J Antimicrob Chemother 2018; 73: 1348–1351

doi:10.1093/jac/dky006 Advance Access publication 31 January 2018

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

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*Corresponding author. Tel: 86-010-69151500; Fax: 86-010-69151502; E-mail: [email protected]

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 retreatment.
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
Methods
caused 113000 deaths.3 During the past three decades, China Patients
has been experiencing a syphilitic epidemic (Figure 1), showing a Data on clinical and laboratory-diagnosed syphilis cases were retrospec-
rise in incidence from 6.4 per 100000 in 2000 to 32.9 per 100000 tively analysed. All syphilitic patients were outpatients who visited the sexu-
in 2013.4,5 Now, syphilis has become the third most reported com- ally transmitted disease (STD) centre of Peking Union Medical College
municable disease in China.6,7 Hospital, China, from January 2001 to January 2013. All cases were diag-
The current guidelines in both the USA8 and the UK9 recom- nosed as having various stages of syphilis according to the national CDC
mend benzathine penicillin as first-line treatment for syphilis. diagnostic standard. According to Chinese national guidelines,13 primary
However, not all cases achieve serological reversal after benza- syphilis is defined as a clinically compatible patient characterized by more
thine penicillin treatment; some cases show persistent reactive than one chancre and inguinal lymphadenopathy, and laboratory confir-
serological tests or fail to achieve serological cure, defined as a mation of Treponema pallidum in clinical specimens by RPR and particle
agglutination assay for antibody to Treponema pallidum (TPPA), or T. pallidum
,4-fold (2 dilution) decline in the rapid plasma reagin (RPR)
haemagglutination (TPHA), and/or fluorescent treponemal antibody absorp-
serological test at 6–12 months,8,10,11 which can be quite tion (FTA-ABS); secondary syphilis is defined as a clinically compatible patient
disconcerting for both the patient and the physician.12 characterized by skin rash and, in many patients, lymphadenopathy, and
Although we often retreat patients in clinical practice, the opti- confirmation by laboratory testing results as for syphilis; and early latent
mal treatment protocol remains uncertain due to the paucity of syphilis is defined as an asymptomatic patient with a possible history of syph-
data regarding serological response to retreatment and long- ilitic infection supported by positive RPR and a positive treponemal test, and
term outcomes. We conducted analyses of data to determine normal CSF. Clinicians from our STD centre ask for the possible infection time;

C The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
V
For Permissions, please email: [email protected].
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Retreatment of serofast early syphilis JAC
500000

450000

400000

350000

300000
Total cases

250000

200000

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150000

100000

50000

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 Statistical analysis
defined as early.
These analyses were performed on patients who were serofast at 6 months
after initial treatment, received re-therapy and had serological test results
Ethics at the 1 year visit. Proportions of subjects with seroreversion, serological
This retrospective study was approved by the Ethics Committee of Peking cure or serofast status after retreatment were defined at 1 year using the
Union Medical College (reference number S-K010). In our study, the infor- definitions above. Subjects who achieved serological cure after retreatment
mation was recorded by the investigator in such a manner that subjects and cases who remained serofast were compared for age and baseline and
cannot be identified; therefore, patient consent was not required. 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 a v2 test. Statistical analysis was performed using the SPSS stat-
Treatment istical package, version 19.0 (SPSS, Chicago, IL, USA).
According to Chinese national guidelines for the treatment of syphilis,13
cases with early syphilis are treated with two or three doses of benzathine
Results
penicillin at 2.4 million units given intramuscularly each week. Alternatives
to benzathine penicillin for the treatment of syphilis are 500 mg of erythro- Data on 1266 patients with early syphilis were collected. Of the
mycin given orally four times per day for 2 weeks, 100 mg of doxycycline 1266 patients, 179 (14.1%) were serofast at 6 months. We identi-
given orally twice per day for 2 weeks or 0.8 million units of procaine penicil- fied 70 eligible subjects with early syphilis who were serofast at
lin given intramuscularly per day for 10 days. After treatment, doctors 6 months after initial therapy with benzathine penicillin (n " 52) or
reviewed the serum RPR titres and clinical symptoms of all patients every
alternatives (n " 18). Study cases ranged in age from 21 to
3 months. The primary outcome was response to treatment, determined
58 years with a mean age of 32 years and a median age of
on the basis of changes in RPR titres at 6 months after therapy.
Seroreversion at 6 months following therapy was defined as becoming
30 years and 45 (64.3%) cases were female. Patients of Han
RPR negative after therapy. Serological cure was defined as either a nega- nationality comprised the majority of cases (n " 69, 98.6%).
tive RPR or a decrease of 2 dilutions (4-fold) in RPR titre. Serofast was The majority consisted of persons with education up to secondary
defined as either no change in RPR titre or a 1 dilution (2-fold) decrease or school (n " 41, 58.6%). Coinfection with other STDs was found in
increase in titre following initial therapy or retreatment. Subjects deter- two patients (2.9%). Only 1 (1.4%) serofast subject had primary
mined to be serofast at 6 months after initial therapy were included if they syphilis, 15 (21.4%) had secondary syphilis and 54 (77.1%) had
were retreated with three doses of benzathine penicillin, 2.4 million units early latent syphilis.
given intramuscularly each week starting at the 6 month visit. Individuals After retreatment with benzathine penicillin, 28 (40%) sub-
were excluded if they were known to be HIV infected; the baseline serologi- jects exhibited a .4-fold decline in RPR titres from their 6 month
cal test revealed a negative RPR test result (because our study was inter-
titres and 42 (60%) remained serofast at 12 months. However,
ested in serological response); they did not attend follow-up testing or
when serological response was determined relative to baseline
follow-up testing was inadequate to determine the serological test result of
treatment (i.e. ,6 months after retreatment); or they were confirmed to titres before initial treatment, 34 (48.6%) patients had achieved
have CNS infection after CSF specimen examination. Cases for whom HIV serological cure and 36 (51.4%) were serofast. Of those with
status was not documented were not excluded as they were expected to serological response following retreatment, 11 had serorever-
constitute a small percentage of study cases, because the prevalence of sion to a non-reactive RPR at the 1 year follow-up. Sex and age
HIV in our STD centre is low. were not associated with likelihood of achieving serological cure

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Wang et al.

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

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Initial treatment, n (%)
retreatment. Therefore, we cannot totally rule out that the sero-
benzathine penicillin 18 (53) 34 (94) ,0.001
alternativesa 16 (47) 2 (6)
logical cure/seroreversion shown by 54.5% of our cases may
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 basis
baseline 1:4, 1:32 and 1:64 1:2, 1:4 and 1:8 ,0.001
for the serofast status and to determine whether serofast cases
6 months 1:8, 1:16 and 1:32 1:2, 1:4 and 1:8 ,0.001
RPR titre, geometric mean (95% CI)
should undergo continued serological monitoring, retreatment or
baseline 23 (15–34) 4 (3–6) ,0.001
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-

Transparency declarations
nificant differences in disease stage, initial treatment regimen
None to declare.
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 References
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