Sexually Transmitted Diseases:
Results of a 25-Year Longitudinal Analysis of the Serologic Incidence of Syphilis in a Cohort of HIV-Infected Patients With Unrestricted Access to Care
Ganesan, Anuradha MD, MPH*; Fieberg, Ann MS*,†; Agan, Brian K. MD*; Lalani, Tahaniyat MD*,‡,‖; Landrum, Michael L. MD*,‡; Wortmann, Glenn MD*,§; Crum-Cianflone, Nancy F. MD, MPH*,¶; Lifson, Alan R. MD†; Macalino, Grace PhD, MPH;*; The Infectious Disease Clinical Research Program HIV Working Group
From the *Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD; †School of Public Health, University of Minnesota, Minneapolis, MN; ‡San Antonio Military Medical Center, San Antonio, TX; §Walter Reed Army Medical Center, Washington, DC; ¶Naval Medical Center San Diego, San Diego, CA; and ‖Naval Medical Center Portsmouth, Portsmouth, VA
The Infectious Disease Clinical Research Program HIV Working Group included the following members: Susan Banks, RN, Irma Barahona, RN, CAPT Mary Bavaro, MD, Helen Chun, MD, Cathy Decker, MD, Lynn Eberly, PhD, Conner Eggleston, LTC Tomas Ferguson, COL Susan Fraser, MD, MAJ Joshua Hartzell, MD, MAJ Joshua Hawley, LTC Gunther Hsue, Arthur Johnson, MD, COL Mark Kortepeter, MD, MPH, Michelle Linfesty, Scott Merritt, LTC Robert O'Connell, MD, Cpt Jason Okulicz, MD, Sheila Peel, PhD, Michael Polis, MD, John Powers, MD, MAJ Roseanne Ressner, MD, ret Col Edmund Tramont, LT Tyler Warkentien, MAJ Paige Waterman, MD, Amy Weintrob, MD, Timothy Whitman, MD, and LTC Michael Zapor, MD. The authors thank William Bradley for his assistance with data acquisition.
The content of this publication is the sole responsibility of the authors and does not necessarily reflect the views or policies of the National Institutes of Health or the Department of Health and Human Services, the DoD, or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.
We certify that all individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the analysis of data (when applicable), the writing of the document, and the approval of the submission of this version; that the document represents valid work; that if we used information derived from another source, we obtained all necessary approvals to use it and made appropriate acknowledgements in the document; and that each takes public responsibility for it.
Some authors on this paper are military service members and/or employees of the U.S. Government. As such, this work was prepared as part of official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person's official duties.
Presented in part at the 16th Conference on Retrovirus and Opportunistic Infections, Montreal, February 16–19, 2009; Abstract number 1057.
All authors have reviewed and approved this manuscript.
A.G. and A.F. had full access to all the data and take responsibility for the accuracy of the data. Study concept and design (A.G., B.A.); acquisition of the data (A.G., N.C.-C., M.L., T.L., G.W.); drafting of the manuscript (A.G., A.F., B.A., and G.M.); critical review of the manuscript (G.W., M.L., T.L., N.C.-C., and A.L.); obtaining funding (A.G., B.A.); study supervision (A.G.).
Supported by the Infectious Disease Clinical Research Program (IDCRP) (IDCRP-000-26), a Department of Defense (DoD) program executed through the Uniformed Services University of the Health Sciences. This project has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), under Inter-Agency Agreement Y1-AI-5072.
Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (http://www.stdjournal.com).
Correspondence: Anuradha Ganesan, MD, MPH, National Naval Medical Center, Division of Infectious Diseases, 8901 Wisconsin Ave, Bethesda, MD 20889.E-mail: Anuradha.email@example.com.
Received for publication September 9, 2011, and accepted January 5, 2012.
Background: The well-described biologic and epidemiologic associations of syphilis and HIV are particularly relevant to the military, as service members are young and at risk for sexually transmitted infections. We therefore used the results of serial serologic testing to determine the prevalence, incidence, and risk factors for incident syphilis in a cohort of HIV-infected Department of Defense beneficiaries.
Methods: Participants with a positive nontreponemal test at HIV diagnosis that was confirmed on treponemal testing were categorized as prevalent cases, and participants with an initial negative nontreponemal test who subsequently developed a confirmed positive nontreponemal test were categorized as incident cases.
Results: At HIV diagnosis, the prevalence of syphilis was 5.8% (n = 202). A total of 4239 participants contributed 27,192 person-years (PY) to the incidence analysis and 347 (8%) developed syphilis (rate, 1.3/100 PY; [1.1, 1.4]). Syphilis incidence was highest during the calendar years 2006 to 2009 (2.5/100 PY; [2.0, 2.9]). In multivariate analyses, younger age (per 10 year increase hazard ratio [HR], 0.8; [0.8–0.9]), male gender (HR, 5.6; [2.3–13.7]), non–European-American ethnicity (African-American HR, 3.2; [2.5–4.2]; Hispanic HR, 1.9; [1.2–3.0]), and history of hepatitis B (HR, 1.5; [1.2–1.9]) or gonorrhea (HR, 1.4; [1.1–1.8]) were associated with syphilis.
Conclusions: The significant burden of disease both at and after HIV diagnosis, observed in this cohort, suggests that the cost-effectiveness of extending syphilis screening to at-risk military members should be assessed. In addition, HIV-infected persons continue to acquire syphilis, emphasizing the continued importance of prevention for positive programs.
Syphilis is a sexually transmitted infection (STI) with protean clinical manifestations. In HIV-infected persons, syphilis often occurs without overt symptoms.1,2 Historically, syphilis has posed a significant threat to military service members.3 With the introduction of penicillin, syphilis rates declined in the military. The mid-1980s saw a resurgence of syphilis cases4; however, rates declined throughout the 90s, and in 1999, rates in the US Navy were similar to that observed in civilian settings.5 In the last decade, syphilis has reemerged as a significant public health problem, largely fueled by an increase in the number of cases among HIV-infected men who have sex with men (MSM).6,7 Syphilis increases the risk of both acquiring and transmitting HIV infection.8,9 The biologic plausible associations that link syphilis to HIV transmission are of particular relevance to the US military, as service members between the ages of 17 to 24 comprise nearly 40% of the US military and represent an age-group that is at a high risk for STI.10,11 Given the resurgence of syphilis among HIV-infected civilians, it is important to define the epidemiology and risk factors associated with the disease in the HIV-infected military population. We used serial serologic testing results to examine the seroprevalence, seroincidence, and risk factors associated with incident syphilis in a cohort of HIV-infected US military members.
MATERIALS AND METHODS
To achieve our objective, we examined data from the US Military HIV Natural History Study (NHS), a cohort comprised of HIV-infected Department of Defense (DoD) beneficiaries (active duty service members, retirees, and their dependents).12,13 HIV infection is documented at NHS entry using a licensed enzyme-linked immunosorbent assay-based assay and confirmed with a Western blot.
While on active duty, HIV-positive service members undergo clinical evaluations every 6 months. In keeping with this schedule, NHS visits are conducted every 6 months at 1 of 7 military treatment facilities. During these visits, participants undergo blood draws (for both study-specific tests and tests required for clinical care), individualized risk-reduction counseling by a trained technician, are evaluated by a HIV specialist, and attend peer education in a group setting. Research personnel collect demographics (including self-reported ethnicity), clinical information (including history of STIs), and updated medication history (including treatment for syphilis). Results of all laboratory tests, including those performed for clinical care, are captured in the NHS database.
Before 2006, screening for syphilis was conducted in accordance with the policies of the treatment facility; since 2006, annual serologic testing has been incorporated as a study-specific test. Syphilis screening is performed using a nontreponemal (NTr) test, primarily the rapid plasma reagin test. Positive NTr test results are confirmed using any licensed treponemal (Tr) test. For this substudy, eligible participants were enrolled in the NHS between 1986 and 2009, and had HIV, NTr, and Tr testing results documented in the database. This substudy was approved by a central institutional review board.
To assess the prevalence of syphilis at HIV diagnosis, we examined all participants who had testing performed within a 6-month window of HIV diagnosis. To improve the accuracy of our estimates, we examined a subset of seroconverters (i.e., individuals with documented HIV-positive and -negative dates within a 2-year interval). We next examined the incidence of the first episode of syphilis after HIV diagnosis. All participants with a positive NTr test after an initial negative NTr test that was subsequently confirmed by a positive Tr test result were categorized as an incident case, and those with a confirmed positive NTr test at HIV diagnosis were considered a prevalent case. The date of the incident episode was defined as the midpoint between the date of last negative NTr test and date of the first positive NTr test. Noncases included participants with an initial positive NTr test that was followed by all negative Tr tests (false-positives). Syphilis staging has not been captured in the NHS database; hence, we used duration of syphilis infection as an approximation to identify participants early in their course of infection. We defined participants as being “early” in infection if they had a negative NTr test in the 365 days before the positive NTr test. Because NTr antibody titer correlates with disease activity, for prevalent cases we considered a titer ≥1:8 as a likely reflection of recent infection.14 Self-reported ethnicity was categorized for analyses as European-American, African-American, Hispanic, or other. Antiretroviral therapy was categorized as none, mono/dual, or highly active antiretroviral therapy (HAART). The NHS definition of HAART, defined as the use of 3 drugs belonging to 2 or more classes of antiretrovirals or the use of a triple nucleotide regimen, was used for this study.15
Descriptive statistics were used to describe the population. Median values are provided with interquartile ranges (IQRs) and compared using the Kruskal-Wallis test. Proportions were compared using either the chi-square or Fisher exact tests.
Incidence rates were calculated per 100 person-years (PY) of follow-up, with exact Poisson 95% confidence intervals (CI). Follow-up time was calculated from the initial negative NTr test to the time of censoring, defined as the time of incident infection or last NTr test. Poisson regression was used to test for trends in rates by calendar year. Univariate and multivariate Cox proportional hazards (PH) methods, stratified by era of diagnosis of HIV infection (pre-1996 vs. 1996 and beyond) and treatment facility, were used to model associations between factors and incident syphilis. Time-updated covariates used all available measurements during the period of observation.
Significance for the multivariate models was defined at P < 0.05; all P values were 2-sided. Age, sex, ethnicity, and time from HIV diagnosis were included in the multivariate model, in addition to the variables with a P < 0.15 in univariate analyses. Hazard ratios (HRs) and rates are presented with 95% CI. The PH assumption was assessed for all fixed effects. Analyses were conducted using SAS software, version 9 (SAS Institute). Figures were generated using the R programming language, version 2.10.1. The “loess” and “predict loess” functions in R were used to generate the local linear robust fit smoothing lines and pointwise 95% CI depicting both the prevalence and incidence of syphilis infection (span = 2/3, degree = 1).16
Because testing rates varied by enrollment center (supplemental Table 1, online only, Supplemental Digital Content 1, available at: http://links.lww.com/OLQ/A35), sensitivity analyses were performed using data from a single center at which the testing rates have exceeded 90% since the inception of the study.
Of the 5125 eligible participants, 4977 (97%) had at least 1 evaluable NTr test and were included in this analysis (Fig. 1). Study participants were 92% male, 43% European-American, and 44% African-American. The proportion of NHS participants tested for syphilis varied by calendar year—it was lowest (78%) in 1998, and since 2003 it has exceeded 90% (Fig. 2A). The proportion tested for syphilis at the time of HIV diagnosis also varied by calendar year, exceeding 80% since 1993 (Fig. 2B).
A total of 3486 (70.0%) participants had NTr testing performed at HIV diagnosis; 202 (5.8%) participants, 56 European-American and 123 African-American, had concurrent syphilis. Approximately half the prevalent cases (n = 98) were likely recently infected. A total of 1676 HIV seroconverters had NTr testing at HIV diagnosis; 4.1% (n = 68) had prevalent disease, and 42 (67%) seroconverters met our criteria for recent syphilis infection. Since 2003, the proportion of newly diagnosed HIV-infected participants who are also coinfected with syphilis has increased (Fig. 3). The majority of the participants diagnosed with syphilis (52%) were likely recently infected as evidenced by a titer ≥1:8 (Fig. 3).
Participants with an initial positive NTr test (n = 319), no follow-up testing (n = 403), or no confirmatory Tr tests after an initial negative NTr test (n = 16) were excluded from the incidence analysis (Fig. 1). The remaining 4239 participants contributed 27,192 PY of follow-up. The median number of NTr tests per subject was 8 (IQR; 5, 16), and the median duration of follow-up was 4.9 years (IQR; 2.2, 9.0). African-American and European-American participants had similar median numbers of NTr tests (European-American: 8 [IQR; 5, 15] and African-American: 9 [IQR; 5, 17], P = 0.23).
During follow-up, 347 participants met the definition of an incident case. Among participants with incident syphilis, 98.6% were male, 68.3% African-American, 21.3% European-American, and 6.7% Hispanic. The median age and CD4 count at syphilis diagnosis were 35.0 years (IQR; 28.8, 40.4) and 509 cells/μL (IQR; 386, 695), respectively. The median time from HIV diagnosis to syphilis infection was 4.0 years (IQR; 1.6, 8.0) (supplemental Fig. 1, online only, Supplemental Digital Content 2, available at: http://links.lww.com/OLQ/A36). Of the participants with incident syphilis, 278 (80.1%) met criteria for early disease. Figure 4 summarizes incidence rates by calendar year for all participants (Fig. 4A), those with early stage disease (Fig. 4B), and for African-American and European-American participants (Fig. 4C).
The overall incidence of syphilis was 1.3/100 PY (95% CI: 1.1–1.4) of follow-up. Incidence rates varied across calendar time and race. Rates of incident syphilis were lowest between 1994 and 1999 at 0.5/100 PY (95% CI: 0.3–0.6). A resurgence of syphilis cases was observed during the calendar years 2000 to 2005 (1.6/100 PY; 95% CI: 1.3–1.8), and a continued increase has been observed during the calendar years 2006 to 2009 (2.5/100 PY; 95% CI: 2.0–2.9) (Fig. 4A). The overall incidence of early disease was 1.0/100 PY (95% CI: 0.9–1.1) and exhibited similar trends (Fig. 4B). The overall incidence of syphilis was higher among African-Americans (2.1/100 PY; 95% CI: 1.8–2.4, P < 0.0001) and Hispanics (1.1/100 PY; 95% CI: 0.7–1.6, P = 0.005) in comparison with European-Americans (0.6/100 PY; 95% CI: 0.4–0.7). Differences in the incidence of syphilis between European-Americans and African-Americans have been consistently observed over calendar time except more recently (2008–2009), during which infection rates were not significantly different ([European-Americans: 2.0/100 PY; 95% CI: 1.1–3.0] vs. [African-Americans: 3.3 cases/100 PY; 95% CI: 1.9–4.6, P = 0.13]). Since 2000, syphilis cases have increased in all 3 ethnic groups; for example, between 2001 and 2009, incident syphilis increased 7-fold among European-American (from a rate of 0.53/100 PY to 3.8/100 PY), African-Americans exhibited an approximately fourfold increase (1.4/100 PY to 5.0/100 PY), and Hispanics had nearly a doubling of the rate (1.1/100 PY to 2.1/100 PY). In a sensitivity analysis, similar trends were observed at the single center where testing rates have exceeded 90% (data not shown).
Risk Factors Associated With Incident Syphilis
Because the PH assumption was violated for age, a time-dependent age term was included in the final multivariate model. Risk factors for incident syphilis were younger age (HR, 0.82; 95% CI: 0.75–0.91), male gender (HR, 5.63; 95% CI: 2.31–13.73), ethnicity (African-American: HR, 3.24; 95% CI: 2.48–4.24; Hispanic: HR, 1.85; 95% CI: 1.15–2.96; other: HR, 2.37; 95% CI: 1.30–4.29; referent European-Americans), history of hepatitis B (HR, 1.52; 95% CI: 1.22–1.91), and gonorrhea (HR, 1.42; 95% CI: 1.12–1.80) (Table 1). HAART use was not associated with disease (HR, 0.92; 95% CI: 0.69–1.23). HIV-specific risk factors including CD4 count, viral RNA levels, and the presence of an AIDS-defining illness were not associated with syphilis.
Using results of serial serologic testing to identify syphilis cases, this longitudinal 25-year study among HIV-infected DoD beneficiaries estimated an overall prevalence of syphilis at HIV diagnosis of approximately 6% and subsequent incidence of 1.3 cases/100 PY of follow-up.
To our knowledge, this is the first study that examines the seroincidence of syphilis over a 25-year period. Compared with other studies in HIV-infected persons, seroincident syphilis rates in the NHS are lower,1,17,18 and are comparable with case-based estimates from a managed care setting in the United States.19 NHS participants have unrestricted access to health care and medications, undergo close clinical monitoring, report low rates of illicit drug use, and possess either a minimum of a high school educational equivalent (enlisted) or an undergraduate college degree (officers).12,13 Further, active duty members of this cohort have stable employment. As low rates of drug use and improved access to health care have been associated with a lower risk of acquiring STIs,20–25 we postulate that the close clinical monitoring and unrestricted access to health care and medications that NHS participants enjoy may in part explain the lower incidence of syphilis observed in this study. Reliance on serologic testing to derive estimates reduces the likelihood that the lower incidence is caused by participants seeking care outside the military health care system, as declines in titers following treatment would be captured at subsequent testing, but does not eliminate the possibility. HIV-infected MSM are disproportionately affected by syphilis and have been the primary focus of studies examining the seroincidence of syphilis.1,17,18 Hence, we compared our rates with published reports among HIV-infected MSM. Although ascertainment of sexual behaviors can be difficult in the military, when last examined, in the early 90s, a third of the surveyed NHS participants reported having sex with women exclusively.12 If the cohort composition has remained the same (namely two-thirds of MSM), it may represent an alternative explanation for our lower syphilis incidence.
In the NHS, ethnic minorities shared a greater burden of syphilis; however, these differences are not as pronounced as that observed nationwide.26 For example, African-American men nationwide were 8 times more likely than European-American men to have a diagnosis of primary or secondary syphilis in 2009, whereas in the NHS, we found that African-American men were 1.2 times more likely to be diagnosed with syphilis in that year.26 The narrowing of ethnic disparities in the NHS in recent years has not been driven by declines in syphilis cases among African-Americans but rather by increases in syphilis cases among European-Americans. In concordance with the nationwide data, we observed increases in incident syphilis rates among Hispanics; however, our sample size for this subset was small.27 Our results suggest to stem the tide of new syphilis infections in the DoD effective prevention must be targeted to at-risk groups and appropriate within varying racial/ethnic contexts.
Factors associated with incident syphilis in this study are similar to those reported previously.28,29 Younger age, non European-American ethnicity, male sex, and a history of STI were associated with an increased risk of syphilis acquisition. Some studies suggest that in the HAART era, HIV-infected men are less concerned about virus transmission, thereby increasing sexual risk-taking.30–32 Our results did not find a significant association between syphilis acquisition and HAART use and are in agreement with 2 large studies that also failed to demonstrate an association with HAART use.2,19
Historically, results of syphilis screening were used to determine military eligibility.3 The changes mandated with the introduction of the Clinical Laboratory Improvement Act led military investigators to examine the cost-effectiveness of universal syphilis screening.33 The study concluded that universal syphilis screening was not cost-effective, and screening was discontinued.33 However, this study was conducted in the 90s when syphilis rates were declining both nationwide and in the US military.5 Since 2000, there has been a resurgence of syphilis cases in HIV-infected persons; our results demonstrate similar trends in the military HIV population.26 A recent analysis of the US military also showed an increase in syphilis rates in 2008 to 2009.34 Taken together, these observations suggest that the current screening policies should be reviewed and the cost-effectiveness of periodic syphilis screening of at-risk military members both at and after enlistment needs examination.
One of the strengths of this analysis is the greater precision of our estimates because of the reliance on serologic testing to derive estimates; however, this strategy too has limitations.35 Serologic testing has reduced sensitivity in very early disease and may fail to capture subjects with early-treated disease.36 Further, incident syphilis is best characterized by measuring rates of early-stage disease (i.e., primary and secondary), as latent infection may have been acquired years earlier. As syphilis staging was not captured in the NHS, we tried to overcome this limitation by defining early- and late-stage disease by measuring duration of infection, but misclassification of cases may have occurred, which might affect our estimates. Other limitations of this study include the fact that the prior policy of “Don't ask Don't tell” limited our ability to capture patterns of sexual activity in this cohort and the need to estimate the date of syphilis seroconversion because of the periodic nature of syphilis screening. We acknowledge that the failure to adjust for risk behavior might have influenced our point estimates. To address the latter, a parallel analysis of time to incident syphilis, with syphilis infection defined as the date of the first positive test, found qualitatively similar results. Finally, the proportion of participants tested in this cohort varied by calendar year and center, and these missing data have the potential for introducing bias. Overall, 2.5% of the participants never had a syphilis test performed, and 30% of the participants did not have a test for syphilis performed within 6 months of HIV diagnosis, although in recent years the proportions of participants tested for syphilis have exceeded 90%. To address this concern, the incidence of syphilis was examined using only data from a center at which the proportion tested exceeded 90% throughout the study period, and we found the pattern of incidence over the years to be similar.
In conclusion, rates of incident syphilis, in this cohort, continue to increase despite equal access to care and low rates of drug use. Acquisition of syphilis in HIV-infected persons is indicative of unsafe behavior and points to the continued need for prevention in positive programs in the military. Overall, African-Americans shared a disproportionate burden of this disease; however, in recent years there has been a marked increase in new infections within our European-American and Hispanic participants. Additional research to understand what risk reduction interventions will work for this and other HIV-positive populations is warranted. The significant burden of syphilis identified at the time of HIV diagnosis in this cohort suggests that the cost-effectiveness of targeted screening of at-risk military members periodically after enlistment needs study.
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