What is the next step in management for a patient with a positive Treponema Pallidum Haemagglutination Assay (TPHA) test and a negative Venereal Disease Research Laboratory (VDRL) test?

Management of TPHA Positive, VDRL Negative Result

This serologic pattern most commonly represents either previously treated syphilis or late latent/tertiary syphilis where nontreponemal antibodies have waned, and you should treat with benzathine penicillin G 2.4 million units IM weekly for 3 weeks unless you can document adequate prior treatment. 1, 2

Understanding the Serologic Pattern

• Treponemal tests (TPHA) remain positive for life in most patients regardless of treatment or disease activity, making them unsuitable for distinguishing active from past infection 1, 2
• Nontreponemal tests (VDRL/RPR) have reduced sensitivity in late-stage disease, with only 61-75% sensitivity in late latent syphilis and 47-64% in tertiary syphilis 3, 2
• A TPHA+/VDRL- pattern occurs in 25-39% of late latent cases due to declining nontreponemal antibodies over time 4
• This pattern can also represent previously treated syphilis where nontreponemal antibodies have resolved, or rarely a false-positive treponemal test 2

Immediate Next Steps

1. Obtain Detailed History

• Document any prior syphilis diagnosis and treatment, specifically whether the patient received appropriate penicillin regimens 1
• Assess timing of last sexual exposure and any high-risk contacts 4
• Screen for symptoms of neurosyphilis (headache, vision changes, hearing loss, confusion) or tertiary syphilis (cardiovascular or gummatous manifestations) 3, 4

2. Perform Confirmatory Testing

• Order a second treponemal test using a different methodology (e.g., FTA-ABS or TP-PA) to confirm the TPHA result, as false-positive treponemal tests can occur 2, 5
• Repeat the nontreponemal test (VDRL or RPR) quantitatively to establish a baseline titer 1, 2

3. HIV Testing

• All patients with syphilis must be tested for HIV infection, as HIV-infected patients may have atypical serologic responses and require more intensive management 1, 4

Treatment Algorithm

If No Documented Prior Adequate Treatment:

• Treat as late latent syphilis with benzathine penicillin G 2.4 million units IM once weekly for 3 consecutive weeks (total 7.2 million units) 2, 4
• This three-dose regimen is required regardless of titer level 4

If HIV-Positive:

• Perform CSF examination to rule out neurosyphilis before treating as late latent syphilis 4
• Plan more frequent follow-up at 3-month intervals instead of 6-month intervals 1

If Documented Adequate Prior Treatment:

• No additional treatment is needed if the patient received appropriate penicillin therapy for the stage of syphilis diagnosed 1
• Consider treatment only if there is evidence of reinfection (new exposure, new symptoms, or fourfold increase in nontreponemal titer) 1

Follow-Up Monitoring

• Perform clinical and serologic evaluation at 6,12, and 24 months after treatment using the same nontreponemal test at the same laboratory 4
• Do not expect significant serologic response in late latent disease—many patients remain "serofast" with persistent low-level titers 1
• A fourfold decline in nontreponemal titer (two dilutions) indicates adequate treatment response, though this may not occur in late-stage disease 1, 4

Critical Pitfalls to Avoid

• Never use treponemal test results to monitor treatment response or assess disease activity—they remain positive regardless of cure 1, 2
• Do not assume a negative VDRL rules out active syphilis in the presence of a positive treponemal test, as 25-39% of late latent cases have non-reactive nontreponemal tests 4
• Do not compare titers between different nontreponemal test types (VDRL vs RPR), as they are not directly comparable 1
• Penicillin remains the only proven effective treatment for late latent syphilis—alternative antibiotics should only be used with compelling contraindication 4