What is the recommended treatment for a patient with a history of primary syphilis, currently on Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide), with increasing syphilis titers from 1:4 to 1:8?

Serologic Relapse in Treated Syphilis: Management Approach

This patient requires re-treatment with benzathine penicillin G 2.4 million units IM weekly for 3 weeks after CSF examination to rule out neurosyphilis. 1

Clinical Interpretation

The titer progression from 1:256 → 1:4 → 1:8 represents a fourfold increase (doubling of dilutions) from the nadir, which meets CDC criteria for either treatment failure or reinfection. 2

• A fourfold rise in titer above the established serofast baseline (1:4 in this case) indicates potential reinfection or treatment failure requiring intervention. 1
• The patient achieved initial serologic response (1:256 to 1:4 represents >4-fold decline), but the subsequent rise to 1:8 is concerning. 2

Mandatory CSF Examination

Lumbar puncture is required before re-treatment in this HIV-infected patient with rising titers. 1

• CDC guidelines specifically state that when nontreponemal titers rise fourfold in HIV-infected patients, CSF examination should be performed unless reinfection is clearly likely. 2
• HIV-infected patients have increased risk for neurosyphilis and demonstrate CSF abnormalities and poorer serologic responses to therapy. 1
• The complexity of managing treatment failure in HIV-infected patients necessitates CSF evaluation to guide appropriate therapy. 2

Treatment Algorithm Based on CSF Results

If CSF is Normal (No Neurosyphilis):

• Benzathine penicillin G 2.4 million units IM weekly for 3 weeks 2, 1
• This is the standard re-treatment regimen recommended by most experts for treatment failure without neurosyphilis. 2

If CSF Shows Neurosyphilis:

• Aqueous crystalline penicillin G 18-24 million units daily IV (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days 2, 1
• Alternative: Procaine penicillin 2.4 million units IM daily plus probenecid 500 mg orally four times daily for 10-14 days (avoid if sulfa allergy due to probenecid cross-reactivity) 2

Biktarvy Considerations

• Continue Biktarvy throughout syphilis re-treatment without modification. 2
• No drug interactions exist between penicillin-based syphilis regimens and Biktarvy components.
• The patient's HIV status necessitates more intensive monitoring but does not change the fundamental treatment approach. 2

Follow-Up Monitoring

HIV-infected patients require more frequent serologic monitoring than HIV-negative patients: 1, 3

• Clinical and serologic evaluation at 3,6,9,12, and 24 months after re-treatment 2, 1
• Expect at least a fourfold decline in titer within 6-12 months if treatment is successful. 3
• If CSF examination was performed and showed neurosyphilis, repeat CSF at 3 and 6 months after completion of therapy, then every 6 months until CSF white blood cell count normalizes and CSF-VDRL becomes nonreactive. 2

Critical Pitfalls to Avoid

• Do not skip CSF examination in HIV-infected patients with rising titers—this is a guideline-mandated step. 1
• Do not use single-dose benzathine penicillin for re-treatment; the 3-week regimen is required. 2
• Do not assume reinfection without investigation—both treatment failure and reinfection require the same initial workup with CSF examination. 2
• Do not use azithromycin as an alternative—treatment failure rates are unacceptably high. 4

Alternative for Penicillin Allergy

If the patient has documented penicillin allergy:

• Penicillin desensitization followed by penicillin therapy is preferred over alternative antibiotics. 2
• If desensitization is refused or contraindicated: Doxycycline 100 mg orally twice daily for 14 days (for non-neurosyphilis) 5 or Ceftriaxone 2 g IV daily for 10-14 days (for neurosyphilis, though data are limited) 2