Syphilis is a sexually transmitted bacterial infection caused by Treponema pallidum and is prevalent among high-risk population such as men who have sex with men (MSM). Patients diagnosed with syphilis are frequently coinfected with HIV.1 In Thailand, the increasing trend of this coinfection may be accounted for by social changes regarding prostitution, the booming sex industry, sex tourism, the use of the Internet to find short-time sex partners, the migration of workers, and lack of knowledge for sexually transmitted infection (STI) prevention.
Bangrak STIs Center is the largest outpatient STI clinic in Thailand, the referral center for tertiary care of STI under the Division of AIDS and STIs of the Department of Disease Control. However, only STI treatment service and not HIV antiretroviral treatment is provided. The center adheres to the Thai National Guidelines for syphilis and US Centers for Disease Control and Prevention guidelines.2,3 Since 2015, reverse syphilis test algorithm with chemiluminescence has been used to diagnosis syphilis.
For individuals infected with HIV, there may be atypical serological response in nontreponemal titers. The association between serological response and HIV status is inconsistent. Some studies indicated that HIV-infected patients had a slower rate of decline in nontreponemal titers, whereas some showed no association.4 CD4+ cell count, HIV viral load, and antiretroviral therapy remained controversial for their associations.5–8
Together with clinical correlation, serological titers are important in monitoring the treatment outcomes.2,3 The rate of decline in Venereal Disease Research Laboratory test (VDRL) titers and seroreversion after syphilis treatment in patients with HIV are found to be slower than those infected with syphilis alone.4,9,10 Characterizing the expected serological responses after treatment is crucial for our interpretation of the nontreponemal titers. Furthermore, determining factors associated with serological decline among syphilis patients based on their HIV status may be beneficial in suggesting appropriate treatment and follow-up schedule for Thailand's syphilis guideline. In view of benzathine penicillin G (BPG) drug accessibility and shortage issues, this study aims to examine the relative effectiveness of BPG versus oral therapy.
MATERIALS AND METHODS
This is a single-center descriptive study of patients diagnosed with syphilis at Bangrak STIs Center in Bangkok, Thailand, from January 1, 2007, to December 31, 2016. Available medical records were reviewed. The inclusion criteria were patients with confirmed syphilis infection by either VDRL titer together with treponemal test or VDRL titer together with evidence of syphilis infection by dark-field microscopy who received initial treatment at Bangrak STIs Center. The patients must have one baseline titer and at least one posttreatment follow-up VDRL titer. Syphilis patients with nonreactive VDRL were excluded from the study.
The 2015 Thai STD Guidelines divide syphilis into 2 stages: early syphilis and late syphilis. Early syphilis composes of primary, secondary, and early latent syphilis, which is treated with 2.4 million units of BPG once intramuscularly. Late syphilis composes of late latent syphilis and latent syphilis of unknown duration, which is treated with 2.4 million units of BPG injected weekly in a total of 3 weeks. All stages of syphilis were recommended to be followed up at 3, 6, 12, and 24 months in non-HIV cases and at 3, 6, 9, 12, and 24 months in HIV patients.
Serological response after treatment is defined according to the Centers for Disease Control and Prevention.2 Serological cure is defined as at least 4-fold decline of nontreponemal titers or seroreversion to nonreactive results. Treatment failure or reinfection is classified as at least 4-fold rise in titer with persistence or recurrence of syphilis signs and symptoms. According to the 2015 Thai STD Guidelines, serological nonresponse was defined as less than 4-fold decline in titer at least 6 months after treatment in early syphilis and 12 months in late syphilis. In this study, we decided to opt for the shortest serological follow-up time to mitigate the risk of patient loss to follow-up. Serofast definition was based on the study by Tong et al.11 as persistently positive low-level nontreponemal titers (<1:8), which neither increases nor decreases by at least 4-fold after 12 months of treatment. This study extended the 12-month follow-up to 400 days to include patients who may have missed their appointments.
The VDRL test (Beckon Dickinson) and treponemal tests (chemiluminescence immunoassay; Roche, Cobas E411) or T. pallidum particle agglutination test (Serodia TP-PA; Fujirebio) were performed on all sera according to the manufacturers' instructions. Serum with VDRL nonreactive in the first visit was tested up to 1:64 dilution to avoid the prozone phenomenon.
Sample Size Calculation
The sample size of 500 was calculated from serological nonresponse of 12.1% calculated based on a previous review by Sena et al.4 A person-time rate and Poisson exact 95% confidence interval (CI) were performed using OpenEpi version 3.01 program. It was assumed that each patient has a 1-year serological follow-up. The annual reports of Bangrak STIs Center between 2010 and 2016 showed an average of 227 syphilis patients attending the clinic per year.12 To obtain a sample size of 500, medical records were collected backward in a chronological order until a sample size of approximately 500 patients was reached.
Patients with missing data were excluded from the analysis. Bivariate analysis was conducted by Pearson χ2 or Fisher exact test as deemed appropriate. The median of 2 continuous variables was analyzed using the Mann-Whitney test or Kruskal-Wallis test. Survival curve analysis with log-rank test was conducted to determine differences in time to serological cure. Significant variables were further analyzed with the Cox regression model to estimate the hazard ratio (HR) associated with serological cure.
The protocol and data collection forms were approved by the ethics committee of the Faculty of Tropical Medicine, Mahidol University (MUTM 2017-061-01), and the Department of Disease Control Ethics Committee (Code 61005).
There were 1393 patients diagnosed with syphilis infection by International Classification of Diseases, Tenth Revision from Bangrak STIs Center between January 1, 2007, and December 31, 2016. Eight hundred ninety-six patients were excluded for the following reasons: 190 syphilis patients were TPHA positive but nonreactive VDRL, 673 syphilis patients had no follow-up VDRL, 31 patients did not have pretreatment VDRL as they did not initiate treatment at Bangrak STIs Center, 1 patient had a false-positive treponemal test result (patient came for general checkup with no symptoms; initial tests showed a positive chemiluminescence immunoassay result and nonreactive VDRL, but subsequent TPHA was negative), and 1 patient had incomplete data, resulting in 497 patients eligible for analysis.
Demographic Characteristics, Sexual Risks, Syphilis Presentations and Treatment
Among 1393 patients, there were altogether 731 (52.4%) that were excluded from the study due to loss to follow-up after initiating treatment. There were no demographical differences between patients included in the study and those lost to follow-up (Table 1; Online Supplementary Table 1, http://links.lww.com/OLQ/A478).
Of 497 patients analyzed, 95.8% were male with the median age of 30 years (interquartile range [IQR], 24–39 years). Approximately, 74.7% lived in Bangkok, 96.6% were Thai citizens, and 80.4% were MSM. In addition, 78.1% reported at least 1 sexual risk within the past 3 months, mainly from sex without condom use or condom break or leakage (74.2%), and 54.3% had sex with new partners, whereas 47.1% had more than 1 sexual partner concurrently.
The 2 main reasons for visiting the STI clinic were STI symptoms (38.4%) and referrals from other institutions (38.0%). Other reasons were sexual health checkup and decision to consult the doctor after their partner(s) showing STIs or abnormal symptoms. Of those who exhibited symptoms, 44.1% presented with rash, whereas 36.8% had no syphilis symptoms at presentation. Although the genitalia was the common site of syphilitic ulcers (12.9%), anal and oral ulcers were also occasionally reported (1.6% and 0.4%, respectively). Alopecia and/or madarosis were less reported (1.6%).
Approximately, 42.3% were found to have HIV coinfection, whereas 44.0% were HIV negative, and 13.7% had unknown HIV status because of denial of HIV testing after routine HIV counseling. Patients with other coinfections included 11.2% with chlamydia, 5.6% with hepatitis B infection, and 5.6% with gonorrhea.
Regarding the stage of syphilis, more than half were secondary syphilis (51.3%), followed by late latent and latent syphilis with unknown duration (31.0%), early latent syphilis (13.5%), and primary syphilis (4.2%). More than half (67.8%) of syphilis patients were treated with BPG, whereas 32.2% with other oral medications including doxycycline (18.3%), roxithromycin (7.2%), erythromycin (4.8%), and tetracycline (1.8%). The median baseline VDRL titer was 1:16 (IQR, 1:4–1:32), with minimum baseline titer being weakly reactive and maximum at 1:4096. After removing the outlier and categorizing by HIV status, the mean baseline titers were 1:32 for HIV-positive patients and as low as 1:16 in HIV-negative patients. By syphilis stage, the median baseline titer was highest in secondary syphilis (1:32), followed by primary (1:8), early latent (1:8), and late latent and latent syphilis with unknown duration (Online Supplementary Table 2, http://links.lww.com/OLQ/A478). Serological cure was achieved in 62.1%, whereas 2.2% was classified as nonresponse, 4.6% as treatment failure or reinfection, and 9.9% as serofast status. Serological response could not be interpreted in 105 patients (21.1%) who had at least one VDRL titer follow-up but lost to follow-up before 6 months in early syphilis and 12 months in late syphilis.
Factors Associated With Serological Cure After Syphilis Treatment
Patients were separated into 2 groups: 309 patients with serological cure and 83 patients who did not achieve serological cure including those with nonresponse, treatment failure or reinfection, and serofast status. Patients with early syphilis (79.6%) were 1.25 times more likely to achieve serological cure as compared with late syphilis (RR, 1.25; 95% CI, 1.07–1.46). Achieving serological cure was 1.14 times more likely in patients with baseline titer ≥1:32 than titer <1:32 (RR, 1.14; 95% CI, 1.03–1.26). However, along with the rest of other factors, there were no significant differences in patients with and without HIV coinfection (46.3% vs. 53.7%; RR, 0.94 [0.84–1.05]; Online Supplementary Table 3, http://links.lww.com/OLQ/A478).
Time to Serological Cure After Syphilis Treatment
Survival analysis with log-rank test was conducted to determine median time to serological cure. One hundred five (21.2%) patients with undetermined serological outcomes due to loss to follow-up were excluded from analysis. The graph showing time to serological cure after treatment up to 400 days is shown in Figure 1.
Overall, time to serological cure in treated syphilis patients was 110 days (95% CI, 100–120 days). In early syphilis, time to serological cure was 99 days (95% CI, 94–104 days), whereas time to cure in late syphilis was 144 (69–219) days. Time to serological cure was 98 days (95% CI, 93–103 days) and 131 days (95% CI, 110–152 days) in patients with baseline titers ≥1:32 and <1:32, respectively. In addition, further stratified with other baseline titers, >1:64 and <1:8, time to serological cure was 123 days (95% CI, 74–172 days) and 192 days (95% CI, 130–254 days), respectively.
Variables that showed the difference between time to serological cure with P < 0.1, namely, occupations, syphilis stages, and baseline titers, were analyzed using the Cox regression model. After adjustment, syphilis stage was the only significant factor. Early syphilis was 1.75 times more likely to be serologically cured after treatment than late syphilis (HR, 1.75 [1.32–2.32]).
Time to serological cure in early syphilis patients with HIV was significantly longer than that in HIV-negative patients with time duration of 124 days (95% CI, 59–189 days) and 94 days (95% CI, 89–99 days), respectively (P = 0.002). A quarter of early syphilis patients were serologically cured at 55 days among HIV-positive patients and 48 days among HIV-negative patients. On the other hand, the difference between time to serological cure was not significant among HIV status in late syphilis patients (P = 0.104). Time to serological cure was 109 days (95% CI, 84–134 days) and 249 days (95% CI, 86–412 days) in HIV-positive and HIV-negative patients, respectively. A quarter of late syphilis patients reached serological cure at 55 days among HIV-positive patients and 112 days among HIV-negative patients (Fig. 1).
In patients with high baseline titer (≥1:32), time to serological cure was significantly longer in patients with HIV (105 days [95% CI, 82–129 days]) as compared with HIV-negative patients (91 days [95% CI, 63–119 days]; P = 0.003). In the meantime, no difference was observed between HIV status among patients with baseline titer <1:32 (P = 0.743).
Because the standard treatment of syphilis was BPG, stratification by HIV status was done to compare time to serological cure between treatment with BPG and oral medications. Although time to serological cure was longer in other oral medication treatment, there was no significant difference between the time to serological cure among patients treated with BPG and other treatments in both HIV-positive and HIV-negative patients (P = 0.588 and P = 0.419, respectively; Fig. 2, Table 2).
This is a large retrospective longitudinal analysis of (primarily MSM) patients diagnosed with syphilis attending an STI clinic in Bangkok, Thailand, from January 2007 to 2016, which seeks to characterize factors associated with serological cure or serofast status as well as a survival analysis assessing time to serological cure, comparing patients based on factors such as HIV status and syphilis stage. In this study, serological cure was achieved by 62.1%. Factors associated with serological cure were early syphilis, baseline titer ≥1:32, and patients with no sexual risks within the past 3 months. Higher baseline titers and earlier stage of syphilis were associated with serological cure or faster rate of decline in titers.11 In general, there was an increased likelihood of cure among patients with early syphilis as compared with late stage of infection.4 However, early syphilis stage was the only factor associated with time to serological cure (by Cox regression model). Time to serological cure among early syphilis patients was significantly longer in HIV-positive than HIV-negative patients (P = 0.002), whereas no difference was observed in late syphilis (P = 0.104).
Regarding the stage of syphilis, most patients were diagnosed with secondary syphilis (51.3%), followed by late latent syphilis and latent syphilis with unknown duration (31.0%). The proportion of secondary syphilis was similar to previous studies (47.3% and 50%),9,13 whereas late syphilis was higher than previous studies (13.0% and 21.9%),9,13 possibly because of referrals of asymptomatic patients from other institutions for treatment. Underreporting of primary syphilis is possible because our study excluded syphilis with nonreactive VDRL. Serological cure was achieved in 62.1% within 1 year as compared with 40.0% to 99.1% in a previous systematic review by Sena et al.4 The variations in study design between studies contributed to the different percentage of MSM, HIV prevalence, and syphilis stages, consequently affecting serological cure. In addition, studies differed with respect to study follow-up periods. The period during which the titers were assessed varied from 6 months to less than 5 years.4 In our study, we followed up patients only 6 months in early syphilis and 12 months for late syphilis. Serological outcome could not be determined in patients who did not complete the designated follow-up. Among serofast patients, slower serological responses may be observed, and upon serologically following them further, we may find a higher percentage of cure. Follow-up for longer periods may be useful. In addition, more research on serological response in serofast group should also be done.
Our study found a strong relationship between early syphilis stage, baseline nontreponemal test titer ≥1:32, and serological cure rate. This finding is consistent with other studies.7,8,10,14–22 A prospective, randomized syphilis trial conducted in the United States and Madagascar showed that serological cure was associated with younger age, fewer sex partners, higher baseline rapid plasma reagin (RPR) titers, and earlier syphilis stage (P ≤ 0.008). A baseline RPR titer >1:32 was associated with a >6-fold increased probability of serological cure, compared with having a baseline RPR titer ≤1:32.16 Another cohort study from Zhongshan Hospital also showed that early syphilis stage was associated with an increased likelihood of a serological cure (odds ratio [OR], 2.391; P < 0.001).11 Most early syphilis patients exhibited high baseline titer, signifying an inflammatory immune response to T. pallidum, which in turn facilitated clearance of the organisms.23 This result emphasizes the importance of syphilis serological screening in patients with risky sexual behaviors for prompt detection of early syphilis.
Time to serological cure was significantly faster in early syphilis (99 days) than late syphilis (144 days). This is consistent with a previous study showing 37 days for primary syphilis, 49 days for secondary syphilis, and 68 days for latent syphilis. However, time to serological cure was overall longer because the follow-up VDRL schedule in this study was 90 days after treatment as compared with 30 days after treatment in a previous study.13
In HIV-infected patients, time to serological cure among early syphilis patients and high baseline VDRL titers (>1:32) was significantly longer in HIV-positive than HIV-negative patients, whereas no difference was observed in late syphilis. A retrospective cohort study among syphilis patients with known HIV status observed serological failure in 29.6% in HIV-positive patients compared with 11.2% in HIV-negative patients (OR, 3.3; P < 0.05). HIV-infected men with late syphilis demonstrated a slower serological response to treatment.14 Some studies showed that HIV patients had slower decline in RPR titer and serological failure.24 Ghanem et al.10 compared serological responses to treatment between HIV-positive and HIV-negative patients attending STD clinics in Baltimore, MD. Treatment failure was defined as lack of a 4-fold decline in RPR titer by 400 days after treatment or a 4-fold increase in titer between 30 and 400 days. HIV-positive patients have an increased risk of serological failure (HR, 6.0; 95% CI, 1.5–23.9). Time to serological response was 278 days in the HIV group (95% CI, 209–350 days) and 126 days in the non-HIV group (95% CI, 108–157 days). In a study by Jinno et al.6 among HIV-positive patients with early syphilis, serological failure was associated with low baseline RPR ≤1:16, syphilis history, and low CD4 cell count <350 cells/mL. Several other studies showed increased risk of serological failure after treatment in HIV infection with lower CD4+ cell counts due to poor T-cell response5 and increased HIV viral load.10,25,26 Unfortunately, CD4+ count and HIV viral load were not available in the records of Bangrak STIs Center.
In contrast, a large-scale cohort study conducted in Zambia and Rwanda involving 933 HIV-infected and 388 HIV-uninfected patients demonstrated that HIV infection did not impact the likelihood of serological response to therapy in a multivariate analysis (OR, 1.00; P = 1.00).17 The study of high-risk patients in Peru by Long et al.22 did not show any difference in treatment success rate between syphilis patients with HIV and those without (90.9% vs. 93.8%). A retrospective cohort study of 264 patients with syphilis by Knaute et al.13 showed no significant associations between serological response and HIV infection in multivariate Cox regression analysis. However, HIV patients with CD4+ cell count <500 cells/μL with primary syphilis had a slower serological response. Our study demonstrated that a quarter of early syphilis patients were cured within 2 months after treatment and half were cured within 5 months after treatment. In late syphilis, a quarter of patients had serological cure within 2 months and half of them within 9 months. From this finding, instead of postponing the appointments, we suggest scheduling for earlier appointments at 2, 5, and 11 months after treatment for those who cannot keep the regular course of 3-, 6-, and 12-month follow-up schedule, and every patient should be followed up until 24 months according to the guideline. All syphilis patients, especially those with HIV coinfection, are encouraged for both clinical and serological follow-up.
The World Health Organization recommends intramuscular BPG as the treatment of choice for syphilis, whereas doxycycline, tetracycline, and ceftriaxone are the alternatives. Azithromycin is an option in special circumstances only when local susceptibility to azithromycin is likely.1 Despite the STI guidelines indicating BPG as the first-line drug for syphilis treatment, only 67.9% of the patients were treated with BPG. Oral medications were prescribed for the following reasons: allergy to penicillin (4.8%), the national shortage of BPG in Thailand from July 2011 to August 2012, the patients' preference for oral medications and physicians' decision.
Together with many previous studies, our study showed similar serological response to treatment between oral medication namely doxycycline, ceftriaxone, tetracycline, and BPG.24,27–29 In HIV-infected patients, the serological failure rates were not significantly different between HIV-infected patients treated with a 14-day course of doxycycline and a single dose of BPG (adjusted OR, 0.92 [95% CI, 0.54–1.58]). Doxycycline can therefore be used as an alternative treatment in HIV-infected patients for syphilis in case BPG is not available.30 Yang et al.15 evaluated the effect on serological responses between treatment with 1 dose or 3 weekly doses of BPG in HIV-infected patients with early syphilis. Serological cure was more likely in 3-weekly-dose regimen as compared with a single dose (adjusted OR, 1.68 [95% CI, 1.20–2.36]). However, other studies in the systematic review showed no association between treatment regimens.4
This retrospective study relied solely on the information from medical records. Bangrak STIs Center was relocated in 2016, causing some records to be unavailable. Because sexual risk information was obtained from the patients' history, it may be subject to interviewers' bias and recall bias. Further studies on populations such as female sex workers, MSM, or HIV-positive patients could give more information on the factors associated with outcome and treatment response.
In conclusion, most patients who reached serological cure and early syphilis stage were associated with faster time to serological cure. Prompt detection and early treatment can improve time to serological cure. HIV patients with early syphilis took a longer time to reach serological cure than HIV-negative counterparts, whereas no such difference was observed in late syphilis. These findings are beneficial for determining a recommended follow-up schedule in future Thai STD Guidelines. In light of BPG accessibility in Thailand, alternative oral medications can be used.
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