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Abstract
Objectives Infectious syphilis has been proposed as an indication for HIV pre-exposure prophylaxis (PrEP) in women. We explored how many women experienced HIV seroconversion after being diagnosed with syphilis in Ontario between 20 April 2010 and 31 December 2021.
Methods Through deterministic linkage of laboratory data at the Public Health Ontario laboratory, which conducts the vast majority of syphilis and HIV testing in Ontario, we quantified the number of females with positive syphilis diagnoses who subsequently exhibited HIV seroconversion between April 2010 and December 2021. New HIV cases were identified by diagnostic serology or HIV viral load test result of ≥20 copies/mL at least 60 days after the positive syphilis test. We report aggregate numbers of women with new laboratory evidence of HIV infection after their first positive syphilis test.
Results Among 7957 women with positive syphilis tests during the study period, 6554 (82.4%) had linkable HIV serology tests and 133 (1.7%) ever tested HIV positive. With further linkage to viral load data, the number of women who ever had laboratory evidence of HIV infection increased to 184 (2.3%). However, when restricting to women whose first positive HIV test or HIV viral load occurred after their first positive syphilis test, this number decreased to 34 (0.4%). The median (IQR) time between the positive syphilis test and the first laboratory evidence of HIV was 551 (IQR=226–1159) days.
Conclusion Although it is clinically appropriate to recommend HIV PrEP to women with syphilis, Ontario surveillance data suggest that the population-level impact of this strategy on the HIV epidemic in Ontario would have been modest during this 11-year period. Future studies should explore additional ways of prioritising women for PrEP.
- SYPHILIS
- Pre-Exposure Prophylaxis
- WOMEN
- Preventive Health Services
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Scale-up of HIV pre-exposure prophylaxis (PrEP) among women in Ontario, Canada would be facilitated by evidence-based clinical indications, but empirical studies that estimate women’s HIV risk according to specific risk factors are scant in this setting.
WHAT THIS STUDY ADDS
We explored syphilis as a potential PrEP indication in women using laboratory data. We found that the population-level impact of PrEP on reducing HIV infections, in our context, would have been modest.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The preliminary insights gleaned from these population-level data can help shape local prevention efforts for women, in the absence of robust evidence from large observational cohorts. Offering PrEP to women with syphilis may still be clinically justified, considering the recent rise in infectious syphilis.
Introduction
In Ontario, HIV pre-exposure prophylaxis (PrEP) uptake has helped curb new HIV infections among gay, bisexual and other men who have sex with men (gbMSM). Yet, PrEP is underused among women in the province; currently, only 2.6% of PrEP users are female (data are not disaggregated by gender identity).1 In 2021, the PrEP-to-Need ratio, the ratio of PrEP users to new HIV diagnoses among females in Ontario, was only 3.0, compared with 28.1 in males.1
An important barrier to increasing PrEP use in women in industrialised world settings has been the relative lack of clear clinical criteria for identifying women at greatest HIV risk. Syphilis has been proposed as an indication for PrEP in women,2 since infection can increase the risk of HIV acquisition. Biologically, the causative agent of syphilis, Treponema pallidum, promotes HIV susceptibility in the female genital tract by eliciting a mucosal inflammatory response that impairs the epithelial barrier and by attracting HIV target cells. Behaviourally, sexual practices that may result in syphilis, like partner concurrency, increase HIV risk.
Studies in several populations have empirically demonstrated this link, mirroring findings in men.3 For instance, research using surveillance registries of 211 603 women in Louisiana over 15 years reported higher HIV rates in those with syphilis than those without a preceding sexually transmitted infection (STI) (177.3 vs 22.4 per 100 000 person-years).4 Similarly, a Florida study found the rate of subsequent HIV infection to be 19.8 times higher for women with syphilis than those without previous STIs (597.9 vs 30.2 per 100 000 person-years).5
In this study, we investigated how often women had a new HIV diagnosis after having a positive syphilis test in Ontario between 2010 and 2021, to quantify missed opportunities for PrEP in women related to this promising clinical indicator.
Methods
We conducted a retrospective cohort study using laboratory data from the Public Health Ontario (PHO) laboratory, which conducts most syphilis and HIV diagnostic testing in Ontario. We deterministically linked syphilis diagnostic, HIV diagnostic and HIV viral load data for females from 20 April 2010 to 31 December 2021, using their health card number, first name, last name and date of birth.
We first identified women who ever had a positive syphilis test, using sample login dates (0–3 days from specimen collection date). We defined a positive syphilis test as the first time a woman had a reactive syphilis screening test (eg, chemiluminescent microparticle immunoassay, CMIA), plus either (1) a reactive rapid plasma reagin test, and/or (2) a reactive/indeterminate T. pallidum particle agglutination test, as per PHO’s syphilis testing algorithm. The number of positive syphilis cases reflects anyone who has ever had a positive syphilis test regardless of whether the infection is old or new, as the laboratory-based data source lacks clinical information.
We then identified the subset of those women who had available HIV serology test results during the study period. Of these, we quantified, using absolute numbers and proportions, those with a positive HIV test at least 60 days after the positive syphilis test. The requirement of 60 days was imposed to avoid capturing individuals who were already HIV positive at the time of their syphilis diagnosis. The HIV diagnostic testing algorithm defines a positive result as a reactive/indeterminate screen test (antigen/antibody CMIA screen) and either a positive confirmatory test (western blot/Geenius confirmatory assay) or a reactive p24 antigen test (p24 Ag enzyme-linked fluorescent assay).
Because anonymous HIV testing results have no demographic information to link to syphilis testing results, we further classified females as having laboratory evidence of HIV infection if they had an HIV viral load test result of ≥20 copies/mL, even in the absence of a positive HIV serology test.
Data are presented descriptively according to the year in which an individual’s first positive syphilis test was performed and the number of days from a positive syphilis test to a positive HIV diagnostic/viral load test.
Results
Of the 7957 women with a positive syphilis test between 20 April 2010 and 31 December 2021, 6554 (82.4%) had HIV diagnostic testing, of whom 133 (1.7%) had a positive HIV serology test on record (table 1). After further including those women classified as being HIV positive based on HIV viral load data, the number of women with a positive HIV serology/viral load test following their first positive syphilis test increased to 184 (2.3%). Notably, the number of women whose first laboratory evidence of HIV infection occurred after their positive syphilis test was 34 (0.4%). Women with a positive HIV/viral load test after syphilis infection had a mean age of 41.7 years (SD=12.7). The median time between a positive syphilis test and the first positive HIV diagnostic/viral load test for these 34 individuals was 551 (IQR=226–1159) days (table 1).
HIV testing data among Ontario women diagnosed with syphilis, by year
Discussion
Between 2010 and 2021, 34 women in Ontario had laboratory evidence of HIV infection after their syphilis diagnosis. These findings are consistent with other North American data showing that women with a previous STI comprise only 1.5% of women diagnosed with HIV.4 While there is a strong association between syphilis and subsequent HIV acquisition in women,4 5 our results suggest that providing PrEP to women with syphilis would have had only modest impact on reducing new HIV infections in Ontario during this period.
In other settings, longitudinal data have more clearly demonstrated the benefit of PrEP for individuals with syphilis. In an international sample of gbMSM and transgender women, the iPrEX Study estimated the number of individuals with syphilis who would need to receive PrEP to prevent one new HIV infection (ie, number needed to treat) was only 10.6
Despite our findings, it remains appropriate to recommend PrEP to syphilis-positive women, given the potential for clinical benefit. Notably, recent guidelines from the USA advise that PrEP be discussed with all sexually active adults, and that it be prescribed to anyone requesting it regardless of clinically validated risk factors, in an effort to decrease barriers to PrEP uptake.2 In Ottawa, Ontario, a nurse-led PrEP programme attempted to increase PrEP uptake among women through a combination of objective criteria and clinical assessments, and among 23 females diagnosed with syphilis between August 2018 and March 2020, successfully initiated PrEP in 9 (39%).7
Our findings provide a starting point for understanding the risk of HIV seroconversion in women with syphilis. Given that follow-up times varied depending on when the individuals in our study were first diagnosed with syphilis, it is possible that more HIV-positive cases may be discovered in the cohort during longer follow-up. This is especially likely for those diagnosed recently, considering the evolving epidemiology of syphilis and HIV in Canada. In Manitoba, the proportion of new female HIV diagnoses grew from 25.4% to 49.7% between 2018 and 2021 following the expansion of syphilis to the heterosexual population.8 This trend may presage similar outcomes in Ontario, where syphilis has been on the rise. Nationally and globally, the rates of infectious syphilis among women have also grown in the past several years. Thus, the extent to which syphilis predicts future HIV infection in women, perhaps according to behaviour, age or region, warrants ongoing study; and the public health value of routinely recommending PrEP to women with syphilis today and in the future may be considerably greater than what we observed for 2010–2021.
Another challenge to the broader rollout of PrEP is the large proportion of people newly diagnosed with HIV in Ontario who have never undergone HIV testing previously, which has ranged from 26.7% to 43.6% between 2011 and 2019.9 This high proportion further restricts our ability to identify opportunities for PrEP and underscores the importance of more frequent HIV screening.
Our study has limitations. First, since syphilis diagnostic data begin on 20 April 2010, individuals’ positive HIV tests prior to this date are not included, some women may have been misclassified as seroconverting after their syphilis diagnosis. This limitation reinforces our conclusion about the modest potential benefit of PrEP in this clinical setting in Ontario. Second, we could only include HIV diagnoses occurring up to 31 December 2021, potentially underestimating the true number of women who may have benefited from PrEP. Third, there may have been missed HIV diagnoses due to changes in health-seeking behaviour during the COVID-19 pandemic, given the 26% drop in HIV tests in Ontario in 2020.10 However, this possibility seems unlikely, since the positivity rate among women undergoing HIV testing that year was consistent with pre-pandemic years.10 Fourth, we did not have access to anonymous HIV testing data, which may have underestimated true seroconversions in our sample, although we used viral load data to mitigate this. Finally, our data reflect syphilis and HIV diagnoses, not actual infections. However, since our purpose was to quantify women who could be readily offered PrEP in the context of sexual health services, our sample represents an appropriate group to prioritise.
For PrEP to close the gap in HIV incidence among women requires evidence on specific risk factors for HIV acquisition. Ontario data from 2010 to 2021 suggest that the absolute number of HIV infections that could be averted through offering PrEP to women with syphilis is modest. Nevertheless, doing so remains clinically appropriate. Diverse strategies for prioritising women for PrEP are urgently needed.
Ethics statements
Patient consent for publication
Ethics approval
Ethics approval was obtained from the PHO Ethics Review Board (file #2023.001.01).
Acknowledgments
The authors wish to acknowledge that they live and work on the traditional territories of the 16 Mississaugas of the Credit, Haudenosaunee, Anishnaabe, Chippewa and Wendat peoples.
Footnotes
Handling editor Stefano Rusconi
Contributors YS contributed to protocol development and wrote the first draft of the manuscript. PN and AS contributed to data extraction and statistical analysis. VA contributed to study design. VT, MH and JL provided insight and expertise with regard to the Public Health Ontario internal resources/databases. DHST conceived the study and oversaw study conduct. All authors critically reviewed and approved the final manuscript.
Funding This work was supported by a grant from the Canadian Institutes of Health Research. DHST is supported by a Tier 2 Canada Research Chair in HIV Prevention and STIs.
Competing interests DHST’s institution has received support from AbbVie and Gilead for investigator-initiated research studies, and from GlaxoSmithKline for participation in industry-sponsored clinical trials. There are no competing interests for any other author.
Provenance and peer review Not commissioned; externally peer reviewed.