Reexamining Syphilis: An Update on Epidemiology, Clinical Manifestations, and Management

Molly E Kent, PharmD; Frank Romanelli, PharmD MPH BCPS


The Annals of Pharmacotherapy. 2008;42(2):226-236. 

In This Article

Syphilis and HIV

Coinfection with syphilis and HIV is common due to shared risk factors related to sexual behavior.[63] In the US, MSM have consistently represented the greatest single atrisk group for HIV acquisition. The trend toward increasing cases of coinfection may be a reflection of increasing instances of unsafe sexual practices.[64] A resurgence of unsafe sex practices may be explained by several potential factors including "safe sex fatigue," increased use of recreational drugs such as methamphetamine, and antiretroviral-related increases in HIV survival.[63,65,66] Some researchers have postulated that oral sex may now be more common among MSM since it is associated with a reduced frequency of HIV transmission; however, syphilitic transmission from oral lesions is highly probable.[63] All patients diagnosed with syphilis should be screened for HIV as well as for all other potential sexually transmitted infections, and vice versa.[24]

Interactions between syphilis and HIV are concerning for several reasons including the propensity for coinfected patients to more effectively transmit HIV through high-risk sexual exposures.[10,11,63,64,65,66,67] Syphilis-induced genital tract inflammation and/or ulcerations may disrupt innate barriers to HIV and lead to more effective transfer of the virus. By altering normal immune responses, HIV may in turn affect the presentation, diagnosis, and natural course of syphilitic disease.[10,11,63,64,65,66,67] Alternatively, syphilis may activate various cytokines, which can lead to enhanced viral replication.[63] Buchacz et al.[68] conducted a retrospective case series study of 52 HIV-infected men with primary or secondary syphilis to examine the effects of syphilis on HIV viral load and CD4+ cell counts. Viral loads were higher during syphilis compared with presyphilis levels by a mean of 0.22 log[10] copies/mL (p = 0.02). Viral loads were also lower following treatment for syphilis (p = 0.05). CD4+ cell counts were significantly lower during syphilis infection (p = 0.04) and increased by a mean of 33 cells/mm3 following treatment. The untoward effects of syphilis on both HIV viral load and CD4+ cell counts were more substantial among patients with secondary syphilis and among those not receiving antiretrovirals. While this case series has several limitations, including its retrospective nature, it does highlight the importance of preventing syphilis infection and treating cases promptly.

As previously described, the natural course of syphilis has 4 well-defined stages. These stages may become less defined in the presence of coinfection with HIV. Primary syphilis in coinfected patients may be associated with a greater number of chancres. In a univariate analysis, Rolfs et al.69 compared 114 patients with only primary syphilis with 25 coinfected patients and found that patients with both HIV and syphilis were more likely to present with multiple chancres. In the same study which examined 253 patients with secondary syphilis, of whom 53 were also HIV-infected, no differences in the duration of rash or frequency of condyloma lata were noted. These findings might represent slower healing of primary lesions or a more rapid acceleration to secondary syphilis among coinfected individuals.

Diagnosis of syphilitic infection in coinfected patients may be more challenging. As would be expected, there is no evidence to suggest that the sensitivity or specificity of darkfield microscopy is affected by HIV. However, nontreponemal serologic tests (eg, RPR, VDRL), which rely on antibody responses, may be altered. HIV is well known to induce several immunologic changes involving both humoral and cell-mediated branches of the immune system. Alterations in humoral immunity often result in hypergammaglobulinemia, which may predispose HIV-infected patients to a higher than normal incidence of false-positive serologic tests.[63,70] In evaluating these serologic assays, clinicians should be careful to consider all clinical findings.

In most instances, patients infected with HIV are treated the same as those without HIV infection ( Table 2 ).[24] Some clinicians advocate treating primary and secondary syphilis in coinfected patients similarly to patients with late syphilis, with 3 penicillin doses at 1-week intervals.[63] The efficacy of alternative nonpenicillin regimens has not been well studied among cohorts of HIV-infected patients. Ceftriaxone appears to be a reasonable alternative to penicillin; however, allergic cross-sensitivity is possible.[63] Therefore, consideration should be given to desensitizing patients presenting with well-documented and serious penicillin allergies. Because treatment failure may be more common among HIV-infected patients, more aggressive follow-up is recommended ( Table 3 ).[24]

In cases of either late latent syphilis or syphilis of unknown duration, an examination of the CSF should be undertaken prior to the initiation of therapy. A more conservative approach to CSF examination in HIV-infected patients is based on the premise that alterations in immune function might predispose this patient population to T. pallidum central nervous system infiltration.[71,72] Standard doses of benzathine penicillin do not provide sufficient drug concentrations to affect T. pallidum within the central nervous system.[44,73] Clinically, this may result in accelerated progression to neurosyphilis as well as increased resistance to treatment among HIV-infected patients, lending to the need for more management and monitoring. Since several HIV-related opportunistic infections often present with or lead to CSF abnormalities, the diagnoses of neurosyphilis in HIV-infected patients may be hindered.[63,64] Additionally, some have reported that upwards of 60-70% of HIV-infected patients with neurosyphilis may be asymptomatic.[49] Marra et al.[49] attempted to define clinical and laboratory features that might identify patients with neurosyphilis and concluded that serum RPR titers 1:32 or greater and CD4+ cell counts less than 350 cells/mm3 are risk factors.

Health centers and providers alike must recognize that coinfection with HIV and syphilis has recently become more frequent. Early and targeted recognition and treatment of both diseases is essential to deterring continued increasing trends in incidence and prevalence. As previously mentioned, any patient presenting with a sexually transmitted infection (STI) should be comprehensively screened for other STIs. All sexually active MSM should be screened yearly for HIV, syphilis, chlamydia, and gonorrhea.[24] Information regarding the prevention and early treatment of syphilis should be made accessible to MSM. Educational programs designed to reduce the incidence of STIs among MSM should address recent epidemiologic information with regards to syphilis. When discussing safer sex practices that are less likely to transmit HIV (eg, oral sex), it should be made clear that high-risk sex of any kind can transmit other STIs, such as syphilis.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.