Syphilis point-of-care tests: an Australian perspective

Introduction – the Australian setting

Syphilis is a sexually and vertically transmitted infection caused by the spirochete Treponema pallidum.¹ The natural history of untreated syphilis follows a course of primary, secondary and tertiary clinical manifestations, as well as periods of latency occurring within and following the first 12 months from infection.² Untreated syphilis in pregnancy can lead to vertical transmission and may result in congenital infection, stillbirth or neonatal death.³

In Australia, notification rates of infectious syphilis have increased by 220% in the last decade, from 7.6 per 100,000 in 2013 to 24.3 per 100,000 in 2022, and remain highest among Aboriginal and Torres Strait Islander peoples living in remote areas, as well as in gay, bisexual and other men who have sex with men.⁴ Since 2016, notifications of infectious syphilis in women and vertically transmitted cases have also risen: among 69 cases of congenital syphilis reported between 2016 and 2022, 18 (26%) resulted in neonatal death or stillbirth – of these, 11 (61%) occurred among Aboriginal and Torres Strait Islander peoples.^4,5 These reports highlight the need for strategies related to enhancing syphilis screening; however, inequitable access to culturally appropriate healthcare, compounded by a history of traumatic colonisation, Stolen Generations and social determinants of health, hinders public health efforts to revert the current epidemiologic syphilis trends.⁶

In Australia, syphilis POC tests have been used for over 1 decade as part of enhanced community screening programmes.^7–9 In this paper, we summarise types of syphilis POC tests available, their role in public health strategies and frameworks for selecting POC tests in screening programmes.

Syphilis point-of-care testing: an opportunity to reach priority populations

Syphilis point-of-care (POC) tests are rapid diagnostic tools designed to facilitate same-day diagnosis, treatment and hasten contact tracing. POC testing for syphilis may support access to care in resource constrained or geographically isolated settings, among groups who face barriers to accessing health services or for highly mobile people where loss-to-follow-up is probable.^10–13 In Australia, the settings and populations where POC tests have most value are influenced by the burden of disease and ability to improve clinical and public health management.

Syphilis POC tests

A range of syphilis POC tests are commercially available globally and have been described elsewhere.^14,15 Briefly, these include treponemal-only tests that detect T. pallidum-specific antibodies in whole blood, plasma or serum (treponemal readout only), a POC test that simultaneously and separately detects treponemal and nontreponemal antibodies (separate treponemal and nontreponemal readouts), and dual human immunodeficiency virus (HIV)–syphilis test that detects HIV antibodies and treponemal-only antibodies (separate HIV and treponemal readouts).¹⁴

Australia’s syphilis POC programmes

The 2017 Federal Government’s Enhanced Syphilis Response (ESR) included a ‘Test and Treat’ model to address the ongoing syphilis epidemic in Aboriginal and Torres Strait Islander peoples living in remote areas.^9,16 This decentralised model led by Aboriginal Community Controlled Health Services complements molecular POC testing strategies delivered in similar remote primary care settings.^17,18 Before the ESR, syphilis POC tests had been used in some limited settings in Australia, including community-based screens and in diagnostic accuracy studies.^8,19–21

The Test and Treat model uses the only syphilis POC test approved by the Australian Therapeutic Goods Administration (Determine Syphilis TP, Abbott), a lateral-flow immune-chromatographic assay that identifies treponemal antibodies in 15 min (sensitivity: 97.3%; 95% CI 95.8–98.3%; specificity: 96.4; 95% CI 94.1–97.8%).¹⁹ Since nontreponemal antibodies are not measured at the POC, this test is unable to distinguish between active (treponemal and nontreponemal test positive) and past treated infections (treponemal test positive and nontreponemal test negative). Interpretation of a positive test relies on access to previous syphilis serology, treatment history and traditional laboratory-based serological methods.²² In principle, the implementation of treponemal POC testing in outbreak affected areas aimed to provide enhanced access to testing in a population with low historical prevalence of infection. This facilitates timely treatment and reduces the time required to initiate treatment and contact tracing, minimising the number of individuals lost to follow-up and easing the follow-up burden on primary care.²³ As a result of the ongoing epidemic, the benefits of using a treponemal-only POC test to guide management in a population with increased prevalence of treated syphilis has limitations. Also, to date, POC tests are not recognised as part of the national syphilis case definition,⁷ and there is no centralised mechanism to integrate results into national databases or syphilis registries.²³ A POC test that simultaneously detects treponemal and quantifies nontreponemal antibodies would be ideal in this context. However, a qualitative readout of nontreponemal antibodies might still be valuable as it can be used to distinguish between current and past infection, enabling prompt and targeted treatment.²⁴

Using a POC test that measures treponemal and qualitative nontreponemal antibodies, along with its electronic microreader has been shown to yield similar sensitivity and specificity compared to visual operator readings in a laboratory-based diagnostic accuracy study – in addition, the test has demonstrated good correlation between the quantitative electronic readout of nontreponemal antibodies and rapid plasma reagin (RPR) titres.²⁵ However, further research is needed to examine the utility for active syphilis case detection and treatment monitoring. Visual and digital readouts show high sensitivity for the nontreponemal line in active syphilis cases with RPR titres ≥1:8, but lower sensitivity with RPR titres ≤1:4 – the latter could potentially result in missing very early and late latent syphilis cases.²⁵ Moreover, conventional laboratory testing would still be necessary in the parent–child dyad as part of the follow-up for congenital syphilis.²⁶ A field diagnostic accuracy study of the dual treponemal–nontreponemal test with its microreader demonstrated that sexual health nurses without laboratory training could accurately identify individuals with infectious syphilis in real-world POC settings.¹² The microreader is now Clinical Laboratory Improvement Amendments (CLIA, 1988, USA)-waived for the dual HIV–syphilis POC test, but not currently approved for use for the dual treponemal–nontreponemal POC assay.²⁷ The impact of the dual treponemal–nontreponemal test on antimicrobial stewardship requires further evaluation. One study suggested that those determined to have past infection were still treated, emphasising the need to enhance health system integration.^28,29

To increase syphilis testing coverage among pregnant people, the World Health Organization recommends the implementation of dual HIV–syphilis POC testing as the first screening test in antenatal care,³⁰ with test performance summarised elsewhere.³¹ The benefits of this technology in countries with overall HIV prevalence <5% is unclear, with modelling reporting cost savings compared to separate rapid HIV and laboratory-based syphilis tests.³² In Australia, for example, given the estimated national population prevalence of 0.14% and female population prevalence of 0.03%,⁴ a dual HIV–syphilis POC test is unlikely to be suitable for antenatal screening, as the false positives would possibly outweigh true HIV diagnoses.

Among the technological innovations to deliver a new diagnostic POC test for syphilis, a lateral-flow immunochromatographic assay for diagnosis of active syphilis developed by the Burnett Institute (Melbourne, Vic., Australia), which detects T. pallidum-specific immunoglobulin A (IgA) is intended to provide an alternative to laboratory-based RPR testing, in conjunction with a treponemal screening test. Diagnostic accuracy evaluations conducted using stored plasma and blood venous samples suggest that the sensitivity and specificity of this prototype for active syphilis diagnosis is greater than 95 and 80% respectively using a T. pallidum hemagglutination assay (TPHA) and RPR laboratory-based reference tests.³³ Future strategies may involve the development of nucleic-acid amplification POC tests capable of detecting both herpes simplex virus (HSV) and T. pallidum in skin or mucosal lesions, as well as clustered regularly interspaced short palindromic repeats (CRISPR)-based POC test for detecting T. pallidum from genital ulcer exudates (M. Y. Chen, unpubl. data).

Selecting a POC test

The selection of a POC test should be co-designed with communities. Although this process traditionally focuses on performance, cost and workflow integration, there are other attributes that are equally important.²⁹ The REASSURED criteria (Fig. 1) provide a framework for considering new POC technologies³⁴ – these are described below.

Fig. 1.

Characteristics of a REASSURED diagnostic test. Adapted from Land et al.³⁴

Conclusion

Syphilis POC tests are being used in Australia to increase access to syphilis testing and treatment in priority areas. Given the ongoing and developing nature of the syphilis epidemic, it is timely to re-evaluate the clinical utility of the treponemal-only POC test and assess if newer POC technologies could improve the uptake and effectiveness of the Test and Treat model. The REASSURED criteria guide the selection of POC tests, alongside simplified pathways to improve access and funding for state-of-the-art and quality assured technologies.