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HIV and Syphilis Coinfection: Trends and Interactions

Recent reports indicate that syphilis incidence is rising in the U.S. This article reviews the current literature on the epidemiology of syphilis, as well as its clinical manifestations, diagnosis, and treatment in the setting of HIV infection.

Syphilis has been a persistent public health challenge for centuries, and is now gaining renewed attention against the backdrop of the HIV pandemic. Recent reports indicate that syphilis incidence is rising in the U.S.,1, 2 leading some epidemiologists to suspect that similar increases in HIV infection may not be far behind. Syphilis infection significantly increases susceptibility to HIV infection. For its part, HIV can alter the clinical course of syphilis, increase the likelihood of relapse, and confound the diagnosis of neurosyphilis. Treatment of syphilis in coinfected patients is complicated, and success may depend on the integrity of host immune response as much as it does on antibiotic effect. This article reviews the current literature on the epidemiology of syphilis, as well as its clinical manifestations, diagnosis, and treatment in the setting of HIV infection.

EPIDEMIOLOGY: REVERSAL OF FORTUNE

Although 1990 marked a peak in the U.S. incidence of syphilis since the introduction of penicillin, the new millennium began with more promising trends. An all-time low case rate was recorded in 2000, prompting the CDC to develop a plan to eliminate syphilis in the U.S.3 However, a few years later, there are once again reports of rising syphilis incidence, especially among focused risk groups, such as men who have sex with men (MSM) in urban foci including New York City, Seattle, Chicago, San Francisco, Los Angeles, and Miami.1, 2 Some epidemiologists have suggested that these trends may reflect an overall increase in risky sexual practices in certain communities, raising concern that the increase in syphilis incidence may be a harbinger of an as yet unrecognized increase in HIV cases.

Recent urban outbreaks of syphilis in MSM have been correlated with rates of HIV coinfection ranging from 20% to 73%.2 In 2001, the number of primary and secondary syphilis cases doubled in New York City. Of the 282 cases identified, 93% were in men, resulting in a case rate of 6.9 per 100,000: the highest case rate in men since 1994. Of the 188 men who provided sexual partner information, 79% were classified as MSM. Of the 103 men who provided behavioral data, 75% reported having more than one sexual partner during the period in which syphilis could have been transmitted or acquired. Of the 86 MSM with known serostatus, 48% were HIV-positive. Between 1999 and 2000, syphilis rates in New York increased in whites from 24% to 33% and decreased in blacks from 47% to 36%.2 Nonetheless, syphilis remains a poignant example of racial health disparities in the U.S., with non-Hispanic blacks making up 70.9% and 62.5% of nationwide cases in 2000 and 2001, respectively (the case rate in this population in 2001 was 15.7 times higher than that in non-Hispanic whites).1 Education, prevention, and treatment programs have been escalated in New York City in response to the recent outbreak; nonetheless, syphilis rates (including those in MSM) continued to rise in 2002.2

Although syphilis is treatable, it increases the efficiency of HIV transmission by 3- to 5-fold and can have serious adverse effects on neonatal health.4 In addition, the burden of syphilis varies widely according to individual variations and the development status of nations (e.g., rates among commercial sex workers in parts of Africa are as high as 47%5). In 1995, the WHO reported 12 million cases of syphilis worldwide, with the highest concentration seen in South and Southeast Asia (5.8 million), followed by Africa (3.5 million). Seroprevalence in prenatal clinics in Africa is estimated at 4% to 15%.5 Several studies have documented rates of >10% in young women and in MSM in developing countries.6, 7

HIV AND SYPHILIS

The course of syphilis in HIV-positive patients with depressed immune function is thought to differ from that in HIV-negative patients. Animal models suggest that cell-mediated immunity plays a role in clearing Treponema pallidum infections; lack of such immunologic control may prevent complete eradication of infection, particularly at sanctuary sites such as the central nervous system (CNS) or the eye.8 HIV coinfection has been associated with a higher titer Rapid Plasma Reagin (RPR), multiple primary chancres, more rapid progression to tertiary manifestations, increased frequency of ocular disease, delay or failure of titer decline following treatment, and predilection for development of the Jarisch-Herxheimer reaction compared with syphilis infection alone.4, 5, 8, Coinfected patients may also experience slower resolution of primary chancres, and, in cases of neurosyphilis, of cerebrospinal fluid (CSF) pleocytosis, protein elevation and Venereal Disease Research Laboratory (VDRL) titer.12, 14, 20 Several reports indicate that HIV-coinfected patients may be at higher risk for syphilis relapse than are HIV-negative patients.12-16, 18, 21 In addition, dermatologic problems (drug rash, eosinophilic folliculitis), genital HPV, and oral lesions (aphthous ulcers, thrush, oral hairy leukoplakia) are commonly seen in HIV disease, and may confound the diagnosis of secondary syphilis manifesting with rash, alopecia, condyloma lata, or oral lesions.22 Features of secondary syphilis may be particularly pronounced in HIV-coinfected patients.

Reports of syphilis prevalence in HIV-infected individuals in the U.S. vary. Reported figures include 8.3% in military recruits and 23% in STD-clinic patients.9-11 Katz and Berger reviewed neurosyphilis in 46 cases of hospitalized patients; 24 (52%)were HIV-positive. The authors estimate a neurosyphilis prevalence of 1.5% in AIDS patients hospitalized at their institution.18 Holtom and colleagues reported a neurosyphilis prevalence of 1.0% among 312 HIV clinic patients.11 Several studies, however, found a neurosyphilis prevalence of 7% to 16% when all HIV-positive patients were offered lumbar puncture (LP).10-12 Because the sensitivity of CSF-VDRL can be as low as 30%,23 the actual rate of neurosyphilis among HIV-infected patients may be much higher. In fact, Holtom and colleagues found abnormal CSF results that could be consistent with neurosyphilis in 30.3% of HIV-infected patients undergoing LP, but could not discriminate these findings from changes caused by HIV disease itself. In addition, some patients refused LP or were lost to follow-up and others with reactive RPR had been recently treated for syphilis and did not undergo LP. For all of these reasons, the investigators comment that the 1% figure likely is an underestimate. All of the patients with positive CSF-VDRL in this study had CD4 counts <100 cells/mm3 and none had RPR titers <1:32.11 These findings are consistent with recent work by Marra and colleagues,24 suggesting that CD4-cell count and RPR titer may be useful markers in risk-stratifying coinfected patients.

NEUROSYPHILIS

Spirochetal Neuroinvasion

In laboratory models and in clinical experience, spirochetes have shown tropism for the CNS. Although no mechanism for this phenomenon has been elucidated definitively, an animal model studying the variable Borrelia Vsp-OspC lipoprotein family suggests a role for these surface proteins in selective tissue localization and evasion of the host immune response. Expression of VspB in Borrelia turicatae has been correlated with high levels of spirochetes in the blood, and expression of VspA has been correlated with early and persistent invasion of the CNS. Zuckert and colleagues found molecular evidence for conservation of neurotropism-associated VspA features with other spirochetal Vsp-OspC family proteins despite significant divergence in this family, suggesting that the shared secondary, tertiary, and quaternary structural characteristics of Vsp-OspC proteins might affect spirochetal escape to the CNS and subsequent evasion of the host response.25 Analogous homing mechanisms may facilitate CNS entry in other spirochetes such as Borrelia burgdorferi and Treponema pallidum.

T. pallidum invades the CNS in 25% of patients with syphilis, regardless of HIV serostatus.12 It has been suggested that infection is cleared from the CNS in 75% of these cases,24 but the remaining patients harbor the organism and remain at risk for developing sequelae of neurosyphilis of varying degrees of severity.

Clinical Manifestations

The numerous manifestations of neurosyphilis are highly variable, ranging from ocular syphilis (most commonly uveitis) to meningovascular disease (manifesting as stroke), to tabes dorsalis (a disease of the posterior columns of the spinal cord and nerve roots). Neurologic manifestations are generally classified as "early" or "late." Early manifestations, which affect tissues derived from mesodermal structures, include syphilitic meningitis, meningovascular disease, labyrinthitis, meningomyelitis, and cranial nerve palsies. Late manifestations, which affect sites of ectodermal origin, include tabes dorsalis, general paresis, CNS gumma, and other parenchymal diseases. Late manifestations generally occur 5 to 15 years from the date of infection but may be accelerated in patients with HIV disease.8, 9, 13, 16, 18, 26, 27 Ophthalmic disease (e.g., uveitis, keratitis, optic neuritis, conjunctivitis, optic atrophy, or chorioretinitis) is particularly common in HIV-coinfected individuals. In a study of 46 patients with neurosyphilis, Katz and colleagues reported ophthalmologic abnormalities in 42% of 24 HIV-positive patients compared with 14% of 22 HIV-negative individuals.18 Patients with neurosyphilis presenting with eye disease may be otherwise asymptomatic. Nonetheless, all patients with ocular syphilis should undergo LP and should be treated with a standard neurosyphilis regimen. The purpose of LP in these patients is to establish whether CSF abnormalities are present; if so, a follow-up CSF exam is indicated 6 months after treatment to establish resolution of these findings. Failure to see either a reduction in pleocytosis or clearance of CSF-VDRL should prompt repeat therapy.

Frequency of Neurosyphilis in HIV-Infected Patients

HIV infection may increase the frequency or accelerate the development of neurologic sequelae of syphilis, including early pathologies such as acute syphilitic meningitis and late pathologies such as CNS gummatous lesions. Berger reported 2 HIV-infected patients (CD4 counts, 274 and 10 cells/mm3) who presented with seizures and who were each found to have an enhancing lesion on head imaging. Toxoplasma serologies and bacterial, fungal, and mycobacterial CSF cultures were all negative; syphilis serologies were positive; biopsy material was consistent with gumma formation; and clinical/radiographic response to intravenous penicillin therapy was seen.13 In 1 patient, contact tracing revealed exposure to syphilis only 6 months earlier. Horowitz and colleagues described a similar case treated for primary syphilis who presented 4 years later with CNS gumma (CD4 count, 9 cells/mm3).16 Such rapid progression to previously regarded "late" complications of neurosyphilis was largely unprecedented in the pre-HIV era.

Gordon and colleagues followed 11 patients with HIV and neurosyphilis (positive CSF-VDRL) for a median of 6 months after standard intravenous penicillin (IV PCN) therapy; 10 of the patients were asymptomatic, but 4 demonstrated serologic failure following treatment, including 1 patient who experienced relapsed infection. Five of the patients had been treated for syphilis in the past (2 with 1 dose of intramuscular penicillin [IM PCN]; 3 with 3 once-weekly doses of IM PCN) and did not have sexual histories suggestive of reinfection, underscoring the potential for repeated relapse in this population.14

The question of enhanced therapy for early syphilis was addressed by Rolfs and colleagues in a prospective study comparing the efficacy of standard penicillin regimens to that of penicillin + amoxicillin/probenecid. Of the 541 subjects, 19% were HIV-infected. Among HIV-infected patients undergoing LP, 16% were found to have a positive CSF-VDRL. The investigators found no difference in overall outcome between the study groups. Surprisingly, however, the overall rate of serologic failure at 6 months was 17%. HIV-positive patients showed a slower response to treatment of primary and secondary syphilis, and were more likely to have serologic failure than were HIV-negative patients. There was one case of clinical relapse in an HIV-positive patient. All other patients were asymptomatic at treatment completion, and no cases of neurosyphilis were seen after treatment. In addition, detection of T. pallidum in the CSF by PCR or rabbit infectivity tests (RIT) before and after treatment did not differ by HIV serostatus or by treatment group. The investigators concluded that CNS involvement in early syphilis was not clinically important and that enhanced antibiotic therapy does not improve outcome.12 The limitations of this study are its small size and short follow-up, with only 52% of patients reaching the 1-year endpoint. Other studies suggest that relapses and neurosyphilitic complications might be expected after 12 months.10 In addition, positive PCR findings did not correlate with clinical disease; in 1 case T. pallidum was detected in an asymptomatic patient just after completing treatment, despite having been negative in baseline CSF analysis before treatment.12

Malone and colleagues found a treponemal seroprevalence of 8.3% in their cohort of 1206 HIV-infected patients. At the time of initial evaluation, the mean CD4 count in these patients was 565 cells/mm3 (3% had a CD4 cell count <200 cells/mm3), and none of the patients had active symptoms of neurosyphilis. However, 15% of patients who underwent LP had a reactive CSF-VDRL. Among patients who received standard treatment and had available follow-up data, serologic or clinical relapse occurred in 18%, of whom 40% had a CD4 count <350 cells/mm3. Although this study was limited by its retrospective design, only 1 newly acquired STD (hepatitis B) was documented during the follow-up period. In addition, patient histories were not suggestive of reinfection, and no primary syphilis lesions were observed.10 Relapses (especially multiple relapses) were correlated with secondary syphilitic rash or with positive CSF-VDRL titers. Relapse occurred >12 months after treatment in 60% of patients; thus, studies with shorter follow-up may not detect any difference in treatment response according to HIV serostatus.19

Two small prospective studies with relatively short follow-up conducted among patients with comparatively well-preserved immune systems (median CD4 counts in both studies were >500 cells/mm3) found no difference in serologic success rates with standard syphilis treatment according to HIV serostatus.28, 29 Several earlier studies also reported no difference in the clinical course of syphilis or response to treatment in HIV-infected populations; however, these are also limited by small size and short follow-up.12, 19 A CDC advisory group reviewing the relevant literature and scientific conference presentations since the STD treatment guidelines' meeting in 1997 has stated that there are no new data to clarify the effect of HIV on either the natural history of syphilis or the response to standard therapy in coinfected patients.30 Further controlled studies with longer-term follow-up are needed to address this issue more definitively.

What are clinicians to make of these apparently contradictory studies? As with other diseases that require CD4-cell function for effective host control, the severity of syphilis in HIV-infected patients probably varies widely depending on host immunity. As seen with TB infection, patients with syphilis who are also immunocompromised appear to be at increased risk for disseminated disease, atypical or flagrant presentations, and poor treatment response. As a result, clinicians should be more cautious in their approach to syphilis treatment in HIV-coinfected patients, maintaining low thresholds for performing additional diagnostic tests and extending or repeating treatment.

DIAGNOSIS

The lack of a practical and readily available gold-standard test makes the diagnosis of neurosyphilis challenging. Diagnosis relies on integrated findings of positive serum non-treponemal and confirmatory antibody in conjunction with neurologic or ophthalmic symptoms, CSF pleocytosis or elevated protein, and/or a reactive CSF-VDRL. In the HIV-infected population, diagnosis may be further challenged by atypical serologic tests (unusually high, low, or fluctuating titers).11, 31 False-positive RPR and treponemal confirmatory tests can occur due to concomitant cross-reacting infections or HIV-related B-cell dysfunction19 (see Table 1).

Waning serum treponemal antibody titers can be seen with AIDS, and false-negative CSF-VDRL results can occur in 20% to 70% of patients with CNS disease. False-positive CSF-VDRL is an infrequent occurrence, but can be seen when blood contaminates the CSF.5, 23 Microhemagglutination T. pallidum (MHA-TP) and fluorescent treponemal antibody absorption (FTABS) tests have been used on CSF samples and are thought to be less specific than CSF-VDRL, though significantly more sensitive. Use of these confirmatory tests in the CSF is therefore regarded as having a high negative predictive value for neurosyphilis -- some experts contend that a negative CSF FTA-ABS may exclude this diagnosis.23, 31 The CSF abnormalities commonly seen with HIV disease make mild pleocytosis or elevated protein very challenging to interpret and present the greatest challenge to current diagnostic schema for neurosyphilis.

Treponemal PCR

Ideally, we would have a reliable test that could serve as the gold-standard for the diagnosis of neurosyphilis, as well as a potential marker for preemptive therapy in cases of incipient relapse. The role of PCR for T. pallidum has not been well defined; the low sensitivity of this test and the lack of correlation between positive PCR findings and clinical or serologic status that have been demonstrated in several studies12, 14 are limiting factors. Other spirochetal CSF PCR tests show similarly inadequate sensitivity, such as the PCR for B. burgdorferi, which is positive in 40% to 50% of patients with Lyme meningitis.8

Wicher and colleagues used experimental models to assess the kinetics of live versus dead treponemal clearance from selected rabbit tissues. Analogous human data will be necessary to understand the kinetics of treponemal elimination from various sites of human infection, as well as the factors affecting clearance (complete or partial, rapid or prolonged) compared with persistent infection.32 With this understanding, PCR technology can be appropriately interpreted and integrated into clinical practice, and prudent interventions can be guided by the results of this test. Furthermore, because PCR assays can amplify nonviable organisms, an RNA-based probe has been suggested as a more specific testing alternative.


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  		Table 1. Causes of False-Positive Syphilis Tests

 

THE ROLE OF LP

Under the current recommendations, the CDC suggests CSF evaluation for any patient with positive RPR and confirmatory serum treponemal antibody in the setting of the criteria specified below:

CDC Recommendations for LP in Patients with Syphilis:

  • Neurologic or ophthalmic symptoms or signs
  • HIV infection with late or latent syphilis or latent disease of unknown duration
  • Failure to respond to therapy
  • Active tertiary manifestations (i.e., cardiovascular, gummatous disease)
  • Congenital syphilis
  • Consider LP in the settings of latent disease and RPR titer >1:32 and HIV disease with any stage of syphilis

Although "high titer" RPR (>1:32) was eliminated as a criterion for CSF evaluation in 1998 due to inadequate supporting data, it is now re-emerging as a correlated marker of increased risk for neurosyphilis. At the 2002 STD Prevention Conference, Marra and colleagues presented preliminary data on 239 patients with syphilis, 18% of whom had neurosyphilis (based on CSF wbc >20 or reactive CSF-VDRL).24 Risk factors for development of neurosyphilis were a CD4 count of </=350 cells/mm3 or serum RPR titer >/= 1:32. Stage of syphilis and duration of infection were not identified as independent risk factors; nor was HIV infection per se. The findings suggest that guidelines for CSF evaluation should include a CD4 count </=350 cells/mm3 or a serum RPR titer >/= 1:32, regardless of HIV serostatus and duration of infection. These criteria have not yet been added to the formal CDC recommendations.

No definitive serologic criteria for cure or failure of neurosyphilis treatment are available.31 Treatment failure should be considered in cases persistent symptoms or in the setting of at least a 4-fold increase in RPR. In latent disease and in HIV-infected patients more strict criteria are prudent, and many experts consider lack of at least a 4-fold titer decrease by 12 to 24 months (latent disease) or 6 to 12 months (HIV-infected individuals) as an indication for reevaluation and retreatment.

Should all HIV-infected patients with newly diagnosed syphilis undergo LP? In the absence of definitive data derived from clinical trials, we offer a criteria incorporating stage of syphilis, RPR titer, and host immunologic status (see Table 2).


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  		Table 2. Proposed Criteria for Performing LP in HIV-Infected Patients with Newly Diagnosed Syphilis

 

TREATMENT

Fifty years after the advent of penicillin, this drug remains the treatment of choice for syphilis, with preserved sensitivity patterns and the best track record of efficacy. IV penicillin is known to achieve treponemicidal levels in the CSF. Mounting data suggest the efficacy of treatment alternatives, particularly for penicillin-allergic patients, but more studies are necessary. Also of cautionary note is the fact that alternative treatment options are not well studied in the HIV-infected population.4

Several studies investigating the role of azithromycin in early syphilis have shown that this drug's high tissue concentrations and long half-life are well suited to T. pallidum's slow doubling time, resulting in successful outcomes at variously studied endpoints, including serologic and clinical response, lack of tertiary syphilis by 4 years' follow-up, and serologic nonreactivity at 6 months.33, 34 However, there is no consensus regarding specific dosing and no data in the setting of late latent or tertiary disease. A direct, large-scale, randomized, controlled study comparing penicillin with azithromycin for treating early syphilis has not yet been completed.

Another newcomer to the treatment arsenal for early- and late-stage syphilis is the third generation cephalosporin, ceftriaxone. In a small prospective study by Marra and colleagues,35 HIV-positive patients with neurosyphilis were randomized to treatment with either 2g IM ceftriaxone for 10 days or standard doses of IV aqueous penicillin G. CSF responses were similar in both groups; however, baseline differences between these groups limit comparison. In a 1998 survey, 19% of responding infectious-disease consultants reported using ceftriaxone to treat syphilis in both HIV-positive and HIV-negative patients. One clinical failure was reported in a patient with secondary syphilis and 5 therapeutic failures (2 clinical) in patients treated for early latent syphilis. Doses, durations, and CD4-cell counts were not specified.36 Ceftriaxone may ultimately prove superior to IM PCN in treating early disease because its CNS penetration may decrease neurorelapse, but this has not been well studied. The CDC has recognized ceftriaxone as a treatment alternative in penicillin-allergic patients with neurosyphilis. The recommendation for pregnant women, however, is desensitization to penicillin--given the risk for congenitial syphilis and the fact that penicillin is the only therapy with documented efficacy for syphilis in pregnancy.31

There is concern that response to standard IV PCN may be inadequate in HIV-infected individuals with neurosyphilis, with failure rates of 23% to 60% reported in various retrospective studies.10, 14, 20, 35 Some investigators have suggested additional benefit can be achieved by following the 10- to14-day IV or IM treatment for neurosyphilis with weekly benzathine treatments for 3 weeks. This practice has shown variable clinical efficacy and has been debated in the literature: Critics cite the poor penetration of benzathine penicillin into the CNS resulting in little projected therapeutic advantage. Advocates promote the hypothesis that latent infection likely coexists with symptomatic (or, even more likely, asymptomatic) neurosyphilis and argue that the additional IM injections would afford serum levels of antisyphilitic activity against slowly dividing organisms for an additional 3 weeks. Others allude to the recommendations of 3 weekly IM PCN injections for nonneurologic tertiary disease, and suggest leveling of relapse risk by prolonging antitreponemal therapy in patients with neurosyphilis. Half of the relapsed cases in the Malone series occurred in patients who received IV PCN as their initial treatment (for positive CSF-VDRL or for late latent disease with CSF pleocytosis), without weekly adjuvant IM antibiotics, raising the question of whether this regimen might be optimal for maximizing serologic response in patients with late latent syphilis or neurosyphilis, but suboptimal in preventing relapse.10

Regardless of the regimen selected, a mainstay in treating syphilis is vigilant monitoring of therapeutic response. Patients should be reexamined clinically and serologically at 6 and 12 months for primary or secondary disease and additionally at 24 months for latent disease. HIV-infected individuals require closer monitoring (at 3, 6, 9, 12, and 24 months). Failure to achieve a 4-fold decline by 6 months is considered a likely sign of treatment failure or reinfection. Patients with CSF pleocytosis are recommended for repeat LP at 6, 12, and 24 months with expected improvement of pleocytosis (protein and CSF-VDRL may lag behind), although specific guidelines for expected CSF response in HIV-infected patients have not been defined. In all cases, inadequate response, new symptoms, or a sustained 4-fold rise in nontreponemal titer should trigger CSF evaluation, HIV testing (if not previously done), and retreatment, as guided by case specifics.

SUMMARY AND FUTURE CONSIDERATIONS

Several studies have shown that HIV coinfection can alter the course of syphilis infection. Manifestations of this difference include multiple and slower resolving primary chancres, higher titer RPR, slower decline of RPR titers, higher rate of serologic failure, increased frequency of CSF abnormalities and CSF-VDRL positivity, higher incidence of ocular disease, and higher rate of relapse. These effects may be blunted in some studies by preserved immune function or settings in which follow-up study time is curtailed. Although the relative contributions and mechanisms are not yet entirely clear, it would appear that "curing" syphilis depends not only on antibiotic effect, but also on the integrity of the host immune response.

Our understanding of the pathophysiology and molecular details of T. pallidum has evolved over 500 years, but we are still faced with clinical conundrums in diagnosing and treating syphilis and its complications. Overall interpretation of data regarding risk factors, incidence, and relapse rate of neurosyphilis is limited by nonstandardized criteria for diagnosis of neurosyphilis, nonstandardized study follow-up, and the lack of a gold standard for diagnosis of recurrence Of note, this article has not dealt with the critical and challenging issue of safe-sex counseling in coinfected patients, which must be a continuing concern for all clinicians treating this population.

Our efforts going forward must be focused on resolution of these inconsistencies, as well as on understanding the kinetics of treponemal clearance, the immunologic factors involved in sequestered CNS disease and its reactivation, and the natural history of syphilis in hosts with and without immunosuppression. Further work on neurotropic homing mechanisms and molecular entry criteria for neuroinvasion may help prevent CNS disease preemptively, obviating downstream approaches to improving diagnosis and monitoring for recurrence. Questions for consideration include: Are there different strains or subtypes of T. pallidum with differential expression of cell surface proteins and subsequent pathogenic sequelae involving specific end organs? Can these subtypes be identified consistently by PCR technology in a model akin to human papilloma virus strains? Equipped with answers, we will be able to generate reliable predictions to guide diagnostic and therapeutic management of our patients. Perhaps we will even be able to develop vaccine technology to complement public education efforts and targeted prevention campaigns in high-risk groups such as MSM in developed countries and women in developing countries, affecting both syphilis outbreaks and the HIV pandemic.

— Sigall Kassutto, MD, and Paul E. Sax, MD

Dr. Kassutto is Clinical Fellow in Infectious Diseases at Beth Israel Deaconess Medical Center and Instructor in Medicine at Harvard Medical School in Boston. Dr. Sax is Research Notes Editor of ACC.

Published in AIDS Clinical Care February 1, 2003

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