Syphilis infection rates have reached their highest levels in the United States since the mid-1990s.1,2 In 2016, Los Angeles County had the fourth highest syphilis rate in the United States (53.2 per 100,000 population),3 with most cases disproportionately affecting men who have sex with men (MSM).4 The laboratory detection of syphilis can be challenging because the causative agent Treponema pallidum cannot be grown in vitro and most laboratories rely on serological tests, for which no gold standard exists.5 The increasing incidence of syphilis warrants reevaluation of serological screening approaches because diagnosis, treatment, and follow-up depend on reliable laboratory testing.
There are 2 basic serological approaches for syphilis screening: traditional or reverse algorithm.6,7 In the traditional algorithm, patient samples are screened with a nontreponemal assay (e.g., rapid plasma reagin, or RPR) and screen-positive samples are confirmed by a treponemal assay (e.g., T. pallidum particle agglutination, or TP-PA).8 The traditional algorithm generally offers good sensitivity and specificity for identifying primary and secondary syphilis infections, but is subject to several limitations including lower throughput, subjective test interpretation, and low sensitivity for early/late-latent syphilis infections.8,9 By contrast, in the reverse algorithm, patient samples are first screened with a treponemal immunoassay (e.g., chemiluminescence immunoassay [CIA]) followed by a nontreponemal assay.6–8,10 Treponemal immunoassays are more amenable to automation and offer objective test interpretation with improved sensitivity and specificity for detecting early/late-latent syphilis.6,8,9 However, some of the cases detected by reverse algorithm screening may correspond to patients with a history of syphilis because treponemal antibodies persist long after the initial infection.11
The algorithm used by laboratories for syphilis screening has important implications for disease control efforts. The US Centers for Disease Control and Prevention recommends that local health jurisdictions follow up with persons newly diagnosed as having syphilis to verify treatment and to identify, test, and treat any sexual contacts of the index case.12 Previous studies suggest that field services can reduce reinfection rates and slow the spread of sexually transmitted infections like syphilis by identifying and treating clusters of infected patients in conserved sexual networks.13–15 However, changing to a reverse algorithm approach may increase the number of syphilis cases identified and more field services would need to be provided.
To know whether or not switching to a reverse algorithm makes sense, the implications of that decision for the local public health department must be well understood. Previous reports have suggested that the reverse algorithm may not be cost-effective, particularly in low-prevalence settings, because use of the reverse algorithm may result in unnecessary treatment or detect too many biological false positives.11,16 Other studies have suggested that the reverse algorithm is cost-effective, especially for high-volume laboratories.17,18 Clearly, further investigation into which specific conditions increase the cost-effectiveness of the reverse algorithm is warranted, particularly in high-prevalence settings. Here, we compare the cost-effectiveness of a traditional and reversed syphilis-screening algorithm for a high-prevalence population by estimating the economic impacts on a local STD Control Program.
MATERIALS AND METHODS
Methods for Cost-Effectiveness Analysis
We created a decision analysis model to compare the costs and effectiveness of the traditional algorithm and reverse algorithm for the Los Angeles County Department of Public Health (LACDPH) in 2015. Patient samples were collected at STD clinics, hospitals, and community outreach programs from various locations around Los Angeles County, excluding residents of Pasadena and Long Beach who are served by independent public health departments. The Los Angeles County Public Health Laboratories (LACPHL, Downey, CA) serve a population with a high prevalence of syphilis (43.8 per 100,000 population in 2015).19 In Los Angeles County, syphilis rates were highest among African American (19% of the population, rate of 114 per 100,000), white (28% of the population, rate of 47 per 100,000), Latino (47% of the population, rate of 46 per 100,000), and Asian (4% of the population, rate of 14 per 100,000 population) males.20 Among males with early syphilis, 89% of cases occurred among MSM and men who have sex with men and women.20 Following Owusu-Edusei et al.,16 we categorized patients by their serostatus into 3 mutually exclusive categories: uninfected, currently infected, or previously infected (history of syphilis with or without current infection).
A schematic of the traditional and reverse algorithms is illustrated in Fig. 1. Following the traditional algorithm used by the LACPHL, all patient samples were screened by RPR (Arlington Scientific Inc, Springville, UT). Positive qualitative RPR samples were further tested by quantitative RPR and confirmed using TP-PA (Fujirebio, Malvern, PA). Patients that were previously infected with syphilis were not tested by TP-PA because of persisting treponemal antibodies after the initial infection. We compared the traditional algorithm to a reverse algorithm in which all patient samples with no known history of syphilis (uninfected or recently infected) were screened with the LIAISON Treponema assay (DiaSorin Inc, Stillwater, MN) followed by reflex testing with RPR. The LIAISON Treponema assay is a qualitative CIA that detects total (IgM and/or IgG) antibodies directed against T. pallidum. We assumed that TP-PA would only be performed on currently infected patients that test negative by RPR (e.g., recently exposed or early/late-latent syphilis infections) and that previously infected patients would be screened only with RPR.
Model probabilities for the traditional and reverse algorithms were based on method comparison studies that evaluated the performance of the Liaison Treponema Assay for use in reverse algorithm syphilis screening.21–25 Baseline probabilities were derived from a method comparison study performed at the LACPHL to evaluate the reverse algorithm.25 We distinguished between previously infected and currently infected patients by querying the LACDPH Casewatch Database for past reactive RPR/TP-PA results. Our screening test positivity rate was 14.4% for the traditional algorithm, of which 2.6% were previously infected and 11.8% were currently infected.25 The positivity rate for the reverse algorithm was 15.1%, of which 12.5% were detected by CIA (current infections) and 2.6% were detected by RPR (previously infected).25 Approximately 90.4% of CIA-positive patients tested positive by reflex RPR for the reverse algorithm.25 The remaining 9.6% of RPR-negative, CIA-positive patients were tested by TP-PA, and the TP-PA positivity rates were 95.8% and 91.5% for the traditional and reverse algorithms, respectively.25 The ranges of probabilities used for CIA and reverse algorithm sensitivity analyses were informed by reports in the literature about the performance of the Liaison Treponema Assay.21–24
For our model, we defined effectiveness as whether or not a patient was brought to treatment. Newly detected seropositive patients that required field services including diagnosis, disease staging, and treatment were given an effectiveness score of 1. Similarly, we assumed that 5% of previously infected patients were reinfected, required field services, and were given an effectiveness score of 1. We assumed that 5% of previously infected patients that test positive by RPR were being tested to monitor efficacy of treatment, and the remaining 20% of previously infected patients had had a past infection and did not require treatment based on the 2015 Syphilis Case Continuum provided by the STD Control Program26; both of these groups were given an effectiveness score of 0. These binary effectiveness scores were used by the model to estimate the total number of patients brought to treatment through each syphilis screening algorithm.
All input variables, ranges, costs, and sources used in the decision analysis model are listed in Table 1. Test costs for nontreponemal and treponemal tests listed on the 2015 clinical laboratory fee schedule were used for modeling and sensitivity analyses to understand the cost-effectiveness of the reverse algorithm from the national perspective.27 To understand the cost-effectiveness of the reverse algorithm from the perspective of the LACDPH, the LACPHL provided the 2015 list price for RPR and TP-PA, whereas the CIA test cost was calculated as the sum of reagent and labor costs per batch of 120 samples (expressed in 2015 US dollars). The Division of HIV and STD Programs (DHSP) provided the salaries for public health investigators, public health nurses, and physician specialists. The DHSP also provided the minimum, average, and maximum times each staff member spent on a typical investigation (2, 5, and 9 hours, respectively). The cost of follow-up was calculated as the sum of the average costs of conducting a public health investigation, the cost of a return visit to the clinic, and treatment with Benzanthine Penicillin G (Bicillin). The cost of Bicillin was established as $70.82 for one 2.4-million-unit dose administered once for early syphilis cases (primary, secondary, or early-latent stages) or 3 times for late-latent syphilis. The analytic time horizon varied, but typically lasted less than 3 months for all PHL and DHSP activities after test results; therefore, no adjustments for inflation or discounting were necessary. The following costs were not included in the model: cost of partner services, subsequent partner examination and/or treatment, and patient repeat testing.
We estimated and compared the total laboratory screening costs, the total number of individuals identified for field services, and overall cost-effectiveness ratio for each algorithm using a Monte Carlo simulation with a sample size of 57,065 (the total number of screening tests performed by the LACPHL in 2015) with 10,000 randomized trials (iterations). Monte Carlo simulations were performed to estimate the cost-effectiveness of each algorithm from the perspectives of the Public Health Department (including LACPHL and STD Control Program costs) using all variable values and ranges listed in Table 1. To estimate the cost-effectiveness from the laboratory perspective, we repeated the Monte Carlo simulations while excluding the cost of follow-up variable. We calculated the incremental cost-effectiveness ratio (ICER) using the following equation: ICER = (CReverse − CTraditional)/(EReverse − ETraditional), where C represents the total cost per test and E represents the total effectiveness score (i.e., the number of syphilis cases detected). We then conducted one-way sensitivity analyses on all variables in the model using ranges presented in Table 1 to estimate costs (or savings) and effectiveness between the traditional and reverse algorithms when individual variables in the model were changed. Variable ranges for sensitivity analyses were informed by laboratory and surveillance data collected in 2013 and 2015.26,28 All analyses were performed using the test costs provided by the Centers for Medicaid Services (CMS) to model the national perspective and the test costs provided by the LACPHL to model the local perspective. We used TreeAge Pro Suite version 2016 (TreeAge Software Inc, Williamstown, MA) to construct the decision tree, conduct Monte Carlo simulations and sensitivity analyses, and illustrate data.
Cost-Effectiveness for Los Angeles County
We estimated the total cost of traditional algorithm screening for the Los Angeles County Public Health Department to be $2,153,225, with an average cost of $37.73 per patient. We projected that the total cost of reverse algorithm screening would have been $2,197,478, with an average cost of $38.51 per patient. Monte Carlo simulations estimated 6524 syphilis cases detected through traditional algorithm screening procedures, whereas the reverse algorithm would have detected 7150 syphilis cases (approximately 9.7% more than the traditional algorithm). The ICER for the reverse algorithm from the perspective of the Public Health Department was $39 per additional syphilis case detected. These results suggest that the reverse algorithm is more expensive, but brought more patients to treatment than the traditional algorithm. A scatterplot for all Monte Carlo simulations (illustrated in Fig. 2) demonstrates that for any individual cost value, the reverse algorithm is always more effective than the traditional algorithm.
From the laboratory perspective, we estimated the cost of traditional algorithm screening to be $367,119.16, with an average cost of $6.43 per patient. We projected that the laboratory cost of reverse algorithm screening would have been $239,854.73, with an average cost of $4.20 per patient. Because the reverse algorithm was cheaper and more effective than the traditional algorithm from the Laboratory perspective, the ICER is not defined. All cost-effectiveness data are summarized in Table 2.
One-Way Sensitivity Analyses for Los Angeles County
To investigate the cost thresholds at which the reverse algorithm would be less expensive than the traditional algorithm from the Los Angeles County Public Health Department's perspective, we performed a one-way sensitivity analysis in which the total cost of each algorithm was calculated for a range of values for one variable when all other variables are held constant (see Supplemental Figure 3, a tornado diagram of 1-way sensitivity analyses for variables demonstrating high potential effect on the decision analysis model using LACPHL test costs, http://links.lww.com/OLQ/A283). Seven variables had the biggest effect on costs in the decision analysis model; the threshold values at which the reverse algorithm is less costly are described hereinafter (data presented in Table 3).
The variable that had the highest impact on total costs was the cost of a follow-up investigation; using a range of $85 to $335 for this variable, the reverse algorithm had lower projected total costs for values lower than $203.08 (Fig. 3). The probability of a positive screening test (RPR for traditional and CIA for reverse) was the next highest contributor of uncertainty in model costs; the reverse algorithm was less expensive if the probability of a positive CIA was less than 12% or if the probability of a positive RPR screening test result was greater than 12%. The cost of CIA contributed more uncertainty to the model than the cost of RPR. The reverse algorithm was less expensive if the cost of CIA was less than $2.81 or if the cost of RPR was greater than $4.53. The traditional algorithm was less expensive than the reverse algorithm for all probabilities of identifying a sexual contact or previous syphilis infections (Fig. 4). Please see Supplemental Figures 4–6 for 2-way sensitivity analyses (http://links.lww.com/OLQ/A284, http://links.lww.com/OLQ/A285, http://links.lww.com/OLQ/A286).
Cost-Effectiveness From the National Perspective
We estimated the total cost of traditional algorithm screening for a Public Health Department to be $2,296,126.56, with an average cost of $40.24 per patient. We projected that the total cost of reverse algorithm screening would have been $3,068,351.65, with an average cost of $53.77 per patient. Monte Carlo simulations estimated 6521 syphilis cases detected through traditional algorithm screening procedures, whereas the reverse algorithm would have detected 7148 syphilis cases (approximately 9.7% more than the traditional algorithm). The ICER for the reverse algorithm from the perspective of the Public Health Department was $1242.17 per additional syphilis case detected. These results suggest that the reverse algorithm is much more expensive, but brought more patients to treatment than the traditional algorithm. A scatterplot for all Monte Carlo simulations (illustrated in Figure S1, http://links.lww.com/OLQ/A281) demonstrates that for any individual cost value, the reverse algorithm is always more effective than the traditional algorithm.
From the laboratory perspective, we estimated the cost of traditional algorithm screening to be $510,587.95, with an average cost of $8.95 per patient. We projected that the laboratory cost of reverse algorithm screening would have been $1,111,263.03, with an average cost of $19.47 per patient. The ICER from the perspective of the laboratory was $987.84 per additional syphilis case detected. These results suggest that the reverse algorithm is more expensive, but more effective than the traditional algorithm.
One-Way Sensitivity Analyses From the National Perspective
To investigate the cost thresholds at which the reverse algorithm would be less expensive from the national perspective, we performed one-way sensitivity analyses for the same 7 variables mentioned previously (see Supplemental Figure 2, a tornado diagram of 1-way sensitivity analyses for variables demonstrating high potential effect on the decision analysis model using CMS test costs, http://links.lww.com/OLQ/A282). The threshold values at which the reverse algorithm is less costly are described in Table S1, http://links.lww.com/OLQ/A287. The variable that had the highest impact on cost-effectiveness of the reverse algorithm was the cost of the CIA screening test. The reverse algorithm was less expensive than the traditional algorithm only when the CIA test cost was less than $4.13 (approximately $1.67 less than the CMS rate for a qualitative nontreponemal test in 2015). The probability of a positive nontreponemal screening test result was the next highest contributor of uncertainty in model costs. The reverse algorithm was less expensive if the probability of a positive nontreponemal screening test result was higher than 16.5%. The cost of CIA contributed more uncertainty to the model than the cost of RPR. The reverse algorithm was less expensive if the CIA positivity rate was less than 7.7%. Under all other scenarios, the traditional algorithm was always less expensive than the reverse algorithm.
Although most laboratories performing syphilis serology continue to use a traditional screening algorithm, larger-volume laboratories are quickly adopting the reverse algorithm in order to improve workflow through automating syphilis screening.29 From the laboratory perspective, it is unknown exactly how many syphilis would justify adopting the reverse algorithm. From the perspective of the public health system, changes in syphilis detection methods by laboratories serving high syphilis prevalence jurisdictions affect the number of sexually transmitted infection investigations conducted by the local health department. We sought to investigate whether or not the reverse algorithm was cost-effective in a high-prevalence population from the perspective of the public health department as well as the perspective of the laboratory.
From the laboratory perspective, our model suggests that the reverse algorithm is more cost-effective than the traditional algorithm. Assuming the LACPHL continues to screen the same number of patients each year, reverse algorithm screening would save approximately $125,000 in laboratory costs annually. Furthermore, our model suggested that there would be no tradeoff between cost and effectiveness in identifying syphilis cases. Our findings could be attributed to the high prevalence of syphilis in Los Angeles County such that the positive predictive value (PPV) of our CIA screening test is higher by virtue of our sample population. A heterogeneous sample population could affect the PPV of the syphilis screening test such that heterogeneous sample populations with a lower prevalence of syphilis would have a lower PPV and lower cost-effectiveness.6,11,18 Because our patient population is not perfectly heterogeneous and has a higher prevalence of syphilis, the cost-effectiveness of reverse algorithm screening for the LACPHL would be higher than laboratories for which the opposite is true.
Although less costly for the laboratory, additional seropositive patients detected through a reverse screening algorithm would increase field services costs to the STD Control Program. Thus, the reverse algorithm is more expensive from the perspective of the Public Health Department, which includes the costs of the laboratory and STD Control Program. The $125,000 in laboratory savings is not enough to offset the cost of follow-up investigations, return visits, and treatment for additional syphilis cases identified through reverse algorithm screening. However, the ICER is low enough to consider the reverse algorithm more cost-effective for the Public Health Department than the traditional algorithm. Paying an additional $39 per patient to detect additional cases of syphilis is a low cost considering the repercussions of untreated syphilis.
Our findings from the Los Angeles County perspective differ from laboratories using the 2015 CMS test costs for nontreponemal and treponemal screening tests. If the test cost for the new treponemal screening assay was $1.67 less than the nontreponemal test cost ($5.80), the reverse algorithm was less expensive and brought more patients to treatment. However, because the CMS test cost for a treponemal test in 2015 was nearly 3 times higher than the nontreponemal test cost, the reverse algorithm was significantly more expensive than the traditional algorithm, with an estimated $1,242.17 per additional case of syphilis detected. In this scenario, it is less clear-cut to determine whether or not the reverse algorithm is more or less cost-effective than the traditional algorithm. One limitation of our study is that we did not calculate the public health benefit (e.g., quality-adjusted life years or disability-adjusted life years) for identifying additional cases of syphilis because some of the parameters required for calculating quality-adjusted life years/disability-adjusted life years were not provided to us under our agreement with the institutional review board. An ICER of $1,242 could very well be cost-effective, but we did not use a method that allows for such a determination.
Previous reports on the cost-effectiveness of the reverse algorithm raised the concern of overtreatment, particularly with respect to false-positive or previously treated cases.16 Indeed, a high number of falsely positive patients may be a barrier for adopting the reverse algorithm for some health jurisdictions because resources are often limited. Overtreatment of seropositive patients with a history of syphilis can be avoided if the laboratory provides the patient's history or if the laboratory offers a “nontreponemal-only” option for screening patients with a history of syphilis. Such an approach would reap the maximum cost-savings of the reverse algorithm while keeping overtreatment to a minimum. However, this approach is not standard practice and health care providers do not always know if their patients have a history of syphilis. To minimize these complications, public health departments must educate their healthcare providers before implementation of a reverse algorithm.
The data presented in this study reflect the economic impacts of switching to a reverse algorithm in Los Angeles County and may be applicable to other health jurisdictions with a high prevalence of syphilis. One of the strengths of this study was the enumeration of cost-effectiveness thresholds through sensitivity analysis, which may be used to inform other laboratories or health jurisdictions that are evaluating the reverse algorithm. Another strength of this study was using percentages based on laboratory and surveillance data collected in Los Angeles County.14
One limitation of our study is that our model does not account for sexual contacts of index cases that were identified during follow-up investigations. According to the STD Control Program, less than half (~43%) of the syphilis cases identified by the LACPHL in 2015 resulted in at least one additional case of syphilis identified.15 This metric was not included in the model to simplify our defined outcomes and because the number of sexual contacts identified through follow-up investigations can vary widely depending on the size of a case cluster. Similarly, transmission effects were not captured by our model. Patients who have infectious syphilis and are treated do not pose further transmission risk to their partners. The magnitude of the difference in outcomes between the traditional and reverse algorithms may be different if transmission is incorporated. Our study relied on epidemiologic data from the STD Control Program for percentages of previous infections, and our findings are contingent upon good recordkeeping and reporting practices. We chose to use the LACPHL fee schedule and CIA test cost estimates rather than the CMS fee schedule for 2 reasons. First, the LACPHL fee schedule and CIA test cost estimates were more relevant to help the LACPHL decide between algorithms. Second, there is no specific Current Procedural Terminology code for a treponemal enzyme Immunoassay/CIA. Generally, automated treponemal antibody tests are less expensive than the listed TP-PA test fee and are more comparable to the RPR fee. As noted in our sensitivity analysis, the traditional algorithm strictly dominates the reverse algorithm under all scenarios when the enzyme Immunoassay/CIA screening test cost is much higher than the RPR screening test cost. The cost of running an automated CIA is typically lower if the laboratory has a high workload of syphilis samples and if the PPV of the screening test is high. Previous investigations have shown that more false positives are detected on treponemal screening assays in low-prevalence populations.6,9 Before adopting a reverse algorithm, public health departments should carefully evaluate reagent costs and the prevalence of syphilis in their population.
Early detection and treatment of syphilis depends on cost-effective testing strategies. Without a gold standard for syphilis detection, laboratories must choose the serological screening algorithm that balances reagent and labor costs with detecting as many active cases of syphilis as possible. Our model suggests that switching to a reverse syphilis-screening algorithm may be more cost-effective than the traditional syphilis-screening algorithm. Public health departments considering a reverse syphilis-screening algorithm should review and include in their decision-making process the following information: prevalence, specimen workload, syphilis serology test costs, labor costs, laboratory overhead costs, specific field services practices, follow-up costs (investigation, clinic visit, and treatment), and inclusion criteria. Laboratories should also consult with epidemiologists or infectious disease control committee to coordinate training for physicians and other clients before implementation of a reverse algorithm. Public health department decision makers should carefully consider the implications for disease management and downstream public health costs when deciding to switch to using a reverse algorithm for syphilis detection.
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