How should syphilis be treated in an HIV‑positive patient according to rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) results (primary/secondary/early latent vs late latent/unknown) and neurologic involvement?

Treatment of Syphilis in HIV-Positive Patients Based on Serology

Primary and Secondary Syphilis (Early Syphilis)

Treat with benzathine penicillin G 2.4 million units IM as a single dose, which is the same regimen used for HIV-negative patients and achieves 90-95% cure rates. 1, 2

• The CDC guidelines consistently recommend this single-dose regimen regardless of HIV status, and available data demonstrate that additional doses of benzathine penicillin G do not enhance efficacy 1
• Some experts advocate for three weekly doses (7.2 million units total), but this approach is not supported by evidence showing improved outcomes 1
• Close serologic monitoring is mandatory at 3,6,9,12, and 24 months after treatment 1, 2

When to Consider CSF Examination in Early Syphilis

While not routinely required, strongly consider lumbar puncture if the patient has CD4 count ≤350 cells/mL and/or RPR titer ≥1:32, as these factors are associated with higher rates of neurosyphilis 1, 2

• CSF examination before treatment is optional for early syphilis in HIV patients, as most respond appropriately to standard therapy 1
• However, neurologic symptoms mandate immediate CSF examination regardless of stage 1, 2

Early Latent Syphilis (Infection <1 Year Duration)

Treat with benzathine penicillin G 2.4 million units IM as a single dose, identical to primary/secondary syphilis management 1, 3

• Follow-up schedule: clinical and serologic evaluation at 6,12,18, and 24 months 1
• Treatment success is defined as a four-fold (two dilution) decrease in RPR/VDRL titers 2, 3

Late Latent Syphilis or Syphilis of Unknown Duration

Treat with benzathine penicillin G 2.4 million units IM weekly for 3 consecutive weeks (total 7.2 million units) 1, 2

Critical Pre-Treatment Consideration

CSF examination is strongly recommended before treatment in HIV-positive patients with late latent or unknown duration syphilis, particularly if CD4 ≤350 cells/mL or RPR ≥1:32 1, 2

• If CSF is normal, proceed with the three-dose benzathine penicillin regimen 1
• If CSF shows neurosyphilis, switch to IV aqueous penicillin regimen (see below) 1
• Follow-up: evaluate at 6,12,18, and 24 months; repeat CSF if titers don't decline four-fold or symptoms develop 1

Neurosyphilis (Any Stage with CNS Involvement)

Treat with aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours) for 10-14 days 2, 3

• This regimen achieves 90-95% cure rates for neurosyphilis 2
• Indications for CSF examination include: neurologic symptoms, visual/auditory symptoms, evidence of tertiary syphilis, treatment failure, or CD4 ≤350 with RPR ≥1:32 1, 2
• Repeat CSF examination every 6 months until cell count normalizes 1

Treatment Failure and Serologic Non-Response

Treatment failure is defined as: persistent or recurrent clinical symptoms, sustained four-fold increase in nontreponemal titers, or failure to achieve four-fold decrease in titers within 6-12 months 1, 2

Management of Treatment Failure

• Perform CSF examination immediately 1
• If CSF is normal, re-treat with benzathine penicillin G 2.4 million units IM weekly for 3 weeks 1
• If CSF shows neurosyphilis, treat with IV aqueous penicillin regimen 1

Risk Factors for Serologic Failure

Patients at highest risk for treatment failure include those with: baseline RPR ≤1:16, previous syphilis history, and CD4 count <350 cells/mL 4

• These patients require intensified monitoring but not necessarily different initial treatment 4
• HIV-positive patients have slower serologic response and higher failure rates (56% vs 38% in HIV-negative patients) 5

Penicillin Allergy

Penicillin is mandatory for all stages of syphilis in HIV-positive patients; if allergic, perform skin testing and desensitize 1

• Alternative regimens (doxycycline, ceftriaxone) are poorly studied in HIV patients and should only be used with close follow-up if desensitization is impossible 1
• For neurosyphilis in penicillin-allergic patients, ceftriaxone 2 grams daily IM or IV for 10-14 days may be considered, though cross-reactivity exists 1

Critical Monitoring Parameters

All HIV-positive patients with syphilis require:

• Screening for other STIs (gonorrhea, chlamydia, hepatitis B/C) 2
• Counseling about Jarisch-Herxheimer reaction risk after first penicillin dose 2
• Partner notification and presumptive treatment of contacts within 90 days 2
• Optimization of antiretroviral therapy, which may improve syphilis treatment outcomes 1

Common Pitfalls to Avoid

• Do not assume standard treatment is inadequate: Single-dose benzathine penicillin remains appropriate for early syphilis despite HIV coinfection 1, 4
• Do not ignore low but stable RPR titers (1:1 to 1:4): These represent "serofast" responses and do not require retreatment in the absence of clinical findings 3
• Do not delay CSF examination in late latent syphilis: HIV patients with late/unknown duration syphilis need CSF evaluation before treatment 1
• Do not use alternative antibiotics without compelling reason: Penicillin desensitization is preferred over non-penicillin regimens 1