Bissessor, Melanie FRACGP*; Fairley, Christopher K FRACP, PhD*†; Leslie, David FRCPA‡; Howley, Kerri RN*; Chen, Marcus Y MRCP, FAChSHM, PhD*†
Syphilis has reemerged as a significant problem among men who have sex with men (MSM) internationally.1-3 In Victoria, Australia, the number of notifications for early syphilis among men, most of whom were MSM, increased from 119 in 2005 to 373 in 2008. The proportion of men who had early syphilis was 23% and 40%, respectively. Forty-six percent of men diagnosed with syphilis in 2008 were HIV positive.2 Surveillance data from several US cities indicate that since 2002, an increasing number of MSM are acquiring syphilis.4
The recent reports of syphilis among MSM have been characterized by high rates of HIV coinfection and high-risk sexual behaviour.1,4 In California, 1489 cases of primary and secondary syphilis were reported in 2005, representing an increase of more than 700% from 1999.4 Seventy-nine percent were MSM, and of these, 61% were HIV positive by self-report with a majority reporting multiple anonymous sex partners.4 Suggested factors behind this resurgence in syphilis among MSM include increases in the number of anonymous sex partners, decreases in condom use, use of the Internet for meeting partners, assortative mixing with other HIV-positive men, and more widespread use of methamphetamine and proerectile agents, among other drugs.1,2,4 Oral sex has been implicated as a significant mode of transmission of syphilis: contributing to 14% of syphilis infections in one US city.4
These epidemiologic trends underscore the importance of clinicians' awareness of key behavioral risk factors, their consideration of syphilis in the differential diagnosis of similarly presenting disorders, and their familiarity with current recommendations regarding screening and clinical management of syphilis. Left untreated syphilis can result in considerable morbidity including neurosyphilis, which may be more common among HIV-positive individuals.5,6 Syphilis infection has been associated with increases in serum HIV viral load and decreases in CD4 cell counts in HIV-positive people.7 Syphilis is also believed to enhance the sexual transmission of HIV.1
The US Centers for Disease Control and Prevention recommends at least annual screening of HIV-positive MSM for syphilis.8 Mathematical modeling suggests that increasing the frequency of syphilis screening among the highest risk MSM would have a much greater impact on reducing the transmission and prevalence of syphilis compared with simply increasing the proportion of all MSM who have at least 1 syphilis test per year.9
This study aimed to determine whether the routine inclusion of syphilis serology in the blood tests that are usually performed as part of HIV monitoring increases the detection of early asymptomatic syphilis among HIV-positive MSM compared with annual screening.
This study was conducted at the Melbourne Sexual Health Centre, the main public sexually transmitted diseases clinic servicing Victoria, Australia. The center provides HIV care to approximately 20% of the HIV-positive MSM in Victoria.2 In January 2007, the center implemented a policy of including syphilis screening with every routine blood sample collected from HIV-positive MSM attending the center's HIV outpatient clinic. The previous policy was to offer syphilis screening to HIV-positive MSM attending the HIV clinic on an annual basis.
To determine the effectiveness of this intervention, we compared the proportion of MSM attending the HIV clinic who were diagnosed with early asymptomatic syphilis during the 18 months before (July 2005 to December 2006) and during the 18 months after (January 2007 to June 2008) the implementation of this new policy. We also sought to compare the impact of the intervention on the likely duration of infection before diagnosis. For the purposes of this analysis, for men with no history of syphilis, we assumed that infection occurred midway between the time of the last negative serology and the time of diagnosis. For those with a history of treated syphilis, we took the midpoint in the time between the last nonreactive or baseline rapid plasma reagin (RPR) titer and the time of diagnosis.
As part of the intervention, a request for syphilis serology was automatically stamped on all pathology request forms used in the HIV clinic for the monitoring of HIV-positive patients. The clinic policy was to recommend blood tests for CD4 count, HIV viral load, routine biochemistry, and hematology on a 3 monthly basis. For syphilis serology not to be performed, the request for syphilis testing had to be deleted from the request form. Posters were placed in each consulting room informing patients of the increase in syphilis cases in Victoria and the policy of routine syphilis screening of patients attending the HIV clinic.
Serum for syphilis serology and testing for Treponema pallidum using polymerase chain reaction (PCR) obtained from patients from Melbourne Sexual Health Centre was forwarded to the Victorian Infectious Diseases Reference Laboratory, which is the only service provider for syphilis testing for the clinic. Specimens for PCR were collected if clinically indicated from suspected lesions of early syphilis. Dark ground microscopy was performed by experienced laboratory staff on-site at the center although none of the syphilis diagnoses in this series were dependent on dark ground microscopy for the diagnosis of syphilis. The algorithm for syphilis testing remained the same over both study periods.
Serological screening for syphilis was undertaken using a combination of RPR (Macro-Vue RPR card; Becton Dickinson, Sparks, MD), Treponema pallidum particle agglutination (Serodia TPPA; Fujirebio, Tokyo, Japan), and enzyme immunoassay (EIA) (Trepanostika TP recombinant; bio-Merieux, Boxtel, the Netherlands). All tests were performed according to the manufacturer's instructions and were subject to quality assurance programs.
The clinical details for all early syphilis infections among MSM during the study period were reviewed using the medical records, and the results for all syphilis testing (serology and PCR) undertaken during the period were obtained from the reference laboratory.
Early syphilis was defined using the following criteria10,11:
1. Seroconversion with prior negative syphilis serology within the previous 12 months;
2. In men previously infected with syphilis, a 4-fold or greater rise in the RPR titer from the last baseline titer within the prior 12 months; or
3. Clinical evidence of primary or secondary syphilis together with laboratory confirmation (PCR or serology).12
For a diagnosis of early syphilis to be made in a patient with a previous history of syphilis, the man's syphilis serology needed to demonstrate a reactive EIA and TPPA with either a 4-fold rise in RPR titer from baseline or a positive PCR was required if the increase in RPR titer was less than 4-fold compared with the baseline titer.
Early infections were classified as primary, secondary, or early asymptomatic syphilis. Late infections and those of unknown duration were excluded from the study. We use the term early asymptomatic syphilis to include early latent syphilis and any infections that may have preceded the latent phase where symptoms were not reported by the patient or signs of syphilis detected by the clinician.11
Data were analyzed using SPSS version 15. The χ2 test was used to compare categorical data, and a Mann-Whitney test was used to compare the time intervals. Ethical approval for this study was granted by the Alfred Hospital Human Research Ethics Committee.
During the 18-month period before the intervention, a total of 444 HIV-positive MSM attended the HIV clinic. The number of serological tests for syphilis performed during this period among these men was 1293, with a median of 1 test per man per year. In the 18 months after the intervention, a total of 587 HIV-positive MSM attended the HIV clinic. The number of serological tests for syphilis performed during this period was 2928, with a median of 2 tests per man per year. The frequency of serological testing among these men during the 2 periods is compared in Table 1. Every MSM who attended the HIV clinic during the 2 periods was serologically tested for syphilis at least once during each of the periods with men in the second period being screened more frequently.
The proportion of HIV-positive MSM attending the HIV clinic who were diagnosed with early syphilis during the 18 months before and after the intervention was 3.1% (14 of 444) and 8.1% (48 of 587), respectively (P = 0.001). The proportion of HIV-positive MSM attending the HIV clinic who were diagnosed with late latent syphilis during the 18 months before and after the intervention was 2.0% (9 of 444) and 4.2% (25 of 587), respectively. Thus, the proportion of syphilis cases-excluding those of unknown duration-that were diagnosed in the 2 periods was 60% and 66%, respectively.
The RPR and treponemal serology were reactive in all cases, and T. pallidum PCR was positive in 5 cases. The characteristics of these men are shown in Table 2. The men with early syphilis diagnosed during the 2 periods did not differ significantly with regard to age, past history of bacterial sexually transmitted infections, CD4 count, HIV viral load, or the proportion on current antiretroviral therapy.
The proportion of HIV-positive MSM with early syphilis who were asymptomatic at the time of diagnosis was 21% before (3 of 14) and 85% after (41 of 48) the intervention (P = 0.006). The clinical presentation and laboratory results for each man are shown in Table 3. During the preintervention period, 3 men presented with a genital chancre, whereas 8 presented with a rash of secondary syphilis. The 3 remaining men were asymptomatic contacts of syphilis and were diagnosed as a result of serological screening. In the postintervention period, 4 men presented with genital chancres. Two of these men did not report symptoms at the time of screening with the chancres only being noted on examination after they screened positive for syphilis. Three men presented with a rash of secondary syphilis, one of whom who was only noted to have a rash after screening positive for syphilis.
In the remaining 41 men, the diagnosis was made as a result of the routine inclusion of syphilis testing as part of HIV monitoring. Seven of these men reported a recent history of genital ulceration (n = 1) or rash (n = 6); however, these were not present at the time of examination and therefore could not be confirmed as being syphilis-related lesions. None of the men during the postintervention period reported being contacts of syphilis.
Previous negative syphilis serology within 12 months of diagnosis was available for 12 of 14 and 36 of 48 men with early syphilis for the 2 respective periods. The remaining men had a previous history of treated syphilis with 2 of 14 and 12 of 48 having baseline low-titer reactive RPR results (indicating previous effective treatment) within 12 months of a subsequent 4-fold or greater rise in RPR titer, indicating a likely reinfection. This increase in RPR was confirmed with serological testing in parallel. None of the patients with a previous history of syphilis were symptomatic at the time of testing; however, 2 men reported a recent rash, but these were not present at the time of examination and therefore could not be confirmed as being syphilis-related lesions.
Assuming infection midway between previous baseline tests and the time of diagnosis, the median duration of infection was estimated to be 107 days (range 9-362) and 45 days (range 23-325) for the 2 periods, respectively (P = 0.018). Among the 41 men with asymptomatic early syphilis in the postintervention period, the median RPR was 32 (range 1-1024). The proportion of men with RPR titers ranging between 1:1-1:16, 1:32-1:128, and 1:256-1:1024 was 34% (n = 14), 46% (n = 19), and 20% (n = 8), respectively. In the preintervention period, the median RPR was 64 (range 1-512).
In this study, we have shown that the inclusion of routine syphilis serology in the blood tests that are usually taken as part of HIV monitoring resulted in a marked increase in the proportion of HIV-positive syphilis infected MSM diagnosed with asymptomatic syphilis. No previously published studies of interventions aimed at increasing syphilis testing of HIV-positive MSM have increased screening rates as much or increased the proportion diagnosed with early asymptomatic infection to the same degree.13-15 The intervention is likely to have enhanced syphilis control through a reduction in the duration of infectiousness while reducing morbidity that would have arisen as a result of undiagnosed infection.
We obtained all syphilis serology performed during the study period at our center's HIV clinic and are therefore confident we have included all serologically confirmed cases of syphilis seen during the study period. The clinical and serological data for all cases were carefully examined, and we intentionally restricted our analysis to those men who had confirmed early infection, excluding those with late infection or infection of unknown duration as we were interested in men who were likely to have been infectious for syphilis.
There are a number of limitations to the study. First, it is possible that some of the increase in frequency of testing for syphilis arose because of an increase in awareness of syphilis among clinicians and clients over the study period. However, given that clinicians had to actually delete syphilis testing from the forms when testing was not indicated, it is likely that almost all the increase in screening was directly attributable to screening that was prompted by the intervention. Second, as this involved the review of medical records without blinding to the date of the syphilis diagnosis and hence period of observation, there was the potential for bias and misclassification into the symptomatic and asymptomatic groups. However, each case was carefully reviewed by M.B. and M.Y.C, and agreement was reached as to which group individuals should be allocated. Third, we could not determine the true duration of infection but rather derived an estimate based on the time of last serology. Only data obtained from our reference laboratory were analyzed in our study as this laboratory is our service provider for laboratory testing. The increase in the proportion of HIV-infected MSM attending the clinic who were diagnosed with early syphilis after the intervention may to some extent have reflected an increase in the incidence of syphilis among MSM in Victoria during the 3-year period of the study. However, an increase in syphilis incidence would not contribute to the observed increase in the proportion of early asymptomatic infection. The yield of asymptomatic syphilis detected was substantially higher compared with the previous policy of offering annual syphilis screening. This simple intervention probably also decreased the duration of infectiousness, given the significant reduction in the likely duration since infection was acquired. Although it is likely that the transmissibility of syphilis was reduced as a result of the intervention, the extent to which this occurred would be difficult to quantify given the paucity of data on transmission, particularly from asymptomatic infection.
Finally, as the study involved MSM only, the findings may not be generalizable to other groups.
The proportion of men with early syphilis who were asymptomatic at the time of diagnosis (85%) was striking. We attribute this high rate of asymptomatic infection to the relatively high frequency of screening achieved through the intervention. A London study that incorporated syphilis serology into computer order sets observed an increase in the frequency of syphilis screening of HIV-positive patients with the proportion of syphilis infections that were asymptomatic from 50% in the first year and 56% in the second. In a study of HIV-infected patients attending a hospital in Amsterdam, patients were screened for syphilis and then rescreened 6 months later. In this study, the proportion of syphilis cases that were asymptomatic was 33% and 24% in the 2 rounds of screening. The average number of tests per person per year in our study was higher than that in these 2 other studies: 3.3 compared with approximately 2 in the Amsterdam study and 2.5 in the London study.14,15
The high proportion of asymptomatic syphilis in our and other studies points to the presence of a large pool of undiagnosed asymptomatic infection among HIV-positive MSM, infections that would otherwise remain undetected in the absence of a comprehensive screening strategy with sufficiently high coverage and frequency of testing. The inclusion of routine syphilis screening of HIV-positive MSM as part of their outpatient care is likely to be cost effective. Based on Medicare rebate rates, the cost of syphilis screening per test was AUS$28.85 (RPR, EIA) or AUS$43.40 if TPPA was added (if RPR or EIA reactive).
As the test is simply added to those bloods that are routinely collected, there is no additional clinic staff time or handling required. Furthermore, in our experience, it is an acceptable approach for clinicians and clients. During the study period, no complaints were received from either clients or doctors about this policy nor had any patients refused to have a syphilis test.
In considering the cost-benefits of this approach, the potential morbidity averted, including the risk of sequelae such as neurosyphilis, the cost of further syphilis transmission and infection, and the potential to facilitate additional HIV transmission need to be considered. Given the difficulties controlling syphilis in populations of MSM that continue to be seen internationally despite efforts focused on both primary and secondary prevention,16-18 we believe that the adoption of this simple intervention warrants consideration. The Australian National Gay Men's Syphilis Action Plan has adopted this intervention as a priority intervention for the control of syphilis in Australian MSM. More than 40% of infectious syphilis in Victoria is diagnosed in MSM who are HIV positive.2 Mathematical modelling of the intervention suggests that adoption of the intervention is likely to lead to a reduction in the prevalence of syphilis among MSM in Australia.19 Studies to determine the cost-effectiveness of the intervention would be of interest.
We thank Afrizal and other staff at the Melbourne Sexual Health Centre who contributed to the collection of data for this study and to the Victorian Infectious Diseases Reference Laboratory for providing data on syphilis testing.
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