Review article
Epidemiology of syphilis infection among drug users at methadone maintenance treatment clinics in China: systematic review and meta-analysis
International Journal of STD & AIDS 2014, Vol. 25(8) 550–558 ! The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0956462413515444 std.sagepub.com
Bing-xiang Wang1, Li Zhang2, Yu-jie Wang1, Jun-wei Yan1, Ya-nan Wan1, Wen-jia Peng1 and Jing Wang1
Summary Illicit drug trade has re-emerged in China since 1979 and the number of drug addicts had increased. Syphilis is mainly spread through sexual contact and blood. The incidence of syphilis is high among drug users. Methadone maintenance treatment (MMT) clinics have been implemented in China since 2004. The aim of this study was to estimate the prevalence and risk factors of syphilis among drug users at MMT clinics in China between 2004 and 2013. Chinese and English databases (CBM, CNKI, Weipu, Pubmed) of literature were searched for studies reporting syphilis among drug users in MMT clinics from 2004 to 2013. The prevalence estimates and risk factors were summarized through a systematic review and meta-analysis of published literatures. In all, 29 eligible articles with a total of 8899 drug users, were selected in this review. The pooled prevalence of syphilis infection was 7.78% (95%CI: 5.83%–9.99%). The metaanalyses demonstrated significant differences in syphilis infection rates between men and women (OR ¼ 0.34 [95%CI: 0.26–0.45]) but not between drug users and non-intravenous drug users (OR ¼ 0.82 [95%CI: 0.51–1.32]). Enhanced detection of syphilis and health promotion is warranted in MMT clinics in China.
Keywords Syphilis, sexually transmitted infection, Treponema pallidum, injecting drug users, opioid addiction, prevalence, methadone maintenance treatment, meta-analysis, China Date received: 8 July 2013; accepted: 14 October 2013
Background China has experienced a relatively drug-free period from the 1950s to the 1970s. With the implementation of open-door and economic reforms policies since 1979, the illicit drug trade has re-emerged in China. As the most populous country in the world, China has observed a rapid increase in drug users (DUs) over the past three decades.1,2 By the end of 2011, ministry of Public Security data suggest the number of officially registered DUs has already reached 1.794 million in China and the number of heroin users is 1.156 million (accounting for 64.5%). Synthetic drugs are becoming more common (accounting for 32.7%), especially in small and medium-sized cities and rural areas.3 Moreover, behind each registered DU, there were estimated 2–4 implicit DUs and the total number of DUs including un-registered DUs was thought to be much higher.4,5
In the year 1505, syphilis was first brought to the southeast coastal area of Guangdong province in China and caused a pandemic. Syphilis then spread to all parts of the country. Before liberation, there remained a serious epidemic of syphilis in China. With the Chinese government taking effective and positive measures after liberation, the disease has been well controlled in the mainland after years of effort. 1 Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China 2 Medical Genetics Center, Anhui Medical College, Hefei, China
Authors Bing-xiang Wang and Li Zhang contributed equally to this work and should be considered co-first authors. Corresponding author: Jing Wang, Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, 230061, China. Email: [email protected]
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However, with the success of economic and social reforms designed to open China to the world, the disease also became prevalent again. Syphilis is a chronic infection caused by Treponema pallidum. It causes acute cutaneous manifestations including genital ulcers, and may progress to serious sequelae of the cardiovascular and nervous systems, and serious effects on reproductive and neonatal health; it primarily spreads through sexual contact and blood.6–10 China’s ministry of health reported 327,433 cases in 2009. The yearly rate of syphilitic cases was 24.66/100,000 and the annual rate of syphilitic increase was 14.3%. The incidence of syphilis was reported as 27.9% among DUs.10,11 Methadone maintenance treatment (MMT) has been used successfully as a substitution therapy to treat heroin addiction. In turn, it reduced the spread of HIV, drug-related crime and other social problems.12 Much research has confirmed that the MMT can reduce drug-using behaviour and control the spread of HIV among injecting drug users (IDUs).13,14 To reduce the spread of HIV/AIDS, MMT clinics were initiated as a pilot programme in eight clinics serving 1029 DUs in 2004 in China.15 DUs in the community participating in MMT clinics have achieved a total of 337,000 by the end of 2011.3 MMT clinics also offer ancillary services including counseling and psychosocial support, testing for HIV and other infections (syphilis, hepatitis C virus [HCV] and hepatitis B virus, etc), referral for antiretroviral treatment and other social supports.16 Although MMT clinics were set up in order to prevent the HIV/AIDS epidemic, we found high rates of DUs infected with syphilis. There have been numerous independent studies about the prevalence of syphilis and risk factors among DUs at MMT clinics at baseline of their treatment. Across these studies, the prevalence of syphilis and risk factors showed wide variation. Many researchers drew incompatible or even contradictory conclusions and the generalizability of any single study was limited. This paper reviews the available evidence in an attempt to provide a comprehensive and reliable tabulation of available data on the epidemiological characteristics and risk factors for syphilis infection among DUs at MMT clinics in China to help inform policy makers developing prevention strategies, and guide further research.
Methods Search Strategy Two investigators independently screened a systematic review of published peer-reviewed research articles by searching the following databases: China Biological Medicine (CBM) (from 2004 to 2013), China National
Knowledge Infrastructure (CNKI) (from 2004 to 2013), Pubmed (from 2004 to 2013) and Weipu (from 2004 to 2013) database. Investigator consensus reconciled any differences in data acquisition consistently. We used the search terms: syphilis OR TP OR syphellolis AND ‘‘drug use’’ OR ‘‘drug abuse’’ OR ‘‘drug addict’’ OR ‘‘substance abuse’’ OR heroin OR ‘‘druggy’’ AND Methadone OR ‘‘Methadone Maintenance Treatment’’ OR ‘‘Methadone Maintenance Therapy’’ OR ‘‘Methadone Maintenance’’ AND China OR Chinese. The reference lists from relevant review articles and all eligible studies were also searched manually. Other relevant articles and reports released by World Health Organization (WHO) and the Chinese Ministry of Health were utilized.
Study selection Studies were eligible for inclusion in this systematic review if they met the following criteria: (1) study published in Chinese or English language; (2) study reported syphilis prevalence estimates among DUs in MMT clinics at baseline of treatment in China; (3) syphilis infection diagnosed from laboratory serologic testing (TRUST: toluidine red unheated serum test. TPPA: treponema pallidum particle agglutination assay ELISA: enzyme-linked immunosorbent assay. RPR: rapid plasma reagin); (4) study design such as study site, time period and sample size reported. Intervention studies among MMT clinics were also included. Exclusion criteria were (1) review papers; (2) studies with overlapping time intervals of sample or collection from the same origin; (3) conference abstracts and presentations; (4) only men-exclusive or women-exclusive studies; (5) dissertations; (6) studies presenting confusing data or probable errors. If the same study data were published in both English and Chinese sources, the articles published in Chinese language were excluded from this study. We extracted the following information from all eligible studies: first author, study site, study period, gender, sample size; laboratory test methods of syphilis, prevalence of syphilis and syphilis and HCV, HIV co-infection among MMT clients at the baseline of the treatment.
Validity assessment The quality of studies was assessed using a validated quality assessment tool for cross-sectional studies.2,17 The following eight items were assessed to calculate a total quality score of being included articles: (1) the target population can be defined clearly; (2) probability sampling was used to identify potential respondents; (3) the characteristics of respondents match the target population; (4) adequate response rate; (5) standardized data
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collection methods; (6) reliable survey measures/instruments; (7) valid survey measures/instruments; (8) appropriate statistical methods. Answers were scored 0 and 1 for ‘No’ and ‘Yes’, respectively. The total quality score varied between 0 and 8 for each article.
697 potentially relevant published articles (1 in PubMed, 643 in CNKI, 43 in CBM, 10 in Weipu)
601 articles excluded: 392 articles by screening the titles, 209 articles by screening the abstracts
Statistical analysis In our review, the pooled estimate of proportion with corresponding 95% confidence intervals (CI) was calculated on the basis of the Freeman-Tukey double arcsine transformation.18,19 Statistical heterogeneity was measured using the Q statistic test by the MantelHaenszel method. I2 statistic indicated heterogeneity.20 The linear regression method was used to assess the potential for publication bias. Similarly, to estimate the magnitude of the effect of sample sources, the type of sample source was stratified into communities for subgroup analyses. All analyses were carried out using the statistical software package R version 2.13.1 (R Foundation for Statistical Computing, Beijing, China) with function metaprop, metabin, metabias, etc. (R package: meta).21
67 full-text articles retrieved for more detailed evaluation
34 articles excluded based on detailed evaluation. 11 articles drug users incompletely come from MMT clines; 19 articles overlapping of time or origin; 4 articles review papers
33 potentially relevant articles
4 articles excluded: one article with female DUs only; 3 articles where syphilis was not diagnosed from laboratory serologic testing
Results In all, 697 articles were identified from four electronic databases (1 in PubMed, 643 in CNKI, 43 in CBM, 10 in Weipu). Because of replication, irrelevance and inaccuracy, we excluded 392 articles by screening the titles. Then we screened the abstracts and found that 209 articles were excluded. Overall, 67 studies (66 Chinese and 1 English) were downloaded with further analyses. Finally, 29 studies were included in the review and were used in the following meta-analysis with strict inclusion criteria and exclusion criteria (Figure 1); 29 eligible articles22–50 with a total of 8899 DUs in MMT clinics, study years from 2004 to 2012, were included in our review. The sample sizes of the selected studies ranged from 100 to 1340. All participants were recruited from MMT clinics in China. Table 1 shows the pooled prevalence of syphilis by regional distribution among MMT clinics in China. The prevalence of each region showed wide variation. As we analyzed the 14 provinces, Guizhou province (15.98%, 95%CI: 13.32–18.85%) had the highest prevalence. The pooled prevalence of syphilis infection among DUs in China was 7.78% (95%CI: 5.83%–9.99%) (Figure 2). There was significant statistical heterogeneity among DUs (Q ¼ 374.35, I2 ¼ 92.5%, p < 0.01) and there was significant publication bias according to linear regression testing (t ¼ 2.76, p ¼ 0.01). The pooled prevalence of HCV infection among IDUs in China was 6.33% (95%CI: 4.40%–8.57%) (Figure 3). There was significant statistical
29 unique articles evaluated in meta analysis
Figure 1. Selection process for study inclusion in this meta-analysis.
heterogeneity among IDUs (Q ¼ 160.59, I2 ¼ 92.5%, p < 0.01) and there was significant publication bias according to linear regression testing (t ¼ 2.44, p ¼ 0.03 < 0.05). Differences in pooled HCV infection rates among DUs were observed. The highest rate was 20% (95%CI: 13%–29%) (J Wang 2009) and the lowest rate was 2% (95%CI: 1%–3%) (Q Liu 2006– 2010). TP-HCV, TP-HIV and TP-HBV co-infection among MMT DUs at baseline of treatment in China were 5.21% (95% CI: 3.61%–7.09%), 1.06% (95% CI: 0.66%–1.56%) and 0.88% (95% CI: 0.39%–1.58%), respectively.
Gender Twenty-five studies included 6096 men and 1466 women. The pooled male and female prevalences of syphilis infection were 7.16% (95%CI: 4.99%–9.70%) and 17.74% (95%CI: 13.34%–22.63%), respectively. There was significant statistical heterogeneity (Q ¼ 43.15, I2 ¼ 44.4%, p ¼ 0.01 < 0.05) between men and women. The meta-analyses with random effects
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Table 1. The pooled prevalence of syphilis by regional distribution among MMT clinics in China. Province
First author
Study year
DUs
TP
The type of studies
Serodiagnosis methods of TP antibody
TP prevalence (95% CI) among MMT clinics
Fujian Gansu Guangdong
LH Wu LF Gao L Xia YM Xie Y Bai XP Zhou J Wang XJ Han DY Luo XH Meng XG Zhang Q Liu YH Yue LF Chen YD Zhou HQ Wei M He MH Zhang JG Xu M Zheng HM Zou W Yao DG Yang HD Mou Y Li HD Shen FY Fu YY Yan J Wang
2006 20072009 20072009 20092012 2009 2007 2009 20082009 20092010 2010 2010 20062010 2010 2007 20082010 2009 2011 20062008 20082011 20072009 20082010 20062008 2011 2009 20102011 2011 20052008 20092010 2009
100 248 249 261 518 170 143 300 228 146 154 1340 126 459 323 278 241 309 262 105 183 743 120 618 280 321 349 118 207
14 14 5 7 19 3 29 50 28 7 6 25 12 18 44 15 38 11 51 10 25 56 16 30 55 7 26 5 11
Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional
TRUST, TPPA ELISA TRUST, TPPA TRUST, TPPA TRUST, TPPA TRUST, TPPA TRUST ELISA ELISA ELISA ELISA TRUST, TPPA TRUST ELISA TRUST TRUST, TPPA ELISA RPR TRUST, TPPA RPR, TPPA RPR, TPPA TRUST, ELISA TRUST, TPPA TRUST, TPPA TRUST, TPPA RPR, TPPA Not mentioned RPR and TPPA Not mentioned TRUST
0.1435 (0.08230.2182) 0.0582 (0.03260.0906) 0.0252 (0.01350.0406)
Guangxi Guizhou
Henan Hubei Hunan
Jiangsu
Shanghai Sichuan
Yunnan Zhejiang Chongqing
study study study study study study study study study study study study study study study study study study study study study study study study study study study study study
0.0328 (0.02080.0474) 0.1598 (0.13320.1885)
0.0462 (0.02550.0727) 0.0190 (0.01240.027) 0.0867 (0.03110.1666)
0.1017 (0.03840.1908)
0.0990 (0.04970.1628) 0.0915 (0.05600.1347)
0.0911 (0.00000.3262) 0.0676 (0.04660.0920) 0.0553 (0.02840.0903)
TP: syphilis.
models demonstrated significant difference in syphilis infection rates between men and women (OR ¼ 0.34 [95%CI: 0.26–0.45], Z ¼ 7.61, p < 0.01) (Figure 4). There was no significant publication bias according to linear regression testing (t ¼ 0.67, p ¼ 0.51).
Drug-injecting practices Eighteen studies included 4863 IDUs and 1386 nonintravenous drug users (non-IDUs). There was significant statistical heterogeneity (Q ¼ 42.91, I2 ¼ 60.4%, p < 0.01) between IDUs and non-IDUs. The meta-analyses with random effects models demonstrated no significant difference in syphilis infection rates between IDUs and non-IDUs (OR ¼ 0.82 [95%CI: 0.51–1.32], Z ¼ 0.81, p ¼ 0.42) (Figure 5). There was no significant
publication bias according to linear regression testing (t ¼ 0.26, p ¼ 0.80).
Discussion The meta-analysis provides the first quantitatively synthesized estimates of the prevalence of syphilis among DUs at MMT clinics in China. The pooled prevalence of syphilis infection among DUs at MMT clinics was 7.78% (95%CI: 5.83%–9.99%). In contrast, the prevalence levels of syphilis among the general population are 0.52% (95% CI 0.33–0.71%).51,52 Many studies have correlated drug use (especially injecting drug use) with increased risk of sexually transmitted infection.53,54 Thus enhanced testing and prevention are warranted in this population.
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Figure 2. Difference in syphilis infection rates among DUs at MMT clinic in China.
In our review, the majority of DUs at MMT clinics were men, accounting for about 80% (6096/7562). Many biologic and environmental factors affect their drug use behavior.54 Studies differ in demonstrating male or female preponderance of syphilis infection. This meta-analysis demonstrated significant difference in syphilis infection rates between men and women (Q ¼ 43.15, p ¼ 0.01 < 0.05). The pooled male and female prevalences of syphilis infection were 7.16% (95%CI: 4.99%–9.70%) and 17.74% (95%CI: 13.34%–22.63%), respectively. The syphilis prevalence rate of men was 0.34 times (95%CI: 0.26–0.45) than the women. This might be due to several factors. First, most female DUs are young adults who are sexually active. Premarital sex, extramarital sex and multiple sexual partners were relatively common among them. In particular, many female DUs are involved in commercial sex and associated high-risk sexual behaviours that might increase risk of syphilis.34,38,39,43,48,55
In our study, 18 studies included 4863 IDUs and 1386 NIDUs. IDUs made up the majority (77.80%) of participants. Though numerous studies reported that IDUs and NIDUs have differing HIV/STI prevalence, the difference does not always have statistical significance.56–58 There was no significant statistical heterogeneity (OR ¼ 0.82 [95%CI: 0.51–1.32) between IDUs and NIDUs in our meta-analysis. We are currently examining possible reasons for this. Sexual risk behaviors, sexual networks and the presence of other STIs might facilitate sexual transmission of syphilis. In addition, those who were IDUs before, but now do not inject drugs, however, at that time may have been infected with syphilis, which may also be the reason for no difference between DUs and IDUs.57,58 A high divorce rate and no regular partner among DUs may also contribute to syphilis resurgence.28 We have insufficient evidence that shared syringes contributed to the spread of syphilis. This suggests that prevention and
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Figure 3. Difference in syphilis infection rates among IDUs at MMT clinic in China.
Figure 4. Difference in syphilis infection rates between male and female DUs at MMT clinic in China. Downloaded from std.sagepub.com at The University of Auckland Library on March 11, 2015
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Figure 5. Risk of syphilis infection of injection DUs compared with NIDUs.
treatment of syphilis should be equally important for both IDUs and NIDUs. TP-HCV, TP-HIV and TP-HBV co-infection among MMT DUs at baseline of treatment were 5.21%, 1.06% and 0.88%, respectively. TP, HCV, HIV and HBV prevalence in the general population were 0.52%, 2.20%, < 0.10%, 9%, respectively.59–61 Merged infection diseases often affect similar patient groups and share common routes of transmission, like HIV and TP. All patients presenting with syphilis should be offered HIV testing and all HIV-positive patients should be regularly screened for syphilis. Syphilis may also impact the course of HIV infection. So detection and treatment of syphilis may help to reduce HIV transmission.62,63 Although MMT clinics were set up in order to prevent HIV infection, we found that there were a lot of DUs infected with syphilis. Without adequate treatment options and effective implementation strategies in DUs, such epidemics will continue to spread in China and result in greater disease burden and social problems.
Limitations Several limitations in this study should be noted. First, because the studies were observational and DUs were not selected at random, selection bias seems inevitable; second, all of the data were extracted from articles written in Chinese, which makes it difficult for non-Chinese reviewers, editors and readers to recheck the original materials; third, self-reported data have obvious limitations and information bias might exist. Acknowledgement This work was partly supported by grants from the Natural Science Foundation of Anhui Province in 2013 (Code: 1308085MH169) and the Academic Leader Foundation of Anhui Medical University, the Key Project of the Education Department of Anhui Province Natural Science Research (Code: KJ2012A165).
Conflict of interest The authors declare no conflict of interest.
Conclusions
Funding
Enhanced detection of syphilis and health promotion is warranted in MMT clinics in China.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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51. Hesketh T, Tang F, Wang ZB, et al. HIV and syphilis in young Chinese adults: implications for spread. Int J STD AIDS 2005; 16: 262–266. 52. Hesketh T, Ye XJ and Zhu WX. Syphilis in China: the great comeback. Emerg Health Threats J 2008; 1: 1–6. 53. Van Den and Hoek A. STD control in drug users and street youth. Genitourin Med 1997; 73: 240–244. 54. Garfein RS, Vlahov D, Galai N, et al. Viral infections in short-term injection drug users: the prevalence of the hepatitis C, hepatitis B, human immunodeficiency, and human T-lymphotropic viruses. Am J Public Health 1996; 86: 655–661. 55. Glynn JR, Carae¨l M, Auvert B, et al. Why do young women have a much higher prevalence of HIV than young men? A study in Kisumu, Kenya and Ndola, Zambia. AIDS 2001; 15: 51–60. 56. Quaglio G, Lugoboni F, Pajusco B, et al. Factors associated with hepatitis C virus infection in injection and noninjection drug users in Italy. Clin Infect Dis 2003; 37: 33–40. 57. Des Jarlais DC, Arasteh K, Perlis T, et al. Convergence of HIV seroprevalence among injecting and non-injecting drug users in New York City. AIDS 2007; 21: 231–235. 58. Strathdee SA and Stockman JK. Epidemiology of HIV among injecting and non-injecting drug users: current trends and implications for interventions. Curr HIV/ AIDS Rep 2010; 7: 99–106. 59. Yang HM, Li XM, Bonita Stanton, et al. Heterosexual transmission of HIV in China: a systematic review of behavioral studies in the past two decades. Sex Transm Dis 2005; 32: 270–280. 60. Jie Liu and Daiming Fan. Hepatitis B in China. Lancet 2007; 369: 1582–1583. 61. Xia X, Luo J, Bai JL, et al. Epidemiology of hepatitis C virus infection among injection drug users in China: Systematic review and meta-analysis. Public Health 2008; 122: 990–1003. 62. Zetola NM and Klausner JD. Syphilis and HIV infection: an update. Clin Infect Dis 2007; 44: 1222–1228. 63. Lynn WA and Lightman S. Syphilis and HIV: a dangerous combination. Lancet Infect Dis 2004; 4: 456–466. 64. Mohamad N, Bakar NH, Musa N, et al. Better retention of Malaysian opiate dependents treated with high dose methadone in methadone maintenance therapy. Harm Reduct J 2010; 7: 30.
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Epidemiology of syphilis infection among drug users at methadone maintenance treatment clinics in China: systematic review and meta-analysis
International Journal of STD & AIDS 2014, Vol. 25(8) 550–558 ! The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0956462413515444 std.sagepub.com
Bing-xiang Wang1, Li Zhang2, Yu-jie Wang1, Jun-wei Yan1, Ya-nan Wan1, Wen-jia Peng1 and Jing Wang1
Summary Illicit drug trade has re-emerged in China since 1979 and the number of drug addicts had increased. Syphilis is mainly spread through sexual contact and blood. The incidence of syphilis is high among drug users. Methadone maintenance treatment (MMT) clinics have been implemented in China since 2004. The aim of this study was to estimate the prevalence and risk factors of syphilis among drug users at MMT clinics in China between 2004 and 2013. Chinese and English databases (CBM, CNKI, Weipu, Pubmed) of literature were searched for studies reporting syphilis among drug users in MMT clinics from 2004 to 2013. The prevalence estimates and risk factors were summarized through a systematic review and meta-analysis of published literatures. In all, 29 eligible articles with a total of 8899 drug users, were selected in this review. The pooled prevalence of syphilis infection was 7.78% (95%CI: 5.83%–9.99%). The metaanalyses demonstrated significant differences in syphilis infection rates between men and women (OR ¼ 0.34 [95%CI: 0.26–0.45]) but not between drug users and non-intravenous drug users (OR ¼ 0.82 [95%CI: 0.51–1.32]). Enhanced detection of syphilis and health promotion is warranted in MMT clinics in China.
Keywords Syphilis, sexually transmitted infection, Treponema pallidum, injecting drug users, opioid addiction, prevalence, methadone maintenance treatment, meta-analysis, China Date received: 8 July 2013; accepted: 14 October 2013
Background China has experienced a relatively drug-free period from the 1950s to the 1970s. With the implementation of open-door and economic reforms policies since 1979, the illicit drug trade has re-emerged in China. As the most populous country in the world, China has observed a rapid increase in drug users (DUs) over the past three decades.1,2 By the end of 2011, ministry of Public Security data suggest the number of officially registered DUs has already reached 1.794 million in China and the number of heroin users is 1.156 million (accounting for 64.5%). Synthetic drugs are becoming more common (accounting for 32.7%), especially in small and medium-sized cities and rural areas.3 Moreover, behind each registered DU, there were estimated 2–4 implicit DUs and the total number of DUs including un-registered DUs was thought to be much higher.4,5
In the year 1505, syphilis was first brought to the southeast coastal area of Guangdong province in China and caused a pandemic. Syphilis then spread to all parts of the country. Before liberation, there remained a serious epidemic of syphilis in China. With the Chinese government taking effective and positive measures after liberation, the disease has been well controlled in the mainland after years of effort. 1 Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China 2 Medical Genetics Center, Anhui Medical College, Hefei, China
Authors Bing-xiang Wang and Li Zhang contributed equally to this work and should be considered co-first authors. Corresponding author: Jing Wang, Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, 230061, China. Email: [email protected]
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However, with the success of economic and social reforms designed to open China to the world, the disease also became prevalent again. Syphilis is a chronic infection caused by Treponema pallidum. It causes acute cutaneous manifestations including genital ulcers, and may progress to serious sequelae of the cardiovascular and nervous systems, and serious effects on reproductive and neonatal health; it primarily spreads through sexual contact and blood.6–10 China’s ministry of health reported 327,433 cases in 2009. The yearly rate of syphilitic cases was 24.66/100,000 and the annual rate of syphilitic increase was 14.3%. The incidence of syphilis was reported as 27.9% among DUs.10,11 Methadone maintenance treatment (MMT) has been used successfully as a substitution therapy to treat heroin addiction. In turn, it reduced the spread of HIV, drug-related crime and other social problems.12 Much research has confirmed that the MMT can reduce drug-using behaviour and control the spread of HIV among injecting drug users (IDUs).13,14 To reduce the spread of HIV/AIDS, MMT clinics were initiated as a pilot programme in eight clinics serving 1029 DUs in 2004 in China.15 DUs in the community participating in MMT clinics have achieved a total of 337,000 by the end of 2011.3 MMT clinics also offer ancillary services including counseling and psychosocial support, testing for HIV and other infections (syphilis, hepatitis C virus [HCV] and hepatitis B virus, etc), referral for antiretroviral treatment and other social supports.16 Although MMT clinics were set up in order to prevent the HIV/AIDS epidemic, we found high rates of DUs infected with syphilis. There have been numerous independent studies about the prevalence of syphilis and risk factors among DUs at MMT clinics at baseline of their treatment. Across these studies, the prevalence of syphilis and risk factors showed wide variation. Many researchers drew incompatible or even contradictory conclusions and the generalizability of any single study was limited. This paper reviews the available evidence in an attempt to provide a comprehensive and reliable tabulation of available data on the epidemiological characteristics and risk factors for syphilis infection among DUs at MMT clinics in China to help inform policy makers developing prevention strategies, and guide further research.
Methods Search Strategy Two investigators independently screened a systematic review of published peer-reviewed research articles by searching the following databases: China Biological Medicine (CBM) (from 2004 to 2013), China National
Knowledge Infrastructure (CNKI) (from 2004 to 2013), Pubmed (from 2004 to 2013) and Weipu (from 2004 to 2013) database. Investigator consensus reconciled any differences in data acquisition consistently. We used the search terms: syphilis OR TP OR syphellolis AND ‘‘drug use’’ OR ‘‘drug abuse’’ OR ‘‘drug addict’’ OR ‘‘substance abuse’’ OR heroin OR ‘‘druggy’’ AND Methadone OR ‘‘Methadone Maintenance Treatment’’ OR ‘‘Methadone Maintenance Therapy’’ OR ‘‘Methadone Maintenance’’ AND China OR Chinese. The reference lists from relevant review articles and all eligible studies were also searched manually. Other relevant articles and reports released by World Health Organization (WHO) and the Chinese Ministry of Health were utilized.
Study selection Studies were eligible for inclusion in this systematic review if they met the following criteria: (1) study published in Chinese or English language; (2) study reported syphilis prevalence estimates among DUs in MMT clinics at baseline of treatment in China; (3) syphilis infection diagnosed from laboratory serologic testing (TRUST: toluidine red unheated serum test. TPPA: treponema pallidum particle agglutination assay ELISA: enzyme-linked immunosorbent assay. RPR: rapid plasma reagin); (4) study design such as study site, time period and sample size reported. Intervention studies among MMT clinics were also included. Exclusion criteria were (1) review papers; (2) studies with overlapping time intervals of sample or collection from the same origin; (3) conference abstracts and presentations; (4) only men-exclusive or women-exclusive studies; (5) dissertations; (6) studies presenting confusing data or probable errors. If the same study data were published in both English and Chinese sources, the articles published in Chinese language were excluded from this study. We extracted the following information from all eligible studies: first author, study site, study period, gender, sample size; laboratory test methods of syphilis, prevalence of syphilis and syphilis and HCV, HIV co-infection among MMT clients at the baseline of the treatment.
Validity assessment The quality of studies was assessed using a validated quality assessment tool for cross-sectional studies.2,17 The following eight items were assessed to calculate a total quality score of being included articles: (1) the target population can be defined clearly; (2) probability sampling was used to identify potential respondents; (3) the characteristics of respondents match the target population; (4) adequate response rate; (5) standardized data
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collection methods; (6) reliable survey measures/instruments; (7) valid survey measures/instruments; (8) appropriate statistical methods. Answers were scored 0 and 1 for ‘No’ and ‘Yes’, respectively. The total quality score varied between 0 and 8 for each article.
697 potentially relevant published articles (1 in PubMed, 643 in CNKI, 43 in CBM, 10 in Weipu)
601 articles excluded: 392 articles by screening the titles, 209 articles by screening the abstracts
Statistical analysis In our review, the pooled estimate of proportion with corresponding 95% confidence intervals (CI) was calculated on the basis of the Freeman-Tukey double arcsine transformation.18,19 Statistical heterogeneity was measured using the Q statistic test by the MantelHaenszel method. I2 statistic indicated heterogeneity.20 The linear regression method was used to assess the potential for publication bias. Similarly, to estimate the magnitude of the effect of sample sources, the type of sample source was stratified into communities for subgroup analyses. All analyses were carried out using the statistical software package R version 2.13.1 (R Foundation for Statistical Computing, Beijing, China) with function metaprop, metabin, metabias, etc. (R package: meta).21
67 full-text articles retrieved for more detailed evaluation
34 articles excluded based on detailed evaluation. 11 articles drug users incompletely come from MMT clines; 19 articles overlapping of time or origin; 4 articles review papers
33 potentially relevant articles
4 articles excluded: one article with female DUs only; 3 articles where syphilis was not diagnosed from laboratory serologic testing
Results In all, 697 articles were identified from four electronic databases (1 in PubMed, 643 in CNKI, 43 in CBM, 10 in Weipu). Because of replication, irrelevance and inaccuracy, we excluded 392 articles by screening the titles. Then we screened the abstracts and found that 209 articles were excluded. Overall, 67 studies (66 Chinese and 1 English) were downloaded with further analyses. Finally, 29 studies were included in the review and were used in the following meta-analysis with strict inclusion criteria and exclusion criteria (Figure 1); 29 eligible articles22–50 with a total of 8899 DUs in MMT clinics, study years from 2004 to 2012, were included in our review. The sample sizes of the selected studies ranged from 100 to 1340. All participants were recruited from MMT clinics in China. Table 1 shows the pooled prevalence of syphilis by regional distribution among MMT clinics in China. The prevalence of each region showed wide variation. As we analyzed the 14 provinces, Guizhou province (15.98%, 95%CI: 13.32–18.85%) had the highest prevalence. The pooled prevalence of syphilis infection among DUs in China was 7.78% (95%CI: 5.83%–9.99%) (Figure 2). There was significant statistical heterogeneity among DUs (Q ¼ 374.35, I2 ¼ 92.5%, p < 0.01) and there was significant publication bias according to linear regression testing (t ¼ 2.76, p ¼ 0.01). The pooled prevalence of HCV infection among IDUs in China was 6.33% (95%CI: 4.40%–8.57%) (Figure 3). There was significant statistical
29 unique articles evaluated in meta analysis
Figure 1. Selection process for study inclusion in this meta-analysis.
heterogeneity among IDUs (Q ¼ 160.59, I2 ¼ 92.5%, p < 0.01) and there was significant publication bias according to linear regression testing (t ¼ 2.44, p ¼ 0.03 < 0.05). Differences in pooled HCV infection rates among DUs were observed. The highest rate was 20% (95%CI: 13%–29%) (J Wang 2009) and the lowest rate was 2% (95%CI: 1%–3%) (Q Liu 2006– 2010). TP-HCV, TP-HIV and TP-HBV co-infection among MMT DUs at baseline of treatment in China were 5.21% (95% CI: 3.61%–7.09%), 1.06% (95% CI: 0.66%–1.56%) and 0.88% (95% CI: 0.39%–1.58%), respectively.
Gender Twenty-five studies included 6096 men and 1466 women. The pooled male and female prevalences of syphilis infection were 7.16% (95%CI: 4.99%–9.70%) and 17.74% (95%CI: 13.34%–22.63%), respectively. There was significant statistical heterogeneity (Q ¼ 43.15, I2 ¼ 44.4%, p ¼ 0.01 < 0.05) between men and women. The meta-analyses with random effects
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Table 1. The pooled prevalence of syphilis by regional distribution among MMT clinics in China. Province
First author
Study year
DUs
TP
The type of studies
Serodiagnosis methods of TP antibody
TP prevalence (95% CI) among MMT clinics
Fujian Gansu Guangdong
LH Wu LF Gao L Xia YM Xie Y Bai XP Zhou J Wang XJ Han DY Luo XH Meng XG Zhang Q Liu YH Yue LF Chen YD Zhou HQ Wei M He MH Zhang JG Xu M Zheng HM Zou W Yao DG Yang HD Mou Y Li HD Shen FY Fu YY Yan J Wang
2006 20072009 20072009 20092012 2009 2007 2009 20082009 20092010 2010 2010 20062010 2010 2007 20082010 2009 2011 20062008 20082011 20072009 20082010 20062008 2011 2009 20102011 2011 20052008 20092010 2009
100 248 249 261 518 170 143 300 228 146 154 1340 126 459 323 278 241 309 262 105 183 743 120 618 280 321 349 118 207
14 14 5 7 19 3 29 50 28 7 6 25 12 18 44 15 38 11 51 10 25 56 16 30 55 7 26 5 11
Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional
TRUST, TPPA ELISA TRUST, TPPA TRUST, TPPA TRUST, TPPA TRUST, TPPA TRUST ELISA ELISA ELISA ELISA TRUST, TPPA TRUST ELISA TRUST TRUST, TPPA ELISA RPR TRUST, TPPA RPR, TPPA RPR, TPPA TRUST, ELISA TRUST, TPPA TRUST, TPPA TRUST, TPPA RPR, TPPA Not mentioned RPR and TPPA Not mentioned TRUST
0.1435 (0.08230.2182) 0.0582 (0.03260.0906) 0.0252 (0.01350.0406)
Guangxi Guizhou
Henan Hubei Hunan
Jiangsu
Shanghai Sichuan
Yunnan Zhejiang Chongqing
study study study study study study study study study study study study study study study study study study study study study study study study study study study study study
0.0328 (0.02080.0474) 0.1598 (0.13320.1885)
0.0462 (0.02550.0727) 0.0190 (0.01240.027) 0.0867 (0.03110.1666)
0.1017 (0.03840.1908)
0.0990 (0.04970.1628) 0.0915 (0.05600.1347)
0.0911 (0.00000.3262) 0.0676 (0.04660.0920) 0.0553 (0.02840.0903)
TP: syphilis.
models demonstrated significant difference in syphilis infection rates between men and women (OR ¼ 0.34 [95%CI: 0.26–0.45], Z ¼ 7.61, p < 0.01) (Figure 4). There was no significant publication bias according to linear regression testing (t ¼ 0.67, p ¼ 0.51).
Drug-injecting practices Eighteen studies included 4863 IDUs and 1386 nonintravenous drug users (non-IDUs). There was significant statistical heterogeneity (Q ¼ 42.91, I2 ¼ 60.4%, p < 0.01) between IDUs and non-IDUs. The meta-analyses with random effects models demonstrated no significant difference in syphilis infection rates between IDUs and non-IDUs (OR ¼ 0.82 [95%CI: 0.51–1.32], Z ¼ 0.81, p ¼ 0.42) (Figure 5). There was no significant
publication bias according to linear regression testing (t ¼ 0.26, p ¼ 0.80).
Discussion The meta-analysis provides the first quantitatively synthesized estimates of the prevalence of syphilis among DUs at MMT clinics in China. The pooled prevalence of syphilis infection among DUs at MMT clinics was 7.78% (95%CI: 5.83%–9.99%). In contrast, the prevalence levels of syphilis among the general population are 0.52% (95% CI 0.33–0.71%).51,52 Many studies have correlated drug use (especially injecting drug use) with increased risk of sexually transmitted infection.53,54 Thus enhanced testing and prevention are warranted in this population.
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Figure 2. Difference in syphilis infection rates among DUs at MMT clinic in China.
In our review, the majority of DUs at MMT clinics were men, accounting for about 80% (6096/7562). Many biologic and environmental factors affect their drug use behavior.54 Studies differ in demonstrating male or female preponderance of syphilis infection. This meta-analysis demonstrated significant difference in syphilis infection rates between men and women (Q ¼ 43.15, p ¼ 0.01 < 0.05). The pooled male and female prevalences of syphilis infection were 7.16% (95%CI: 4.99%–9.70%) and 17.74% (95%CI: 13.34%–22.63%), respectively. The syphilis prevalence rate of men was 0.34 times (95%CI: 0.26–0.45) than the women. This might be due to several factors. First, most female DUs are young adults who are sexually active. Premarital sex, extramarital sex and multiple sexual partners were relatively common among them. In particular, many female DUs are involved in commercial sex and associated high-risk sexual behaviours that might increase risk of syphilis.34,38,39,43,48,55
In our study, 18 studies included 4863 IDUs and 1386 NIDUs. IDUs made up the majority (77.80%) of participants. Though numerous studies reported that IDUs and NIDUs have differing HIV/STI prevalence, the difference does not always have statistical significance.56–58 There was no significant statistical heterogeneity (OR ¼ 0.82 [95%CI: 0.51–1.32) between IDUs and NIDUs in our meta-analysis. We are currently examining possible reasons for this. Sexual risk behaviors, sexual networks and the presence of other STIs might facilitate sexual transmission of syphilis. In addition, those who were IDUs before, but now do not inject drugs, however, at that time may have been infected with syphilis, which may also be the reason for no difference between DUs and IDUs.57,58 A high divorce rate and no regular partner among DUs may also contribute to syphilis resurgence.28 We have insufficient evidence that shared syringes contributed to the spread of syphilis. This suggests that prevention and
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Figure 3. Difference in syphilis infection rates among IDUs at MMT clinic in China.
Figure 4. Difference in syphilis infection rates between male and female DUs at MMT clinic in China. Downloaded from std.sagepub.com at The University of Auckland Library on March 11, 2015
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Figure 5. Risk of syphilis infection of injection DUs compared with NIDUs.
treatment of syphilis should be equally important for both IDUs and NIDUs. TP-HCV, TP-HIV and TP-HBV co-infection among MMT DUs at baseline of treatment were 5.21%, 1.06% and 0.88%, respectively. TP, HCV, HIV and HBV prevalence in the general population were 0.52%, 2.20%, < 0.10%, 9%, respectively.59–61 Merged infection diseases often affect similar patient groups and share common routes of transmission, like HIV and TP. All patients presenting with syphilis should be offered HIV testing and all HIV-positive patients should be regularly screened for syphilis. Syphilis may also impact the course of HIV infection. So detection and treatment of syphilis may help to reduce HIV transmission.62,63 Although MMT clinics were set up in order to prevent HIV infection, we found that there were a lot of DUs infected with syphilis. Without adequate treatment options and effective implementation strategies in DUs, such epidemics will continue to spread in China and result in greater disease burden and social problems.
Limitations Several limitations in this study should be noted. First, because the studies were observational and DUs were not selected at random, selection bias seems inevitable; second, all of the data were extracted from articles written in Chinese, which makes it difficult for non-Chinese reviewers, editors and readers to recheck the original materials; third, self-reported data have obvious limitations and information bias might exist. Acknowledgement This work was partly supported by grants from the Natural Science Foundation of Anhui Province in 2013 (Code: 1308085MH169) and the Academic Leader Foundation of Anhui Medical University, the Key Project of the Education Department of Anhui Province Natural Science Research (Code: KJ2012A165).
Conflict of interest The authors declare no conflict of interest.
Conclusions
Funding
Enhanced detection of syphilis and health promotion is warranted in MMT clinics in China.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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