J Antimicrob Chemother

doi:10.1093/jac/dky006

Serological response to therapy following retreatment of serofast early

syphilis patients with benzathine penicillin
Zhong-Shuai Wang, Xiao-Ke Liu and Jun Li*

Department of Dermatology and Venereology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences
and Peking Union Medical College, Beijing 100730, China

*Corresponding author. Tel: 86-010-69151500; Fax: 86-010-69151502; E-mail: lijun35@hotmail.com

Received 19 October 2017; returned 13 December 2017; revised 22 December 2017; accepted 2 January 2018

Background: Some syphilitic patients remain in a serologically positive state after the recommended therapy.
Although we often retreat patients in clinical practice, the optimal treatment protocol remains uncertain due to
the paucity of data regarding serological response to retreatment and long-term outcomes.
Methods: We examined rapid plasma reagin serological test results of 70 serofast early syphilis cases who
were retreated with 2.4 million units of benzathine penicillin weekly for 3 weeks. Serological retreatment
success was defined as a minimum 4-fold decrease in baseline rapid plasma reagin test antibody titre within 6
months.
Results: Thirty-four (48.6%) of the patients who failed to achieve serological cure at 6 months after initial
therapy achieved serological cure at 12 months. Patients who had higher non-treponemal titres at baseline and
at 6 months were more likely to exhibit serological cure after retreatment than those with lower titres.

Conclusions: Our results suggest that the incremental benefit of retreating serofast patients with early syphilis
is moderate, considering the almost 1:1 ratio of serological response to serofast state at follow-up.

Introduction the serological response of serofast early syphilis cases after

Since the year 2000, the incidence of syphilis has been
increasing in the UK, the USA, Canada, Europe and Australia.1
In sub-Saharan Africa, it contributes to 20% of perinatal deaths. 2
During 2010, it caused 113000 deaths.3 During the past three
decades, China has been experiencing a syphilitic epidemic
(Figure 1), showing a rise in incidence from 6.4 per 100000 in
2000 to 32.9 per 100000 in 2013.4,5 Now, syphilis has become
the third most reported com-municable disease in China.6,7
The current guidelines in both the USA 8 and the UK9 recom-
mend benzathine penicillin as first-line treatment for syphilis.
However, not all cases achieve serological reversal after benza-
thine penicillin treatment; some cases show persistent reactive
serological tests or fail to achieve serological cure, defined as a ,
4-fold (2 dilution) decline in the rapid plasma reagin (RPR)
serological test at 6–12 months,8,10,11 which can be quite
disconcerting for both the patient and the physician. 12 Although
we often retreat patients in clinical practice, the opti-mal
treatment protocol remains uncertain due to the paucity of data
regarding serological response to retreatment and long-term
outcomes. We conducted analyses of data to determine
retreatment.
Methods
Patients
Data on clinical and laboratory-diagnosed syphilis cases were retrospec-tively
analysed. All syphilitic patients were outpatients who visited the sexu-ally
transmitted disease (STD) centre of Peking Union Medical College Hospital, China,
from January 2001 to January 2013. All cases were diag-nosed as having various
stages of syphilis according to the national CDC diagnostic standard. According to
Chinese national guidelines,13 primary syphilis is defined as a clinically compatible
patient characterized by more than one chancre and inguinal lymphadenopathy,
and laboratory confir-mation of Treponema pallidum in clinical specimens by RPR
and particle agglutination assay for antibody to Treponema pallidum (TPPA), or T.
pallidum haemagglutination (TPHA), and/or fluorescent treponemal antibody
absorp-tion (FTA-ABS); secondary syphilis is defined as a clinically compatible
patient characterized by skin rash and, in many patients, lymphadenopathy, and
confirmation by laboratory testing results as for syphilis; and early latent syphilis is
defined as an asymptomatic patient with a possible history of syph-ilitic infection
supported by positive RPR and a positive treponemal test, and normal CSF.
Clinicians from our STD centre ask for the possible infection time;

VC The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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 Wang et al.

500 000

450 000

400 000

350 000

300 000
Total cases
250 000

200 000

150 000

100 000

50 000

0 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 Year

Figure 1. Reported total syphilis cases in China from 1985 to 2015.

when initial infection has occurred within the previous year, latent
syphilis is defined as early.
Ethics
This retrospective study was approved by the Ethics Committee of Peking
Union Medical College (reference number S-K010). In our study, the infor-
mation was recorded by the investigator in such a manner that subjects
cannot be identified; therefore, patient consent was not required.
Treatment
13
According to Chinese national guidelines for the treatment of syphilis, cases
with early syphilis are treated with two or three doses of benzathine penicillin
at 2.4 million units given intramuscularly each week. Alternatives to
benzathine penicillin for the treatment of syphilis are 500 mg of erythro-mycin
given orally four times per day for 2 weeks, 100 mg of doxycycline given
orally twice per day for 2 weeks or 0.8 million units of procaine penicil-lin
given intramuscularly per day for 10 days. After treatment, doctors reviewed
the serum RPR titres and clinical symptoms of all patients every 3 months.
The primary outcome was response to treatment, determined on the basis of
changes in RPR titres at 6 months after therapy.
Seroreversion at 6 months following therapy was defined as
becoming RPR negative after therapy. Serological cure was defined as
either a nega-tive RPR or a decrease of 2 dilutions (4-fold) in RPR titre.
Serofast was defined as either no change in RPR titre or a 1 dilution (2-
fold) decrease or increase in titre following initial therapy or retreatment.
Subjects deter-mined to be serofast at 6 months after initial therapy were
included if they were retreated with three doses of benzathine penicillin,
2.4 million units given intramuscularly each week starting at the 6 month
visit. Individuals were excluded if they were known to be HIV infected;
the baseline serologi-cal test revealed a negative RPR test result
(because our study was inter-ested in serological response); they did not
attend follow-up testing or follow-up testing was inadequate to determine
the serological test result of treatment (i.e. ,6 months after retreatment);
or they were confirmed to have CNS infection after CSF specimen
examination. Cases for whom HIV status was not documented were not
excluded as they were expected to constitute a small percentage of
study cases, because the prevalence of HIV in our STD centre is low.
Statistical analysis
These analyses were performed on patients who were serofast at 6 months
after initial treatment, received re-therapy and had serological test results at
the 1 year visit. Proportions of subjects with seroreversion, serological cure or
serofast status after retreatment were defined at 1 year using the definitions
above. Subjects who achieved serological cure after retreatment and cases
who remained serofast were compared for age and baseline and 6 month
RPR titres using a Wilcoxon two-sample test, and were compared for sex,
geometric mean RPR titres, initial treatment regimen and disease stage using
2
a v test. Statistical analysis was performed using the SPSS stat-istical
package, version 19.0 (SPSS, Chicago, IL, USA).
Results
Data on 1266 patients with early syphilis were collected. Of the
1266 patients, 179 (14.1%) were serofast at 6 months. We
identi-fied 70 eligible subjects with early syphilis who were
serofast at 6 months after initial therapy with benzathine
penicillin (n " 52) or alternatives (n " 18). Study cases ranged in
age from 21 to 58 years with a mean age of 32 years and a
median age of 30 years and 45 (64.3%) cases were female.
Patients of Han nationality comprised the majority of cases (n "
69, 98.6%). The majority consisted of persons with education up
to secondary school (n " 41, 58.6%). Coinfection with other
STDs was found in two patients (2.9%). Only 1 (1.4%) serofast
subject had primary syphilis, 15 (21.4%) had secondary syphilis
and 54 (77.1%) had early latent syphilis.
After retreatment with benzathine penicillin, 28 (40%) sub-
jects exhibited a .4-fold decline in RPR titres from their 6 month
titres and 42 (60%) remained serofast at 12 months. However,
when serological response was determined relative to baseline
titres before initial treatment, 34 (48.6%) patients had achieved
serological cure and 36 (51.4%) were serofast. Of those with
serological response following retreatment, 11 had serorever-
sion to a non-reactive RPR at the 1 year follow-up. Sex and age
were not associated with likelihood of achieving serological cure

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Retreatment of serofast early syphilis JA
C
Table 1. Characteristics and serological outcomes of serofast patients at 6 months, only a small proportion (2/82) exhibited seroreversion
with early syphilis retreated with benzathine penicillin after retreatment, whereas we reported a much higher proportion
(11/70) exhibiting seroreversion after retreatment with 2.4 million
Outcome at 12 months after initial
units of benzathine penicillin weekly for 3 weeks.
treatment (i.e. 6 months
after retreatment) Thirty-three of our patients who were serofast at 6 months
returned for additional follow-up at 2 years after initial therapy,
seroreversion/cure serofast showing a serological cure of 54.5% (18/33) when serological
Characteristic (N " 34) (N " 36) P
response was determined relative to baseline titres before initial
Male, n (%) 13 (38) 12 (33) 0.669 treatment. The limitation of this study is the lack of a comparison
Age (years), 25th, 50th and 75th 26, 30 and 37 28, 30 and 39 0.564 group by which to determine the expected decline in non-
Percentiles
treponemal titres among serofast cases in the absence of
Initial treatment, n (%)
retreatment. Therefore, we cannot totally rule out that the sero-
benzathine penicillin 18 (53) 34 (94) ,0.001
logical cure/seroreversion shown by 54.5% of our cases may
alternativesa 16 (47) 2 (6)
Syphilis stage, n (%) have been due to the natural decrease in RPR titres after initial
Primary 1 (3) 0 (0) 0.016 therapy, rather than due to the additional three doses of benza-
Secondary 11 (32) 4 (11) thine penicillin.
early latent 22 (65) 32 (89) Clinical management of syphilitic cases who are in a serologi-
RPR titre, 25th, 50th and cally active state after the recommended therapy is challenging.
75th percentiles Further investigations are essential to elucidate the biological
Baseline 1:4, 1:32 and 1:64 1:2, 1:4 and 1:8 ,0.001
basis for the serofast status and to determine whether serofast
6 months 1:8, 1:16 and 1:32 1:2, 1:4 and 1:8 ,0.001
cases should undergo continued serological monitoring,
RPR titre, geometric mean (95% CI)
Baseline 23 (15–34) 4 (3–6) ,0.001
retreatment or CSF examination for T. pallidum involvement.
6 months 14 (10–20) 4 (3–5) ,0.001

a
Erythromycin, doxycycline or procaine penicillin. Funding
This study was carried out as part of our routine work.

after retreatment (Table 1). However, there were statistically sig-

nificant differences in disease stage, initial treatment regimen
and the baseline and 6 month RPR titres between cases with
serological cure and serofast cases. The median baseline RPR
titre among the former was 1:32 compared with the median
baseline titre of 1:4 among serofast cases (P , 0.001). There
were similar differences in RPR titres at the 6 month visit
between groups; patients with serological cure had a higher
median RPR titre prior to retreatment than did patients who
remained sero-fast at the 1 year follow-up (Table 1).
Furthermore, geometric mean RPR titres were significantly
different between cases with serological cure and serofast status
at baseline and at 6 months (Table 1).
Discussion
After retreatment with 2.4 million units of benzathine penicillin
weekly for 3 weeks, 48.6% of cases with early syphilis who failed to
achieve serological cure at 6 months after initial treatment achieved
serological cure at 12 months, which is much higher than in a similar
14
study by Sena~ et al. [27% (22/80)]. However, Sena~ et al.
provided only one dose of benzathine penicillin for retreat-ment,
which may be the reason for the lower serological cure rate. Early
syphilis cases who had higher RPR titres at baseline ( 1:32) and at 6
months ( 1:16) were more likely to exhibit serological cure after
retreatment than those with lower RPR titres. In the sim-ilar study by
14
Sena~ et al., among the patients who were serofast
Transparency declarations
None to declare.
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