Prozone phenomenon

The prozone phenomenon refers to a false negative serological test result that occurs due to excessive antibody titers. The prozone effect occurs more frequently in secondary syphilis (SS) and is relatively more common in syphilis with concomitant human immunodeficiency virus(HIV) infection and in pregnancy (Awake P et al.2022).

In patients with syphilis and HIV co-infection, there is excessive antibody production due to abnormal B cell behavior, which leads to an overreaction to antigen stimulation (Cebolla-Verdugo M et al. 2025). Homosexuals have a higher risk of undetected clinical syphilis and HIV due to the painless and transient nature of the primary chancre. They may have a higher incidence of prozone due to HIV-induced B-cell dysfunction, which in turn may increase the likelihood of syphilis going undiagnosed and thus untreated. The simultaneous presence of an HIV infection influences the clinical appearance of previously clearly defined diseases and their natural course as well as the response to therapy.

The incidence of the prozone phenomenon is reported to be between 0.5 % and 2 % (Spangler AS et al. 1990). It is assumed to be higher in HIV co-infection. The incidence of prozone phenomenon is gaining clinical importance due to the increasing number of people at risk of sexually transmitted diseases, especially HIV-positive individuals (Awake P et al. 2022).

Case report (Awake P et al.2022): A 20-year-old man presented with an asymptomatic reddish-brown rash on the palms of his hands and the sole of his left foot that had been present for 25 days. He was treated by his GP with topical steroids. The symptoms hardly improved and the rash persisted. A thorough examination revealed erosion on the glans penis and a mucosal lesion on the hard palate. Therefore, SS was strongly suspected clinically. The patient denied any history of sexual contact. A further systemic physical examination was performed but revealed no abnormalities. The RPR test was non-reactive. In addition, his CBC, chest X-ray, electrocardiogram (ECG) and other routine tests were all within normal limits. Therefore, we requested a repeat RPR test at a higher dilution, which was reactive at a dilution of 1:320. A Treponema pallidum hemagglutination test was performed, which was also positive. The patient underwent an HIV test and was found to be seropositive. Therapy: Intramuscular injection of 2.4 MU benzathine penicillin; initiation of antiretroviral therapy (ART).

1. Awake P et al.(2022) Prozone phenomenon in secondary syphilis with HIV co-infection: Two cases. Indian J Sex Transm Dis AIDS 43:183-185
2. Cebolla-Verdugo M et al. (2025) Syphilis in people living with HIV: Diagnostic challenges. J Dtsch Dermatol Ges 23: 887-888.
3. Syphilis with a negative blood test reaction. JAMA 189:87-90.
4. Musher DM et al. (1990) Effect of human immunodeficiency virus (HIV) infection on the course of syphilis and on the response to treatment. Ann Intern Med 113:872-81.
5. Liu LL et al. (2014) Incidence and risk factors for the prozone phenomenon in serologic testing for syphilis in a large cohort. Clin Infect Dis 59:384-389.

Clinical and laboratory abnormalities in syphilis and HIV co-infection (Awake P et al.2022)

• Simultaneous occurrence of primary syphilis and SS, asymptomatic neurosyphilis: Increased rate of negative serologic tests for both primary syphilis and SS
• Longer treatment duration than expected and relapse of infection after treatment: Increased number of false-negative non-treponemal antibody tests due to the prozone phenomenon
• Rapid progression to secondary and neurosyphilis: seroreversion to negative specific treponemal antibody tests after treatment
• Greater number of primary chancres and extensive and deeper ulcers: Significant increase in plasma HIV viral load
• Atypical manifestations: Significant decrease in CD4 cell count
• Aggressive secondary syphilis: High rate of serologic failure in the clearance of the non-treponemal antibody test after treatment
• Systemic manifestations such as uveitis, syphilitic aortitis, encephalitis, arteritis, gastric syphilis and syphilitic hepatitis: Increased risk of serologic failure in late-stage syphilis and HIV-infected patients