular
By contrast with neurosyphilis there have been few reports
of vascular involvement in HIV-positive patients. Arterial
aneurysms can be seen in HIV infection and commonly
involve the common carotid artery and abdominal aorta.131
These may be multiple and can also be associated with
syphilis.132 In HIV-negative patients vascular disease is one
of the late manifestations of syphilis (figure 2). Thus, it is
possible that the paucity of reports of vascular syphilis in
HIV-positive patients is simply due to the relatively short
duration of infection and to the high rate of detection and
treatment of latent syphilis in HIV.
Other systems
Oral lesions can occur in syphilis
with and without HIV infection and are
usually seen in secondary disease
(figure 7).133 Rarely the lung and pleura
can become involved.134 Spirochetes
may be detected in pleural fluid
associated with pneumonia even in
patients with good CD4+ lymphocyte
counts.134 Nephrotic syndrome is a
recognised complication of HIV
infection and progresses to renal failure
without antiretroviral therapy.135 In
association with syphilis, however, it is
reversible with treatment.136
Treatment of syphilis
Penicillin remains the mainstay of
therapy for all stages and sites of
syphilis and in all patient groups.105,106,137
Guidelines vary (table 2) but the
general principle is one of maintaining
prolonged serum treponemocidal
concentrations. In HIV-negative
Infectious Diseases Vol 4 July 2004 http://infection.thelancet.com
 Syphilis and HIV
Review

patients with early syphilis (less than

2 years’ duration) it is not necessary
either to investigate for neurosyphilis or
to use therapy that achieves tre-
ponemocidal concentrations of anti-
biotics in CSF (table 2).20,105 For example,
CDC guidelines recommend a single
dose of intramuscular benzathine
penicillin for primary and secondary
disease.105 In late syphilis (greater than
2 years’ duration) CDC guidelines
recommend CSF examination in the
presence of ophthalmic or neurological
signs, treatment failure, evidence of
tertiary syphilis, or if the patient is co-
infected with HIV.105 If CSF is normal
then benzathine penicillin is still
recommended but the duration of
treatment is increased to three doses at
weekly intervals (table 2). Benzathine Figure 7. Lateral view of the tongue in a patient with secondary syphilis and undiagnosed
penicillin does not achieve adequate underlying HIV infection. Patches of oral hairy leucoplakia due to advanced HIV are seen on the
CSF concentrations and so is not lateral border (white arrows). There are also serpiginous ulcers and a mucous patch on the tongue
recommended where there is evidence of typical of secondary syphilis (black arrow).
neurosyphilis.
When treating syphilis in the HIV-positive patient it is despite augmenting the weekly benzathine penicillin
important to use a drug regimen that will achieve adequate injections with oral amoxicillin.138 Thus, daily intramuscular
CSF concentrations.20 This requires intravenous benzyl procaine penicillin plus probenecid should be the
penicillin, which is impractical in most cases, or daily recommended first-line therapy for primary, secondary, or
intramuscular procaine penicillin plus oral probenecid to latent syphilis in HIV-positive patients (table 2).20 Where
reduce renal excretion (table 2). When benzyl penicillin or compliance and personal choice make this regimen
procaine penicillin has been used as first-line therapy there is untenable then weekly benzathine penicillin plus oral
a low clinical treatment-failure rate. Long-acting benzathine amoxicillin and probenecid may be considered.138 In the
penicillin preparations have been reported to have higher penicillin-allergic patient doxycycline is often used as a
rates of serological failure, for example 18% in one study second-line agent. There is uncertainty about whether

Table 2. Guidelines for the treatment of syphilis in adults in the UK and USA

Syphilis stage USA guidelines (CDC)105 UK guidelines20,106,137 Alternative agents in

Early disease (<2 years, primary,
secondary, and early
latent infection)
Early syphilis in HIV-positive
Late latent disease
(>2 years since acquisition)
Late disease in HIV positive
Neurosyphilis
Neurosyphilis in HIV positive
IM=intramuscular; IV=intravenous; CDC=US Centers for Disease Control and Prevention; OD=once daily; BD=twice daily;TDS=three times daily; QDS=four times daily.
Benzathine penicillin G 50 000
units/kg IM, up to the adult
dose of 2·4 million
units in a single dose
As above, some clinicians recommend
3 doses at weekly intervals
Benzathine penicillin G 2·4 million
units IM weekly
3 doses
Benzathine penicillin G 2·4 million
units IM weekly
3 doses
Aqueous crystalline penicillin
G 18–24 million units per day,
administered as 3–4 million units IV every QDS
17 days or
4 h or continuous infusion, for 10–14 days. Benzyl penicillin 3–4 million units
As above
Procaine penicillin G 750 mg
IM daily
10 days or
Benzathine penicillin
G 2·4 million
units IM in a single dose
Procaine penicillin 2 million
units IM OD + probenecid
500 mg QDS
17 days
Procaine penicillin G 750 mg
IM daily
17 days or
benzathine penicillin G 2·4 million
units IM weekly
3 doses
Procaine penicillin 2 million units
IM OD + probenecid 500 mg QDS
for 17 days
Procaine penicillin 2 million units
IM OD + probenecid 500 mg
IV every 4 h for 17 days
As above
UK guidelines
Doxycycline 100 mg BD
14 days
Erythromycin 500 mg QDS
14 days
Amoxicillin 500 mg QDS plus
probenecid 500 mg QDS
14 days
Doxycycline 200 mg BD
28 days
Amoxycillin 2 g TDS plus probenecid
500 mg QDS
14 days
Doxycycline 200 mg BD
28 days
Amoxycillin 2 g TDS plus probenecid
500 mg QDS
14 days
Doxycycline 200 mg BD
28 days
Amoxycillin 2 g TDS plus probenecid
500 mg QDS
14 days
Doxycycline 200 mg BD
28 days
Amoxycillin 2 g TDS plus probenecid
500 mg QDS
14 days
As above

Infectious Diseases Vol 4 July 2004 http://infection.thelancet.com 463

For personal use. Only reproduce with permission from The Lancet.
 Review Syphilis and HIV

Search strategy and selection criteria

Data for this review were identified by searches of Medline,
Current Contents, and the Cochrane Database, and by
reviewing the bibliographies of papers retrieved using this
strategy. All articles published after 1966 were considered, as
were articles in all languages. Search terms were “HIV”,
“STD”, “STI” “syphilis”, “neurosyphilis”, “ocular”, “uveitis”,
“retinitis”, “vitritis”, “cardiovascular”, “bone”, “skin”,
“congenital”, and “malignant”. The websites of the World
Health Organization, US Centers for Disease Control and
Prevention, and the UK Health Protection Agency were
searched for epidemiological data.
adequate CSF concentrations of doxycycline are achieved
but treatment failure is rare and doxycycline remains a
useful agent. Erythromycin is used as a second-line agent in
the HIV-negative patient but has very poor CSF penetration
and should not be considered in HIV-positive patients.20
Furthermore, recent reports have described the emergence
of resistance to erythromycin.139 Azithromycin is a macrolide
antibiotic with activity against T pallidum. The long half-life
of azithromycin allows for once-daily dosing and small
studies have been encouraging.140 Caution must be expressed
regarding the use of azithromycin in the light of reports of
treatment failure.141
Where an HIV-positive patient has evidence of
neurosyphilis, with clinical and/or imaging abnormalities
plus an abnormal CSF, then high-dose intravenous benzyl
penicillin may be the preferred choice. There are no clear
data, however, to suggest that this is superior to
intramuscular procaine penicillin plus probenecid (table 2).
In both neurosyphilis and pregnancy there is no agreed
alternative to penicillin. Treatment failures in neurosyphilis
are likely with doxycycline and doxycycline is
contraindicated in pregnancy. In this setting consideration
can be given to desensitisation for penicillin allergy.106
Ceftriaxone has good treponemocidal activity and CSF
penetration. In a small pilot study of HIV-positive patients
with neurosyphilis ceftriaxone was been reported to be
at least equivalent to procaine penicillin142 but more data
are required before ceftriaxone could be routinely
recommended.
Treatment of syphilis may be complicated by the Jarisch-
Herxheimer reaction mediated by cytokine release induced
by treponemal lysis after therapy.106 The reaction occurs
within 4–24 h of penicillin administration and consists of an
acute febrile illness and may include increased inflammation
at the site of clinical disease. If the Jarisch-Herxheimer
reaction is severe or involves a critical body site then
corticosteroids are indicated.106 Jarisch-Herxheimer
reactions have been reported in HIV-positive patients but
do not seem to be more severe or frequent than in HIV-
negative patients.
The vast majority of HIV-negative patients will show a
steady fall in serum non-treponemal antibody levels and
have negative VDRL or RPR tests within 1–2 years of
effective therapy. Persistence of serum antibodies is much
more likely in HIV-positive patients and does not necessarily
indicate inadequate treatment. Current guidelines suggest
repeating serology at 3 month intervals for the first year after
treatment and then annually for life.20 A fourfold rise in
serum VDRL or RPR titre should be considered to indicate
relapse or reinfection, and retreatment offered.
Best practice would be for all people with syphilis to be
counselled regarding safer sexual practices. They should be
also be referred for partner notification and contact
tracing.
Future prospects
So what does the future hold? It is remarkable that penicillin
remains the mainstay of therapy and there is little prospect
that newer antibiotics will displace penicillin in the near
future particularly following the emergence of macrolide
resistance. An effective vaccine would offer great hope but
insufficient research efforts have directed against syphilis.
Despite some success143 our understanding of the
determinants of protective immunity to T palllidum remain
poor with little prospect for an effective vaccine in the near
future. Unless there is a concerted global and politically
supported public-health drive to reduce the transmission of
syphilis then syphilis will continue to lead to substantial
morbidity and further fuel the HIV pandemic.
Conflicts of interest
SL is a member of the international advisory board of The Lancet.

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