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This study was approved by the Human Research Ethics Committee of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan (G-002009-00). The study protocol did not require written informed consent since the study only used data of anonymized patients obtained from a routine practice and from stored serum samples, which were obtained with written informed consent [7]. The study was conducted according to the principles expressed in the Declaration of Helsinki.
The AIDS Clinical Center, NCGM, Tokyo, was established in 1997 and had accumulatively registered approximately 4000 patients [6]. Considering that the total reported number of patients with HIV-1 infection in Japan is 27,413 by the end of 2015, this clinic treats approximately 15% of the HIV-1 infected patients in Japan [3].
The study population was HIV-1-infected MSM who visited our clinic for the first time between January 2008 and December 2013. The following exclusion criteria were applied; 1) patients who visited the clinic for a second opinion or those who were referred to other facilities on their first/second visit, because some baseline data were likely missing and the follow-up period was short in these patients, 2) patients younger than 20 years of age, because the Ethical Guidelines for Medical and Human Research Involving Human Subjects published by the Japanese Ministry of Health, Labour and Welfare require a written consent by parents/guardians for patients under age of 20 and it is impractical to obtain such consent for this study. Based on the results of baseline data analysis, we also excluded the following patients; 3) patients who had a confirmed active syphilis at baseline based on serum Rapid Plasma Reagin (RPR) titer ≥1:8 and positive Treponema pallidum Latex Hemagglutination Assay (TPHA) [8], and 4) patients who lacked follow-up syphilis test. At our clinic, the follow-up syphilis tests were generally performed at least every year and at the discretion of the treating physician. The study patients were followed up until December 31, 2015.
Serum Rapid Plasma Reagin test (RPR) [“Sankoh” (EIDIA Co, Tokyo)], Treponema pallidum latex hemagglutination assay (TPHA), CD4 cell count (categorized into 3 groups: CD4 count <200 /μL, 200–349 /μL, and ≥350 /μL), HIV-1 viral load, hepatitis C antibody (HCVAb), hepatitis B surface antigen (HBsAg), core antibody (anti-HBc), surface antibody (anti-HBs), and anti-Entamoeba histolytica antibody (anti-Eh) are performed routinely for each patient on the first visit to our clinic. History of syphilis was defined as baseline positive TPHA and RPR titer <1:8. Exposure to hepatitis B virus (HBV) was defined as those either with positive HBsAg, anti-HBs, or anti-HBc [6], because in Japan, universal HBV vaccination is not conducted, except for health care professionals [9]. Patient visit our clinic at least every three months to receive renewal prescription of medications, since the prescription period under the Japanese health care system is limited to three months. Laboratory data, as well as baseline demographics (age, sex, ethnicity, treatment status for HIV infection, history of syphilis, history of AIDS, and history of HBV vaccination) on the first visit were collected from the medical records. Social demographics variables were collected through a structured interview conducted by a clinical nurse specialist on the first visit as part of routine clinical practice [10]. The interview included the following behavioral variables: perceived route of transmission, sexuality (MSM status was based on self-identification), history and type of illicit drug used (intravenous injection or methamphetamine), gay’s bathhouse use, and health insurance status. Because the interview could underestimate the prevalence of illicit drug use, we also reviewed the medical records for information on illicit drug use and related variables covering the period from the first visit to December 2015. Incident syphilis was defined as development of syphilis in the study patients. The diagnosis of syphilis was based on both serum RPR ≥8 and positive TPHA result [8], either with or without clinical symptoms/signs suggestive of syphilis. At our clinic, written informed consent is obtained from each patient to routinely store blood samples at the first and subsequent visits, thus we had the stored samples collected from each patient at least every three months [7]. Except for the patients who were clinically diagnosed of incident syphilis, the result of either the latest serum syphilis test conducted in clinical practice or the same test using the latest stored serum sample were used to determine the status of syphilis, whichever the follow-up time was longer. Censoring was performed for cases with incident syphilis, those referred to other hospitals, those who were lost to follow-up, or those who died, or at end of the observation period (December 31, 2015). Incident syphilis was classified into early syphilis (including primary, secondary, and early latent syphilis), late syphilis (including late latent syphilis and syphilis with unknown duration), and others, including neurosyphilis and ocular syphilis [11,12]. We used the standard definitions for stages of syphilis; early latent being asymptomatic syphilis that was confirmed to be infected within a year from diagnosis, late latent being asymptomatic syphilis confirmed to be infected more than a year before diagnosis, and syphilis with unknown duration being asymptomatic syphilis that could not be classified into either early latent or late latent [11,12]. The date of development of incident syphilis was defined as the day of clinical diagnosis for patients with early syphilis. For patients who developed late or neurosyphilis or those diagnosed with syphilis based on stored serum samples, stored samples were backwardly tested for syphilis using samples collected every three months to determine the day of the first positive syphilis result, and thence the date of development of incident syphilis.
The study patients were categorized into two groups; patients with incidence syphilis and those without syphilis. The incidence of syphilis was calculated by dividing the number of incident syphilis by person-time at risk. Person-time represented the time from the first visit to the date of incident syphilis as described above in patients who developed incident syphilis, and to the last negative syphilis test in patients without incident syphilis. Poisson regression was used to compare the incidence of syphilis among four observation periods (2008–2009, 2010–2011, 2012–2013, and 2014–2015). Patients’ characteristics and social demographics were compared between patients with incident syphilis and those without such infection using the Student’s t-test for continuous variables and using either the χ2 test or Fisher’s exact test for categorical variables. The univariable Cox proportional hazards regression analysis was used to estimate the effect of each variable on the incidence of syphilis infection, and each variable with p value less than 0.1 was incorporated into multivariable analysis. Incarceration due to drugs and AIDS were not added to the multivariable model because of their multicollinearity with illicit drug use and CD4 count, respectively. Statistical significance was defined at two-sided p values of <0.05. We used the hazard ratios (HRs) and 95% confidence intervals (95% CIs) to estimate the effect of each variable on the incidence of syphilis infection. All statistical analyses were performed with The Statistical Package for Social Sciences ver. 23.0 (SPSS, Chicago, IL).
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