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Syphilis has been a subject of intrigue and controversy since it was first recognized in the 15th century. Coined “the great imitator,” it can manifest in a variety of ways depending on the host and stage of infection, thus making diagnosis and management difficult. HIV infection creates an additional layer of complexity: Both pathogens are sexually transmitted, and the presence of one may facilitate infection with the other. In addition, the presentation, diagnosis, and management of syphilis differ in subtle ways between HIV-infected and HIV-uninfected patients. In this review, we summarize the epidemiology, clinical presentation, diagnosis, treatment, and monitoring of syphilis in HIV-infected patients.
Syphilis is a global public health problem, resulting in an estimated 12 million new infections per year.1 In the U.S., the incidence of primary and secondary syphilis has been rising and falling in 10-year cycles since the 1940s, with the lowest recorded rates occurring in 2000, followed by a resurgence over the next 10 years. Some researchers have attributed these decade-long cycles to social and behavioral changes2 — and, indeed, several recent outbreak investigations have implicated high-risk behaviors, such as anonymous sex, sex under the influence of drugs, and unprotected sex, as the basis for the latest rise in syphilis incidence.3,4,5 However, mathematical modeling suggests that these cycles are better predicted by the natural dynamics of syphilis infection than by external, behavioral factors.6 At this point, the exact contribution of each factor remains uncertain.
Similar to the HIV epidemic, the current syphilis epidemic predominantly affects three groups: men who have sex with men (MSM), injection-drug users, and individuals who engage in sex for money or drugs. The CDC estimates that, in 2008, MSM accounted for more than 60% of all new diagnoses of primary and secondary syphilis in the U.S.7 Women account for a much smaller proportion of cases, but the incidence in this group has been increasing during the past 10 years7 — a trend that could be related to the high proportion of MSM who engage in sex with women. In one study from sub-Saharan Africa, that proportion was >90%.8
HIV and Treponema pallidum coinfection is relatively common, accounting for approximately 25% of cases of primary and secondary syphilis reported in the U.S.9 Syphilis facilitates both HIV transmission and HIV acquisition, reflecting the complex interplay between the two diseases. Chancres cause epithelial and mucosal breaches, facilitating the transmission of HIV virions.10 In addition, T. pallidum and its pro-inflammatory components can induce expression of CCR5 (the major coreceptor for HIV entry) on human monocytes within chancres, thereby enhancing the susceptibility of these cells to HIV infection.10 Furthermore, flow-cytometric studies have demonstrated that during the course of secondary syphilis, T. pallidum induces a potent innate and adaptive cellular immune response in both skin and peripheral blood.11 This immune activation, measured by the increased percentage of activated CD4 cells, may enhance transmission of HIV; however, the immune response has no meaningful effect on the course of syphilis, nor does it prevent recurrent infection.
Whether HIV infection alters the natural history of syphilis remains controversial. Early in the HIV epidemic, case reports and case series suggested that HIV coinfection results in a more aggressive course of syphilis.12,13,14 However, more-recent studies describe only a few notable differences in presentation, which likely occur as a result of immune dysfunction among HIV-infected patients.15,16,17 Those differences are highlighted below, with more detail in Table 1:
HIV-infected patients may present with multiple chancres that are deeper and slower to resolve than the solitary chancre typically seen in HIV-uninfected patients.1,18
Primary and secondary syphilis overlap more often in patients with HIV infection than in those without.13,15 In fact, one quarter of coinfected patients present with concurrent primary and secondary disease.1
HIV-infected patients may progress to tertiary syphilis more rapidly than HIV-uninfected patients, resulting in earlier onset of cardiovascular and neurologic sequelae.19,20,21,22
Optic neuritis, uveitis, and other ocular manifestations of syphilis are common among HIV-infected patients but not among HIV-uninfected patients. This atypical presentation of syphilis is clinically important: One study showed that 85% of HIV-infected patients with ocular syphilis had concomitant neurosyphilis.23
Given these differences, clinicians should have a heightened suspicion for neurosyphilis among HIV-infected patients, particularly those presenting with ocular symptoms.
Serologic testing is the primary tool for diagnosing syphilis in both HIV-infected and HIV-uninfected patients. Two types of serologic tests are required for diagnosis:
Treponemal tests, such as fluorescent treponemal antibody absorbed (FTA-ABS), T. pallidum particle agglutination (TP-PA), or immunoglobulin G to T. pallidum as detected by enzyme immunoassay (EIA)
Nontreponemal tests, such as the Venereal Disease Research Laboratory (VDRL) test or the rapid plasma reagin (RPR) test
Traditionally, a nontreponemal test is administered first; if the result is positive, a treponemal test is performed. However, some high-volume clinical laboratories have recently begun to reverse this process to save money. In a report from such labs, 3% of the >100,000 specimens tested had a reactive treponemal test followed by a nonreactive nontreponemal test.24 Management strategies for this scenario, particularly in HIV-infected patients, are not yet fully developed. The latest CDC guidelines, from 2006, recommend obtaining a thorough history and physical exam to elicit evidence of prior or current syphilis; if the patient is asymptomatic, a second treponemal test can be done as the “tie breaker,” with positive results suggesting a diagnosis of late latent syphilis.25 However, the evidence to support this approach is scant, and clinical judgment must be used.
In most instances, serologic testing for syphilis is reliable in HIV-infected patients, especially those who are not significantly immunocompromised. However, problems may arise in the following scenarios:
Unusual serologic responses, such as higher-than-expected titers. In one study, the geometric-mean RPR titer was generally higher among HIV-infected than HIV-uninfected individuals, particularly during secondary syphilis.16 Inappropriate B-cell activation as a result of concomitant HIV infection may be responsible for this finding.
False-negative results or delayed seroreactivity. False-negative results may be due to either prozone phenomena (nonvisualization of agglutination as a result of an overabundance of antibodies interfering with clumping of antigen-antibody complexes) or B-cell failure in late-stage HIV infection.26 Impaired responses to polysaccharide and protein antigens have been reported among HIV-infected individuals, making serologic diagnosis of some infections, including syphilis, unreliable.27 In fact, at least two cases of seronegative secondary syphilis have been reported in patients with AIDS.28,29
Biological false-positive results, as a consequence of HIV infection and antigen cross-reactivity. Such false-positive results can occur, but clinicians must be careful not to attribute positive nontreponemal test results to HIV infection alone, even when the titers are very low. This could lead to undertreatment of syphilis in a high-risk population, which would have serious downstream public health consequences.
When serologic results seem questionable, clinical and laboratory data should be considered together in arriving at a proper diagnosis. If uncertainty remains, it is probably best to err on the side of overtreating to avoid potential long-term clinical and public health consequences.
Once syphilis is diagnosed, clinicians must consider the possibility of neurosyphilis and decide whether a lumbar puncture (LP) is indicated. In HIV-infected patients, neurosyphilis can occur at any stage of disease, often causes atypical symptoms or none at all, and may not be adequately treated with benzathine penicillin G (the standard treatment for early syphilis). Experts agree that LP is necessary in HIV-infected patients with syphilis who present with neurologic symptoms, but the question of how to manage HIV-infected patients with asymptomatic syphilis has not been settled.
The CDC guidelines from 2006 recommend LP for three groups of asymptomatic HIV-infected patients: those who present with late latent syphilis, those with syphilis of unknown duration, and those who do not demonstrate appropriate serologic response after syphilis treatment.25 However, several recent studies suggest that CD4-cell counts and RPR titers might have significant value in determining the best candidates for examination of cerebrospinal fluid (CSF).30,31,32 In one cross-sectional study, patients who had both a serum RPR titer ≥1:32 and a CD4 count ≤350 cells/mm3 were 18.6 times more likely to have neurosyphilis than those who had neither of these features.30 In a more recent retrospective cohort study, application of these clinical criteria yielded much greater sensitivity and specificity for asymptomatic neurosyphilis than did application of the CDC criteria (sensitivity, 100% vs. 80%; specificity, 87% vs. 76%).31 Thus, in patients with HIV infection and syphilis, determination of CD4-cell count and RPR titer may be useful in selecting appropriate patients for LP and improving the detection of neurosyphilis.
Several serologic tests can be performed on CSF obtained during LP, but each test has limitations. Consequently, no single one can be used to diagnose all cases of neurosyphilis. In general, the diagnosis of neurosyphilis should be made if one or more of the following criteria are met:
A VDRL test on CSF is reactive in the absence of significant blood contamination. Although the diagnostic sensitivity of the CSF VDRL test is only about 50%, its specificity is quite high.
The CSF leukocyte count is elevated (>5 white blood cells/mm3, although some experts recommend a higher threshold in HIV-infected persons) in the absence of other reasons for CSF pleocytosis.
The value of a CSF FTA-ABS test for diagnosing neurosyphilis is uncertain, and many experts do not advise its use. The test is much less specific than the CSF VDRL test, and a positive test must be interpreted in conjunction with appropriate clinical features to make the diagnosis. The CSF FTA-ABS test has been suggested to have a strong negative predictive value and, thus, may be better suited for ruling out neurosyphilis (i.e., if this test is negative, the patient is very unlikely to have neurosyphilis). The use of this test is not advised for most persons in whom asymptomatic neurosyphilis is suspected.
HIV-infected patients with syphilis should receive the same treatment as HIV-uninfected patients. As shown in Table 2, treatment for early syphilis involves benzathine penicillin G, whereas treatment for neurosyphilis involves aqueous crystalline penicillin G. Some experts advise that HIV-infected individuals receive more-aggressive treatment, such as >1 intramuscular benzathine penicillin injection for early syphilis, but this approach has not been evaluated clinically and remains in the realm of “expert opinion.”
Several treatment alternatives are available for patients with early syphilis who are allergic to penicillin25:
Doxycyline 100 mg orally twice daily for 14 days
Tetracycline 500 mg orally four times daily for 14 days
Ceftriaxone 1 g intramuscularly once daily for 8 to 10 days
Azithromycin 2 g orally in a single dose
Clinicians should exercise caution when choosing a regimen for the penicillin-allergic, HIV-infected patient with early syphilis. Azithromycin may seem like an attractive choice, because it can be administered in a single dose, and that single dose has been shown in two randomized controlled trials (RCTs) to be as efficacious as a single injection of benzathine penicillin G (2.4 million units) in achieving serologic cure in patients with early syphilis.33,34 However, several caveats should be noted:
HIV-infected patients were excluded from the more recent RCT, thus making the results less generalizable.34
Azithromycin resistance, due to a 23S ribosomal mutation, has been documented in several reports and may lead to higher rates of treatment failure.35,36
Azithromycin has different pharmacokinetic properties than benzathine penicillin G. A shorter half-life and the inability to cross the blood-brain barrier may have ramifications in HIV-infected patients with early syphilis, who are more likely to develop atypical neurologic sequelae.
Follow-up after syphilis treatment is similar in HIV-infected and HIV-uninfected patients, except that some experts recommend that the former group be assessed more frequently. HIV-infected patients with early latent, primary, or secondary syphilis should have repeat VDRL or RPR testing at 3, 6, 9, 12, and 24 months following treatment or until the test becomes nonreactive. The same test (i.e., VDRL or RPR) done in the same lab helps assure that comparisons are valid over time. Patients should undergo retreatment if they experience any of the following: (1) recurrence or persistence of symptoms; (2) lack of a fourfold decline in nontreponemal titers within 12 months after treatment in primary syphilis, 24 months in secondary or latent syphilis, or 5 years in late syphilis; or (3) a confirmed fourfold rise in nontreponemal titers at any time after treatment.25,37
Notably, serologic responses to treatment in HIV-infected patients may be challenging to interpret. HIV-infected patients treated for syphilis are less likely than HIV-uninfected patients to have a fourfold decrease in RPR titer, are more likely to have persistently reactive nontreponemal titers even when they do have such a decrease 17, and tend to have a longer time to achieving successful serologic response38, particularly if they have advanced HIV infection. However, these differences do not seem to be worrisome from a clinical standpoint: In a randomized trial of patients receiving enhanced therapy for early syphilis, the rate of clinical success was comparable between HIV-infected and HIV-uninfected patients.17
Regardless of HIV serostatus, all patients with neurosyphilis should undergo clinical evaluation with repeat CSF examination at 6-month intervals for 24 months or until pleocytosis normalizes.25 Notably, CSF normalization tends to be slower in HIV-infected patients, with at least one study pointing toward immune dysfunction as the culprit. In that study, patients with CD4 counts >200 cells/mm3 were 3.7 times more likely to normalize CSF on VDRL testing than those with CD4 counts ≤200 cells/mm3.39 A recent study demonstrated that serum RPR was not an accurate predictor of CSF normalization in HIV-infected patients, particularly those who were not receiving antiretroviral therapy, which suggests that poorly controlled HIV infection, rather than incompletely treated neurosyphilis, might be responsible for some of the documented CSF abnormalities.40 Thus, follow-up CSF examination in conjunction with clinical assessment is recommended to assess all patients with neurosyphilis.
The recent syphilis epidemic among HIV-infected individuals reminds clinicians of an old pathogen with new features. The complex immunologic interplay between syphilis and HIV results in subtle but clinically relevant differences in presentation, diagnosis, and management strategies that must be recognized by those caring for HIV-infected patients.
Syphilis facilitates HIV transmission and acquisition as a result of local and systemic immune activation.
Syphilis may progress more rapidly and follow a more aggressive course in HIV-infected individuals.
Neurosyphilis is common among HIV-infected patients and often presents atypically (e.g., asymptomatic infection, ocular syphilis).
Serologic testing remains the primary tool for diagnosing syphilis in both HIV-infected and HIV-uninfected patients.
Clinicians must maintain a high level of suspicion for asymptomatic neurosyphilis in HIV-infected individuals and should obtain a thorough history, perform a careful physical exam, and use clinical parameters (CD4-cell count and RPR titer) to help guide the decision to perform lumbar puncture.
Treatment of syphilis does not vary between those who are HIV-infected and those who are not.
The immunologic consequences of HIV infection may result in delayed serologic responses to nontreponemal tests following syphilis treatment.
HIV-infected and HIV-uninfected patients experience comparable clinical responses to treatment.
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