MAJOR ARTICLE
Factors Determining Serologic Response
to Treatment in Patients with Syphilis
Julio J. González-López, Manuel L. Fernández Guerrero, Rodolfo Luján, Sagrario Fernández Tostado,a
Miguel de Górgolas, and Luis Requena
Division of Infectious Diseases and Dermatology, Department of Medicine, Fundación Jiménez Dı́az, Universidad Autónoma de Madrid, Spain
Background. The goal of this study was to describe the clinical and epidemiologic manifestations of a syphilis
outbreak in downtown Madrid, Spain. Because human immunodeficiency virus (HIV)–positive patients may be
at increased risk of serologic failure during syphilis treatment, analysis of factors determining the response to
treatment was performed in a cohort of HIV-positive and HIV-negative patients with syphilis.
Methods. We performed a longitudinal, retrospective study of patients with syphilis who received the diagnosis
at a university-affiliated hospital in Madrid from 2003 through 2007.
Results. Three hundred forty-seven cases of syphilis were identified and treated (30 primary, 164 secondary,
77 early latent, and 76 late cases of syphilis). Forty-one percent of patients were immigrants, mostly from South
America and the Caribbean, and 49.3% were known to be HIV positive. Syphilis incidence increased from 15.6
to 35 cases per 100,000 person-years from 2003 to 2007. Most patients were men, and 50.4% were men who had
sex with other men. Meningitis (4.9%) and uveitis (2.9%) were the complications most frequently observed, and
their frequency did not differ between HIV-positive and HIV-negative patients. Serologic failure was observed in
44 (23.5%) patients: 37 (29.6%) of 125 HIV-positive patients and 7 (11.2%) of 62 HIV-negative patients (odds
ratio, 3.3; 95% confidence interval, 1.38–7.93; P ! .05 ). Men (hazard ratio [HR], 0.38), patients in the late stage
of syphilis (HR, 0.46), and HIV-positive persons (HR, 0.61) demonstrated slower serological responses to treatment.
HIV-negative patients responded more frequently to treatment, but after 2 years of follow-up, both groups shared
similar response rates. Antiretroviral treatment reduced the time to serologic response (HR, 2.08; 95% confidence
interval, 1.35– 3.20; P ! .001).
Conclusion. Syphilis incidence rose 223% from 2003 to 2007, affecting mostly HIV-positive men, men who
have sex with men, and immigrants. Men, patients in the late stages of syphilis, and HIV-positive persons may
be at increased risk of serologic failure. Antiretroviral therapy significantly reduced the time to achieve response
to syphilis treatment in HIV-positive patients.
Syphilis is a sexually transmitted disease of considerable
public health importance that poses a great threat to
patients when not properly diagnosed and treated. After
inoculation, a primary lesion associated with regional
lymphadenopathy is noted. A secondary bacteremic
stage with mucocutaneous manifestations is followed
by a latent period of subclinical infection. In about onethird of untreated cases, a tertiary stage characterized
Received 29 March 2009; accepted 24 June 2009; electronically published 20
October 2009.
a
Deceased.
Reprints or correspondence: Dr Manuel L Fernández Guerrero, Dept of Medicine, Fundación Jiménez Dı́az. Ave, Reyes Católicos 2, 28040 Madrid, Spain
([email protected]).
Clinical Infectious Diseases 2009; 49:1505–11
2009 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2009/4910-0007$15.00
DOI: 10.1086/644618
by destructive skin, mucous, or skeletal lesions, aortitis,
and central nervous system disease appears [1]. Treponema pallidum, the pathogenic agent of syphilis, can
be treated easily and inexpensively with antibiotics,
which also are the most useful way for preventing its
spread [1, 2].
Re-emergence of syphilis, a disease previously believed to be close to eradication, is a matter of increasing
global concern [3, 4]. The incidence of syphilis has been
rising in western countries since the year 2000, after
having decreased to a historical minimum in the early
1990s [5]. Social changes regarding prostitution, sex
tourism, the use of Internet for finding sporadic sex
partners, and the decreasing use of barrier contraceptive
methods have been proposed as possible causes for the
re-emergence of syphilis [5]. Cases in men who have
sex with men (MSM) and human immunodeficiency
Serologic Response to Syphilis Treatment • CID 2009:49 (15 November) • 1505
virus (HIV)–infected persons account for most of the recent
increase in syphilis prevalence in Europe and the United States.
Factors such as the comfort and sense of false security caused
by taking antiretroviral drugs, as well as the increasing use of
crystal methamphetamine and drugs to treat erectile dysfunction among MSM, have been suggested to be the main causes
for the increasing prevalence of syphilis in this population
[3–8].
Infection with HIV may affect both the natural course of
syphilis and the response to treatment. Some previous studies
have found a greater number of serological failures after treatment and a greater risk of developing complications, particularly neurosyphilis, among HIV-positive MSM [9–12]. Therefore, a closer follow-up is recommended for HIV-positive
persons with syphilis [13]. The aims of our study were to describe the recent changes in the epidemiology and clinical features of syphilis in Madrid and to assess the factors that may
determine serologic response to treatment.
PATIENTS AND METHODS
Data recovery and definitions. We reviewed the cases of all
patients with syphilis who were enrolled in a longitudinal study
from January 2003 through December 2007 at the Fundación
Jiménez Dı́az, a tertiary referral hospital affiliated to the Universidad Autónoma de Madrid that provides service for a population of 300,000 people in downtown Madrid. All patients
with active syphilis who were not previously treated and had
positive nontreponemal test results confirmed by treponemal
tests or dark field microscopy were included in the study. Patients with congenital syphilis, patients with syphilis that was
previously treated, and those with primary syphilis with nonreactive reaginic tests were excluded.
Disease stage was classified as early when the patient presented with primary, secondary, or early latent syphilis. A patient was considered to be in the early latent stage when signs
of primary or secondary syphilis occurred within a year before diagnosis. The disease stage was classified as late for patients with tertiary syphilis and those with syphilis of unknown
duration.
Patients were diagnosed with symptomatic neurosyphilis if
they had positive syphilis serology and an otherwise unexplained neurological finding (meningitis, brain infarct, or cranial nerve paralysis) with or without abnormal cerebrospinal
fluid results on lumbar puncture (pleocytosis [white blood cell
count 110 cells/mL], protein level 150 mg/dL, and reactive venereal diseases research laboratory result). Cerebrospinal fluid
samples were not routinely examined. However, in HIV-positive
patients who did not exhibit serologic response and who had
rapid plasma reagin (RPR) titers ⭓1:32 at 3 or 6 months after
penicillin treatment, a lumbar puncture was performed. Uveitis was diagnosed by means of ophthalmoscopic examination.
1506 • CID 2009:49 (15 November) • González-López et al
Rheumatologic complications (periostitis and osteitis) were diagnosed by means of clinical examination and computed tomography scan.
Measurements. RPR and the microhemagglutination assay
for antibodies to T. pallidum were performed following recommendations for the laboratory diagnosis of syphilis by Larsen et al [14]. HIV serology, CD4+ T cell count, and determination of viral load were assessed by conventional procedures
[15]. RPR tests were performed at the time of diagnosis and
were scheduled at 3-month intervals after treatment.
Definition of serologic failure. Serologic failure was defined
as a lack of a 4-fold decrease—2 dilutions—in RPR titers at 13
months after treatment (eg, from 1:32 to 1:8) or a 4-fold
increase in RPR titers ⭓30 days after treatment. Because other
reports have shown that many patients do not return for timely
follow-up in serologic studies [10, 16, 17], we used a 13-month
cut-off in an attempt to capture most patients for their 1-year
follow-up serologic testing. Patients whose RPR titers decreased
after treatment and subsequently increased 4-fold were deemed
to be reinfected and were excluded from the analysis of serologic
response. Time to serologic response was measured as the time
from administration of treatment to the first day when serologic
response was detected.
Data analysis. Data were introduced twice into a computerized database. Discordant pieces of data were corrected 1
by 1 on the basis of the original information.
Qualitative variables were expressed as percentages. Quantitative variables were expressed as mean values ( standard
deviation [SD]) if they followed a normal distribution or as
median values (interquartile range) if they did not. Association
was tested with x2 test or with Fisher’s exact test when necessary.
The strength of associations was measured with either a hazard
ratio (HR) or an odds ratio (OR), with 95% confidence intervals (95% CIs).
Differences between 2 means were tested with the independent samples T test, and comparisons among 12 mean values
were tested with a 1-factor analysis of the variance, when normality and homocedasticity conditions allowed it. When analysis of variance was not possible, the Mann-Whitney test for
2 independent samples or the Kruskal-Wallis test for k-independent samples were performed. Post hoc analysis of analysis
of variance results was performed with Tuckey-Kramer test.
Differences between 2 means were measured with Cohen’s D
statistic and its 95% CI.
Bivariate analysis of time to detection of serological response
to treatment was performed through the study of Kaplan-Meier
curves and analysis with the Breslow test. Multivariate analysis
was performed with Cox proportional hazards models, after
confirming the proportional risks assumption through the analysis of Schoenfeld residuals. All patients with at least 2 RPR
results were entered in the model. The selection of variables in
Figure 1. Incidence of syphilis in downtown Madrid, 2003–2007.
the final model was performed by a forward-conditional
method, with significance levels of ⭐.05 for inclusion and ⭓.1
for exclusion. Cox-Snell residuals were used to assess the overall
model fit. Data were analyzed using SPSS, version 16.0 (SPSS),
and Stata/SE, version 10.0 (StataCorp).
RESULTS
Four hundred twelve patients with syphilis were seen during
the study period. Sixty-three patients who were already treated,
who had primary syphilis with nonreactive RPR tests, or who
Table 1. Risk Factors, Clinical Features, Laboratory Findings, and Complications of Patients with Syphilis
Early syphilis
Variable
Percentage of total patients
Risk factor
Age, mean years SD
Primary
(n p 30)
Secondary
(n p 164)
8.6
47.3
Early latent
(n p 77)
Late syphilis
(n p 76)
22.2
21.9
37.42 11.55
49.68 18.33
Total
(n p 347)
100
34.97 7.67
36.32 8.02
Male sex
28 (93.3)
158 (96.3)
55 (71.4)
56 (73.7)
39.37 12.95a
298 (85.4)
Other STD
Any
HIV
HBV
17 (56.7)
12 (40)
3 (10)
124 (75.6)
105 (64)
27 (16.5)
47 (61)
32 (41.6)
7 (9.1)
34 (44.7)
23 (30.3)
7 (9.2)
222 (63.6)
172 (49.3)
44 (12.6)
Gonorrhoea
MSM
0 (0)
15 (50)
9 (5.5)
95 (57.9)
6 (7.8)
25 (32.5)
1 (1.3)
16 (21.1)
16 (4.6)
151 (43.3)
142 (41.5)
Immigrant
8 (26.7)
64 (39)
43 (55.8)
29 (38.2)
Alcoholism
6 (20)
50 (30.5)
17 (22.1)
21 (27.6)
94 (26.9)
Chronic liver disease
4 (13.3)
22 (13.4)
5 (6.5)
20 (26.3)
51 (14.6)
Cocaine use
Marijuana use
Clinical features
Mucocutaneous
Lymphadenopathy
Syphilitic chancre
RPR result, median titer (IQR)
Complications
Neurosyphilis
4 (13.3)
29 (17.7)
7 (9.1)
9 (11.8)
49 (14)
3 (10)
15 (9.1)
4 (5.2)
7 (9.2)
29 (8.4)
0 (0)
14 (46.7)
138 (84.1)
60 (36.6)
0 (0)
0 (0)
0 (0)
0 (0)
30 (100)
1:16 (1:8–1:64)
41 (25)
1:32 (1:8–1:64)
0 (0)
0 (0)
1:4 (1:2–1:32)
0 (0)
1:2 (1:1–1:8)
138 (39.8)
74 (21.3)
71 (20.4)
1:8 (1:2–1:64)b
14 (8.5)
0 (0)
8 (10.5)
Rheumatologic
1 (3.3)
7 (4.3)
0 (0)
2 (2.6)
22 (6.3)
9 (2.6)
Any complication
1 (3.3)
26 (15.9)
0 (0)
10 (13.2)
37 (10.7)
NOTE. Data are no (%) of patients, unless otherwise indicated. HBV, hepatitis B virus; HIV, human immunodeficiency virus; IQR, interquartile range; MSM,
men which have sex with men; RPR, rapid plasma regain test; SD, standard deviation; STD, sexually transmitted disease.
a
b
Significant differences according to 1-factor analysis of variance.
Significant differences according to Kruskal-Wallis test.
Serologic Response to Syphilis Treatment • CID 2009:49 (15 November) • 1507
Table 2. Comparison of Clinical and Laboratory Findings of Human Immunodeficiency Virus (HIV)–Positive
and HIV-Negative Patients with Syphilis
HIV positive
(n p 184)
Variable
Percentage of total patients
Age, mean years SD
Male sex
MSM
53
36.7 7.6a
183 (99.5)
115 (62.5)
Disease stage
Primary
HIV negative
(n p 163)
OR (95% CI)
46.9
…
41.8 17.2a
115 (70.6)
36 (22.1)
…
78.7 (10.7–577)
5.9 (3.7–9.5)
13 (7.1)
17 (10.4)
0.6 (0.3–1.4)
Secondary
Early latent
116 (63)
32 (17.4)
48 (29.4)
45 (27.6)
4.1 (2.6– 6.4)
0.6 (0.3–0.9)
Late
Complication
23 (14.3)
53 (32.5)
0.3 (0.17–0.5)
10 (5.4)
8 (4.3)
7 (4.3)
2 (1.2)
1.28 (0.48–3.45)
3.66 (0.77–17.5)
21 (11.4)
16 (9.8)
1.18 (0.6–2.35)
CNS involvement
Uveitis
Any complication
Laboratory value
RPR result median titer (IQR)
CD4+ lymphocyte count, mean cells/mL SD
Viral load, mean RNA copies/mL (IQR)
Treatment received
1:32 (1:4–1:64)b
502 265
21,800 (ND–85,250)
HAART
Penicillin
Doxycyclin
Serologic failure, proportion (%) of patients
1:4 (1:2–1:32)b
NA
NA
…
…
…
73 (39.7)
170 (92.4)
NA
139 (85.3)
…
2.09 (1.05–4.21)
14 (7.6)
37/125 (29.6)
24 (14.7)
7/62 (11.2)
…
3.3 (1.38–7.93)
NOTE. Data are no (%) of patients, unless otherwise indicated. CI, confidence interval; CNS, central nervous system; HAART,
highly active antiretroviral therapy; IQR, interquartile range; MSM, men who have sex with men; NA, not applicable; ND, not
detectable; OR, odds ratio; RPR, rapid plasma reagin.
a
b
Cohen’s D statistic (95% CI) was 0.39 (0.18–0.6).
P ! .001, by Mann-Whitney test.
had neonatal syphilis (n p 2 ) were excluded from further analysis. Therefore, 347 patients with active syphilis constitute the
group herein analyzed.
Figure 1 shows the incidence of syphilis from 2003 through
2007. A 223% increase in syphilis incidence was observed (from
15.67 to 35 cases per 100,000 persons per year).
Table 1 summarizes the most relevant clinical findings of this
series: 85.4% of patients were men (ratio of male to female
patients, 6:1), of whom 51.7% were MSM; 41.5% of patients
were not native Spaniards (29.2% from South America or the
Caribbean, 6.3% from the European Union, 2.6% from Africa,
2.3% from Eastern Europe, and 0.3% from Asia). The mean
age ( SD) was 39.37 12.9 years, and age was significantly
higher among patients with late syphilis. Forty-nine percent of
all patients had received a diagnosis of HIV infection before
the development of syphylis.
Most patients (47.3%) presented with secondary syphilis.
Noteworthy, 25% of patients with clinical signs of secondary
syphilis still had a genital or oral chancre in different stages of
evolution. HIV-positive patients had coincidental chancre and
rash more frequently than HIV-negative individuals (25 of 184
1508 • CID 2009:49 (15 November) • González-López et al
vs 16 of 163 patients; OR, 1.45; 95% CI, 0.84–2.81). Among
patients with late syphilis, 10 (2.8%) had tertiary syphilis. Eight
patients received a diagnosis of meningovascular syphilis, and
2 had gummatous osteomyelitis.
Table 2 shows some epidemiologic, clinical, and laboratory
findings for cases of syphilis in HIV-positive and HIV-negative
individuals. HIV-positive patients were younger, more frequently were men, and presented with secondary syphilis more
frequently than HIV-negative persons. In addition, they had
higher RPR titers (P ! .001). We did not find that complications
occurred significantly more often in the HIV-positive than in
HIV-negative groups (Table 2).
Eighty-seven percent of the patients were treated with 1–3
intramuscular doses of 2.4 ⫻ 10 6 international units of benzathine penicillin G given weekly. In addition, 6.7% of the patients
who had neurosyphilis or were pregnant women were treated
intravenously with crystalline penicillin G over 10–14 days.
Eleven percent of patients received an alternative treatment with
oral doxycycline (100 mg every 12 h) over 3 weeks. Most of
these patients had a history of penicillin allergy.
Two patients died during follow-up because of causes other
than syphilis or HIV infection. Among patients treated who
had at least 1 follow-up visit within the first 12 months after
treatment, all seemed to respond and clinical failures were not
documented. Serologic response was assessed in 187 patients
(53.9%) who had their RPR titers tested periodically during a
12-month period or longer. One hundred sixty patients (46%)
were excluded from this analysis. These excluded patients had
not return for serial evaluations, were older (age SD,
42.7 14.1 vs 37.2 10.2 years), had late-stage syphilis (28%
vs 17%), and were HIV negative (62% vs 32) more frequently
than those included in the analysis. Among the 187 patients
for whom serologic response was serially tested, HIV-positive
patients had a previous history of sexually transmitted disease
(113 [90.4%] of 125 vs 25 [40.3%] of 62 patients; OR, 13.9;
95% CI, 6.4–30.5) and had early syphilis (112 [89.6%] of 125
vs 43 [69.4%] of 62 patients; OR, 3.81; 95% CI, 1.73–8.37)
more frequently than HIV-negative individuals. Otherwise, the
2 groups of patients did not differ in terms of RPR titers at
baseline or treatment administered.
Serologic failure was observed in 44 (23.5%) patients, 37
(29.6%) of 125 HIV-positive patients and 7 (11.2%) of 62 HIVnegative individuals (OR, 3.3; 95% CI, 1.38–7.93). HIV-positive
patients who experienced serologic failure and had persistent
RPR titers ⭓1:32 were selected to undergo lumbar puncture.
Abnormal cerebrospinal fluid results consistent with neurosyphilis were not observed.
Figure 2 shows the time to detection of serologic response
to treatment in both HIV-positive and HIV-negative groups.
This time was significantly longer among the HIV-infected patients (P p .001, by Breslow test). Although HIV-negative patients responded more frequently to treatment during most of
the follow-up, it seemed that in the long term (after 2 years
of follow-up), both groups shared similar response rates. Seroreversion was infrequent, and RPR titers ⭐1:16 persisted in
84.6% and 20% HIV-positive and HIV-negative individuals,
respectively, after 400 days (OR, 22; 95% CI, 2.1–232).
To assess the possible interaction of variables heterogeneously
distributed between the 2 groups, a Cox proportional hazards
model was created. Age, sex, RPR baseline titer, disease stage,
antibiotic treatment (penicillin G vs doxycycline), number of
penicillin doses (1 vs 3), HIV status, and levels of platelets and
leukocytes in blood were included as possible predictors of the
time to response to treatment. Only sex, disease stage, and HIV
status were predictors of the response. Multivariate analysis
indicated that men (HR, 0.38), patients in the late stage of
syphilis (HR, 0.46), and HIV-positive persons (HR, 0.61) demonstrated a slower serological response to treatment (Table 3,
model A).
To explain these findings and the slower response observed
among HIV-positive persons, time to response was analyzed
according to viral load, CD4+ T lymphocyte count, percent of
CD4+ T cells, and the slope of increase in CD4+ T cells. Bivariate
analysis did not find any significant difference between groups,
even though a trend to a slower response was observed among
those with greater viral loads and lower CD4+ T cell counts.
A new Cox model, including viral load, CD4+ T cell count,
and antiviral treatment as possible predictors, was created (Table 3, model B). Antiretroviral treatment was the single variable
that significantly reduced the time to serologic response (HR,
2.08; 95% CI, 1.35– 3.20; P p .001).
DISCUSSION
Our study confirms the rapid increasing trend of syphilis in
Madrid, which has happened before in other large European
and American cities, particularly among MSM, people infected
with HIV, and immigrants [3, 4, 11]. The increased ratio of
male to female patients observed in this series was probably a
reflection of the disproportionate burden of disease among
MSM, but considering the high number of patients self-identified as being heterosexual, it is tempting to speculate that the
diagnosis may be missed in a high proportion of women.
Another alarming observation was the fact that 53% of the
patients were coinfected with the HIV, and most were aware
of their HIV status before the onset of syphilis. These persons
had not modified their sexual habits despite of the risk of
acquiring other sexually transmitted diseases and of transmitting HIV to other individuals [6]. This behavior may cause an
increase in the incidence of HIV infection, as has occurred with
other sexually transmitted diseases such as gonorrhoea and
lymphogranuloma venereum, together with an enormous pressure on the health care systems [3, 6, 18, 19]. In addition, the
occurrence of cases of gummatous osteitis and meningovascular syphilis in this series suggests the emergence of severe
complications of tertiary syphilis among people who are currently being infected but not diagnosed or treated in the
years to come.
Some reports have shown an increased risk of neurosyphilis
in patients coinfected with HIV [11, 20]. However, in our series,
in which the estimated risk for having symptomatic early neurosyphilis was even higher than that estimated by others [11,
Table 3. Factors Determining Serologic Response to
Treatment in Patients with Syphilis
Factor
Model A (n p 187)
Men
Late stage syphilis
HIV positive
Model B (n p 125)
Antiretroviral treatment
Hazard ratio (95% confidence interval)
P
0.38 (0.18–0.79)
.010
0.46 (0.25–0.84)
0.61 (0.39–0.96)
.012
.035
2.08 (1.35–3.20)
.001
Serologic Response to Syphilis Treatment • CID 2009:49 (15 November) • 1509
Figure 2. Serologic response (rapid plasma reagin titers) to treatment in human immunodeficiency virus (HIV)–positive and HIV-negative patients
with syphilis. SE, standard error.
21], we did not find an increased frequency of this or other
complications among HIV-infected patients when compared
with HIV-negative persons. Similar data have been reported
elsewhere [22]. However, because cerebrospinal fluid samples
were not routinely examined and only HIV-positive patients
with serologic failure and persistent RPR titers ⭓1:32 were
selected for lumbar puncture, it is possible that diagnosis of
silent neurosyphilis could have been missed in some cases.
As shown by others [10], we did observe a higher number
of serologic failures among HIV-positive patients, compared
with HIV-negative individuals. This observation may have some
important clinical implications.
In the pre-AIDS penicillin era, documented serologic failures
to syphilis treatment were exceedingly rare. A 4-fold decrease
in RPR titers by the third or fourth month and an 8-fold
decrease in titers by the sixth to eight month was observed,
and for most patients treated for early syphilis, seroreversion
was documented after the first year [14, 23]. Clearly, this is not
the case in HIV-infected patients. This investigation showed
that HIV infection was associated with a slower serologic response to syphilis treatment. Time to response was significantly
longer among HIV-infected patients, and these patients were
less likely to experience serologic improvement after recommended therapy than were HIV-negative persons [12]. Low
RPR titers persisted in most HIV-positive patients at 1 year
after treatment, but as far as can be determined, this persistent
seropositivity did not signify treatment failure or reinfection.
Specifically, these patients were carefully followed up, lumbar
1510 • CID 2009:49 (15 November) • González-López et al
puncture performed in those with RPR titers 11:32 did not
show abnormalities, and at the time of writing, all of them
remain asymptomatic.
Analysis of the serologic response to treatment in our cohort
showed that men and patients with late syphilis exhibited a
slow response to treatment. This more gradual decrease in RPR
titers in patients with late stages of syphilis has been observed
by others [24]. However, to the best of our knowledge, this is
the first study to detect an influence of sex on the time to
serologic response to syphilis treatment. The significance of this
observation is unknown at the present time.
In contrast to other reports, neither the initial RPR titer nor
the CD4+ lymphocyte cell count significantly influenced serologic response to therapy [12, 25], although a trend toward a
faster response in patients with lower viral loads and higher
CD4+ T cell counts was observed. Remarkably, antiretroviral
therapy was the single variable associated with a significant
reduction of the time to serologic response in HIV-infected
patients with syphilis. This fact suggests that immune restoration, viral suppression, or improved B lymphocyte functions
may accelerate the decrease of RPR titers after treatment of
syphilis. In agreement with these data, others have shown that
antiretroviral therapy reduced the rate of serologic failures in
HIV-positive patients, and that in the absence of antiretroviral
therapy, serum RPR titers less accurately predicted treatment
success in patients with neurosyphilis [25, 26].
Our study has limitations. First, 32% of the HIV-positive
and 62% of the HIV-negative patients were not followed up,
a problem also found in other recent series [10, 16, 17]. HIVpositive patients had their RPR titers measured more frequently
than HIV-negative patients. This fact could have led us to underestimate the time to serologic response to treatment in the
HIV-negative group. Second, a large number of cases included
in the late syphilis group involved individuals with syphilis of
unknown duration. Although these patients were asymptomatic and did not show complications, it is possible that some actually had early syphilis.
Definition of serologic failure was arbitrary and similar to
that used by others; we chose a cut-off value of 13 months to
pick up a larger number of patients returning for 1-year followup tests [10]. However, taking into account the prolonged time
needed to achieve serologic response, a shorter period of time
would have been even less reliable to assess such response.
In summary, this study shows that an epidemic of syphilis
is taking place in downtown Madrid, affecting mostly MSM,
HIV-positive persons, and immigrants from South America and
the Caribbeans. Men, patients in the late stages of syphilis, and
HIV-positive persons may be at increased risk of serologic failure. Despite the recommendations for more frequent serological follow-up for HIV-positive patients with syphilis [13], most
patients did not have documentation of serologic response until
the end of the first year after treatment. Testing at 3–4 months
or even at 6 months, as recommended by guidelines, has a low
efficiency, and only a minority of patients responded by that
time. Therefore, early testing adds little benefit and may introduce a bias that leads to unnecessary retreatment. Low titers
will persist in most HIV-positive patients 1 year after treatment.
As far as can be determined, this persistent seropositivity does
not signify treatment failure or reinfection.
Acknowledgments
Potential conflicts of interest. All authors: no conflicts.
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