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Brief Report: Syphilis Incidence and Effect on Viral Load, CD4, and CD4/CD8 Ratio in a Thai Cohort of Predominantly Men Who Have Sex With Men Living With HIV

Muccini, Camilla MDa,b; Crowell, Trevor A. MD, PhDc,d; Pinyakorn, Suteeraporn MScc,d; Kroon, Eugène MDb; Sacdalan, Carlo MDb; Ananworanich, Jintanat MD, PhDb,e; Vasan, Sandhya MDc,d; Phanuphak, Nittaya MD, PhDb; Colby, Donn J. MDb,c,d, on behalf of the RV254 Study Group

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: February 1, 2021 - Volume 86 - Issue 2 - p 219-223
doi: 10.1097/QAI.0000000000002542

Abstract

INTRODUCTION

Syphilis is a common sexually transmitted infection (STI) with approximately 6 million new cases every year.1 Although syphilis has decreased in the general population over the past 3 decades,2 it has reemerged since the early 2000s among key populations, such as men who have sex with men (MSM), transgender people, people who inject drugs, and sex workers.3–5 A study of MSM in 41 countries throughout the world found that syphilis prevalence was 6.0% between 2016 and 2017.6 In Thailand, the prevalence of syphilis among MSM was an even more alarming 24.4%.6 Furthermore, the Thai Department of Disease Control announced that 36.9% of new cases of syphilis in Thailand in 2018 were diagnosed in young adults aged 15–24 years.7 Understanding factors associated with syphilis acquisition among young MSM is necessary to inform interventions to prevent new infections in this risk group.

Young MSM are also disproportionately impacted by the HIV pandemic. Syphilis and HIV have a shared route of transmission through sexual contact and have a synergistic effect that facilitates transmission and disease progression of both infections. For this reason, coinfection is not unusual.8 In the past decade, other factors such as a markedly improved quality of life because of recent antiretroviral therapy (ART) regimens, increased illicit drug use, and the widespread use of mobile apps to meet partners have played a role in enhancing risky sexual behavior and consequently coinfection rates.9,10

Among persons living with HIV (PLWH), syphilis can lead to a transient decrease of CD4 cell counts and an increase of HIV RNA, factors that raise the risk of HIV transmission.11–18 In most patients, these laboratory abnormalities resolve after appropriate treatment.11–14

We evaluated syphilis prevalence and incidence in a cohort of participants diagnosed during acute HIV infection (AHI) in Thailand and assessed the effects of syphilis on virological and immunological aspects of HIV infection, including HIV RNA, CD4, and the CD4/CD8 ratio.

METHODS

Study Participants

The RV254/SEARCH010 study (NCT00796146) enrolled participants with AHI at the Thai Red Cross AIDS Research Centre in Bangkok, Thailand, as previously described.19,20 Participants were offered ART, usually within 24 hours of AHI diagnosis, and were followed every 12 weeks thereafter. Participants who enrolled from April 2009 through December 2018 were included in these analyses.

All participants provided written informed consent before enrollment. The study protocol was approved by the Institutional Review Boards of Chulalongkorn University (Bangkok, Thailand), Walter Reed Army Institute of Research (Silver Spring, MD), and all collaborating institutions.

Syphilis and Laboratory Data

Participants were screened for syphilis using a qualitative treponemal chemiluminescent microparticle immunoassay (TP-CMIA, ARCHITECT Syphilis TP, Abbott GmbH & Co., Wiesbaden, Germany), at enrollment, every 24–48 weeks thereafter, and also when clinically indicated. Positive results were confirmed with rapid plasma reagin (RPR) titer (Plasmatec RPR Carbon Antigen, Lab 21 Healthcare Ltd., Dorset, United Kingdom). Positive TP-CMIA and nonreactive RPR without a history of previously treated syphilis was resolved with the Treponema pallidum particle agglutination assay (TPPA, Serodia TP-PA, Fujirebio Inc., Japan, Tokyo). Syphilis was diagnosed by any of (1) both treponemal and nontreponemal tests positive in a participant without a previoushistory of syphilis, (2) a four-fold increase in RPR titer, (3) seroconversion from nonreactive to reactive RPR in a participant with a previous history of syphilis, or (4) both TP-CMIA and TPPA positive without a previous history of syphilis treatment.21 Benzathine benzylpenicillin was the preferred drug for treatment and was administered intramuscularly in a single dose or in 3 doses of 2.4 million units each at one-week intervals, depending on syphilis stage21; alternative regimens were used in cases of penicillin allergy or treatment failure.

CD4 and CD8 testing, HIV RNA testing, and clinical evaluation were performed every 12 weeks.22 CD4+ T-cell count was measured by dual-platform flow cytometry (Becton–Dickinson). HIV-RNA in plasma and cerebrospinal fluid was performed using the COBAS AMPLICOR HIV-1 Monitor Test v1.5 or COBAS Taqman HIV-1 Test v2.0 (Roche Molecular Systems), with lower limits of detection at 50 and 20 copies/mL, respectively. For these analyses, results were extracted from the last available visit before syphilis diagnosis, at syphilis diagnosis, and at the visit after syphilis treatment. Loss of viral suppression was considered at the measurement of HIV RNA >50 copies/mL.

Statistical Analysis

The prevalence and incidence rates were compared by calendar year using the χ2 test for trend. Potential risk factors of syphilis incidence were modelled using Cox proportional hazards regression; hazard ratios (HRs) with their respective 95% confidence intervals (CIs) were reported. Factors with P value < 0.05 in the univariate analysis were included in the multivariate analysis. All tests were 2-sided, with a significant level of 5%. All statistical analyses were performed using StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC.

RESULTS

Among 579 participants enrolled during AHI, the median age was 26 [interquartile range (IQR) 22–31] years, 564 (97.4%) were men, and 544 (94.0%) were MSM (Table 1). Syphilis prevalence at enrollment was 14.3% (n = 83), rising from 4.4% in 2010 to 20.0% in 2017 and declining to 14.3% in 2018 (the χ2 test for trend P < 0.01). Overall incidence was 10.2 cases per 100 person-years (PY), increasing from 3.1/100 PY in 2010 to 16.5/100 PY in 2015 and remaining in the range of 11–14/100 PY through 2018 (the χ2 test for trend P = 0.03) (Fig. 1).

TABLE 1. - Baseline Characteristics
Characteristics
N 579
Age, median (IQR) 26 (22–31)
Gender, n (%)
 Male 564 (97.4)
 Female 15 (2.6)
Behavior risk, n (%)
 Heterosexual female 15 (2.6)
 Heterosexual male 20 (3.4)
 MSM 544 (94.0)
Fiebig stage, n (%)
 I 81 (14.0)
 II 132 (22.8)
 III 262 (45.3)
 IV 68 (11.7)
 V–VI 36 (6.2)
Thai, n (%) 567 (97.9)
VDRL+/RPR+ at wk 0, n (%) 83 (14.3)
CD4 (cells/mm3), median (IQR) 359 (262–495)
CD4/CD8 ratio, median (IQR) 0.71 (0.43–1.06)
HIV RNA (log10copies/mL), median (IQR) 5.9 (5.2–6.7)
VDRL, Venereal Disease Research Laboratory.

F1
FIGURE 1.:
Syphilis incidence (per 100 persons years of follow up, PYFU) and prevalence (%) among a Thai cohort of predominantly men who have sex with men living with HIV. Syphilis prevalence at enrollment was 14.3%, increasing from 2010 to 2017 and declining in 2018. Overall incidence was 10.2 cases PYFU, rising from 2010 to 2015.

Cumulatively, 227 participants (39.2%) had at least one episode of syphilis. Of those diagnosed with syphilis, 41.4% had at least one episode of reinfection during the follow-up period. No syphilis cases were diagnosed among female participants.

In the multivariable model, incident syphilis infection was more common among participants who were MSM (HR 3.68, 95% CI: 1.16 to 11.62), used methamphetamine (HR 2.31, 95% CI: 1.51 to 3.54), and had hepatitis C coinfection (HR 2.63, 95% CI: 1.59 to 4.34) (see Table, Supplemental Digital Content, https://links.lww.com/QAI/B564). Syphilis was not associated with group sex.

Among 155 participants who had 222 episodes of syphilis, HIV RNA <50 copies/mL before syphilis diagnosis and viral load test results available before syphilis, at syphilis diagnosis, and after treatment, 12 (7.7%) had detectable viremia within 12 weeks of syphilis diagnosis, 6 (3.9%) had viremia (HIV RNA >50 copies/mL) at syphilis diagnosis, and an additional 6 (3.9%) had viremia at the next visit 12 weeks later. The median (IQR) detectable HIV RNA (log10copies/mL) was 3.8 (1.9–5.2) and 2.6 (2.2–4.1). Eight participants had peak HIV RNA >3 log10copies/mL; 5 of 8 participants self-reported good adherence to ART. Two-thirds regained viral suppression within 12 weeks; the remaining 4 participants had viral suppression within 24–48 weeks. The median (IQR) peak HIV RNA (log10copies/mL) was 2.7 (2.0–3.6) and 5.1 (5.1–5.3) in those who had viral suppression at 12 or 24–48 weeks, respectively (P < 0.01). By comparison, among cohort participants on ART >1 year without syphilis history in 2017, only 6 of the 249 (2.4%) participants had detectable viremia within 24 weeks after an initial viral load <50 copies/mL (P = 0.02).

The median (IQR) CD4 counts (cells/mm3) were before syphilis 663 (532–813) vs 624 (501–774) at syphilis diagnosis (P = 0.07), rising to 660 (547–826) after syphilis treatment (P < 0.01, at syphilis diagnosis vs. after syphilis). The median CD8 counts (cells/mm3) were 639 (491–840) before syphilis vs. 607 (460–837) at syphilis diagnosis (P = 0.12) and increased to 679 (527–870) after syphilis treatment (P < 0.01, at syphilis diagnosis vs. post syphilis). The CD4/CD8 ratio was 1.02 (0.78–1.38) before syphilis and then changed from 1.04 (0.80–1.39) at syphilis diagnosis to 1.00 (0.77–1.31) after treatment (P = 0.03, at syphilis diagnosis vs. after syphilis).

DISCUSSION

Syphilis prevalence was high at 14.3% among MSM with AHI in Bangkok, Thailand. Moreover, cumulative incidence over time was 39.2% and reinfection occurred in 41.4%. Syphilis incidence increased in this cohort over the 9-year period of observation, consistent with a worldwide trend of rising syphilis incidence, especially among MSM and transgender women. Between 1999 and 2014, the seroprevalence of syphilis was 17.0% among 891 PLWH enrolled at the Thai Red Cross AIDS Research Center (HIVNAT-006 cohort) in Bangkok,23 and in 2015, it was 17.6% among transgender women in Ho Chi Minh, Vietnam.24

Risk factors associated with syphilis in other studies of PLWH have included young age, being MSM, history of previous syphilis, and high CD4 cell count.25–27 We also found associations with methamphetamine use, which has been linked to risky sexual practices in Thai MSM,28 and hepatitis C coinfection, recently described as a predictor of syphilis infection among female PLWH.29 Furthermore, syphilis outbreaks are especially common in large cities with significant populations of MSM, such as Bangkok.30,31

Reinfection was alarmingly high in our cohort. Western guidelines recommend syphilis screening at HIV diagnosis and then at least annually among PLWH.21,32 The new Thai HIV treatment guidelines issued in 2017 expanded the recommendation for syphilis screening to every 6 months for MSM and every 3 months for sex workers.33 Our data support more frequent testing for high-risk groups. Unfortunately, there is a low rate of STI testing among key populations in Southeast Asia,34 even in the high-income countries. Both counseling and screening programs need to be implemented and expanded throughout the region.

Tackling the syphilis epidemic is a worthwhile challenge linked closely to ending the HIV epidemic because several studies have shown increased levels of HIV RNA concomitantly with incident syphilis infection among PLWH, enhancing the risk of HIV transmission.11–18,35 Although syphilis seems to have coincided with viremia among 7.7% of participants with syphilis in our cohort only, this was significantly higher than the 2.4% occurrence of viremia in participants without syphilis. In addition, the viral loads at syphilis diagnosis and after treatment in two-thirds of viremic participants were > 3 log10copies/mL. The occurrence of viremia might have been due to syphilis,11–18 but we cannot rule out ART nonadherence as causing the loss of virologic control. Although most participants with viremia self-reported good ART adherence, it is possible that adherence was overestimated because of biases associated with self-report, such as recall bias and social desirability bias. However, regardless of the etiology of the viremia, these PLWH who had loss of viral suppression were mainly sexually active MSM with an STI that causes genital ulcers and therefore were at a high risk of transmitting HIV to their sexual partners. Fortunately, in all cases the viremia resolved with syphilis treatment and continued ART within 12–48 weeks, confirming an earlier report that syphilis is not associated with virologic failure among MSM with previously undetectable HIV RNA.36

In line with previous studies, we noted a modest decline in the median CD4 count (less than 40 cells/μL), probably related to increased CD4 turnover.35 A transient depletion in CD4 has been reported at syphilis diagnosis regardless of HIV status37 and usually resolves after appropriate antibiotic therapy.11–14 We also observed a numeric but statistically nonsignificant decrease in CD8 cells that showed a similar trend to CD4 count, resulting in a stable CD4/CD8 ratio at different study time points. The effect of untreated syphilis on CD8 cells among PLWH requires further investigation.

This study has some important limitations. This analysis did not differentiate between different stages of syphilis infection, such as primary or secondary. However, given the frequency of syphilis screening every 24–48 weeks, almost all of the incident syphilis cases were likely to be in the early phase. In addition, our cohort mainly included young MSM, nearly all of whom started ART during acute infection. These results may not be generalizable to other populations, such as older people, women, or PLWH who start ART in more advanced stages of immunosuppression.

In conclusion, syphilis prevalence and incidence were high among MSM in Bangkok both at AHI diagnosis and during follow-up but had only a marginal impact on HIV RNA among participants on otherwise suppressive ART. Syphilis was associated with a temporary and modest decline in CD4. Based on our findings we suggest that routine syphilis screening and behavioral risk reduction counseling be implemented at HIV diagnosis and every 6–12 months thereafter among MSM living with HIV in Thailand.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the contribution to this work by the Thai Red Cross AIDS Research Centre and USAMC-AFRIMS in Bangkok.

REFERENCES

1. Hook EW III. Syphilis. Lancet. 2017;389:1550–1557.
2. Smolak A, Rowley J, Nagelkerke N, et al. Trends and predictors of syphilis prevalence in the general population: global pooled analyses of 1103 prevalence measures including 136 million syphilis tests. Clin Infect Dis. 2018;66:1184–1191.
3. Abara WE, Hess KL, Neblett Fanfair R, et al. Syphilis trends among men who have sex with men in the United States and Western Europe: a systematic review of trend studies published between 2004 and 2015. PLoS One. 2016;11:e0159309.
4. Solomon MM, Mayer KH. Evolution of the syphilis epidemic among men who have sex with men. Sex Health. 2015; 12:96–102.
5. Heffelfinger JD, Swint EB, Berman SM, et al. Trends in primary and secondary syphilis among men who have sex with men in the United States. Am J Public Health. 2007; 97:1076–1083.
6. UNAIDS, Report on Global Sexually Transmitted Infection Surveillance. 2018; Available at: https://apps.who.int/iris/bitstream/handle/10665/277258/9789241565691-eng.pdf?ua=1. Accessed August 31, 2019.
7. DDC Warns of Syphilis Upswing. Available at: https://www.bangkokpost.com/thailand/general/1674248/ddc-warns-of-syphilis-upswing. Accessed August 31, 2019.
8. Roberts CP, Klausner JD. Global challenges in human immunodeficiency virus and syphilis coinfection among men who have sex with men. Expert Rev Anti Infect Ther. 2016; 14:1037–1046.
9. Chew Ng RA, Samuel MC, Lo T, et al. Sex, drugs (methamphetamines), and the Internet: increasing syphilis among men who have sex with men in California, 2004-2008. Am J Public Health. 2013; 103:1450–1456.
10. Nerlander LMC, Hoots BE, Bradley H, et al.. HIV infection among MSM who inject methamphetamine in 8 US cities. Drug Alcohol Depend. 2018; 190:216–223.
11. Sadiq ST, McSorley J, Copas AJ, et al. The effects of early syphilis on CD4 counts and HIV-1 RNA viral loads in blood and semen. Sex Transm Infect. 2005; 81:380–385.
12. Dyer JR, Eron JJ, Hoffman IF, et al. Association of CD4 cell depletion and elevated blood and seminal plasma human immunodeficiency virus type 1 (HIV-1) RNA concentrations with genital ulcer disease in HIV-1-infected men in Malawi. J Infect Dis. 1998; 177:224–227.
13. Buchacz K, Patel P, Taylor M, et al. Syphilis increases HIV viral load and decreases CD4 cell counts in HIV-infected patients with new syphilis infections. AIDS. 2004; 18:2075–2079.
14. Kofoed K, Gerstoft J, Mathiesen LR, et al. Syphilis and human immunodeficiency virus (HIV)-1 coinfection: influence on CD4 T-cell count, HIV-1 viral load, and treatment response. Sex Transm Dis. 2006; 33:143–148.
15. Taylor MM, Newman DR, Schillinger JA, et al. Viral loads among HIV-infected persons diagnosed with primary and secondary syphilis in 4 US cities: New York city, Philadelphia, PA, Washington, DC, and Phoenix, AZ. J Acquir Immune Defic Syndr. 2015; 70:179–185.
16. Cooley LA, Pearl ML, Flynn C, et al. Low viral suppression and high HIV diagnosis rate among men who have sex with men with syphilis—Baltimore, Maryland. Sex Transm Dis. 2015; 42:226–231.
17. Palacios R, Jiménez-Oñate F, Aguilar M, et al. Impact of syphilis infection on HIV viral load and CD4 cell counts in HIV-infected patients. J Acquir Immune Defic Syndr. 2007; 44:356–359.
18. Taylor MM, Li WY, Skinner J, et al. Viral loads among young HIV-infected men with early syphilis. J Int Assoc Provid AIDS Care. 2014; 13:501–505.
19. De Souza MS, Phanuphak N, Pinyakorn S, et al. Impact of nucleic acid testing relative to antigen/antibody combination immunoassay on the detection of acute HIV infection. AIDS. 2015; 29:793–800.
20. Phanuphak N, Teeratakulpisarn N, van Griensven F, et al. Anogenital HIV RNA in Thai men who have sex with men in Bangkok during acute HIV infection and after randomization to standard vs. intensified antiretroviral regimens. J Int AIDS Soc. 2015; 18:19470.
21. Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2015; Available at: https://www.cdc.gov/std/tg2015/default.htm. Accessed August 31, 2019.
22. Crowell TA, Colby DJ, Pinyakorn S, et al. Acute retroviral syndrome is associated with high viral burden, CD4 depletion, and immune activation in systemic and tissue compartments. Clin Infect Dis. 2018; 66:1540–1549.
23. Putcharoen O, Chumpangern W, Avihingsanon A. The prevalence, characteristics and outcomes of syphilis in Thai HIV-infected patients: an experience from 12-year observational cohort in Thailand. ECCMID. 2018: 28th European Congress of Clinical Microbiology and Infectious Diseases, Madrid, Spain, April 21–24, 2018. Abstract P1879.
24. Colby D, Nguyen NA, Le B, et al. HIV and syphilis prevalence among transgender women in Ho Chi Minh city, Vietnam. AIDS Behav. 2016; 20:379–385.
25. Novak RM, Ghanem A, Hart R, et al. Risk factors and incidence of syphilis in human immunodeficiency virus (HIV)-Infected persons: the HIV outpatient study, 1999-2015. Clin Infect Dis. 2018; 67:1750–1759.
26. Shilaih M, Marzel A, Braun DL, et al. Factors associated with syphilis incidence in the HIV-infected in the era of highly active antiretrovirals. Medicine. 2017; 96:e5849.
27. Nishijima T, Teruya K, Shibata S, et al. Incidence and risk factors for incident syphilis among HIV-1-Infected men who have sex with men in a large urban HIV clinic in tokyo, 2008-2015. PLoS One. 2016; 11:e0168642.
28. Guadamuz TE, Boonmongkon P. Ice parties among young men who have sex with men in Thailand: pleasures, secrecy and risks. Int J Drug Pol. 2018; 55:249–255.
29. Dionne-Odom J, Westfall A, Mugavero MJ, et al. Incident Syphilis Rates and Predictors in US Women with HIV, 2005–2016. CROI 2019: 26th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, March 4–7, 2019. Abstract 47.
30. Centers for Disease Control and Prevention. HIV and syphilis infection among men who have sex with men–Bangkok, Thailand, 2005-2011. MMWR Morb Mortal Wkly Rep. 2013; 62:518–520.
31. Kukanok S, Kiertiburanakul S. Prevalence of positive syphilis serology among HIV-infected patients: role for routine screening in Thailand. Southeast Asian J Trop Med Public Health. 2014; 45:435–441.
32. European AIDS Clinical Society, Guidelines Version 9.1, 2018. Available at: http://www.eacsociety.org/files/2018_guidelines-9.1-english.pdf. Accessed August 31, 2019.
33. Thailand National Guidelines on HIV/AIDS Treatment and Prevention 2017. Available at: http://www.thaiaidssociety.org/images/PDF/hiv_thai_guideline_2560.pdf. Accessed October 1, 2020.
34. Weiss KM, Jonas KJ, Guadamuz TE. Playing and never testing: human immunodeficiency virus and sexually transmitted infection testing among app-using MSM in southeast Asia. Sex Transm Dis. 2017; 44:406–411.
35. Jarzebowski W, Caumes E, Dupin N, et al. Effect of early syphilis infection on plasma viral load and CD4 cell count in human immunodeficiency virus-infected men: results from the FHDH-ANRS CO4 cohort. Arch Intern Med. 2012; 172:1237–1243.
36. Grewal R, Allen VG, Bayoumi AM, et al. Brief report: syphilis coinfection is not associated with an increased risk of virologic failure among HIV-positive men who have sex with men on antiretroviral therapy. J Acquir Immune Defic Syndr. 2019; 80:585–589.
37. N'Gom PT, Jaffar S, Ricard D, et al. Immune stimulation by syphilis and malaria in HIV-2-infected and uninfected villagers in West Africa. Br J Biomed Sci. 1997; 54:251–255.
Keywords:

HIV; viremia; syphilis

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