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Abstract
Objectives Syphilis outbreaks in urban men who have sex with men (MSM) are an ongoing public health challenge in many high-income countries, despite intensification of efforts to screen and treat at-risk individuals. We sought to understand how population-level coverage of asymptomatic screening impacts the ability to control syphilis transmission.
Methods We developed a risk-structured deterministic compartmental mathematical model of syphilis transmission in a population of sexually active MSM. We assumed a baseline level of treatment of syphilis cases due to seeking medical care in all scenarios. We evaluated the impact of sustained annual population-wide screening coverage ranging from 0% to 90% on syphilis incidence over the short term (20 years) and at endemic equilibrium.
Results The relationship between screening coverage and equilibrium syphilis incidence displayed an inverted U-shape relationship, with peak equilibrium incidence occurring with 20–30% annual screening coverage. Annual screening of 62% of the population was required for local elimination (incidence <1 case per 100 000 population). Results were qualitatively similar in the face of differing programmatic, behavioural and natural history assumptions, although the screening thresholds for local elimination differed. With 6-monthly or 3-monthly screening, the population coverage required to achieve local elimination was reduced to 39% or 23%, respectively.
Conclusions Although screening has the potential to control syphilis outbreaks, suboptimal coverage may paradoxically lead to a higher equilibrium infection incidence than that observed in the absence of intervention. Suboptimal screening programme design should be considered as a possible contributor to unsuccessful syphilis control programmes in the context of the current epidemic.
- SYPHILIS
- SCREENING
- MODELING
- MATHEMATICAL MODEL
- CONTROL PROGRAMS
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Introduction
Despite the dramatic decline in incidence following the introduction of penicillin in the 1940s, syphilis continues to cause outbreaks and epidemics. These have tended to occur in distinct populations over time.1–3 In North America and northern and western Europe, an epidemic resurgence in syphilis, focused in men who have sex with men (MSM) has been ongoing since approximately 2001.4 ,5 Elevated incidence continues to be seen in MSM in the face of significant public health responses, including public awareness campaigns, and intensified screening and partner notification efforts.6
The reasons for syphilis re-emergence and persistence are unclear. Among the possible epidemic drivers are: changes in sexual behaviour, including increased rates of new partner acquisition and concurrent partnerships,7 high rates of population turnover8 and changes in the intensity of syphilis control programmes.7 ,8 Treatment-induced interruption of the development of protective immunity to reinfection has also been proposed as a contributor to syphilis persistence, by replenishing the supply of susceptible individuals in a population.8 This could suggest that the current MSM-focused syphilis epidemic is persisting because of, rather than despite, enhanced public health control measures aimed at curbing spread by treating infectious syphilis cases.
Cases with untreated syphilis appear to be protected from reinfection, while those previously treated for syphilis can be reinfected.9 However, despite clinical observations of repeat syphilis infections in treated cases,10–12 there is some evidence to suggest a degree of transient acquired immunity in individuals treated for latent syphilis.13 ,14 The development of immunity to syphilis reinfection and the durability of such a response, remain areas of uncertainty, with the development of an immune response appearing to depend on duration of infection prior to treatment.13 ,14
Previous modelling work15 ,16 has demonstrated that frequent and sustained screening of at-risk populations is required to control syphilis outbreaks. We hypothesised that when screening coverage is suboptimal, this may itself contribute to observed syphilis dynamics in outbreak situations. We used a mathematical model to evaluate the relationship between population-level coverage of syphilis screening and the ability to control syphilis transmission. We also explored how alternate assumptions about epidemic drivers might influence our model projections.
Methods
Model overview
We developed a dynamic compartmental mathematical model of syphilis transmission in a population of sexually active MSM. An overview of how individuals transition through the model is presented in web only figure 1. Model parameters (see web only table 1) were literature-derived where available, or estimated via model calibration. Additional model details are provided in online supplementary appendix 1.
Disease natural history
The population was divided into compartments representing different disease states: susceptible (S), exposed (E; infected but not infectious), primary syphilis (I1, I1_2), secondary syphilis (I2, I2_2), early latent syphilis (L1, L1_2) and late latent syphilis (L2). We did not model recurrent syphilis and assumed that only the primary and secondary stages were infectious. The model included two susceptible compartments—one for infection-naïve individuals (S) and one for those with previously treated infection (Sr)—to calculate seroprevalence, which was used for model calibration. Transmission of infection occurred through sexual contact between susceptible and infectious individuals. In the absence of treatment, infected individuals progressed through the various stages of disease and remained in the late latent stage until model exit. We assumed that untreated individuals were not susceptible to reinfection with different syphilis strains (ie, no superinfection). As we did not model the health consequences of syphilis, we did not include tertiary syphilis.
Sexual mixing
The model included three levels of sexual activity: high, moderate and low. The different activity levels were characterised by their relative rates of partner acquisition. The proportion of the population in each group was approximated based on reported partner numbers in a survey of urban MSM.17 We assumed that individuals remained in a given activity group for the duration of their sexual lifespan. Mixing between risk groups was described by the term ε, which could range from 0 (proportionate or random mixing between groups) to 1 (assortative mixing, where individuals partner exclusively with individuals of the same risk class). The total population size was assumed to remain constant.
Screening and treatment
Individuals with syphilis infections could receive treatment by actively seeking medical care for their infection, by participating in opportunistic screening programmes or through receipt of antibiotic treatment for another medical indication. Individuals were assumed to seek medical care because they were symptomatic or had an infected partner (ie, partner notification). For individuals actively seeking treatment, treatment of infection was assumed to occur at the midpoint of the infection stage.
We assumed a constant hazard of screening (α), with probability of screening converted to a rate, assuming an exponential distribution:18
where interval was the average time between screening events (1 year in our base case), in years, and coverage was the proportion of the population screened in each interval.19 For simplicity, we assumed that all individuals had their infection status correctly identified, were successfully treated if infected, and screening and treatment were applied equally across all sexual activity groups. We assumed that there was a background rate of antibiotic use leading to inadvertent treatment of syphilis in some individuals, who were moved to the appropriate treatment compartment but were not counted as diagnosed cases.
Immunity from reinfection
To examine the impact of different assumptions about how treatment influences the development of immunity, we included transiently immune states following treatment for primary and secondary (T1), early latent (T2), and late latent (T3) syphilis. Treated individuals passed through one of these immune states before returning to the susceptible state. In our base case we assumed that individuals were transiently immune only after treatment for late latent infection. Those treated for early infection (primary, secondary or early latent infection) were not considered biologically immune to reinfection but dwelled in the immune state for 1 week after treatment as a means of representing abstinence from unprotected sexual activity after medical treatment.
Model calibration and outcomes
To capture the impact of the introduction of antibiotic treatment on syphilis dynamics, we allowed prevalent syphilis to reach endemic equilibrium following model initiation, followed by a 20-year period of treatment (including background antibiotic treatment). After this period, we assumed that opportunistic screening was increased rapidly once syphilis incidence increased above 1 case per 1000 person-years in the population. This marked the beginning of the 5-year calibration period. In addition to individuals seeking medical care, annual screening was assumed to reach 30% of the population during this period, based on estimates for the Canadian city of Toronto.15 Mean rate of partner acquisition and the mixing parameter ε were estimated by calibration. We used data from Toronto on early syphilis diagnoses in MSM, proportion of cases by stage (primary, secondary or early latent)15 ,20 and syphilis seroprevalence17 for model calibration, minimising the sum-of-squares difference between model projections and data. Additional details about model calibration are provided in online supplementary appendix 1.
After the calibration period, coverage of asymptomatic syphilis screening was changed, with population coverage ranging from 0% to 90%. We evaluated the impact of screening on short-term (over a 20-year time horizon) and long-term disease trends. In the short term, we examined syphilis incidence and diagnoses of early syphilis cases (ie, cases that would be observed via public health surveillance). For long-term effects, we determined syphilis incidence at endemic equilibrium and the necessary screening conditions for syphilis elimination (defined as the reduction of incidence to <1 case per 100 000 population per year).
Alternate assumptions
We examined the impact of different potential epidemic drivers by changing base case assumptions. For each alternate assumption, we recalibrated the model using the same procedure as in the base case. Parameter values for each of the scenarios are presented in web only table 2. For these analyses, we evaluated screening every 6 months or every 3 months in addition to annual screening.
Development of immunity
In the base case, the development of protective immunity was assumed to occur only after an individual entered the late latent syphilis stage. Individuals with early syphilis were thus assumed to immediately reacquire biological susceptibility to infection following receipt of treatment (though as noted above would abstain from unprotected sexual activity for 1 week after treatment). We evaluated the impact on results if immunity developed during infectious syphilis or during early latent syphilis. We also varied the duration of immune protection following treatment for individuals in each stage.
Sexual mixing
We examined how mixing between risk groups impacted syphilis dynamics. We used a previously described approach21 to vary mixing between groups from random (proportionate mixing with sexual partners chosen in relation to the number of potential sexual partnerships supplied by people in a given activity class21) to assortative (sexual partnerships with individuals of the same activity group only). Individuals were assigned to a single sexual activity group and remained at this level for the duration of their sexual life. Sexual risk was defined by rate of partner acquisition.
Antibiotic use
In our base case, we assumed that there was a low background rate of antibiotic use leading to inadvertent treatment of syphilis. We evaluated the effect of higher proportions of the population receiving antibiotics sufficient to treat syphilis on thresholds required for syphilis elimination.
Role of the funding source
The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Results
Model calibration
The model reproduced cumulative early syphilis diagnoses reported among MSM in Toronto, Canada. While average incidence was reproduced well, the model was less effective at capturing year-to-year variability observed over the 5-year calibration period (see web only figure 2).
Base case
Sustained annual population screening at coverage levels ranging from 50% to 90% resulted in an initial transient increase in diagnosed early syphilis cases, relative to continued screening at the 30% level used during the calibration period (figure 1). Removing screening resulted in an initial decline and subsequent increase in diagnosed cases.
Model-projected syphilis trends with different population-level annual screening coverage. (A) Annual diagnosed early syphilis cases and (B) incident syphilis cases per 100 person-years are shown for a 20-year period following intervention initiation (indicated by vertical grey line). In the preintervention period, asymptomatic screening was assumed to occur in 30% of the population annually. In all scenarios, there was a baseline level of treatment of early syphilis cases, as described in web only table 1.
By contrast, total (diagnosed and undiagnosed) incident cases were projected to immediately decrease with higher coverage levels and increase in the absence of screening. At the end of the 20-year period, diagnosed and total incident cases were projected to be higher with intermediate levels of screening (30% and 50%) than those observed in the absence of screening. When screening reached a relatively large proportion of the population (≥70%), syphilis incidence and diagnoses declined over the 20-year period. Note that in all scenarios, including the no screening scenario, treatment of syphilis could still occur by cases actively seeking medical care or by receipt of antibiotics for another reason leading to inadvertent syphilis cure.
We also evaluated syphilis incidence at endemic equilibrium assuming continued screening at different coverage levels. Consistent with the observed short-term dynamics, we observed an inverted U-shape relationship between screening coverage and equilibrium syphilis incidence (figure 2). Peak equilibrium incidence was projected to occur when 20–30% of the population was screened annually. Greater than 60% of the population needed to be screened annually to achieve local elimination.
Model-projected syphilis incidence at equilibrium. Syphilis incidence at endemic equilibrium is shown for different population coverage of screening. For all levels of screening, there was a baseline level of treatment of early syphilis cases.
Alternate assumptions
Results were qualitatively similar in the face of differing programmatic, behavioural and natural history assumptions, although the screening thresholds for local elimination differed (figure 3). Higher background antibiotic use leading to inadvertent syphilis treatment was expected to reduce the screening coverage required for elimination. In a population with highly assortative sexual mixing, greater screening coverage was required for syphilis elimination. Results were particularly sensitive to screening frequency. With 6-monthly or 3-monthly screening, the population coverage required to achieve local elimination was reduced to 39% or 23%, respectively.
Thresholds for local syphilis elimination under alternate assumptions. The required population coverage of syphilis screening required for local elimination is shown for different assumptions about immunity, sexual mixing and background antibiotic use. Horizontal lines denote the base case model thresholds. In the base case, 5 years of protective immunity were assumed following treatment of cases with late latent infection only, sexual mixing (ε) was 0.37 and background antibiotic use was 1% per year. Results are presented for annual, semiannual and 3-monthly screening.
We did not observe large differences in elimination thresholds for different assumptions around development of immunity to reinfection; required coverage estimates ranged from 58% in the complete absence of immunity to 63% if immunity developed during early latent infection and lasted for 5 years. However, when population coverage was below these threshold values, the durability and timing of development of a protective immune response did impact equilibrium incidence (figure 4). For immune protection of shorter duration (none or 1 year), intermediate levels of screening resulted in higher equilibrium incidence than that observed with 5 years of protection.
Impact of assumptions relating to development of protective immunity on equilibrium syphilis incidence. Syphilis incidence at endemic equilibrium was estimated for different levels of population syphilis screening, for differing assumptions around the durability and stage of development of protective immunity to syphilis reinfection following treatment. In the base case (black line), 5 years of protective immunity were assumed following treatment of cases with late latent infection. The duration of protection and stage of infection at which immunity first develops for each scenario are indicated in the figure legend. Cases treated before entering a stage at which immunity developed were assumed to experience protection from reinfection for 1 week prior to the return to the susceptible compartment.
Discussion
Using a mathematical model, we have shown that increasing screening in populations with initially low levels of coverage may lead to increases in observed diagnoses of early syphilis cases, and increases in underlying infection incidence (ie, recognised and unrecognised cases). Although screening has the potential to control syphilis outbreaks, suboptimal screening coverage may ultimately result in the establishment of higher equilibrium infection incidence than that observed in the absence of the intervention. Other studies have examined the role of screening in syphilis elimination,13 ,15 ,16 ,22 ,23 and the impact of mass treatment or transient increases in coverage on syphilis trends,8 ,23 ,24 but to our knowledge this is the first to look at the impact of sustained, suboptimal screening coverage on infection dynamics.
Our results suggest that screening alone, at low levels, alters infection dynamics in such a way that the replenishment of susceptible individuals is sufficient to drive up equilibrium incidence. We therefore propose that screening be considered an additional possible mechanism for syphilis persistence in MSM. As screening coverage needed for true incidence to decline was projected to be in excess of that which has been achieved in Toronto, it might be argued that persistently elevated incidence of syphilis may partly result from ongoing screening activities, rather than occurring in spite of these activities. Our analysis does not argue against the utility of ‘screen-and-treat’ as a potentially useful approach to control syphilis epidemics. By showing that screening frequency thresholds exist beyond which screening can reduce syphilis incidence, we suggest that screening can have the desired impact when it reaches high enough population coverage or frequency.
Our main findings were robust in the face of variation in model parameters and assumptions, including modifiable programmatic ones. Consistent with previous modelling studies,15 ,16 we found that syphilis elimination could be achieved with more frequent screening of a smaller proportion of the population. When we explored the impact of assumptions related to duration and timing of development of immunity to reinfection on the ability to control syphilis with screening, we found little impact on coverage thresholds for disease elimination. However, findings with suboptimal screening coverage were influenced by assumptions related to immunity, in terms of magnitude of equilibrium incidence and the coverage levels at which incidence was projected to peak. In particular, at suboptimal coverage levels, assuming that immunity develops earlier in the course of infection results in lower equilibrium incidence compared with immunity that takes longer to develop. Importantly, we observe that the phenomenon of low levels of screening leading to higher equilibrium incidence than those observed in the absence of screening occurs even in the complete absence of any protection from reinfection following treatment of syphilis infection, regardless of stage at treatment. The interplay between treatment and timing of development of protective immunity is likely to be important when population screening for syphilis occurs at low levels, as treatment becomes a source of newly susceptible individuals to fuel ongoing syphilis transmission.25
As with any mathematical modelling study, ours has limitations. We have purposely developed a simple risk-structured model of syphilis transmission, with the aim of increasing model transparency and interpretability. As such, the insights gained from this model should be considered qualitative rather than quantitative. We do not suggest that the thresholds for elimination represent hard targets. Rather, they can provide some guidance into the relative importance of different potential epidemic drivers in the ongoing syphilis outbreak in MSM. Another limitation is that we have used partnership acquisition rate as the only marker of sexual risk. We do not distinguish types of sexual partnerships (casual vs regular, concurrent vs serial) and assume that risk of transmission is instantaneous within a partnership. We have focused our analysis on the impact of syphilis screening on infection dynamics at the population level and have not explicitly modelled the impact of increased incidence on downstream occurrence of neurosyphilis or tertiary syphilis. Finally, screening was applied equally across the model population. Targeted screening, based on rates of partner acquisition, may represent a more impactful approach to screening.
If correct, our findings present an important ethical challenge for the design of programmes aimed at controlling syphilis transmission and preventing syphilis sequelae in MSM. On the one hand, failure to identify and treat syphilis places infected individuals at risk of severe long-term sequelae, including cardiovascular, neurovascular and neurological disease,26 but suboptimal attempts at control of transmission through screening could paradoxically increase the number of individuals at risk for such sequelae. Further work is needed to better quantify the trade-offs between disease impact and disease incidence that are likely to occur as a result of suboptimal screening levels, though we note that if screening could occur at high coverage and frequency, this challenge would be resolved: incidence and long-term sequelae would be reduced. In populations where high uptake of screening cannot be sustained, alternate and novel public health interventions may be warranted.27
Key messages
A mathematical model of syphilis shows that increasing screening in populations with initially low levels of coverage may lead to paradoxical increases in infection incidence.
The intensity of syphilis screening, and not simply the availability of syphilis screening, determines the effectiveness of this approach to epidemic control.
Screening has the potential to control syphilis outbreaks, but this potential can only be realised when men who have sex with men are screened with high frequency and/or high coverage.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
- Data supplement 1 - Online supplement
- Data supplement 2 - Online supplement
Footnotes
Handling editor Jackie A Cassell
Twitter Follow Ashleigh Tuite at @ashtuite
Contributors Both authors were involved in study conception and design, interpretation of data and revision of the manuscript. AT designed and developed the model, performed the analysis and drafted the manuscript.
Funding Banting and Best Canada Graduate Scholarship from the Canadian Institutes of Health Research.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Model equations and parameters are provided in the supplementary material.