Abstract
Persistent non-treponemal titres after treatment are common among patients with latent syphilis. Although retreatment is often done in clinical practice, optimal management remains uncertain due to the paucity of data regarding serological response to retreatment and long-term outcomes. We compared the serological responses of serofast latent syphilis patients retreated with 7.2 million units of benzathine penicillin with the responses of patients who did not receive retreatment (control group). We retrospectively analysed the serological response to therapy following retreatment of 35 serofast latent syphilis patients at 12 months with benzathine penicillin 2.4 million units weekly for 3 weeks. In all, 74.3% (26/35) of the cases with latent syphilis who failed to achieve serological cure at 12 months after initial therapy achieved serological cure after retreatment and after an additional 12 months of follow-up. However, statistically similar serological cure rate was observed in 80.0% (28/35) of the control group (p > .05). Our findings illustrate no improvement in serological response among serofast latent patients retreated with three doses of benzathine penicillin.
Keywords
Introduction
Syphilis is a spirochete infection with multiple manifestations. In the past two decades, syphilis has made a dramatic resurgence in China. During the Cultural Revolution (1966–1976), sexually transmitted infections (STIs) were so uncommon that they were removed from standard Chinese medical training curricula.
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As China’s market economy expanded during the 1980's economic reforms, reported STIs, including syphilis, quickly reappeared. An evolving STI reporting infrastructure, largely assembled in the 1990s, has noted increasing syphilis cases, particularly during the past 5 years (Figure 1). Now, syphilis is among the top three reported communicable diseases in China.2,3
Reported total syphilis cases in China from 1985 to 2013.
Early syphilologists noted that ‘the effective treatment of early syphilis is one of the critical medical problems of modern times’. 4 A continuing challenge to determine the response to treatment of latent syphilis is exemplified by the substantial proportion of patients who fail to achieve serological cure and remain serofast, defined as a <4-fold (2-dilution) decline in non-treponemal antibody titres at 6–12 months or as persistently low titres after treatment that was quite disconcerting for both the physician and patient.5,6 It remains unclear whether the persistent positive serological reaction indicates persistent foci of spirochetes or progressive syphilitic lesions or whether it reflects the persistence of reagin in the circulating blood following antisyphilitic therapy. Although retreatment is recommended for serofast patients if follow-up cannot be ensured, optimal management remains uncertain due to the paucity of data regarding serological response to retreatment and long-term outcomes. We conducted a retrospective case-control study to compare the serological response rates of serofast latent syphilis (late latent and latent of unknown duration) retreated with three doses benzathine penicillin and absence of any retreatment (control group).
Methods
Study population and setting
Demographic, clinical, and laboratory data of 697 late latent syphilis patients and 971 latent syphilis of unknown duration were retrospectively analysed. All syphilitic cases were outpatients who visited the STI clinic of Peking Union Medical College Hospital, China, from January 2001 to January 2012. In our STI clinic, socio-demographic, behavioural, and clinical data were recorded for all patients. Clinical data included stage of diagnosis, symptoms present at the time of diagnosis, treatment information, follow-up clinical symptoms, and lab testing. Socio-demographic characteristics investigated were gender, age, ethnicity (self-reported), relationship status, residence, occupation, and education. Behavioural information was sexual orientation, condom use, and lifetime number of sexual partners (self-reported). Our department is one of the largest public STI clinics in Beijing (population = 21,150,000), China, and often receives patients from distant areas within mainland China. Routine STIs screening and treatment are available at our clinic. The present retrospective study was approved by the Institutional Review Board of the Peking Union Medical College Hospital on 15 July 2014 (reference number S-K010).
According to national guidelines, 7 latent syphilis was defined as an asymptomatic case with a possible history of infection supported by reactive rapid plasma reagin (RPR) and a reactive treponemal test, and normal cerebrospinal fluid (CSF). Clinicians from our Institution asked their patients to self-report a possible infection time: when initial infection has occurred greater than 12 months previously, latent syphilis is classified as late; when the date of initial infection cannot be established, latent syphilis is classified as latent of unknown duration. Serological cure was defined as either a negative RPR or ≥4-fold (2 dilutions) decrease in titre. Serofast status for latent syphilis was defined as either no change in RPR titre or a 2-fold (1 dilution) decrease or increase in titre following initial therapy or retreatment. Latent syphilis patients determined to be serofast at 12 months after initial treatment were included in retreatment group (control group) if they were retreated (not treated) with three doses of benzathine penicillin (2.4 million units intramuscular each, separated by 1 week) at the 12-month visit and had serological data at the 24-month visit. Patients were excluded if the patient was known to be human immunodeficiency virus (HIV)-infected; the baseline serology showed a non-reactive RPR test (because our study was interested in serological response); follow-up was inadequate to determine serological outcome of treatment (i.e. minimum of 24 months after initial retreatment). Records from patients whose HIV status was undocumented were not excluded as they were expected to constitute a small proportion of study subjects, because the prevalence of HIV in our Institution is low during our study period (148/8473 [1.75%]).
Laboratory testing
Blood (4 mL) was collected from each patient during the first time they visited our STI clinic. RPR and treponemal T. pallidum hemagglutination (TPHA), or particle agglutination assay for antibody to T. pallidum (TPPA) (FUJIREBIO, Japan), and/or fluorescent treponemal antibody absorption (FTA-ABS) tests were performed on the blood samples at a central laboratory (Quality control: Syphilis Serology Proficiency Testing Survey, Laboratory Code Number 990077, Centers for Disease Control and Prevention Atlanta, WHO). Each test was performed by laboratory staff on sera according to manufacturer’s instructions.
Each patient’s stage of syphilis was assessed based on physical examination and serology results using criteria described previously.
Treatment
Patients were treated according to the Chinese National Programme for STIs from the Centers for Disease Control and Prevention. 7 Those with diagnosis of latent syphilis received benzathine penicillin G 7.2 million units in total, administered as three doses of 2.4 million units intramuscularly each at 1-week intervals. Alternatives to this treatment of syphilis were erythromycin 500 mg given orally four times daily for 14 days, doxycycline 100 mg orally twice daily for 14 days, or procaine penicillin 0.8 million units intramuscularly daily for 20 days.
Baseline characteristics of patients in the benzathine penicillin retreatment group, patients in the absence of retreatment (control) group, and retreatment results analysis.
Erythromycin, doxycycline, or procaine penicillin.
Statistical analysis
These analyses were performed on subjects who were serofast at 12 months after initial therapy, received retreatment or not, and had serological data at the 24-month visit. Proportions of subjects with serological cure or serofast status after retreatment were determined at 24 months using the definitions above. The χ2 test was used to compare categorical variables. The Mann-Whitney U test was used to compare ordinal data. p Values <.05 were considered to represent statistical significance. Data were analysed using SPSS for Windows, version 22.0 (IBM).
Results
A total of 35 serofast latent syphilis patients were included in each group. Table 1 summarises the demographic and clinical characteristics of the benzathine penicillin retreatment group and control group. There were no statistically significant differences in demographic or clinical characteristics between the two groups. The median age of both groups was 30 years, subjects were mostly women (24/35 in penicillin-retreated patients compared with 25/35 in control group), most (>97.1%) of the patients were Han nationality. Among the 35 latent serofast syphilis patients, 21 were late latent syphilis in penicillin-retreated group compared with 24 in control group (p > .05). The initial therapy and initial RPR titres were also similar. When serological response was determined relative to baseline titres before initial therapy, a statistically similar serological cure rate was observed in 74.3% (26/35) of penicillin-retreated patients when compared with 80.0% (28/35) of the control group (p > .05) (Table 1).
Discussion
Despite retreatment with 2.4 million units of benzathine penicillin weekly for 3 weeks, nine of the 35 patients with latent syphilis who failed to achieve serological cure at 12 months after initial therapy remained serofast at 24 months. However, in the control group, only seven of the 35 patients with latent syphilis who failed to achieve serological cure at 12 months after initial therapy remained serofast at 24 months. Our findings illustrate no improvement in serological response among latent serofast patients retreated with three doses of benzathine penicillin. Thus, we concluded that the seroreversion/serological cure exhibited in our participants may have been due to the natural decline in RPR titres after initial therapy, rather than due to the additional dose of benzathine penicillin. However, we need prospectively designed studies to confirm this hypothesis. Actually, male patients outnumber the female patients in our STI clinic, however, only a small part of serofast latent patients received retreatment at the 12-month visit and an even more less serofast latent patients visit our clinic at 24 moths for the RPR test. In this study, we included all the eligible serofast latent patients and the predomination of female patients reflect the selection bias.
Non-treponemal tests measure immunoglobulin M (IgM) and IgG antibodies to T. pallidum and potentially to lipoidal and cardiolipin material released from damaged host cells during syphilis infection, which may also result from other illnesses that can produce tissue damage. 8 Thus, stable non-treponemal antibody titres following therapy could represent persistent low-level infection with T. pallidum, variability of host response to infection, or possibly other confounding non-treponemal inflammatory conditions in the host, such as connective tissue disease or other infection. Therefore, assessing the biological significance of the serofast state is difficult. Although non-treponemal antibody titres generally correlate with syphilitic stage/disease activity, 5 the implications of high titres vs. low titres in the serofast state are unknown. However, our previous study 9 findings suggest that higher non-treponemal titres at treatment are associated with a higher probability of serological response to therapy. So, we tried to find the comparable initial RPR titre in both groups.
Clinical management of patients who remain serofast after treatment or retreatment for latent syphilis is challenging. Treatment failure, which is usually defined as a sustained 4-fold increase in non-treponemal titres after therapy, is considered to be an indication for CSF examination for T. pallidum involvement. 5 However, some experts also recommend CSF examination for patients who do not demonstrate serological response after treatment (≥4-fold decrease in non-treponemal test titre or sustained seroreversion occurring within 6 months of treatment). 10 Though we did not conduct CSF examinations for all of the serofast patients at the 12 - and 24-month visits, we excluded patients who were confirmed with neurosyphilis after CSF examinations. None with the patients available for follow-up who had not undergone CSF examinations exhibited symptoms suggestive of neurosyphilis during the study period.
Our study provides the first evaluation of serological response following retreatment of serofast latent syphilis cases with 2.4 million units of benzathine penicillin weekly for 3 weeks, though this is often done in clinical practice. Prior to our study, there has been only one study which focused on the serological response to therapy following retreatment of serofast early syphilis cases with only one dose of benzathine penicillin. 11 Our results suggest that there is no obvious benefit of retreating serofast patients with latent syphilis, which will avoid costly overtreatment of serofast latent syphilis and save a lot of money, especially in the situation that syphilis has reached alarming rates in China.2,3 Further, our findings provide further evidence for addressing the unresolved questions about the serofast state and its management. At present, the management of individual serofast patients will continue to require clinical judgment, consideration of non-treponemal antibody titres, underlying medical conditions such as HIV infection, and/or the likelihood that the patient will return for subsequent serological monitoring after treatment.12,13
We acknowledge that our study provides the first evaluation of serological response following retreatment of serofast latent syphilis, but we also have to admit some limitations of our study. First, the data originated from a retrospective study design which is generally considered inferior to prospective study design. Second, a high number of lost-to-follow-up patients constitute some bias for our study. Third, the results obtained in our study cannot be generalised to larger population due to the above reasons and long-term, close follow-up and better study design are needed for future studies.
Footnotes
Declaration of Conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: We acknowledge support from the Training Programme Foundation for the Beijing Municipal Excellent Talents (2013D009008000005) and young scientific research fund of Peking Union Medical College Hospital (PUMCH-2013-064).