Examining patient characteristics and HIV-related risks among women with syphilis as indicators for pre-exposure prophylaxis in a nurse-led program (PrEP-RN)

Abstract

Current HIV pre-exposure prophylaxis (PrEP) guidelines primarily target men who have sex with men (MSM) as candidates for HIV prevention; however, such recommendations often come at the expense of other ethnic and gender minorities, including women. To address barriers to PrEP care among non-MSM, we developed and implemented the first nurse-led PrEP program in Canada, known as PrEP-RN. As part of PrEP-RN, patients who meet objective indicators of HIV risk are offered a referral for PrEP, regardless of sexual orientation. One such measure is syphilis, which has increased in incidence among various population groups and is known to cause biological vulnerabilities to HIV. To better understand HIV-related risks and assess intentions for PrEP use among women, we undertook an 18-month retrospective review of syphilis diagnoses within this group in Ottawa, Canada. As part of this review, we examined 23 patient files, noting their unique characteristics, socio-behavioural risk factors, and noted barriers to PrEP uptake. While none of the women diagnosed with syphilis were diagnosed with HIV, the findings raise some important considerations to facilitate opportunities for HIV prevention among non-MSM, which must take into consideration individual risk practices, sexual health histories, and population groups.

Keywords

Pre-exposure prophylaxis HIV prevention women syphilis

Pre-exposure prophylaxis (PrEP) is an HIV prevention strategy that can reduce the risk of HIV acquisition by 96–99%.¹ Despite this success, in North America, PrEP has primarily been targeted at men who have sex with men (MSM). While focusing on these men is an effective strategy to reduce HIV transmission at the population level (as these men account for most HIV infections in many Western countries),² targeting MSM alone means that other populations that are affected by HIV are overlooked.

Other researchers have raised this critique about disparities in extant PrEP guidelines for non-MSM who are at-risk for HIV in North America. For example, Nelson et al. noted that Canadian guidelines do not adequately assess HIV risk among women, African, Caribbean, and Black (ACB) communities, Indigenous groups, and persons who inject drugs.³ The same can be said for transgender persons, with Canadian guidelines recommending PrEP for transwomen, and not transmen.¹ Calabrese et al.⁴ raised similar critiques about the US guidelines, arguing that they require women to recognize their risk as well as that of their partners – which could result in women at-risk for HIV not being offered PrEP unless they perceive themselves as “at-risk”. Despite the lack of guidance for PrEP among non-MSM, PrEP uptake among some groups, including women, may also be inhibited by personal perceptions of being lower-risk for HIV acquisition, which can affect both intentions for PrEP initiation and long-term adherence for those who do initiate PrEP.⁵ However, considering that women who have sex with men account for nearly 25% of all HIV diagnoses in Canada² and 16% in the US,⁶ we feel that HIV prevention screening and PrEP referrals should continue to expand beyond standard guidelines to include screening for high-risk behaviours among non-MSM groups.

In North America, syphilis is an important risk factor for HIV acquisition that could identify people for PrEP. Studies have identified that up to 1 in 20 MSM become HIV-positive within 12 months of a syphilis diagnosis.⁷ While estimates of HIV acquisition in women with syphilis are not as exact, several studies from the US have shown that women with a history of sexually transmitted infections (STIs), including syphilis, were diagnosed with HIV at higher rates compared to those without previous STIs.⁸,⁹ Notably, women with prior syphilis diagnoses accounted for a small proportion of the overall HIV diagnosis in the areas where these studies occurred.

Notwithstanding this fact, syphilis can alter immune responses in the genital tract causing increased expression of target cells in the cervical mucosa leading to heightened susceptibility for HIV infection.¹⁰,¹¹ This occurs for two reasons. On the one hand, syphilitic lesions compromise skin integrity and create direct portals of entry for HIV. That is, the ulcerative nature of primary syphilis lesions compromises innate immunity and allows HIV direct access to underlying vasculature and immune system structures.¹⁰,¹¹ On the other hand, many of the adaptive immune system cells that respond to – and are present within – syphilitic lesions are CD4+ immune cells. The issue with this is that CD4+ cells are the exact target cells for HIV, meaning that the biologic susceptibility to HIV is likely simultaneously increased both due to structural and immunologic changes that occur directly due to syphilitic lesions.¹¹ As a result, syphilis is a risk factor for HIV acquisition.

In light of this known association between syphilis/STI diagnoses and HIV acquisition, as well as the biologic vulnerabilities to HIV caused by syphilis infection, a syphilis diagnosis could be an indication that someone is a good candidate for PrEP. While in Canada, most cases of syphilis are diagnosed among men, the rates of syphilis among women have doubled from 2014 to 2018.¹² Similar increases in the rates of syphilis infection were seen in Ontario among women, with syphilis rates increasing by 160% between 2014 and 2018 (from 0.5/100,000 to 1.3/100,000).¹³ Locally, in Ottawa (study location) these rates increased by 228% from 2014 to 2018 (from 4.6/100,000 to 15.1/100,000).¹³ The concern here is that increasing rates of syphilis among women could be a harbinger for the possibility of coinciding increases in HIV rates among women with syphilis in time.

Considering rising rates of syphilis in women and limited indications for PrEP for this group, we sought to (1) evaluate PrEP referrals offered to women diagnosed with syphilis in a registered nurse-led PrEP program (PrEP-RN), and (2) understand the characteristics of this group to enhance HIV prevention. Based on previous analyses of PrEP-RN, we knew that most persons being offered and accepting PrEP were MSM. In this analysis, we wanted to understand PrEP access for women. To do this, we completed a retrospective analysis of PrEP referrals for women with syphilis, and reported on their characteristics, HIV-related risk factors, and referrals for PrEP care.

Methods

Project design

We implemented PrEP-RN as the first wholly nurse-led PrEP service in Canada involving both systematic referrals for PrEP by public health nurses and a PrEP clinic in an STI clinic. Two other unique elements to PrEP-RN are, first, registered nurses and nurse practitioners perform the referrals, patient intake, result monitoring, prescriptions, and follow-up.¹⁴ Second, the PrEP-RN referral system uses objective indicators of HIV risk based on recommendations in PrEP guidelines¹ and supporting literature on the sexual transmission of HIV, including diagnoses of rectal bacterial STIs (chlamydia, gonorrhea) or infectious syphilis.^a These diagnoses, while primarily observed in MSM, are indications for PrEP referrals for any patient, regardless of gender or sexual orientation. We also offer PrEP to persons who initiate HIV post-exposure prophylaxis at our STI clinic, patients whose partners are recently diagnosed with HIV (“contacts”), and/or individuals deemed at high-risk based on nurses’ clinical judgement.¹⁵ The latter referral criteria allows nurses the autonomy to offer PrEP to persons who might be at risk for HIV based on history or risk factors, but who may not meet the exact criteria listed – for example, patients with a new or historical diagnosis of chlamydia and/or gonorrhea of the cervix, pharynx, or urethra, persons involved in sex trade, or contacts of STIs, etc.

As part of the PrEP-RN referral service, patients who meet any of the above indications for PrEP are offered a referral either to the PrEP-RN clinic or one of three infectious diseases services available in Ottawa. Patients who self-select for PrEP (e.g., do not meet high-risk criteria but request PrEP) are offered a referral to one of the local infectious diseases clinics in the city. This referral system therefore provides rapid access to PrEP care for those at highest risk for HIV through the PrEP-RN clinic, while at the same time ensuring that persons who perceive themselves as at-risk for HIV can access HIV prevention services.

The program launched August 5, 2018 and was funded by the Ontario HIV Treatment Network. This funding helped provide PrEP medications at a reduced cost for persons without medication coverage. Research ethics approval was obtained from the University of Ottawa and Ottawa Public Health.

Study recruitment

Public health nurses made PrEP referrals during mandated follow-up with patients diagnosed with reportable STIs (chlamydia, gonorrhea, syphilis). As part of this, public health nurses identified anyone who met the foregoing criteria, counselled them about PrEP, and offered them a PrEP referral – either to an infectious diseases specialist or PrEP-RN (as detailed above). Patient responses were captured on a referral sheet by the public health nurse and entered into a data spreadsheet for analysis. Nurses also recorded who met the risk criteria but were ineligible to receive PrEP (e.g., those without provincial health insurance [required for processing PrEP monitoring tests], previously diagnosed with HIV, secondary health issues preventing PrEP use).

Data collection and analysis

We completed a 19-month chart review of women diagnosed with syphilis in our health unit from August 5, 2018 to March 5, 2020. Data were extracted from the Ontario Ministry of Health and Long-Term Care Integrated Public Health Information System (iPHIS) on March 5, 2020. From this, we reviewed patients’ files, which included demographic information, reason for completing syphilis testing, presence or absence of symptoms, and syphilis treatment. Treatment was recorded in accordance with Canadian STI Guidelines,¹⁶,¹⁷ which recommended one intramuscular dose of 2.4 million units of benzathine penicillin G or oral doxycycline 100 mg tablets twice daily for 14 days as an alternative treatment for patients with known penicillin allergies.

Patient files also included information on social, behavioural, and medical risk factors using criteria established by the Ontario Ministry of Health and Long-Term Care, number of identified sexual partners prior to syphilis diagnosis, STI diagnoses, and if PrEP was offered – all which were collected as part of syphilis follow-up under provincial regulations.¹⁷ Risk factor information was collected based on identified behaviours or activities reported within one year of syphilis diagnosis (as the time parameter for infectious syphilis is up to one year).¹⁸ We also reviewed the nursing documentation in these patients’ files, as well as the public health nurses’ notes on the PrEP referral sheets (submitted as part of the PrEP-RN study protocol) to obtain additional information about PrEP offers and patients’ responses.

For inclusion criteria, we used (1) a clinical diagnosis of primary, secondary, or early latent syphilis with positive direct fluorescence antibody test result (from a lesion) and/or confirmatory serology using the reverse screening algorithm (treponemal screening test using enzyme immunoassay [EIA], followed by quantitative non-treponemal rapid plasma reagin [RPR] test, and second confirmatory treponemal T.pallidum particle agglutination assay [TPPA] test¹⁹); and; (2) persons registered as “female” on their government-issued health cards; and (3) persons residing in Ottawa. Cases were excluded if they were (1) classified as late latent syphilis, syphilis of unknown duration, or were pending staging; (2) registered as male on their health cards, or whose gender was listed as “unknown” or “trans”; (3) diagnosed prior to August 5, 2018, as PrEP referrals were not included as standard of care before this time; (4) identified as sexual contacts of syphilis who had negative syphilis test results; and (5) cases outside of Ottawa.

Cases who met the above-noted criteria were logged in an Excel spreadsheet using a unique identifier. Patient characteristics were analyzed using descriptive statistics and coded for frequencies and similarities. Study approval was obtained from the Research Ethics Boards at the University of Ottawa and Ottawa Public Health as part of the PrEP-RN study.

Results

From August 5, 2018 to March 5, 2020, 254 cases of infectious syphilis were reported to Ottawa Public Health. Of these diagnoses, 23 were female and 231 were non-female (i.e., men, trans, or gender unspecified). We evaluated the same rates in the nineteen months preceding PrEP-RN (January 7, 2017 – August 2, 2018) and found a total of 193 infectious syphilis diagnoses – 8 of which were in females and 185 of which were in non-females. This constitutes a 163% increase in infectious syphilis cases among women in the timeframe prior to and following PrEP-RN implementation, compared to a 25% increase in rates for non-females.

Focusing on the 23 women diagnosed with syphilis during the study period, all identified as “female” and ranged in age from 19–57 years (median: 28 years old). For country of birth, 60.8% (n = 14) were born in Canada, 8.6% (n = 2) in Europe, and 30.4% (n = 7) had no country indicated. For ethnicity, 14 were White, two Indigenous, and seven had no available information. For STI history, 39.1% (n = 9) of the women in our group had a previous diagnosis. Five women had a chlamydia diagnosis, two had multiple chlamydia diagnoses, one had a history of chlamydia and syphilis (both diagnosed in the past year), and one had been treated for hepatitis C.

Of these 23 women, 69.5% (n = 16) were seen at primary care clinics,17.4% (n = 4) attended our STI clinic, and 13.0% (n = 3) presented to the emergency department. The reasons for patients’ visits to care primarily related to presence of syphilis-related symptoms (65.2% or n = 15) or having a partner recently diagnosed with syphilis (21.7% or n = 5); only three women presented for routine STI screening. Notably, 15 women presented to care for queries related to new symptoms and three had signs on examination, signalling that 78% (n = 18/23) had clinical features of syphilis. These included painless lesions on mouth and/or genital area, non-pruritic rash, mucosal lesions, headache, flu-like illness, or patchy hair-loss. Of this group, 21.7% (n = 5) were asymptomatic, but were diagnosed with syphilis during routine STI screening or during follow-up as a syphilis contact. For diagnosis, 17.4% (n = 4) were staged as primary, 60.8% (n = 14) were secondary, and 21.7% (n = 5) were early latent. Following diagnosis, all women received syphilis treatment as recommended in Canadian guidelines.

Social, behavioural, and medical risk factor information were available for all but one of the 23 women. All reported that their sexual partners were exclusively male, 54.5% (n = 12/22) reported condomless sex, and 36.4% reported having more than one sexual partner in the 6 months preceding their syphilis diagnosis. The number of sexual partners prior to syphilis diagnosis ranged from 1–6 (average: 1.9). Forty percent (n = 9/22) of women reported anonymous sex partners. Additional risk factors identified in our group were insufficient housing, which was noted for 18.2% (n = 4/22), and injection or inhalation drug use, which was reported among 13.6% (n = 3/22) patients. We also noted that 18.2% (n = 4/22) of these women were pregnant or had recently given birth at the time of their syphilis diagnosis. See Table 1.

Table 1.

Social, behavioural, and medical risk factors.

Risk factors	N/22 (%)
Sex with opposite sex partners	22 (100)
More than one syphilis diagnosis in past 6 months	1–6 (mean 1.9)
Condomless sex	12 (54.5)
Anonymous sexual partners	9 (40.9)
Online, bars/clubs	4/9 (44.4)
Travel outside of country	2/9 (22.2)
Underhoused/homeless	4 (18.8)
Injection or inhalation drug use	3 (13.6)
Pregnant or recent delivery	4 (18.8)
Previous STI diagnosis	9 (39.1)
Subsequent diagnosis	3 (13.0)

As part of this review, we identified that 13.4% (n = 3) of the 23 women in our group were diagnosed with a subsequent STI following syphilis treatment. One was diagnosed with chlamydia and gonorrhea within 6 months, one with chlamydia on two separate instances within the proceeding 7 months, and one was named as a syphilis contact 7 months after treatment. The women who had a subsequent STI diagnosis were different than the five women who had a documented previous history of STIs. Notably, no one was diagnosed with HIV. As for HIV testing information at the point of syphilis diagnosis, this was only available for 43.5% (n = 8/23) of the women in our cohort, all of whom were negative. While in our local area, HIV and syphilis testing are often ordered simultaneously, the provincial reportable infection database (iPHIS) does not record negative test results, and therefore we were unable to verify HIV testing for the remaining 57.5% of our group. We were, however, able to confirm that no subsequent HIV diagnoses were recorded in these patients’ records (at the point of chart review/data collection).

Lastly, we reviewed PrEP offers and referrals made by public health nurses during syphilis follow-up for these women. During the study period, PrEP referrals were offered to 39.1% (n = 9) of patients in our group (based on PrEP-RN referral criteria to offer PrEP to all persons diagnosed with infectious syphilis), all of whom declined. The reasons for patients declining PrEP primarily related to lack of interest or personal perceptions of being “low-risk” for HIV. We were unable to obtain additional information in the patients’ charts for those who were not offered PrEP beyond a marking of “not applicable” by nurses; in three instances, however, the patient was lost to follow-up and therefore PrEP counselling could not occur as the patient could not be located. There were no noted differences between those who were, and were not, offered PrEP during follow-up by public health nurses in terms of clinical stage, identified risk factors, STI history, and subsequent STI diagnoses. Notably, the number of PrEP referrals offered by nurses to women in our cohort increased after the first six months of the initiation of PrEP-RN referral process.

Discussion

We operate a nurse-led PrEP referral and clinical service through our public health unit and STI clinic; this is known as PrEP-RN. Access to PrEP-RN is based on an STI diagnosis, using PEP, being an HIV contact, or nursing clinical assessments. One key STI diagnosis that predicts future HIV acquisition among MSM is syphilis. If syphilis predicts HIV acquisition among women, however, is less clear. Considering increased syphilis diagnoses among women since 2014, we reviewed the public health files of women diagnosed with syphilis to identify their characteristics and STI/HIV-related outcomes. In the first 19-months of operating PrEP-RN, we identified 23 women who were diagnosed with syphilis, of whom 60.9% were deemed as not sufficiently at risk for HIV (whether based on clinical or personal perception). Of these women, 13.4% were diagnosed with another STI after their syphilis diagnosis and 0% were diagnosed with HIV. We also identified that 78% of these women had syphilis symptoms. These findings raise a few points for discussion.

First, it is important to acknowledge the low rate (39.1%) of PrEP uptake and referrals in our study. While the women in our cohort could be at elevated risk for HIV acquisition based on their syphilis diagnosis, and thus be eligible candidates for PrEP, PrEP uptake among women is often inhibited by personal perceptions of women as being a lower-risk population for HIV acquisition.⁵ Indeed, many women in heterosexual relationships often underestimate their risk for HIV acquisition (and corresponding candidacy for PrEP) despite (1) belonging to a population with elevated HIV prevalence, (2) possessing certain socio-behavioural risk factors (e.g., STIs, incarceration, substance use, involvement in sex trade etc.), or (3) having sexual partners who are from higher-risk groups.⁵,²⁰,²¹ In addition, fear of stigma and judgement from peers for using HIV prevention medications, and challenges with accessing healthcare services (physical location, transportation issues, lack of insurance to pay for follow-up visits) were identified as possible barriers to PrEP uptake and low rates of acceptance among women.²⁰,²¹ Finally, healthcare providers may be less apt to identify systemic risk factors for HIV acquisition among women, and consequently may miss opportunities to discuss HIV prevention interventions such as PrEP.⁵ That 60.9% of our cohort were considered to not be sufficiently at-risk signals that more work needs to be done at a provider-level to (1) improve risk assessments among non-MSM and (2) increase education, and referrals for PrEP to alternate groups to reduce future HIV acquisition.

A second point for discussion is that to the best of our knowledge, none of our 23 women with syphilis was diagnosed with HIV. As noted in the results, while HIV testing information was only available for 43.5% of our cohort, none of the women had a recorded positive result on file at the time of data collection, indicating a zero HIV positivity rate among women with infectious syphilis in this study. This suggests that, among women, syphilis may not predict future HIV acquisition in the same way as it does in MSM. Supporting this assertion is that, despite recent increases in syphilis in women, corresponding increases in HIV diagnoses have not materialized.²,¹³ Further supporting this is that, in contrast to no HIV diagnoses, 13.4% of our 23 women were diagnosed with another STI, highlighting ongoing risk practices but no HIV diagnoses. Together, this information suggests that Nelson et al.’s assertions³ that syphilis should warrant PrEP for women may be an over-generalization, and that the 39% referral rate for PrEP we observed may have been appropriate.

It could be, however, that our sample was simply too small to detect HIV diagnoses and that PrEP should be offered to women with syphilis. The lack of HIV diagnoses among these 23 women could also have occurred because nearly two-thirds of these women were White and born in Canada, which corresponds with lower risk of HIV.² Our finding might have changed had the sample included more women who were born outside Canada or Black or Indigenous – with ethnicity relating to structural inequities, not behavioral or biological differences.²² This zero-rate of HIV diagnoses may have also occurred because we did not have HIV test results for women who did HIV testing outside our province or who tested anonymously. Moreover, we were not able to confirm if HIV screening was completed at the time of syphilis diagnosis in over 50% of our cohort. It is possible that our zero-positivity rate related to a lack of HIV testing, not a lack of risk.

Due to the limitations in our study and the individual and population-level sequelae of missed HIV prevention, we recommend that PrEP be offered to women with syphilis. We do not feel that the appropriate threshold to determine that women warrant PrEP is an HIV diagnosis. Waiting for diagnoses seems unethical. Instead, we opt to follow the Health Canada²³ and FDA²⁴-approved product monographs, which state that PrEP should be offered to anyone who:

[1] engages in sexual activity within a high [HIV] prevalence area or social network, and [(2) has] one or more of the following: inconsistent or no condom use, diagnosis of [STI], exchange of sex for commodities (such as money, food, shelter, or drugs), use of illicit drugs or alcohol dependence, incarceration, partner(s) of unknown HIV-1 status with any of the factors listed above.²³,²⁴

This would mean it is be appropriate to offer PrEP to women who are in high-risk sexual networks, with a history of chlamydia and/or gonorrhea (cervical, vaginal, pharyngeal or rectal), and who have condomless sex and/or who share needles and other injection drug equipment. We also feel that, due to epidemiologic studies identifying that upwards of 40% of persons diagnosed with syphilis are HIV-positive, that a diagnosis of syphilis makes a woman a candidate for PrEP; indeed, she is an STI diagnosis in a network with possibly elevated HIV prevalence.²⁵

Conclusion

In closing, despite none of our 23 women being diagnosed with HIV after a syphilis diagnosis, we feel our study reinforces the need to offer PrEP to women. Our study highlighted the presence of multiple risk factors for HIV acquisition among this cohort, which fulfills the product monograph indications for PrEP. That no one was diagnosed with HIV does not undermine this statement. We believe that, to withhold PrEP to these women could worsen their health status. To address this situation, we suggest that more women be offered PrEP. Contrary to indications in current guidelines,¹ we recommend practitioners offer PrEP to all women with a recent HIV contact, diagnosis of syphilis, diagnosis of chlamydia and/or gonorrhea, or who have syndemic factors for HIV acquisition, including belonging to a higher-risk population group, engaging in substance use, having multiple sexual partners and/or involvement in sex trade. Because the risks of PrEP are minimal and the risks of HIV acquisition are great (even if the risk of exposure may be smaller than for MSM), offering PrEP to women seems clinically appropriate. Waiting for studies to show missed opportunities is inappropriate and unethical. The time to act is now.

Footnotes

Acknowledgements

We would like to thank the Ontario HIV Treatment Network (OHTN) for their funding on this project. Patrick O’Byrne would like to acknowledge the OHTN for the appointment of his Research Chair in HIV Prevention and Public Health.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Note

ORCID iDs

Lauren Orser

Patrick O’Byrne

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