Asymptomatic neurosyphilis may need early intervention in people living with HIV

Syphilis is a sexually transmitted infection caused by the spirochete Treponema pallidum (T. pallidum) and is of global and historic significance. People living with HIV (PLWH) infection are frequently coinfected with syphilis, because of the overlapping modes of pathogen acquisition. Neurosyphilis can occur at any stage of syphilis infection, and PLWH are at a greater risk of developing neurosyphilis in early and late latent syphilis, including asymptomatic central nervous system (CNS) infection than those without HIV infection. Some patients with neurosyphilis present neurological manifestations such as meningitis, stroke, cranial nerve dysfunction, auditory or ophthalmic abnormalities, and acute changes in mental status. However, some neurosyphilis cases in PLWH lack signs or symptoms of CNS infection. Asymptomatic neurosyphilis is diagnosed in the absence of neurological signs or symptoms and can only be detected in the presence of cerebrospinal fluid (CSF) abnormalities indicative of CNS infection, including mononuclear pleocytosis, increased protein concentration, and/or a reactive CSF venereal disease research laboratory (VDRL) assay. This has raised concerns that a persistent reservoir of T. pallidum although asymptomatic in the CNS, may result in treatment failure and neurological sequelae in PLWH. Neurosyphilis might lead to cranial nerve palsies, syphilitic meningitis, general paresis, and tabes dorsalis even several years after infection. Thus, early intervention may be needed for asymptomatic neurosyphilis in PLWH.

The latest Centers for Disease Control and Prevention (CDC) treatment guidelines for sexually transmitted disease suggests that lumbar puncture (LP) should only be performed on those with neurological signs or symptoms, but not in PLWH presenting with no neurological symptoms.^[1] While the investigation of individuals with neurological symptoms is well established, there are more controversies around PLWH with potential asymptomatic neurosyphilis. The incidence of asymptomatic neurosyphilis remains high in PLWH,^[2] but the exact clinical circumstances dictating when an LP should be performed in PLWH who may be asymptomatic is still unclear.

A previous study showed that LP was performed in 46 PLWH patients, of whom ten patients (22%) with asymptomatic neurosyphilis were detected during early infection.^[3] Another study analyzed data for 117 PLWH with CSF abnormalities consistent with neurosyphilis, and approximately 33% were asymptomatic.^[4] Owing to the relatively high rate of asymptomatic neurosyphilis in PLWH, the criteria of LP application should be expanded to exclude asymptomatic neurosyphilis, considering potentially serious complications of late neurosyphilis (42.1% showing infarction lesions, 47.4% mild-to-severe brain atrophy, and 15.8% white matter demyelination after treatment).^[5] The CD4⁺ T cell count <350 cells/mL and/or VDRL titer ≥1:32 was the most reliable in identifying asymptomatic neurosyphilis in PLWH (sensitivity: 100% [95% confidence interval (CI) 70–100]; specificity: 87% [95% CI: 72–96]).^[3] The European guidelines suggested that PLWH may have an increased risk of neurological involvement and recommend CSF examination in all patients with VDRL titers >1:32 and CD4⁺ T cell count <350 cells/mL.^[6] In addition, a retrospective cohort showed that repeat syphilis is more likely to present asymptomatically than initial syphilis in HIV-infected individuals, which should also be verified by LP.^[7] Although asymptomatic neurosyphilis can only be diagnosed by CSF examination, several risk factors are also associated with asymptomatic neurosyphilis in PLWH, including low CD4 T-cell count, high rapid plasma reagin titer, and poor HIV virological control,^[8] indicating that HIV could have an impact on neurosyphilis progression.

However, a portion of patients who meet the criteria refuse to undergo LP in clinical practice. A Polish group who reviewed their HIV cohort from 2006 to 2010 reported that only 52 of 109 patients (47.7%) with VDRL titers ≥1:32 agreed to undergo LP, and 44 of those 52 (82.60%) cases were diagnosed with neurosyphilis.^[9] Therefore, the treatment of syphilis in PLWH should be discussed further in patients who are at high risk of developing neurosyphilis. Benzathine penicillin G (BPG) has been used to treat syphilis for decades with no penicillin-resistant strains being documented thus far. Recent international treatment guidelines concur in endorsing that syphilis should be treated with the same regimen regardless of the HIV status, namely, a single-dose, long-acting intra-muscular BPG 2.4 million units (MU) in early syphilis and three doses of intra-muscular BPG 2.4 MU in late latent syphilis, including neurosyphilis.^[10] However, different suggestions were given to patients with HIV coinfection because of impaired host immunity and higher rates of asymptomatic neurosyphilis. In the absence of LP, a full neurosyphilis regimen must be administered. A retrospective analysis of 130 HIV-coinfected individuals in the United Kingdom recommended the following treatment with a neuropenetrative regimen regardless of syphilis stage: 17 days of intra-muscular procaine benzylpenicillin (2.4 MU) and oral probenecid (500 mg, q.i.d.). This UK study identified a serological treatment success rate of 98%, which was higher than that previously recorded elsewhere, and the team reported successful patient adherence to this longer course of treatment.^[11]

In contrast, a randomized clinical trial compared a single vs. three-dose BPG regimen in PLWH and showed that the three-dose regimen did not improve syphilis serological outcomes, which provides further support for the recent CDC recommendation.^[12] In another retrospective analysis of 478 cases in the USA from 1986 to 2013, HIV-infected patients with early syphilis were treated with one dose of 2.4 MU BPG (29%), ≥2 doses of 2.4 MU BPG (53%), or other regimens including non-penicillin-based regimens (18%).^[13] The study found no statistically significant difference in serologic response to treatment in HIV-infected patients receiving a single dose of BPG compared to those receiving ≥2 doses of BPG. This phenomenon might be explained by the fact that BPG does not reach effective levels in the CNS, even with the prolonged treatment course. It would be preferable to use treatments with good CNS penetration, such as ceftriaxone in all HIV-positive patients with early syphilis.^[14]

Given the lack of high-quality, randomized, prospective data with adequate follow-up periods, it is challenging to derive firm conclusions about clinical outcomes. The optimal antimicrobial regimen to treat syphilis in PLWH is still unknown. Further prospective studies should recruit enough PLWH that have undergone LP to confirm the optimal regimen for neurosyphilis. Importantly, careful follow-up is essential for observing treatment response and adverse effects such as the Jarisch-Herxheimer reaction, regardless of the regimen used. A study suggested that the incidence of Jarisch-Herxheimer after BPG treatment was higher among HIV-infected than HIV-uninfected individuals.^[15] In addition, repeated courses of BPG therapy may be needed in patients who have not responded to antimicrobial treatment or syphilis reinfection.

In conclusion, the criteria for LP may need to be expanded given the diagnostic difficulty of asymptomatic neurosyphilis in PLWH. A longer course of BPG and other good CNS penetrative treatment should be considered if asymptomatic neurosyphilis cannot be excluded.

Funding

This work was supported by grants from the Major Science and Technology Special Project of China (No. 2017ZX09304016, No. 2017ZX10302201004008); the National Natural Science Foundation of China (No. 81971949); and the Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (No. LC2016PY003).

Conflicts of interest

None.