The impact of antenatal syphilis point of care testing on pregnancy outcomes: A systematic review.

BACKGROUND: Mother-to-child transmission of syphilis remains a leading cause of neonatal death and stillbirth, disproportionally affecting women in low-resource settings where syphilis prevalence rates are high and testing rates low. Recently developed syphilis point-of-care tests (POCTs) are promising alternatives to conventional laboratory screening in low-resource settings as they do not require a laboratory setting, intensive technical training and yield results in 10-15 minutes thereby enabling both diagnosis and treatment in a single visit. Aim of this review was to provide clarity on the benefits of different POCTs and assess whether the implementation of syphilis POCTs is associated with decreased numbers of syphilis-related adverse pregnancy outcomes. METHODS: Following the PRISMA guidelines, three electronic databases (PubMed, Medline (Ovid), Cochrane) were systematically searched for intervention studies and cost-effectiveness analyses investigating the association between antenatal syphilis POCT and pregnancy outcomes such as congenital syphilis, low birth weight, prematurity, miscarriage, stillbirth as well as perinatal, fetal or infant death. RESULTS: Nine out of 278 initially identified articles were included, consisting of two clinical studies and seven modelling studies. Studies compared the effect on pregnancy outcomes of treponemal POCT, non-treponemal POCT and dual POCT to laboratory screening and no screening program. Based on the clinical studies, significantly higher testing and treatment rates, as well as a significant reduction (93%) in adverse pregnancy outcomes was reported for treponemal POCT compared to laboratory screening. Compared to no screening and laboratory screening, modelling studies assumed higher treatment rates for POCT and predicted the most prevented adverse pregnancy outcomes for treponemal POCT, followed by a dual treponemal and non-treponemal POCT strategy. CONCLUSION: Implementation of treponemal POCT in low-resource settings increases syphilis testing and treatment rates and prevents the most syphilis-related adverse pregnancy outcomes compared to no screening, laboratory screening, non-treponemal POCT and dual POCT. Regarding the benefits of dual POCT, more research is needed. Overall, this review provides evidence on the contribution of treponemal POCT to healthier pregnancies and contributes greater clarity on the impact of diverse diagnostic methods available for the detection of syphilis.

Maternal Syphilis: An Independent Risk Factor for Mother to Infant Human Immunodeficiency Virus Transmission.

Syphilis is associated with increased human immunodeficiency virus acquisition and sexual transmission; we examined impact on human immunodeficiency virus mother-to-child transmission among mother-infant pairs enrolled in the India Six-Week Extended-Dose Nevirapine study. Maternal syphilis, diagnosed serologically using Venereal Disease Research Laboratory titer plus Treponema Pallidum Hemagglutination Assay, was associated with 2.5-fold greater risk.

Use of Treponemal Screening Assay Strength of Signal to Avoid Unnecessary Confirmatory Testing.

BACKGROUND: Our reverse syphilis testing algorithm consists of a treponemal IgG multiplex flow immunoassay (MFI) followed by both rapid plasma reagin titer and the Treponema pallidum particle agglutination (TPPA) test on specimens with a reactive MFI result. We report here the impact of a modified reverse algorithm, in which the strength of signal of the MFI is used to avoid unnecessary TPPA testing. METHODS: The Bioplex syphilis IgG MFI was used as the syphilis screening assay, and specimens with equivocal (antibody index 0.9 or 1.0), or reactive (antibody index ≥ 1.1) results were further tested by rapid plasma reagin titer and TPPA test. We performed a retrospective, descriptive analysis of all specimens received for syphilis screening between January and May of 2014. A cost analysis was performed, taking into account labor and reagent expenses. RESULTS: In our diverse patient population consisting of high-risk incarcerated persons, low-risk obstetrical/gynecological patients and high-risk miscellaneous clinic and inpatients, 430 (65%) of 665 MFI-positive specimens had antibody indices of 8 or greater. Greater than 99% of these specimens were reactive by the TPPA test. Avoiding TPPA testing of specimens with an MFI antibody index ≥8 would save over US $4800 annually in laboratory costs. CONCLUSIONS: The TPPA testing is unnecessary on specimens with MFI antibody indices ≥8. This would substantially reduce the TPPA testing volume and also reduce laboratory expenses.

The cost-effectiveness of 10 antenatal syphilis screening and treatment approaches in Peru, Tanzania, and Zambia.

OBJECTIVE: Rapid plasma reagin (RPR) is frequently used to test women for maternal syphilis. Rapid syphilis immunochromatographic strip tests detecting only Treponema pallidum antibodies (single RSTs) or both treponemal and non-treponemal antibodies (dual RSTs) are now available. This study assessed the cost-effectiveness of algorithms using these tests to screen pregnant women. METHODS: Observed costs of maternal syphilis screening and treatment using clinic-based RPR and single RSTs in 20 clinics across Peru, Tanzania, and Zambia were used to model the cost-effectiveness of algorithms using combinations of RPR, single, and dual RSTs, and no and mass treatment. Sensitivity analyses determined drivers of key results. RESULTS: Although this analysis found screening using RPR to be relatively cheap, most (>70%) true cases went untreated. Algorithms using single RSTs were the most cost-effective in all observed settings, followed by dual RSTs, which became the most cost-effective if dual RST costs were halved. Single test algorithms dominated most sequential testing algorithms, although sequential algorithms reduced overtreatment. Mass treatment was relatively cheap and effective in the absence of screening supplies, though treated many uninfected women. CONCLUSION: This analysis highlights the advantages of introducing RSTs in three diverse settings. The results should be applicable to other similar settings.

Finding a needle in the haystack: the costs and cost-effectiveness of syphilis diagnosis and treatment during pregnancy to prevent congenital syphilis in Kalomo District of Zambia.

BACKGROUND: In March 2012, The Elizabeth Glaser Pediatric AIDS Foundation trained maternal and child health workers in Southern Province of Zambia to use a new rapid syphilis test (RST) during routine antenatal care. A recent study by Bonawitz et al. (2014) evaluated the impact of this roll out in Kalomo District. This paper estimates the costs and cost-effectiveness from the provider's perspective under the actual conditions observed during the first year of the RST roll out. METHODS: Information on materials used and costs were extracted from program records. A decision-analytic model was used to evaluate the costs (2012 USD) and cost-effectiveness. Basic parameters needed for the model were based on the results from the evaluation study. RESULTS: During the evaluation study, 62% of patients received a RST, and 2.8% of patients tested were positive (and 10.4% of these were treated). Even with very high RST sensitivity and specificity (98%), true prevalence of active syphilis would be substantially less (estimated at <0.7%). For 1,000 new ANC patients, costs of screening and treatment were estimated at $2,136, and the cost per avoided disability-adjusted-life year lost (DALY) was estimated at $628. Costs change little if all positives are treated (because prevalence is low and treatment costs are small), but the cost-per-DALY avoided falls to just $66. With full adherence to guidelines, costs increase to $3,174 per 1,000 patients and the cost-per-DALY avoided falls to $60. CONCLUSIONS: Screening for syphilis is only useful for reducing adverse birth outcomes if patients testing positive are actually treated. Even with very low prevalence of syphilis (a needle in the haystack), cost effectiveness improves dramatically if those found positive are treated; additional treatment costs little but DALYs avoided are substantial. Without treatment, the needle is essentially found and thrown back into the haystack.

The costs of accessible quality assured syphilis diagnostics: informing quality systems for rapid syphilis tests in a Tanzanian setting.

OBJECTIVES: To determine the costs of Rapid Syphilis Test (RSTs) as compared with rapid plasma reagin (RPR) when implemented in a Tanzanian setting, and to determine the relative impact of a quality assurance (QA) system on the cost of RST implementation. METHODS: The incremental costs for RPR and RST screening programmes in existing antenatal care settings in Geita District, Tanzania were collected for 9 months in subsequent years from nine health facilities that varied in size, remoteness and scope of antenatal services. The costs per woman tested and treated were estimated for each facility. A sensitivity analysis was constructed to determine the impact of parameter and model uncertainty. FINDINGS: In surveyed facilities, a total of 6362 women were tested with RSTs compared with 224 tested with RPR. The range of unit costs was $1.76-$3.13 per woman screened and $12.88-$32.67 per woman treated. Unit costs for the QA system came to $0.51 per woman tested, of which 50% were attributed to salaries and transport for project personnel. CONCLUSIONS: Our results suggest that rapid syphilis diagnostics are very inexpensive in this setting and can overcome some critical barriers to ensuring universal access to syphilis testing and treatment. The additional costs for implementation of a quality system were found to be relatively small, and could be reduced through alterations to the programme design. Given the potential for a quality system to improve quality of diagnosis and care, we recommend that QA activities be incorporated into RST roll-out.

Cost-effectiveness of a dual non-treponemal/treponemal syphilis point-of-care test to prevent adverse pregnancy outcomes in sub-Saharan Africa.

BACKGROUND: A dual nontreponemal/treponemal point-of-care test (Dual-POC) that simultaneously detects both nontreponemal and treponemal antibodies has been developed and evaluated. In this study, we compare the health and economic outcomes of the new test with existing syphilis tests/testing algorithms in a high prevalence setting. METHODS: We used a cohort decision analysis model to examine 4 testing/screening algorithms; the Dual-POC test, the laboratory-based rapid plasma reagin and Treponema pallidum haemagglutination assay (RPR+TPHA) algorithm, an onsite RPR testing, and point-of-care treponemal immunochromatographic strip (ICS) testing. Outcomes included miscarriage, stillbirth, congenital syphilis, low birth weight, and neonatal death. Disability-adjusted life-years were estimated for all health outcomes. The analytic horizon was the life expectancy for the mother and child. RESULTS: For a cohort of 1000 pregnant women in a historically high syphilis prevalence population (10% infected and 15% previously infected), the model predicted a total of 39 adverse pregnancy outcomes if no serologic screening were performed; 13 for the laboratory-based RPR+TPHA; 11 for the on-site RPR strategy; 5 for the Dual-POC strategy; and 2 for the ICS strategy. On the basis of assumption that the cost of ICS and the Dual-POC tests were the same, the ICS strategy was the most cost saving (saved $30,000) followed by the Dual-POC strategy (saved $27,000). CONCLUSIONS: The dual-POC test may help save cost in resource-poor settings where disease prevalence (and loss to follow-up) is high, while substantially reducing overtreatment.

Serologic testing for syphilis in the United States: a cost-effectiveness analysis of two screening algorithms.

BACKGROUND: The introduction of automated treponemal enzyme immunoassays and chemiluminescence assays (EIA/CA) tests has led some laboratories in the United States to use new syphilis screening algorithms that start with a treponemal test. We compared the economic and health outcomes of this new algorithm with the standard algorithm from the perspective of the United States health system. METHODS: We used a cohort decision analysis to estimate the expected costs and effects (including follow-ups and overtreatment) of the 2 algorithms from a health-care system perspective. In the standard algorithm, rapid plasma reagin (RPR) is followed (if reactive) by EIA/CA (Nontreponemal-First). In the new algorithm, EIA/CA is followed (if reactive) by RPR. If the RPR is negative, Treponema pallidum passive particle agglutination assay (TP-PA) test is used (Treponemal-First). RESULTS: For a cohort of 200,000 individuals (1000 current infections and 10,000 previous infections), the net costs were $1.6 m (Treponemal-First) and $1.4 m (Nontreponemal-First). The Treponemal-First option treated 118 more cases (986 vs. 868) but resulted in a substantially higher number of follow-ups (11,450 vs. 3756) and overtreatment (964 vs. 38). Treating the additional 118 cases might prevent 1 case of tertiary syphilis. The estimated cost-effectiveness ratios were $1671 (Treponemal-First) and $1621 (Nontreponemal-First) per case treated. The overtreatment was a function of the specificity of the EIA/CA and the lack of independence of EIA/CA and TP-PA. CONCLUSION: The Treponemal-First option costs slightly more and results in more unnecessary treatment.

The tale of two serologic tests to screen for syphilis--treponemal and nontreponemal: does the order matter?

BACKGROUND: Standard syphilis screening involves an initial screening with a nontreponemal test and confirmation of positives with a treponemal test. However, some laboratories have reversed the order. There is no detailed quantitative and qualitative evaluation for the order of testing. In this study, we analyzed the health and economic outcomes of the order of testing for the 2 serologic tests used in syphilis screening under pure screening settings. METHODS: We used a cohort decision analysis to examine the health and economic outcomes of the screening algorithms for low and high prevalence settings. The 2-step algorithms were nontreponemal followed by treponemal (Nontrep-First) and treponemal followed by nontreponemal (Trep-First). We included the 1-step algorithms (treponemal only [Trep-Only] and an on-site nontreponemal only [Nontrep-Only]) for comparison. We estimated overtreatment rates and the number of confirmatory tests required for each algorithm. RESULTS: For a cohort of 10,000 individuals, our results indicated that the overtreatment rates were substantially higher (more than 3 times) for the 1-step algorithms, although they treated a higher number of cases (over 15%). The 2-step algorithms detected and treated the same number of individuals. Among the 2-step algorithms, the Nontrep-First was more cost-effective in the low prevalence setting ($1400 vs. $1500 per adverse outcome prevented) and more cost-saving ($102,000 vs. $84,000) in the high prevalence setting. CONCLUSIONS: The difference in cost was largely due to the substantially higher number of confirmatory tests required for the Trep-First algorithm, although the number of cases detected and treated was the same.

Cost effectiveness of enzyme immunoassay and immunoblot testing for the diagnosis of syphilis.

The burden of disease and associated health-care costs of syphilis are significant despite widespread screening and treatment. Our objective was to conduct an economic evaluation using a simulation model when comparing enzyme immunoassay (EIA) initial testing and Inno-Lia (IL) confirmatory testing (EIA + IL) with rapid plasma reagin (RPR) initial testing and Treponema pallidum particle agglutination assay (TPPA) and fluorescent treponemal antibody absorption assay (FTA-ABS) confirmatory testing (RPR + TPPA/FTA). Estimates of prevalence, test costs and utilization of services for 2006 were derived from Alberta databases. Estimates of test characteristics were derived from the available literature. The incremental cost-effectiveness ratio was Canadian $461 per additional correct diagnosis (less costly and more effective). EIA + IL is cost-effective when compared with RPR + TPPA/FTA for screening and diagnosis of syphilis.

Field evaluation of the performance and testing costs of a rapid point-of-care test for syphilis in a red-light district of Manaus, Brazil.

OBJECTIVES: To assess the performance, usefulness and cost of a rapid treponemal antibody assay (VisiTect Syphilis) to detect syphilis in high risk populations. METHODS: People who attended STI clinics in Manaus, Brazil, were screened for syphilis using the fluorescent treponemal antibody absorption (FTA-Abs) test and a non-treponemal test (Venereal Diseases Research Laboratory (VDRL)), and for HIV. Finger prick blood samples were tested with VisiTect Syphilis. The rapid test was evaluated against the reference FTA-Abs and for its usefulness in detecting active syphilis (FTA-Abs and VDRL positive). Operational performance was assessed through providers' and patients' interviews. An economic evaluation was conducted from the provider's perspective. RESULTS: 510 patients (60% men) were enrolled, of whom 13 (2.5%) were HIV-1 seropositive. Syphilis prevalence (FTA-Abs) was 18% and active syphilis prevalence was 7.5%. 11% (57/506) of samples were positive by VisiTect. The sensitivity, specificity, positive and negative predictive values of VisiTect Syphilis were 57% (95% CI 45.8 to 66.7), 99% (95% CI 97.0 to 99.6), 91% (95% CI 80.0 to 96.7) and 91% (95% CI 88.0 to 93.5), respectively. VisiTect Syphilis identified 79% (30/38) of active syphilis cases. The cost per case of syphilis was $16.8 for VDRL, $33.2 for low cost and $56.3 for high cost VisiTect Syphilis; the cost per case of active syphilis was $21.3, $57.5 and $97.6, respectively. Patients identified finger prick pain and preference for venous blood collection as minor barriers to test use. CONCLUSION: VisiTect Syphilis had low sensitivity in field use and was less cost effective than conventional VDRL. However, rapid and correct identification of a high proportion of active syphilis cases combined with operational characteristics suggest a role in high risk populations.

Comparative evaluation of 15 serological assays for the detection of syphilis infection.

Fifteen commercial syphilis kits were assessed against the same moderately sized specimen panel that included 114 serum and plasma specimens from syphilis cases and 249 specimens from unselected blood donors. The 114 specimens from syphilis cases comprised 40 from cases of primary syphilis, 43 from cases of secondary syphilis, 19 from cases of early latent syphilis, and 12 from cases of late latent syphilis. Of the 15 kits, ten were enzyme immunoassays, four were Treponema pallidum haemagglutination assays, and one was a T. pallidum particle agglutination assay. Thirteen of the 15 kits gave final specificities of 100%; the other two kits were repeatedly reactive with one to two specimens. Initial sensitivities ranged from 93.9 to 99.1%. Most variation between kits was observed in results for the groups with untreated primary and treated late latent disease, although the differences were not statistically significant. The comparative data on kit performance derived from this study is useful for examining syphilis testing guidelines and for making informed purchasing decisions.

Screening for syphilis in pregnancy: which is the proper method?

BACKGROUND: Consequences of syphilis in mother, pregnancy, fetus and child are considerable, but preventable. Serological screening must be offered at the first prenatal visit. Presently, the diagnosis of syphilis is dependent mainly on serological tests. The most widely used screening tests for syphilis are the VDRL and the rapid plasma reagin (RPR) and for confirmation the fluorescent treponemal antibody (FTA) and the treponema pallidum hemagglutination (TPHA) tests. METHOD: The four alternative nodes for diagnosis of can be a) VDRL + FTA, b) VDRL + TPHA, c) RPR + FTA and d) RPR + TPHA. Here the author reports an evaluation of cost utility of those tests in obstetrical practice. According to this study, it can be shown that the cost per accurate diagnosis for VDRL + TPHA is the least expensive choice and for RPR + FTA is the most expensive choice. CONCLUSION: Therefore, this alternative is the best method for serological diagnosis of syphilis, based on medical laboratory economics principles.

Cost-effectiveness of on-site antenatal screening to prevent congenital syphilis in rural eastern Cape Province, Republic of South Africa.

OBJECTIVES: On-site screening and same-day treatment of maternal syphilis in underresourced settings can avert greater numbers of congenital syphilis cases, but health outcomes and associated costs must be evaluated jointly. METHODS: We used decision analysis to estimate the incremental cost-effectiveness of two on-site antenatal syphilis screening strategies to avert congenital infections-qualitative RPR (on-site RPR) and treponemal immunochromatographic strip assay (on-site ICS)-compared to the current practice (off-site RPR/TPHA). FINDINGS: With antenatal active syphilis prevalence of 6.3%, the incremental cost-effectiveness of on-site ICS in averting congenital infections was estimated to be USD104, averting 82% of cases expected in absence of a program. The incremental cost-effectiveness of off-site RPR/TPHA was USD82 but would avert only 55% of congenital syphilis cases. On-site RPR was dominated by the other screening strategies. CONCLUSIONS: In settings of high maternal syphilis prevalence, on-site antenatal screening with ICS is a cost-effective approach to reduce the incidence of congenital syphilis.

On-site rapid antenatal syphilis screening with an immunochromatographic strip improves case detection and treatment in rural South African clinics.

OBJECTIVES: Congenital syphilis is a significant cause of adverse pregnancy outcomes. In South Africa, rural clinics perform antenatal screening offsite, but unreliable transport and poor client follow up impede effective treatment. We compared 3 syphilis screening strategies at rural clinics: on-site rapid plasma reagin (RPR), on-site treponemal immunochromatographic strip (ICS) test, and the standard practice offsite RPR with Treponema pallidum hemagglutination assay (RPR/TPHA). METHODS: Eight rural clinics performed the on-site RPR and ICS tests and provided immediate treatment. Results were compared with RPR/TPHA at a reference laboratory. Chart reviews at 8 standard practice clinics established diagnosis and treatment rates for offsite RPR/TPHA. FINDINGS: Seventy-nine (6.3%) of 1,250 women screened on-site had active syphilis according to the reference laboratory. The on-site ICS resulted in the highest percentage of pregnant women correctly diagnosed and treated for syphilis (89.4% ICS, 63.9% on-site RPR, 60.8% offsite RPR/TPHA). The on-site RPR had low sensitivity (71.4% for high-titer syphilis). The offsite approach suffered from poor client return rates. One percent of women screened with the ICS may have received penicillin unnecessarily. There were no adverse treatment outcomes. CONCLUSIONS: The on-site ICS test can reduce syphilis-related adverse outcomes of pregnancy through accurate diagnosis and immediate treatment of pregnant women with syphilis.

Modelling the cost-effectiveness of introducing rapid syphilis tests into an antenatal syphilis screening programme in Mwanza, Tanzania.

OBJECTIVES: A study found screening (with rapid plasma reagin (RPR)) pregnant women for maternal syphilis was cost-effective in Mwanza, Tanzania. Recently, four rapid point-of-care (POC) syphilis tests were evaluated in Mwanza, and found to have reasonable sensitivity/specificity. This analysis estimates the relative cost-effectiveness of using these POC tests in the Mwanza syphilis screening intervention. METHODS: Empirical cost and epidemiological data were used to model the potential benefit of using POC tests instead of RPR. Reductions in costs relating to training, supplies, and equipment were estimated, and any changes in impact due to test sensitivity were included. Additional modelling explored how the results vary with prevalence of past infection, misclassified RPR results, and if not all women return for treatment. RESULTS: The cost-effectiveness of using POC tests is mainly dependent on their cost and sensitivity for high titre active syphilis (HTAS). Savings due to reductions in training and equipment are small. Current POC tests may save more disability-adjusted life years (DALYs) than the RPR test in Mwanza, but the test cost needs to be <0.63 US dollars to be as cost-effective as RPR. However, the cost-effectiveness of the RPR test worsens by 15% if its HTAS sensitivity had been 75% instead of 86%, and by 25-65% if 20-40% of women had not returned for treatment. In such settings, POC tests could improve cost-effectiveness. Lastly, the cost-effectiveness of POC tests is affected little by the prevalence of syphilis, false RPR-positives, and past infections. DISCUSSION: Although the price of most POC tests needs to be reduced to make them as cost-effective as RPR, their simplicity and limited requirements for electricity/equipment suggest their use could improve the coverage of antenatal syphilis screening in developing countries.