Artigos

Introduction
Worldwide, more than 6 million new cases of syphilis were reported in the 15-49 age group in 2016, and the burden is greatest in lower-middle-income countries (LMIC), including Brazil1. Although in the first months of 2020, the number of people diagnosed with gonorrhea and syphilis decreased in the U.S2, which is attributed to the isolation promoted by COVID-19, the data show that the number of Sexually Transmitted Infection (STI) cases remains very high. Even in the face of the COVID-19 pandemic, 2.4 million cases of STI were reported in the U.S., among them, 677,769 cases of gonorrhea and 133,945 cases of syphilis, up 45% and 52%, respectively, from 2016 to 20202.
In Brazil, an increase in the number of cases in recent years indicates that syphilis is emerging as a major STI. The detection rates of acquired syphilis in Brazil showed continuous growth until 2018 and stabilized in 2019, when they reached 77.8 cases per 100,000 inhabitants3. In 2020, the impact of the COVID-19 pandemic contributed to a decline in the syphilis detection rate by 24.1% compared with 2019. However, in 2021, the detection rate returned to pre-pandemic levels, with 78.5 cases per 100,000 people3.
Increased syphilis transmission is also a concern because of its biological and epidemiological association with HIV infection4. Both infections have the same route of infection and have disproportionally affected the same population, often reinforcing a cycle in which HIV-infected individuals have an increased risk for severe complications of syphilis4.
Men who have sex with men (MSM) are disproportionately affected by syphilis infection globally. The pooled global prevalence of syphilis among MSM from 2000 to 2020 was 7.5%5. This rate is 15 times higher than that of men in the general population5. This is associated with frequent unprotected receptive anal intercourse, inadequate adherence to antiretroviral therapy, limited partner notification, ?2 anal sex partners in the past six months, low monthly income, and low level of schooling6.
The objective of this study was to report the prevalence of active syphilis and its associated factors among MSM in a national coverage survey in Brazil that took part in the National Biological and Behavioral Surveillance Survey (BBSS) in 2016.

Materials and methods

Type of study
This cross-sectional study used respondent-driven sampling (RDS) to recruit participants and analyze the results. RDS was chosen as the most appropriate method among the available alternatives, due to the mostly hidden social networks of MSM, and to allow for comparison with Brazil's first national HIV BBSS that used RDS in 20067. The surveys were conducted from June to December 2016 in 12 Brazilian state capitals in five Regions of Brazil: Manaus and Belém (North Region); Fortaleza, Recife, and Salvador (Northeast Region); Brasília and Campo Grande (Central West Region); Belo Horizonte, Rio de Janeiro, and São Paulo (Southeast Region); and Curitiba and Porto Alegre (South Region). A detailed methodology regarding the recruitment of participants and study development was described by Kendall et al8.
Formative research was conducted among 184 MSM between December 2015 and March 2016 to explore sex and gender identities, changes in HIV-related behaviors, organization of the MSM communities, incentive level, willingness to participate and to provide a biological specimen, potential bottlenecks, and other operational issues, as the best site in each study site.

Study Population
The sample started with five to six seeds in each city, and eligibility was limited to men aged 18 years or older who reported oral or anal sex with another man in the last 12 months and who resided, worked, or studied in one of the 12 cities. Individuals under the influence of drugs or alcohol and those identified as transgender women were excluded.
The RDS requires a design effect (DE) multiplier. The DE is the ratio of the actual variance to the expected variance using simple random sampling. Johnston et al9 reviewed several studies that recommended a DE slightly above 2 (2.33). The sample size was calculated for each city using a DE of two and HIV prevalence by city in previous studies as follows: Belém (393), Manaus (204), Salvador (193), Fortaleza (131), Recife (116), Brasília (299), Campo Grande (143), Belo Horizonte (267), Rio de Janeiro (450), São Paulo (474), Porto Alegre (393), and Curitiba (210). In this study, the funding institution limited the sample size to 350 MSM per city, which resulted in a DE of at least two, except for São Paulo, Rio de Janeiro, and Porto Alegre. However, all sites reached convergence on major outcomes in waves 5 and 6, before reaching a sample size of 350 participants.
Three coupons were distributed to each respondent to recruit others to participate in this study. Each participant who completed the survey received a primary and secondary incentive of R$25 (25 Reais, the Brazilian currency, or about US$7). The social network size question cascade is summarized in the following question: “How many men do you know, who also know you, who have had sex with other men (oral or anal) in the last 12 months, who live, study, or work in (municipality), are 18 years old or older, and that you encountered or spoke with in the last 2 months, and you would invite to participate in this study?” The questionnaire was administered through an audio-computer assisted personal interview (ACASI). The questionnaire was self-administered, and the interviewers assisted the participants if requested.
Following the interviews, blood samples were collected via venipuncture for rapid point-of-care and follow-up testing. The prevalence of lifetime syphilis infection was determined using the rapid point-of-care syphilis treponemal antibody test (RST), which detects antibodies against Treponema pallidum. RST (TR DPP® Sífilis, Biomanguinhos, Fiocruz, Brazil) was performed on all study participants following the manufacturer’s instructions. Rapid test-reactive samples were retested using a nontreponemal test, the Venereal Disease Research Laboratory (VDRL), and serially diluted to determine whether the infection was active. A positive RST confirmed by a positive VDRL titer (equal to or greater than 1/8) indicates active syphilis, according to the Brazilian Ministry of Health10. If the RST was positive but the VDRL was negative the Fluorescent Treponemal Antibody absorption (FTA-abs) test was performed. If FTA-abs were positive, the participant was considered syphilis-positive. Confirmatory serological tests were conducted at Adolfo Lutz Institute, São Paulo, Brazil.

Analysis
Data from the 12 cities were merged and analyzed using Stata 14.0 complex survey data analysis tools, in which each city was treated as its own strata. Gile’s sampling estimator was used to produce weighted estimates of syphilis prevalence rates using the RDS-Analyst. The seeds were included in the sample for analysis. The initial data analysis consisted of univariate analysis to describe the study variables. The socioeconomic strata (A–E) standard developed by the Brazilian Association of Research Organizations11 was used to define social class. Bivariate analyses were performed using the chi-square test and the prevalence ratio (PR). Variables associated with the outcome (active syphilis) at the 20% significance level were used in the multivariate model. Variables associated with active syphilis at the 5% level of statistical significance remained in the final logistic multivariate model.

Ethics statement
The study was approved by the Research Ethics Committee of the Federal University of Ceará, accredited by the Brazilian National Research Commission (#1.024.053-23/06/2015). All participants provided written consent to participate in the interview and consented separately for each test offered. There appeared to be little reluctance to participate in both parts of the study, confirming the results obtained in the formative research.

Results
A total of 4,176 individuals consented to participate in this study. Most participants (56.5%; 95% CI: 53.4 – 59.5) were less than 25 years old and had completed high school or attended higher education (71.3%; 95%CI: 68.8 – 73.7). The majority were from the middle or lower socioeconomic class (C/D-E) (56.7%; 95%CI: 53.8 – 59.6). Almost two-thirds (64.4%; 95%CI: 61.3 – 67.3) of MSM had used the Internet to seek sexual partners in the previous six months. Almost 50% (48.2%; 95%CI: 45.1 – 51.3) scored as hazardous alcohol users. Approximately 70% (67.0%; 95%CI: 64.3 – 69.5) reported experiencing discrimination and 20.3% (95%CI: 18.0 – 22.9) experience discrimination. Approximately one-fourth of the patients had a previous diagnosis of an STI (27.8%; 95%CI: 25.1 – 30.8) and 16.2% (95%CI: 14.2 – 18.4) reported having had a female partner. Less than half of the interviewees had been tested for syphilis in the last 12 months (42.0%; 95%CI: 39.0 – 45.0) and almost two-thirds (65.9%; 95%CI: 62.9 – 68.9) reported having used a condom during their last sexual intercourse (Table 1).

Tab.1

Nearly 90% (91.6%; 95%CI: 89.7 - 93.1) of the participants agreed to the RST during the survey. The lifetime syphilis prevalence was 26.9% (95%CI: 24.0 - 29.9) ranging from 14.7% (95%CI: 10.8 – 19.7) in Brasília to 35.4% (95%CI: 29.5 – 41.7) in Recife. Half of the positive cases (49.8%; 95%CI: 43.3 - 56.4) were classified as active syphilis. The general prevalence of active syphilis was 13.2% (95%CI: 11.1 - 15.6) (Table 2). Active syphilis cases were more frequent in Belém (19.6%; 95%CI: 15.1 - 25.2), Recife (17.6%; 95%CI: 13.2 - 23.2) and Campo Grande (17.4%; 95%CI: 12.9 – 23.0). Brasília (7.1%; 95%CI: 4.6 – 10.8) had the lowest prevalence of active syphilis among the 12 Brazilian cities (Table 2).

Tab.2

Active syphilis was associated with age < 25 years (PR: 1.83; 95%CI: 1.41 – 2.37), use of the internet (PR: 1.52, 95%CI: 1.12 – 2.07) to seek sexual partners, experience of sexual abuse (PR: 1.33, 95%CI: 1.02 – 1.74), and previous diagnosis of an STI (PR: 1.49, 95%CI: 1.13 – 1.95) (Table 3).

Tab.3

The following variables remained associated with active syphilis in the multivariate analysis: age<25 years (PR: 1.67, 95%CI: 1.29– 2.17), use of internet for partners (PR: 1.35, 95%CI: 1.01– 1.80), and a previous diagnosis of an STI (PR: 1.33, 95%CI: 1.03 – 1.70) (Table 4).

Tab.4

Discussion
This study showed the worrying prevalence of both lifetime and active syphilis among MSM in Brazil. Two RDS surveys conducted among MSM in the country showed that the prevalence tripled from 9% (2010)12 to 27% (2016). Almost half of those who tested positive 2016 were active cases of syphilis, although the infection was easily identifiable and treatable. Moreover, the annual screening rate among MSM in this study was below the recommended level to achieve local elimination of syphilis13.
These results suggest that preventive efforts do not effectively reach MSM. Currently, syphilis prevention and testing in Brazil are focused on pregnant women. Thus, it is not surprising that, while less than half of the participants in this study had been tested for syphilis in the last 12 months (42%; 95%CI: 39.0% – 45.0%), the syphilis testing coverage rate was almost 90% among Brazilian pregnant women14. Brazil shows that it is possible to achieve high screening coverage among pregnant women and demonstrates its ability to address the problem among MSM and other populations.
Although a resurgence of syphilis among MSM in high-income countries has been observed15, approximately 90% of syphilis cases among MSM still occur in LMIC, which continue to report endemic levels of this STI16. This scenario is due to multiple factors; however, structural conditions such as violence, poverty, sexism, racism, stigma, discrimination, and criminalization stand out, given that they intersect with barriers to citizenship, rights, and comprehensive health care17.
Multiple behavioral factors among MSM are associated with a high prevalence, such as unprotected sex, multiple sexual partners, alcohol and drug use, and a previous diagnosis of STI18. Our study also showed that people with a previous diagnosis of STI were 1.33 (95%CI: 1.03 – 1.70). Furthermore, co-infection between syphilis and other STIs is more frequent among MSM19.
The highly active syphilis prevalence found in this MSM population may be due to irregular condom use20, and finding sexual partners using the internet. In this study, MSM who used the Internet to seek sexual partners in the last six months were 1.35 (95%CI:1.01 – 1.80) times more likely to have syphilis. MSM who exclusively use mobile apps and social media to find sexual partners are also more likely to use recreational drugs and alcohol, have sex with HIV-positive partners, disclose their HIV status to sexual partners, and self-report as HIV-positive to other MSM21. Moreover, the emergence of new HIV infection prevention technologies and strategies, such as treatment as prevention (TasP) and pre-exposure prophylaxis (PrEP), has been associated with unprotected sex, which is likely associated with the alarming increase in new cases of syphilis22.
Another important finding of this study was the higher prevalence of syphilis in YMSM. MSM under 25 years of age were 1.67 (95%CI: 1.29 – 2.17) times more likely to have syphilis than those aged ? 25 years. A study conducted with conscripts across Brazil showed that syphilis is on the rise among all groups of young Brazilian males, particularly among MSM who are more than three times more likely to have syphilis than other young men in Brazil23. This high prevalence is accompanied by low rates of testing, poor linkage to care, and increased exposure to risky behaviors among young MSM worldwide24.
The diagnosis and prevention of syphilis transmission is not only feasible but also inexpensive, and cost-effective25. Although penicillin is the drug of choice for the treatment of syphilis, the pharmaceutical industry has priorities other than penicillin production, which are undoubtedly related to profit. Penicillin shortages have been reported worldwide. More than 110 countries have investigated this shortage in the treatment of mother-to-child transmission of syphilis26. The results showed that, among the 95 countries that responded to the study, 41% reported a BPG shortage. Almost half of the countries that did not report shortages used alternative treatments, including ceftriaxone, amoxicillin, and erythromycin26. This situation is aggravated for MSM because in times of penicillin shortage in Brazil, priority is given to the treatment of pregnant women and children with congenital syphilis, discontinuing the treatment of other key populations such as MSM.
Our study has some limitations. Regarding sample representativeness, the RDS makes many assumptions, and there are potential selection and other biases for sampling social networks using the RDS7. Formative research, design, careful operationalization of the study, analysis, and specific diagnostics for data collected using this method built into RDS-Analyst seek to reduce these potential biases and aid interpretability, as described by Kendall et al. (2019)8.
In conclusion, our results point to a worrying picture regarding the prevalence of active syphilis among MSM, particularly YMSM. The COVID-19 pandemic is another challenge that has occurred since this study was conducted, and it is by itself another major recent change that directly affect sexual behaviors among MSM27. An increase in STDs was detected after the pandemic during and after the lockdown in 202028. A reduction in specialized assistance, the growth of online dating services that contributed to the expansion of sexual networks, and the decline in condom use among MSM who take PrEP29 have also been reported.
MSM have less access to health services due to structural barriers motivated by stigma, and discrimination has increased due to the general reduction in resources in Brazil’s health sector under the Bolsonaro government30. Changing this scenario involves the intensification or resumption of health programs focusing on the prevention, testing, and early treatment of new syphilis infections specifically targeted at this key population, including diminishing barriers to their integral care in the public health system. The interventions should be built on sound scientific principles of social and behavioral change programs for MSM and a solid evaluation of past efforts, especially what has worked in the past, addressing knowledge of a broad range of STIs, the importance of condoms even in a time of undetectable viral loads, and alcohol and drug abuse and sex. Targeting sexual minority youth with age-specific interventions that discuss sexual exploitation, identity, sexual citizenship, stigma, discrimination, STIs, and HIV risks needs to be developed.
Despite the need for such interventions, many Brazilian health programs and active LGBTQI+ non-governmental organizations have been discontinued. This fact is accompanied by the strengthening of gender and sexual orientation conservatism and the election of religious leaders, whose main agenda is to fight against the rights of the LGBTQI+ population in Brazil. We recently discovered the outcome when infectious diseases are ignored in any population and when science is disregarded in the creation and implementation of public health policies and programs.


Acknowledgment
The authors also thank all the participants and their enthusiastic participation in this troubled time for sexual minorities, without them this study would not be possible.

Contribution statement
LK, ARCMC and CK conceived the paper. LK, ML, CK and RMSM developed the analysis plan. LK, ML, ARCMC, CK and RSS carried out the analysis and wrote the initial draft of the manuscript. All the authors contributed to the analysis and interpretation of results. All authors reviewed earlier versions of the draft and approved the final manuscript.

Conflict of interest
There are no competing interests for any author.

Funding statement
The authors thank the ?nancial support provided by the Brazilian Ministry of Health, through the Secretariat for Health Surveillance and the Department of Chronic Diseases and Sexually Transmitted Infections (Project # 914BRZ1138).

Ethical standard
The study protocol was approved in 2015 by the Committee on Research Ethics of the Federal University of Ceará (UFC), accredited by the Brazil National Commission on Research (#1.024.053-23/06/2015).

Informed consent statement
All respondents signed a consent form to participate in the interview and separately consented for each test that was offered.

Data Availability Statements
The data underlying this article will be shared on reasonable request to the corresponding author.

References

1. Rowley J, Vander Hoorn S, Korenromp E, Low N, Unemo M, Abu-Raddad LJ, Chico RM, Smolak A, Newman L, Gottlieb S. Chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016. Bulletin of the World Health Organization 2019; 97(8):548-562.
2. CDC. Sexually Transmitted Disease Surveillance. 2020; Available at: https://www.cdc.gov/std/statistics/2020/overview.htm#Syphilis. Accessed 2020 Dec 7.
3. Brazil. Boletim Epidemiológico de Sífilis 2022. 2022; Available at: https://www.gov.br/saude/pt-br/centrais-de-conteudo/publicacoes/boletins/epidemiologicos/especiais/2022/boletim-epidemiologico-de-sifilis-numero-especial-out-2022/view. Accessed 2022 Dec 07.
4. Buchacz K, Patel P, Taylor M, Kerndt PR, Byers RH, Holmberg SD, Klausner JD. Syphilis increases HIV viral load and decreases CD4 cell counts in HIV-infected patients with new syphilis infections. AIDS 2004; 18(15):2075-2079.
5. Tsuboi M, Evans J, Davies EP, Rowley J, Korenromp EL, Clayton T, Taylor MM, Mabey D, Chico RM. Prevalence of syphilis among men who have sex with men: a global systematic review and meta-analysis from 2000–20. The Lancet Global Health 2021; 9(8):e1110-e1118.
6. Weng RX, Hong FC, Yu WY, Cai YM. Compare HIV/syphilis infections between age groups and explore associated factors of HIV/syphilis co-infections among men who have sex with men in Shenzhen, China, from 2009 to 2017. PloS one 2019; 14(10):e0223377.
7. Kendall C, Kerr LR, Gondim RC, Werneck GL, Macena RHM, Pontes MK, Johnston LG, Sabin K, McFarland W. An empirical comparison of respondent-driven sampling, time location sampling, and snowball sampling for behavioral surveillance in men who have sex with men, Fortaleza, Brazil. AIDS and Behavior 2008; 12(1):97-104.
8. Kendall C, Kerr L, Mota RS, Guimarães MDC, Leal AF, Merchan-Hamann E, Dourado I, Veras MA, Brito AMd, Pontes AK. The 12 city HIV surveillance survey among MSM in Brazil 2016 using respondent-driven sampling: a description of methods and RDS diagnostics. Revista Brasileira de Epidemiologia 2019; 22:1-17.
9. Johnston LG, Chen YH, Silva-Santisteban A, Raymond HF. An empirical examination of respondent driven sampling design effects among HIV risk groups from studies conducted around the world. AIDS Behav Jul 2013; 17(6):2202-2210.
10. Brazil. Manual técnico para diagnóstico da sífilis. 2016; Available at: http://www.aids.gov.br/pt-br/pub/2016/manual-tecnico-para-diagnostico-da-sifilis. Accessed 2022 Dec 7.
11. Brazil. Critério de classificação econômica Brasil. 2008; Available at: https://www.abep.org/criterio-brasil. Accessed 2022 Dec 7.
12. Kerr L. Behaviour, attitudes, practices and prevalence of HIV and syphilis among men who have sex with men (MSM) in 10 Brazilian cities. 2010; Available at: https://www.gov.br/saude/pt-br. Accessed Feb 28, 2023.
13. Tuite A, Fisman D. Go big or go home: impact of screening coverage on syphilis infection dynamics. Sexually Transmitted Infections 2016; 92(1):49-54.
14. Domingues RMSM, Szwarcwald CL, Souza Junior PRB, Leal MdC. Prevalence of syphilis in pregnancy and prenatal syphilis testing in Brazil: Birth in Brazil study. Revista de saude publica 2014; 48:766-774.
15. Peeling RW, Mabey D, Kamb ML, Chen X-S, Radolf JD, Benzaken AS. Syphilis. Nature Reviews Disease Primers 2017/10/12 2017; 3(1):17073.
16. Newman L, Kamb M, Hawkes S, Gomez G, Say L, Seuc A, Broutet N. Global estimates of syphilis in pregnancy and associated adverse outcomes: analysis of multinational antenatal surveillance data. PLoS medicine 2013; 10(2):e1001396.
17. Grangeiro A, Castanheira ER, Nemes MIB. A re-emergência da epidemia de aids no Brasil: desafios e perspectivas para o seu enfrentamento. Interface 2015; 19(52):5-8.
18. Guimarães MDC, Kendall C, Magno L, Rocha GM, Knauth DR, Leal AF, Dourado I, Veras MA, de Brito AM, Kerr LRFS. Comparing HIV risk-related behaviors between 2 RDS national samples of MSM in Brazil, 2009 and 2016. Medicine 2018; 97(1 Suppl):62-68.
19. Pinho-Bandeira T, Ricoca Peixoto V, Dias S, Sá Machado R. Factors associated with coinfection and reinfection by chlamydia, gonorrhoea and syphilis in Portugal. European Journal of Public Health 2020; 30(Supplement_5):v199.
20. Traeger MW, Schroeder SE, Wright EJ, Hellard ME, Cornelisse VJ, Doyle JS, Stoové MA. Effects of pre-exposure prophylaxis for the prevention of human immunodeficiency virus infection on sexual risk behavior in men who have sex with men: a systematic review and meta-analysis. Clinical Infectious Diseases 2018; 67(5):676-686.
21. Ko NY, Tseng PC, Huang YC, Chen YC, Hsu ST. Seeking sex partners through the internet and mobile phone applications among men who have sex with men in Taiwan. AIDS care 2016; 28(7):927-931.
22. Hoornenborg E, Coyer L, Achterbergh RC, Matser A, van der Loeff MFS, Boyd A, van Duijnhoven YT, Bruisten S, Oostvogel P, Davidovich U. Sexual behaviour and incidence of HIV and sexually transmitted infections among men who have sex with men using daily and event-driven pre-exposure prophylaxis in AMPrEP: 2 year results from a demonstration study. The lancet HIV 2019; 6(7):e447-e455.
23. Motta LRd, Sperhacke RD, de Gregori Adami A, Kato SK, Vanni AC, Paganella MP, de Oliveira MCP, Giozza SP, da Cunha ARC, Pereira GFM. Syphilis prevalence and risk factors among young men presenting to the Brazilian Army in 2016: results from a national survey. Medicine 2018; 97(47):1-7.
24. Raifman J, Beyrer C, Arrington-Sanders R. HIV education and sexual risk behaviors among young men who have sex with men. LGBT health 2018; 5(2):131-138.
25. Kahn JG, Jiwani A, Gomez GB, Hawkes SJ, Chesson HW, Broutet N, Kamb ML, Newman LM. The cost and cost-effectiveness of scaling up screening and treatment of syphilis in pregnancy: a model. PloS one 2014; 9(1):e87510.
26. Nurse-Findlay S, Taylor MM, Savage M, Mello MB, Saliyou S, Lavayen M, Seghers F, Campbell ML, Birgirimana F, Ouedraogo L. Shortages of benzathine penicillin for prevention of mother-to-child transmission of syphilis: an evaluation from multi-country surveys and stakeholder interviews. PLoS medicine 2017; 14(12):e1002473.
27. Pampati S, Emrick K, Siegler AJ, Jones J. Changes in sexual behavior, PrEP adherence, and access to sexual health services because of the COVID-19 pandemic among a cohort of PrEP-using MSM in the South. Journal of acquired immune deficiency syndromes 2021; 87(1):639-643.
28. Sentís A, Prats-Uribe A, López-Corbeto E, Montoro-Fernandez M, Nomah DK, de Olalla PG, Mercuriali L, Borrell N, Guadalupe-Fernández V, Reyes-Urueña J. The impact of the COVID-19 pandemic on Sexually Transmitted Infections surveillance data: incidence drop or artefact? BMC Public Health 2021; 21(1):1-7.
29. Coyer L, Prins M, Davidovich U, van Bilsen WP, Schim van der Loeff MF, Hoornenborg E, Matser A, Boyd A. Trends in sexual behavior and sexually transmitted infections after initiating human immunodeficiency virus pre-exposure prophylaxis in men who have sex with men from Amsterdam, the Netherlands: A longitudinal exposure-matched study. AIDS Patient Care and STDs 2022; 36(6):208-218.
30. Massuda A. Primary health care financing changes in the Brazilian Health System: advance ou setback? Ciencia & saude coletiva 2020; 25:1181-1188.