Predictors of serological cure and serofast stage after treatment in patients with syphilis: A retrospective study from India

Abstract

Background:

Patients with syphilis, who receive appropriate treatment, fail to achieve serological cure and have persistent nontreponemal titers. This study was conducted to analyze the factors associated with serofast stage after the treatment of patients.

Methods:

A retrospective study was conducted from January 2019 to June 2022, involving 70 patients with syphilis who were followed up for 12 months using the Venereal Disease Research Laboratory (VDRL) test.

Results:

Primary syphilis was observed in 11.4% (8), secondary syphilis in 77.2% (54), and latent syphilis in 11.4% (8) of the patients. The serological cure rates at 3, 6, 9, and 12 months were 10% (7/70), 41.4% (29/70), 50% (35), and 62.8% (44), respectively. Patients <25 years and with higher baseline VDRL titers (>1:16) had a better response to treatment. HIV-positive patients had 1.7-fold higher odds of serological failure compared to HIV-negative patients.

Conclusion:

In conclusion, our study underscores the need for tailored approaches to syphilis management and highlights the importance of ongoing research to enhance our understanding of treatment response predictors and optimize patient outcomes.

Introduction

Syphilis is caused by the obligate human pathogen Treponema pallidum (T. pallidum) subspecies pallidum.[1] The disease can be acquired via the sexual route, blood transfusion, or mother-to-child transmission. If left untreated, syphilis can last for years, and disease may progress, leading to irreversible neurological disease and death.[2] Early diagnosis and treatment monitoring is mandatory to prevent disease progression. Treatment typically involves injectable benzathine penicillin, with dosages adjusted based on the disease stage.[3] Posttreatment, clinical and serological monitoring is recommended to assess treatment efficacy. Nontreponemal antibody tests, such as rapid plasma reagin or Venereal Disease Research Laboratory (VDRL), are the gold standard for monitoring treatment. The Centers for Disease Control and Prevention (CDC) recommend regular nontreponemal testing at 3, 6, and 12 months posttreatment to monitor serological response, with a fourfold or greater reduction in titers within 3–6 months indicative of serological cure.[3,4] Patients with increase or <4-fold decrease in titers without reinfection are considered serofast.[3] The nontreponemal test titers that fail to decline >4-fold within 12 months of therapy may indicate treatment failure.[3] However, some patients exhibit slow titers’ decline or fail to achieve serological cure despite appropriate treatment.[5,6] According to recent studies, the recommended regimen results in serological cure rates ranging from 79% to 95%, while 10%–20% of patients treated adequately with the recommended therapy do not achieve the 4-fold decline in nontreponemal titers.[5,6] Previous studies have identified factors such as early disease stage, younger age, and high initial nontreponemal antibody titers (>1:16) as predictors of greater serological response.[5,7,8] Given the variability in treatment outcomes, it is essential to investigate factors influencing serological response to guide treatment guidelines. This study aims to evaluate the time to serological response and identify predictors of serological cure and serofast stage following syphilis therapy.

Methods

Syphilis staging was determined based on the STD treatment guidelines (2021) from the CDC.

Participants >18 years were included in this retrospective study conducted at a tertiary care center over a 2.5-year period from January 2019 to June 2022. Patients with reactive syphilitic serology who were expected to be in the vicinity of our follow-up for 1 year (except those who are migrating to other cities) were enrolled. Venereal Disease Research Laboratory (VDRL) test was performed as per the World Health Organization guidelines.[9] The T. pallidum hemagglutination test was conducted using the PLASMATEC kit (Novacyt Group, UK) following the manufacturer’s instructions.[10] The syphilis staging was determined based on the STD treatment guidelines (2021) from the CDC.[3] Data on demographic variables such as age, gender, sexual status/orientation, syphilis stage, and HIV status were collected. Treatment regimens prescribed by physicians consisted of a single intramuscular injection of 2.4 million units of benzathine penicillin G for early syphilis and three weekly doses for late syphilis. Complications such as Jarisch–Herxheimer reaction were documented. Patients were followed up at 3, 6, 9, and 12 months until resolution of symptoms and titers. VDRL titers were recorded at each visit. Serological cure was defined as a ≥4-fold decline in nontreponemal titer posttreatment. Serofailure was defined as failure to achieve a ≥4-fold decline in nontreponemal titer within a year. Serofast state was defined as nontreponemal titers with either a <4-fold decline or rise without reinfection posttreatment. The study was approved by the Institutional Ethics Committees (Ethics approval no. INT/IEC/2019/000188).

Statistical analysis

The statistical analysis was performed using Statistical Package for Social Sciences (SPSS, version 22.0, IBM Corp., Armonk, NY, USA). GraphPad Prism (version 9) was used to generate graphical representation. The Chi-square and independent t-test were used to compare differences in the categorical data and continuous variables. The odds ratio with 95% confidence interval (CI) was also calculated. P < 0.05 was considered statistically significant.

Results

Among the 120 syphilis cases initially assessed, 70 individuals with complete 12-month follow-up were included in the study. The median age of the cohort was 31 years (range: 19–67), with 59.3% being males. In our study, 11.4% had primary syphilis, 77.2% had secondary syphilis, and 11.4% had early latent syphilis. Serological cure rates were 62.5%, 63%, and 62.5% for primary, secondary, and early latent stages, respectively, with no significant difference observed based on clinical staging (P = 0.999) [Table 1]. The median time to achieve serological response in primary, secondary, and latent stage was 225 (range: 3–12 months), 365 (range: 3–12 months), and 180 (range: 6–12 months) days, respectively [Figure 1]. Among the 70 patients, 37.2% (26/70) were serofast, while 62.8% (44/70) achieved serological cure. The cure rate increased over time. The serological cure rate was 10% (7/70) at 3 months and improved to 41.4% (29/70) at 6 months. At 9 and 12 months, 50% (35) and 62.8% (44) patients achieved serological response. Of the 41 individuals not achieving a 4-fold reduction in VDRL titers at 6 months, 36.5% (15/41) responded to retreatment, while the remainder remained serofast (26/41). Females exhibited decreased odds of serological cure compared to males, as did patients older than 25 years compared to those under 25 years (odds ratio [OR]: 1.508 [0.737–3.084]) [Table 1]. Baseline VDRL titers > 1:16 were associated with higher odds of serological cure (OR: 1.244, CI: 0.615–2.517) [Table 1]. HIV-positive patients (8/70) on antiretroviral therapy had 1.7-fold higher odds for serological failure compared to HIV-negative patients [Table 1].

Table 1.

Variables associated with serological cure and serofast individuals

	Serofast participants (n=26), n (%)	Serological cure participants (n=44), n (%)	P	OR (95% CI)
Age (years), mean
≤25	19 (42.2)	26 (57.8)	0.179	1.508 (0.737–3.084)
>25	7 (28)	18 (72)		0.802 (0.566–1.138)
Gender (male)	20 (37)	34 (63)	0.597	0.993 (0.645–1.528)
HIV status
Yes	5 (2.5)	3 (37.5)	0.119	1.763 (0.7084.390)
No	21 (33.9)	41 (66.1)		0.542 (0.286–1.027)
Syphilis stage
Primary	3 (37.5)	5 (62.5)	0.999	1.006 (0.569–1.779)
Secondary	20 (37.0)	34 (63)		0.993 (0.645–1.528)
Early latent (<1 year)	3 (37.5)	5 (62.5)		1.006 (0.569–1.779)
Baseline VDRL/RPR
≤1:16	7 (31.8)	15 (68.2)	0.363	0.886 (0.615–1.278)
>1:16	19 (39.6)	29 (60.4)		1.244 (0.615–2.517)
VDRL or RPR titre at the time of presentation
1:1	0	2 (100)	0.543
1:4	0	1 (100)
1:8	5 (27.8)	13 (72.2)
1:16	7 (35)	13 (65)
1:32	10 (47.6)	11 (52.4)
1:64	4 (50)	4 (50)

VDRL=Venereal disease research laboratory; RPR=Rapid plasma regain; HIV=Human immunodeficiency virus; OR=Odds ratio; CI=Confidence interval

Figure 1.

Pictorial representation of the days to resolution in primary, secondary, and latent syphilis, where each dot represents the patient

Discussion

This study aimed to investigate the factors influencing serological cure and the persistence of the serofast state following syphilis treatment. The CDC recommends clinical and serologic reassessment every 6 months for 12–24 months which is indicated by decline in nontreponemal serological test titers by >4-fold or more.[3,4] However, serological response in effectively treated individuals is seldom universal, and 15%–20% of patients with early syphilis may have serofast titers.[11] In our study, we observed a serofast prevalence of 37.2%, consistent with previous reports, which demonstrates the serofast stage in 30%–40% of the population.[8,12] What variables affect the probability of achieving a serological cure? We observed that individuals who are younger, or have greater serological test titers at the time of diagnosis, and HIV negative were associated with a serological cure.

We observed that patients >25 years had a reduced odds of serological cure than individuals <25 years of age. This finding aligns with existing literature suggesting that older age may compromise immunological response to syphilis therapy due to immunosenescence and immunosuppression.[5,11,13,14,15] The serological response rates in our study varied over time, with gradual improvement from 10% at 3 months to 62.8% at 12 months posttreatment.

However, the overall serological response rate in this study was lower in comparison to other studies, where 78%–80% and 87%–91% attained serological response at 6 and 12 months after treatment, respectively.[5,13] These data largely reflect previous research findings that a significant decrease in the serofast proportion over time is low.[5,13] It is also critical to comprehend the clinical significance and influence of the stage of syphilis on the serological response. Sena et al. observed higher percentage of serological cure early syphilis than later stages of syphilis. However, we did not observe difference according to our findings.[11] The serofast stage could suggest therapeutic failure or reinfection, necessitating a retreatment. We observed that retreatment of serofast patients with benzathine benzylpenicillin at 6 months resulted in a serological response in 36.5% of the patients. Our results highlight the similar findings in various studies, which suggests that only a small proportion of patients who remain serofast following therapy benefit from additional treatment, and the second retreatment did not appreciably increase the patient’s serological cure rate.[16,17] This suggests that the serofast state could be the result of fluctuating host antibody response or persistent nonsyphilitic inflammatory diseases.[17] In our study, higher baseline VDRL titers (>1:16) were associated with better treatment response. Our findings also largely support previous research that the patients with higher baseline nontreponemal titers achieved greater serological cure.[11] This may be attributed to enhanced inflammatory and induced immune response facilitating T. pallidum clearance in a patient with high baseline nontreponemal titer.[18] Conversely, HIV coinfection was associated with a higher risk of serological failure, likely due to impaired immune function compromising antibody production as reflected from previous studies.[19]

Conclusion

Our study highlights the complexity of serological response to syphilis treatment and the persistence of serofast states. Factors such as age, baseline VDRL titers, and HIV status significantly influence treatment outcomes, emphasizing the need for tailored management strategies and further research into the immunological mechanisms underlying treatment response in syphilis patients.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.