Indian Journal of Medical Specialities

: 2021  |  Volume : 12  |  Issue : 1  |  Page : 15--18

Protective antibody levels against hepatitis B among serodiagnosed syphilis cases: Need to integrate national control programs with immunization guidelines?

Bineeta Kashyap, Rituparna Saha, Narendra Pal Singh, Krishna Singha 
 Department of Microbiology, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India

Correspondence Address:
Dr. Bineeta Kashyap
Department of Microbiology, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi


Background: The intersecting routes of transmission in conjunction with hepatocyte injury caused by hepatotropic viruses and Treponema pallidum independently add to the importance of hepatitis B virus (HBV) seroprotection in syphilis. Furthermore, the deficit in the clinical suspicion and stigma associated could at least be partially responsible for the underdiagnosis of syphilitic hepatitis, which is caused by the effect of T. pallidum on hepatocytes. Materials and Methods: Sera from eighty patients, serologically confirmed for syphilis by conventional algorithm, were included in the study. Levels of anti-HBs antibody were determined by ELISA for all serologically confirmed cases of syphilis. Results: Majority of the patients who tested positive for syphilis as per conventional algorithm, hailed from antiretroviral therapy (ART) and sexually transmitted infection (STI) clinics. Levels of anti-HBs antibody of all the patients were found to be below 10 mIU/ml. Conclusion: The absence of protective levels of anti-HBs antibody among all the patients in the study group, despite the inclusion of HBV vaccination in the national immunization program and proximity to tertiary health-care facilities, underscores the pressing need to reinforce and revise our approach to immunization. High-risk groups, such as ART and STI clinic attendees, solicit further enforcement of accelerated immunization strategies in excess to existing dosing schedules.

How to cite this article:
Kashyap B, Saha R, Singh NP, Singha K. Protective antibody levels against hepatitis B among serodiagnosed syphilis cases: Need to integrate national control programs with immunization guidelines?.Indian J Med Spec 2021;12:15-18

How to cite this URL:
Kashyap B, Saha R, Singh NP, Singha K. Protective antibody levels against hepatitis B among serodiagnosed syphilis cases: Need to integrate national control programs with immunization guidelines?. Indian J Med Spec [serial online] 2021 [cited 2021 Jan 25 ];12:15-18
Available from:

Full Text


Syphilis, a disease known since antiquity, presents in a spectrum of clinical forms ranging from primary, secondary, latent, and tertiary stages, when left untreated. It classically presents as a painless primary chancre which subsequently heals over time, but the patient remains highly contagious in the subsequent stages, especially during secondary syphilis. The known natural history, widespread availability of potent antibiotics, and inclusion of the disease in health programs seem to be no deterrents to its escalating number of cases.[1]

In fact, coinfection with other sexually transmitted diseases such as hepatitis B and C viruses (HBV and HCV) and human immunodeficiency virus (HIV) in the preexisting setting of syphilis mandates the screening of sexually transmitted infection (STI) clinic attendees. Furthermore, such coinfections add to the systemic involvement and end-organ damage caused by Treponema pallidum itself. This becomes of paramount importance with regard to liver injury, induced by various hepatotropic viruses (HBV and HCV) and T. pallidum, considering shared routes of transmission and intersecting high-risk population groups. Thus, HBV seroprotection becomes all the more pertinent in these vulnerable population to prevent superadded liver cell damage.

“Syphilitic hepatitis” caused by T. pallidum-induced hepatocyte injury, in conjuction with secondary syphilis, is rarely reported.[2] A dearth of clinical suspicion and the stigma associated with syphilis could be at least partially responsible for the underdiagnosis of syphilitic hepatitis. Furthermore, the number of cases of syphilitic hepatitis are expected to rise with the increasing trend of T. pallidum infections.[3]

The conventional diagnostic algorithm for syphilis employs a basic nontreponemal test (rapid plasma reagin [RPR], VDRL, etc.) followed by a specific treponemal test (TPHA, FTA-ABS, MHA-TP, etc.). However, there is still a dearth of definitive data on the level of protection prevalent against these HBVs in cases of syphilis diagnosed by conventional algorithm. Thus, the present study aims at bridging this gap by assessing the protective titers of anti-HBs in diagnosed cases of syphilis in a high-risk setting.

 Materials and Methods

The present study involves a cross-sectional assessment of anti-HBs levels in eighty consecutive serodiagnosed cases of syphilis. The study was conducted in the Department of Microbiology, University College of Medical Sciences, Delhi. Samples received from all clinically suspected cases of syphilis between May 2019 and August 2019, which came for routine screening for syphilis, hepatitis B and Hepatitis C and were negative for Hepatitis B antigen, were subjected to conventional algorithm testing. Serum samples from eighty patients, who were serologically confirmed for syphilis by conventional algorithm, were included in the study. We have excluded samples from antenatal clinics which came for the screening of syphilis.

Conventional algorithm for diagnosis of syphilis

RPR card test was performed on all eighty samples. The serum samples were subjected to RPR Card Test/Carbogen Antigen for syphilis testing (Tulip Diagnostics Goa, India), a macroscopic non-treponemal flocculation test employed for detection and quantitation of anti-lipoidal antibodies. All RPR-reactive specimens were confirmed by T. pallidum hemagglutination assay (TPHA), TPHA (IMMUTREP TPHA kit of Omega Diagnostics Ltd., Scotland, United Kingdom).

Determination of anti-HBs antibody levels

Levels of anti-HBs antibody were determined for all serologically confirmed cases of syphilis by commercial ELISA (Bioneovan, Beijing, China) as per manufacturer’s instructions. The cutoff value of anti-HBs corresponded to 10 mIU/ml.


We have assessed the levels of HBV seroprotection in cases of syphilis, who have been confirmed by the conventional algorithm of testing. The major bulk of patients, who were reactive for syphilis by conventional algorithm, were male patients (66%), while females comprised 33% of the cases. The median age of the study population was 27.5 years with young adults (age 18–25 years), attributing 53% of the total serologically confirmed cases of syphilis.

ART clinic attendees accounted for 56% of the study population, whereas 25% of the cases were from STI clinic. The other inpatient departments such as medicine, obstetrics, and gynecology, and surgery collectively contributed to 19% of all cases.

[Figure 1] depicts the department-wise frequency in a variation of the RPR titers, whereas [Figure 2] illustrates a comparison among the proportion of patients with different RPR titers, from various departments. The ART clinic attendees showed a wider range of distribution of syphilis titers in comparison to other departments.{Figure 1}{Figure 2}

Anti-HBs levels in serodiagnosed cases of syphilis

Among the sera from eighty patients, who were analyzed by a double antigen sandwich ELISA for anti-HBs, none of the samples exceeded the cutoff OD value. Although one out of eighty samples exhibited visible color reaction, the level of HBV antibody was well below the cutoff OD value, set as per manufacturer’s specifications (10 mIU/ml). This cutoff value corresponded to the Centers for Disease Control and Prevention (CDC) protection level. Seroprotection against hepatitis B was considered inadequate, if anti-HBs level was below 10 mIU/ml (CDC).


The diagnosis of syphilitic hepatitis essentially rests upon raised liver enzymes in serologically confirmed syphilis patients in the absence of any other infectious or immune etiology, which resolve upon treatment. Immunohistochemistry augments the diagnosis; however, demonstration of T. pallidum in liver biopsies remains a challenge.[4] The primary association with perianal ulcers among homosexuals, the mild or often asymptomatic presentation of the disease, and the social stigma associated with syphilis could be partially attributable to the underdiagnosis of syphilitic hepatitis.[5] As per the fact sheet published by CDC (Atlanta), in the year 2014, the incidence of syphilitic hepatitis was 3%.[6] However, there is a discord in the number of cases reported in the existing literature and the CDC fact sheet data. With roughly a mere 144 cases of syphilitic hepatitis, mentioned in all PubMed and OVID databases, we can speculate a lacuna in the index of clinical suspicion and consequent underreporting.[7]

Coinfection of syphilis with other STIs rationalizes the routine screening of all cases of syphilis for HBV, HCV, HIV, etc. The levels of seroprotection become pertinent in the context of preventable liver injury by HBVs in the setting of preexisting syphilis. HBV vaccination has been incorporated in the Universal Immunization Program (UIP) in India since 2007–2008.[8] The Indian Association of Pediatrics (IAP) and UIP guidelines advocate HBV vaccination within 24 h of birth followed by 6, 10, and 14 weeks. Studies have reported >95% seroconversion rates, conferring protection for 8–10 years when vaccinated as per IAP schedule.[9] The Association of Physicians of India – Expert panel guidelines recommend HBV vaccination of adults in high-risk settings at 0, 1, and 6 months, followed by a booster after 5 years, only for immunocompromised.[10]

However, in adults below 40 years, rates of seroconversion are relatively low (90%), which further dips to 65%–75% beyond 60 years of age.[11]

Approximately 10% of the 34 million people living with HIV worldwide carry chronic hepatitis B infection.[12] The prevalence of coinfections of STIs is known to vary with geographical settings and patient demographics. Studies have established higher prevalence of chronic HBV infection among homosexual men and intravenous drug users. Furthermore, the risk of HBV infection is known to increase 20 fold in HIV-infected population in comparison to noninfected.[13] Several studies have established higher prevalence of coinfection with HBV and other STIs in association with HIV.[14-16] However, despite the ample amount of research targeted at coinfections with HIV and other STIs, there is a relative vacuum of data pertaining to HBV in light of preventable STI.

Several studies have depicted a higher prevalence of HIV-HBV and syphilis-HBV coinfections in comparison to coinfections with other STIs.[17,18] Contrasting findings have been reported by Mehta et al. in their study conducted in antenatal patients, showing no coinfections among syphilis and other STIs.[19] In the present study, however, we have excluded patients from antenatal clinics. Nevertheless, suffering from the limitation arising from the omission of HBV vaccination status, the findings of the present study underscore the vulnerability of these syphilis patients to HBV.

The proximity of these syphilis cases to preexisting tertiary care facilities and the risk of superadded HBV infection warrants a revisit to our immunization strategies. The vast scope of reinforcement of HBV protection among cases of syphilis by accelerated immunization strategies should be delved into. Despite the existing programs for STI and immunization, there is a dearth of clear guidelines for immunization in STI cases. The existing platforms of STI programs can be further broadened to encompass routine HBV immunization.


The levels of anti-HBs below 10 mIU/ml in the entire study population reflect the susceptibility of these high-risk groups to HBV. Hepatocyte injury, cell transformation potential, and chronicity of HBV infection may get compounded by the independent liver damage caused by T. pallidum.

Coinfection of STIs such as (HBV-HIV, syphilis-HBV, and HIV-HCV) though frequently complicates the disease progression and treatment; they form an interface to these patients through the existing control programs. People living with HIV often exhibit a diminished immune response to the conventional dosage and routes of HBV vaccines. Several studies have established double-dose HBV rescue vaccination (0, 1, and 2 months), increased dose, intradermal administration, and addition of adjuvants, effective in increasing the seroconversion among nonresponding adults.[20,21] Despite the abundance in data establishing vulnerability of STI clinic attendees to HBV infection, much of the studies have been essentially focused on HIV. There is a relative vacuum in the data related to the seroprotection levels and HBV seroconversion kinetics among the cases of syphilis. The findings of the present study emphasize the vast scope of improvement in our approach to HBV immunization in high-risk settings. The integration of preexisting platforms of STI control programs along with accelerated and targeted HBV immunization strategies is of logistic essence and paramount importance.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Suzuki M 4th , Orfanidis M, Moleski M, Katz M, Leo C, Kastenberg M. The “Great Imitator” Presents with Abnormal Liver Enzymes. The Medicine Forum; 2009. p. 17.
2Sabbatani S, Manfredi R, Attard L, Chiodo F. The “Great imitator.” Syphilis as causative agent of isolated, concurrent, acute hepatitis and meningitis. Infect Dis Clin Pract 2005;13:261-4.
3Patton ME, Su JR, Nelson R, Weinstock H, Centers for Disease Control and Prevention (CDC). Primary and secondary syphilis--United States, 2005-2013. MMWR Morb Mortal Wkly Rep 2014;63:402-6.
4Adachi E, Koibuchi T, Okame M, Sato H, Kikuchi T, Koga M, et al. Liver dysfunction in patients with early syphilis: A retrospective study. J Infect Chemother 2013;19:180-2.
5Lo JO, Harrison RA, Hunter AJ. Syphilitic hepatitis resulting in fulminant hepatic failure requiring liver transplantation. J Infect 2007;54:e115-7.
6Control CFD, Prevention. Syphilis-CDC Fact Sheet (Detailed). CDC; 2015.
7Huang J, Lin S, Wan B, Zhu Y. A systematic literature review of syphilitic hepatitis in adults. J Clin Transl Hepatol 2018;6:306-9.
8Lahariya C, Subramanya BP, Sosler S. An assessment of hepatitis B vaccine introduction in India: Lessons for roll out and scale up of new vaccines in immunization programs. Indian J Public Health 2013;57:8-14.
9Lodha R, Jain Y, Anand K, Kabra SK, Pandav CS. Hepatitis B in India: A review of disease epidemiology. Indian Pediatr 2001;38:349-71.
10Guidelines for vaccination in normal adults in India. Indian J Nephrol. 2016;26 (Suppl 1):S7-14.
11Van Herck K, Leuridan E, Van Damme P. Schedules for hepatitis B vaccination of risk groups: Balancing immunogenicity and compliance. Sex Transm Infect 2007;83:426-32.
12Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol 2006;44:S6-9.
13Spradling PR, Richardson JT, Buchacz K, Moorman AC, Brooks JT, HIV Outpatient Study (HOPS) Investigators. Prevalence of chronic hepatitis B virus infection among patients in the HIV Outpatient Study, 1996-2007. J Viral Hepat 2010;17:879-86.
14Schuelter-Trevisol F, Custódio G, Silva AC, Oliveira MB, Wolfart A, Trevisol DJ. HIV, hepatitis B and C, and syphilis prevalence and coinfection among sex workers in Southern Brazil. Rev Soc Bras Med Trop 2013;46:493-7.
15Silverman JG, Decke MR, Gupta J, Dharmadhikari A, Seage GR 3rd, Raj A. Syphilis and hepatitis B Co-infection among HIV-infected, sex-trafficked women and girls, Nepal. Emerg Infect Dis 2008;14:932-4.
16Katamba C, Chungu T, Lusale C. HIV, syphilis and hepatitis B coinfections in Mkushi, Zambia: A cross-sectional study. F1000Res 2019;8:562.
17Hussain T, Kulshreshtha KK, Sinha S, Yadav VS, Katoch VM. HIV, HBV, HCV, and syphilis co-infections among patients attending the STD clinics of district hospitals in Northern India. Int J Infect Dis 2006;10:358-63.
18Shimelis T, Tassachew Y, Tadewos A, Hordofa MW, Amsalu A, Tadesse BT, et al. Coinfections with hepatitis B and C virus and syphilis among HIV-infected clients in Southern Ethiopia: A cross-sectional study. HIV AIDS (Auckl) 2017;9:203-10.
19Mehta KD, Antala S, Mistry M, Goswami Y. Seropositivity of hepatitis B, hepatitis C, syphilis, and HIV in antenatal women in India. J Infect Dev Ctries 2013;7:832-7.
20Kim JH, Psevdos G Jr., Groce V, Sharp V. Persistence of protective hepatitis b surface antibody titers after successful double-dose hepatitis b virus rescue vaccination in HIV-infected patients. Gut Liver 2012;6:86-91.
21Whitaker JA, Rouphael NG, Edupuganti S, Lai L, Mulligan MJ. Strategies to increase responsiveness to hepatitis B vaccination in adults with HIV-1. Lancet Infect Dis 2012;12:966-76.