University of California, San Francisco Logo

University of California, San Francisco | About UCSF | Search UCSF | UCSF Medical Center

Home > Treatment > OI Adult Guidelines > Syphilis
Syphilis
gray line
transparent gif
transparent gif
Epidemiology

Syphilis is associated with increased risk for HIV sexual acquisition and transmission (516Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect 1999;75:3-17., 517Rottingen JA, Cameron DW, Garnett GP. A systematic review of the epidemiologic interactions between classic sexually transmitted diseases and HIV: how much really is known? Sex Transm Dis 2001;28:579-97.). Recent reports indicate a resurgence of syphilis among men in several U.S. cities and in Western Europe (518Blocker ME, Levine WC, St Louis ME. HIV prevalence in patients with syphilis, United States. Sex Transm Dis 2000;7:53-9., 519Torian LV, Makki HA, Menzies IB, Murrill CS, Weisfuse IB. HIV infection in men who have sex with men, New York City Department of Health sexually transmitted disease clinics, 1990-1999: a decade of serosurveillance finds that racial disparities and associations between HI V and gonorrhea persist. Sex Transm Dis 2002;29:73-8., 520CDC. Outbreak of syphilis among men who have sex with men--Southern California, 2000. MMWR 2001;50:117-20., 521Stolte IG, Dukers NH, de Wit JB, Fennema JS, Coutinho RA. Increase in sexually transmitted infections among homosexual men in Amsterdam in relation to HAART. Sex Transm Infect 2001;77:184-6., 522Peterman TA, Heffelfinger JD, Swint EB, Groseclose SL. The changing epidemiology of syphilis. Sex Transm Dis 2005;32(10 Suppl):S4-10., 523Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA 2003;290:1510-4., 524Paz-Bailey G, Meyers A, Blank S, et al. A case-control study of syphilis among men who have sex with men in New York City: association With HIV infection. Sex Transm Dis 2004;31:581-7.). Although coexistent HIV infection, particularly in the advanced stages, can modify the diagnosis, natural history, or management of Treponema pallidum infection, the principles of syphilis management are the same for persons with and without coexistent HIV infection (525Calza L, Manfredi R, Marinacci G, et al. Efficacy of penicillin G benzathine as antimicrobial treatment of cutaneous secondary syphilis in patients with HIV infection. J Chemother 2002;14:533-4., 526Rompalo AM, Lawlor J, Seaman P, et al. Modification of syphilitic genital ulcer manifestations by coexistent HIV infection. Sex Transm Dis 2001;28:448-54., 527Musher DM, Hamill RJ, Baughn RE. Effect of human immunodeficiency virus (HIV) infection on the course of syphilis and on the response to treatment. Ann Intern Med 1990;113:872-81., 528Radolf JD, Kaplan RP. Unusual manifestations of secondary syphilis and abnormal humoral immune response to Treponema pallidum antigens in a homosexual man with asymptomatic human immunodeficiency virus infection. J Am Acad Dermatol 1988;18:423-8., 529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11).). Recent syphilis treatment recommendations are available in the 2006 CDC STD Treatment Guidelines (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11)., 530Stoner B: Current controversies in the management of adult syphilis. Clin Infect Dis 2007;44(Suppl 3):S130-46.).

Clinical Manifestations

Despite multiple case reports and small case series, limited large studies have documented the effect of coexistent HIV on the protean manifestations of syphilis. The few larger studies suggest that HIV infection might shift the clinical manifestations of syphilis, making clinical lesions more apparent, and might accelerate progression of syphilitic disease (526Rompalo AM, Lawlor J, Seaman P, et al. Modification of syphilitic genital ulcer manifestations by coexistent HIV infection. Sex Transm Dis 2001;28:448-54., 527Musher DM, Hamill RJ, Baughn RE. Effect of human immunodeficiency virus (HIV) infection on the course of syphilis and on the response to treatment. Ann Intern Med 1990;113:872-81.). Early syphilis in HIV-infected persons may also cause a transient decrease in CD4+ count and increase in HIV viral load that improves with standard treatment regimens (531Buchacz K, Patel P, Taylor M, et al. Syphilis increases HIV viral load and decreases CD4 cell counts in HIV-infected patients with new syphilis infections. AIDS 2004;18:2075-9., 532Koefoed K, Gerstoft J, Mathiesen LR, Benfield T. Syphilis and human immunodeficiency virus (HIV)-1 coinfection: influence on CD4 T-cell count, HIV-1 viral load, and treatment response. Sex Transm Dis 2006;33:143-8., 533Palacios R, Jimnez-Oate F, Aguilar M, et al. Impact of syphilis infection on HIV viral load and CD4 cell counts in HIV-infected patients. J Acquir Immune Defic Syndr 2007;44:356-9.).

Primary syphilis commonly exhibits a single painless nodule at the site of contact that rapidly ulcerates to form a classic chancre; however, among HIV-infected persons, multiple or atypical chancres occur and primary lesions might be absent or missed (526Rompalo AM, Lawlor J, Seaman P, et al. Modification of syphilitic genital ulcer manifestations by coexistent HIV infection. Sex Transm Dis 2001;28:448-54., 534Rompalo AM, Joesoef MR, O'Donnell JA, et al. Clinical manifestations of early syphilis by HIV status and gender: results of the syphilis and HIV study. Sex Transm Dis 2001;28:158-65.).

Progression to secondary syphilis typically follows 2-8 weeks after primary inoculation. Although more rapid progression or severe disease might occur among HIV-infected persons with advanced immunosuppression, the clinical manifestations are similar to those among HIV-uninfected persons. The manifestations of secondary syphilis involve virtually all organ systems. The most common manifestations, macular, maculopapular, papulosquamous, or pustular skin lesions, usually begin on the trunk and spread peripherally, involving palms and soles and accompanied by generalized lymphadenopathy and fever, malaise, anorexia, arthralgias, and headache (527Musher DM, Hamill RJ, Baughn RE. Effect of human immunodeficiency virus (HIV) infection on the course of syphilis and on the response to treatment. Ann Intern Med 1990;113:872-81., 528Radolf JD, Kaplan RP. Unusual manifestations of secondary syphilis and abnormal humoral immune response to Treponema pallidum antigens in a homosexual man with asymptomatic human immunodeficiency virus infection. J Am Acad Dermatol 1988;18:423-8., 529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11).). Condyloma lata, moist, flat, papular lesions in warm intertrigenous regions, might resemble papilloma virus infection. Secondary syphilis, particularly acute syphilitic meningitis, can resemble acute primary HIV infection; constitutional symptoms, along with nonfocal CNS symptoms and CSF abnormalities (e.g., lymphocytic pleocytosis with a mildly elevated CSF protein), are common to both (534Rompalo AM, Joesoef MR, O'Donnell JA, et al. Clinical manifestations of early syphilis by HIV status and gender: results of the syphilis and HIV study. Sex Transm Dis 2001;28:158-65., 535Bayne LL, Schmidley JW, Goodin DS. Acute syphilitic meningitis: its occurrence after clinical and serologic cure of secondary syphilis with penicillin G. Arch Neurol 1986;43:137-8., 536Berry CD, Hooton TM, Collier AC, Lukehart SA, Lukehart SA. Neurologic relapse after benzathine penicillin therapy for secondary syphilis in a patient with HIV infection. N Engl J Med 1987;316:1587-9., 537Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis 2004;189:369-76., 538CDC: Symptomatic early neurosyphilis among HIV-positive men who have sex with men-four cities, United States, January 2002-June 2004. MMWR 2007;56:625-8., 539Marra CM, Maxwell CL, Tantalo L, et al. Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis 2004;38:1001-6.).

Signs and symptoms of secondary syphilis can persist from a few days to several weeks before resolving and evolving to latent or later stages. Latent syphilis lacks overt clinical signs and symptoms, but relapse of manifestations of secondary syphilis might occur, most commonly during the first 1-4 years following infection.

Manifestations of "late" syphilis generally include neurosyphilis, cardiovascular syphilis, and gummatous syphilis or a slowly progressive disease that can affect any organ system. Neurosyphilis can occur at any stage of syphilis. Asymptomatic neurosyphilis is defined as one or more CSF abnormalities (i.e., elevated protein, lymphocytic pleocytosis, or positive VDRL) in the absence of symptoms or signs. Manifestations of symptomatic neurosyphilis (i.e., meningitis or meningovascular or parenchymatous disease) among HIV-infected persons are similar to those in the HIV-uninfected persons. However, clinical manifestations of neurosyphilis, such as concomitant uveitis and meningitis, might be more common among HIV-infected persons (538CDC: Symptomatic early neurosyphilis among HIV-positive men who have sex with men-four cities, United States, January 2002-June 2004. MMWR 2007;56:625-8.).

Diagnosis

The diagnosis of syphilis depends on direct detection of the organism (e.g., by darkfield microscopy, direct fluorescent antibody-Treponema pallidum, biopsy with silver stain), or on presumptive serologic diagnosis based upon nontrepomenal tests (e.g., Venereal Disease Research Laboratory [VDRL] and rapid plasma reagin [RPR]) and treponemal tests (e.g., FTA-ABS and TP-PA). The serologic diagnosis of syphilis traditionally has involved screening for nontreponemal antibodies with confirmation of reactive tests by treponemal-based assays (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11)., 540Wicher K, Horowitz HW, Wicher V. Laboratory methods of diagnosis of syphilis for the beginning of the third millennium. Microbes Infect 1999;1:1035-49.). Recently, some laboratories have initiated a testing algorithm using treponemal-based enzyme immunoassay (EIA) as a screening test with nontreponemal testing for confirmation. This latter strategy may more often identify those with a previous syphilis infection along with those having untreated infection (541Pope V. Use of treponemal tests to screen for syphilis. Infect Med 2004;21:399-404.). Clinical experience suggests that concurrent HIV infection probably does not change the performance of standard tests for the diagnosis of syphilis. However, false-positive nontreponemal serologic tests that are not confirmed by treponemal serologic tests might be more common among HIV-infected persons (542Rompalo AM, Cannon RO, Quinn TC. Association of biologic false-positive reactions for syphilis with human immunodeficiency virus infection. J Infect Dis 1992;165:1124-6., 543Augenbraun MH, DeHovitz JA, Feldman J, et al. Biological false-positive syphilis test results for women infected with human immunodeficiency virus. Clin Infect Dis 1994;19:1040-4.).

Early-stage disease (i.e., primary, secondary, and early-latent syphilis) among HIV-infected persons is confirmed by the identical procedures used for the HIV-uninfected person (e.g., darkfield microscopy of a mucocutaneous lesion and standard serologic tests). HIV infection does not decrease the sensitivity or specificity of darkfield microscopy. Responses to nontreponemal serologic tests (i.e., VDRL and RPR) might be atypical (i.e., higher, lower, or delayed) among HIV-infected versus HIV-uninfected persons with early-stage syphilis (543Augenbraun MH, DeHovitz JA, Feldman J, et al. Biological false-positive syphilis test results for women infected with human immunodeficiency virus. Clin Infect Dis 1994;19:1040-4., 544Rolfs RT, Joesoef MR, Hendershot EF, et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N Engl J Med 1997;337:307-14.). No data indicate that treponemal tests perform differently among HIV-infected compared with -uninfected patients (545Augenbraun M, Rolfs R, Johnson R, Joesoef R, Pope V. Treponemal specific tests for the serodiagnosis of syphilis. Sex Transm Dis 1998;25:549-52.). Similar to HIV-uninfected persons, false-negative serologic tests for syphilis can occur both among HIV-uninfected and HIV-infected persons with documented T. pallidum infection (546Kingston A, Vujevich J, Shapiro M, et al. Seronegative secondary syphilis in 2 patients coinfected with human immunodeficiency virus. Arch Dermatol 2005;141:431-3., 547Hicks CB, Benson PM, Lupton GP, Tramont EC. Seronegative secondary syphilis in a patient infected with the human immunodeficiency virus (HIV) with Kaposi sarcoma: a diagnostic dilemma. Ann Intern Med 1987;107:492-5.). Therefore, if serologic tests do not confirm the diagnosis of suspected syphilis, other diagnostic procedures (e.g., repeat serology in 1-2 weeks, exclusion of prozone phenomenon, biopsy, darkfield examination, or direct fluorescent antibody staining of lesion material) should be pursued. By definition, persons with latent syphilis have serological evidence of syphilis in the absence of clinical or other laboratory abnormalities (i.e., normal CSF profiles). Patients with early-latent syphilis have documented infection of <1 year; persons with late-latent syphilis have documented infection for >1 year or the duration of infection is not known. The diagnostic testing recommended for detection of late-stage syphilis (e.g., cardiovascular and gummatous syphilis) among HIV-infected persons is the same as for the HIV-uninfected person.

All persons with syphilis, regardless of disease stage, should be evaluated for clinical evidence of CNS or ocular involvement. CSF abnormalities (elevated protein and mononuclear pleocytosis) are common in early syphilis and in persons with HIV infection. However, whether the prognostic significance of such CSF abnormalities differs between HIV-infected persons and HIV-uninfected persons with primary, secondary, or early-latent syphilis is unknown.

CSF examination should be performed in persons with neurologic or ocular signs or symptoms, active tertiary syphilis, and treatment failure. CSF examination is also recommended for HIV-infected persons with late-latent syphilis, including those with syphilis of unknown duration. Some specialists recommend CSF examination for all HIV-infected persons with syphilis regardless of stage, particularly if serum RPR is 1:32 or with a CD4+ count of <350 cells/µL (537Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis 2004;189:369-76., 539Marra CM, Maxwell CL, Tantalo L, et al. Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis 2004;38:1001-6.). The risk for developing clinical neurosyphilis in this circumstance is unknown. CSF abnormalities consistent with neurosyphilis should be treated using standard neurosyphilis treatment regimens.

Among persons without HIV infection, diagnosis of neurosyphilis is established by CSF examination, which might indicate mild mononuclear pleocytosis (e.g., 10-200 cells/µL), normal or mildly elevated protein concentration, or a reactive CSF-VDRL (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11)., 537Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis 2004;189:369-76., 539Marra CM, Maxwell CL, Tantalo L, et al. Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis 2004;38:1001-6.). The CSF-VDRL is specific but not sensitive, and a reactive test establishes the diagnosis of neurosyphilis, but a nonreactive test does not exclude the diagnosis. In comparison, CSF treponemal tests (e.g., the CSF FTA-ABS) are sensitive but not specific, with a nonreactive test excluding the diagnosis of neurosyphilis. Calculated indices (e.g., TPHA-index) are of limited value in establishing the diagnosis of neurosyphilis. PCR-based diagnostic methods are not currently recommended as a diagnostic test for neurosyphilis. A reactive CSF-VDRL and a CSF WBC >10 cells/µL support the diagnosis of neurosyphilis; the majority of specialists would not base the diagnosis solely on elevated CSF protein concentrations in the absence of these other abnormalities.

Establishing the diagnosis of neurosyphilis can be more difficult among persons with HIV infection, because HIV infection itself might be associated with mild mononuclear CSF pleocytosis (5-15 cells/µL), particularly among persons with peripheral blood CD4+ counts >500 cells/µL. If neurosyphilis cannot be excluded by a nonreactive CSF treponemal test, such persons should be treated for neurosyphilis, despite the acknowledged uncertainty of the diagnosis.

Preventing Exposure

The resurgence of syphilis among persons with HIV infection in the United States underscores the importance of primary prevention of syphilis among persons with HIV infection. This should begin with routine discussion of sexual behaviors. Providers should discuss client-centered risk reduction messages and provide specific actions that can reduce the risk for acquiring sexually transmitted infections and for transmitting HIV (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11)., 548Kamb ML, Fishbein M, Douglas JM, Jr. et al. Efficacy of risk-reduction counseling to prevent human immunodeficiency virus and sexually transmitted diseases: a randomized controlled trial. JAMA 1998;280:1161-7., 549Fisher JD, Cornman DH, Osborn CY, et al. Clinician-initiated HIV risk reduction intervention for HIV-positive persons: formative research, acceptability, and fidelity of the Options Project. J Acquir Immune Defic Syndr 2004;37(Suppl 2):S78-87., 550Richardson JL, Milam J, Stoyanoff S, et al. Using patient risk indicators to plan prevention strategies in the clinical care setting. J Acquir Immune Defic Syndr 2004;37(Suppl 2):S88-94.). Routine serologic screening for syphilis is recommended at least annually for all sexually active HIV-infected persons, with more frequent screening (every 3-6 months) for those with multiple partners, unprotected intercourse, sex in conjunction with illicit drug use, methamphetamine use, or partners who participate in such activities (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11)., 551CDC, HRSA NIH, HIVMA/IDSA, and the HIV Prevention in Clinical Care Working Group. Recommendations for incorporating human immunodeficiency virus (HIV) prevention into the medical care of persons living with HIV. Clin Infect Dis 2004;38:104-21.). The occurrence of syphilis in an HIV-infected person is an indication of high-risk behavior and should prompt intensified counseling messages and strong consideration of referral for behavioral intervention. Persons undergoing screening or treatment for syphilis also should be evaluated for all common sexually transmitted diseases (STDs) (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11).).

Preventing Disease

The same measures that apply to preventing exposure apply to preventing disease.

Treatment of Disease

Management of syphilis in HIV-infected persons is similar to the management in HIV-uninfected persons (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11)., 530Stoner B: Current controversies in the management of adult syphilis. Clin Infect Dis 2007;44(Suppl 3):S130-46., 544Rolfs RT, Joesoef MR, Hendershot EF, et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N Engl J Med 1997;337:307-14.). However, closer follow-up is recommended to detect potential treatment failure or disease progression.

Penicillin remains the treatment of choice for syphilis regardless of HIV status. HIV-infected persons with early-stage (i.e., primary, secondary, or early-latent) syphilis should receive a single intramuscular (IM) injection of 2.4 million units of benzathine penicillin G (AII). Although most HIV-infected persons with early syphilis respond appropriately to standard benzathine penicillin, some specialists recommend two additional weekly benzathine penicillin injections. The benefit of this treatment approach remains unproven. Enhanced penicillin therapy (i.e., standard benzathine penicillin with high-dose oral amoxicillin and probenecid) did not improve clinical outcome in early-stage syphilis (544Rolfs RT, Joesoef MR, Hendershot EF, et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N Engl J Med 1997;337:307-14.) and is not recommended (DII).

The efficacy of alternative nonpenicillin regimens in HIV-infected persons with early syphilis, including oral doxycycline, ceftriaxone, and azithromycin, has not been evaluated sufficiently in HIV-infected persons to warrant use as first-line treatment. Regardless of HIV infection status, the use of any alternative penicillin treatment regimen should be undertaken only with close clinical and serologic monitoring (BIII). Similarly, although some evidence suggests that a single 2-gram oral dose of azithromycin might have efficacy for treating early syphilis (552Kiddugavu MG, Kiwanuka N, Wawer MJ, et al. Effectiveness of syphilis treatment using azithromycin and/or benzathine penicillin in Rakai, Uganda. Sex Transm Dis 2005;32:1-6., 553Riedner G, Rusizoka M, Todd J, et al. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med 2005;353:1236-44.), molecular resistance of T. pallidum to macrolides and clinical treatment failures with azithromycin have been reported (554CDC. Azithromycin treatment failures in syphilis infections-San Francisco, California, 2002-2003. MMWR 2004;53:197-8., 555Lukehart SA, Godornes C, Molini BJ, et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med 2004;351:154-8., 556Mitchell SJ, Engelman J, Kent CK, et al. Azithromycin-resistant syphilis infection: San Francisco, California, 2000-2004. Clin Infect Dis 2006;42:337-45.); such treatment should be used only with close clinical and serologic monitoring to detect treatment failure (CII).

In HIV-infected persons with late-latent syphilis for whom the CSF examination excludes the diagnosis of neurosyphilis, treatment with three weekly IM injections of 2.4 million units benzathine penicillin G is recommended (AIII). Alternative therapy with doxycycline 100 mg by mouth twice a day for 28 days has not been sufficiently evaluated in HIV-infected persons to warrant use as first-line treatment (BIII). If the clinical situation requires the use of an alternative to penicillin, treatment should be undertaken with close clinical and serologic monitoring.

HIV-infected persons with clinical evidence of late-stage (tertiary) syphilis (cardiovascular or gummatous disease) should have a CSF examination to rule out neurosyphilis before initiating therapy. The complexity of tertiary syphilis management is beyond the scope of these guidelines and providers are advised to consult an infectious disease specialist.

HIV-infected persons with clinical or laboratory evidence of neurosyphilis (i.e., CNS, otic, or ocular disease) should receive IV aqueous crystalline penicillin G, 18-24 million units daily, administered 3-4 million units IV every 4 hours or by continuous infusion for 10-14 days (AII) or procaine penicillin 2.4 million units IM once daily plus probenecid 500 mg orally four times a day for 10-14 days (BII) (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11)., 537Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis 2004;189:369-76., 539Marra CM, Maxwell CL, Tantalo L, et al. Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis 2004;38:1001-6.). HIV-infected persons who are allergic to sulfa-containing medications should not be administered probenecid because of potential allergic reaction (DIII).

Because neurosyphilis treatment regimens are of shorter duration than those used in late-latent syphilis, some specialists recommend 2.4 million units IM once per week for up to 3 weeks after completion of neurosyphilis treatment to provide a comparable duration of therapy (CIII) (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11).). Among patients who are allergic to penicillin, penicillin desensitization is the preferred approach to treating neurosyphilis (BIII). However, limited data indicate that ceftriaxone (2 g daily IV for 10-14 days) might be an acceptable alternative regimen (CIII) (557Smith NH, Musher DM, Huang DB, et al. Response of HIV-infected patients with asymptomatic syphilis to intensive intramuscular therapy with ceftriaxone or procaine penicillin. Int J STD AIDS 2004;15:328-32.). Other alternative regimens for neurosyphilis have not been evaluated adequately.

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Clinical and serologic responses to treatment of early-stage (i.e., primary, secondary, and early-latent) disease should be monitored at 3, 6, 9, 12, and 24 months after therapy. Serologic responses to treatment are similar in persons with and without HIV infection; however, subtle variations might occur, including the temporal pattern of response (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11)., 530Stoner B: Current controversies in the management of adult syphilis. Clin Infect Dis 2007;44(Suppl 3):S130-46., 544Rolfs RT, Joesoef MR, Hendershot EF, et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N Engl J Med 1997;337:307-14., 558Long CM, Klausner JD, Leon S, et al. Syphilis treatment and HIV infection in a population-based study of persons at high risk for sexually transmitted disease/HIV infection in Lima, Peru. Sex Transm Dis 2006;33:151-5.).

After successful treatment for syphilis (HIV-infected and -uninfected persons), 15%-20% of persons might remain "serofast," meaning that serum nontreponemal test titers remain reactive at low and unchanging titers, usually <1:8, for prolonged periods (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11)., 544Rolfs RT, Joesoef MR, Hendershot EF, et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N Engl J Med 1997;337:307-14.). This serofast state probably does not represent treatment failure. Serologic detection of potential reinfection should be based on an at least a fourfold increase in titer above the established serofast baseline.

Response to therapy of late-latent syphilis should be monitored using nontreponemal serologic tests at 6, 12, 18, and 24 months to ensure at least a fourfold decline in titer. Some retrospective studies have documented concomitant HIV infection associated with poorer CSF and serologic responses to neurosyphilis therapy (559Marra CM, Longstreth WT, Jr., Maxwell CL, Lukehart SA. Resolution of serum and cerebrospinal fluid abnormalities after treatment of neurosyphilis: influence of concomitant human immunodeficiency virus infection. Sex Transm Dis 1996;23:184-9., 560Gordon SM, Eaton ME, George R, et al. The response of symptomatic neurosyphilis to high-dose intravenous penicillin G in patients with human immunodeficiency virus infection. N Engl J Med 1994;331:1469-73.). CSF examination should be repeated at 6 months after completion of therapy. If clinical symptoms develop or nontreponemal titers rise fourfold, a repeat CSF examination should be performed and treatment administered accordingly. The earliest CSF indicator of response to neurosyphilis treatment is a decline in CSF lymphocytosis. The CSF VDRL might respond more slowly. Nontreponemal serum titers should be monitored during the next 12-24 months and if the titers do not decline fourfold, consultation with an infectious disease specialist is recommended (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11).).

No IRIS has been described in association with syphilis and treatment with ART in HIV-infected persons.

Management of Treatment Failure

Retreatment of persons with early-stage syphilis should be considered for those who 1) have a sustained fourfold increase in serum nontreponemal titers after an initial reduction after treatment, or 2) have persistent or recurring clinical signs or symptoms of disease (BIII). Certain specialists recommend retreating persons with early syphilis who do not experience at least a fourfold decrease in serum nontreponemal titers 6-12 months after therapy (BIII). If CSF examination does not confirm the diagnosis of neurosyphilis, such persons should receive 2.4 million units IM benzathine penicillin G administered at 1-week intervals for 3 weeks (BIII). Certain specialists also recommend a course of aqueous penicillin G administered IV or procaine penicillin administered IM plus probenecid for treatment of neurosyphilis in this setting, although data to support this practice are lacking (CIII). If titers do not respond appropriately after retreatment, the value of repeated CSF examination or additional therapy has not been established. Persons with HIV infection might be at increased risk for treatment failure and neurologic complications; the magnitude of these risks is not precisely defined but is likely low (536Berry CD, Hooton TM, Collier AC, Lukehart SA, Lukehart SA. Neurologic relapse after benzathine penicillin therapy for secondary syphilis in a patient with HIV infection. N Engl J Med 1987;316:1587-9., 561Walter T, Lebouche B, Mialhes P, et al. Symptomatic relapse of neurologic syphilis after benzathine penicillin G therapy for primary or secondary syphilis in HIV-infected patients. Clin Infect Dis 2006;43:787-90.).

Persons with late-latent syphilis should have a repeat CSF examination and be retreated if they have clinical signs or symptoms of syphilis, have a fourfold increase in serum nontreponemal test titer, or experience an inadequate serologic response (less than four-fold decline in nontreponemal test titer) within 12-24 months of therapy (BIII). If the CSF examination is consistent with CNS involvement, retreatment should follow the neurosyphilis recommendations (AIII). Persons with latent syphilis and a normal CSF examination should be treated with benzathine penicillin, 2.4 million units IM weekly for 3 weeks (BIII); certain specialists also recommend adding a neurosyphilis regimen in this setting (CIII). Retreatment for neurosyphilis should then be considered if the CSF WBC count has not decreased 6 months after completion of treatment or if the CSF-VDRL remains reactive 2 years after treatment (BIII).

Preventing Recurrence

No recommendations indicate the need for secondary prophylaxis or prolonged chronic maintenance antimicrobial therapy for syphilis in HIV-infected persons. Targeted mass treatment of high-risk populations has not been demonstrated to be effective and is not recommended. Azithromycin is not recommended as secondary prevention because of azithromycin treatment failures reported in HIV-infected persons and reports of macrolide-resistant T. pallidum (554CDC. Azithromycin treatment failures in syphilis infections-San Francisco, California, 2002-2003. MMWR 2004;53:197-8., 555Lukehart SA, Godornes C, Molini BJ, et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med 2004;351:154-8., 556Mitchell SJ, Engelman J, Kent CK, et al. Azithromycin-resistant syphilis infection: San Francisco, California, 2000-2004. Clin Infect Dis 2006;42:337-45.).

Special Considerations During Pregnancy

Pregnant women should be screened for syphilis at the first prenatal visit. In areas where syphilis prevalence is high or among women at high risk (e.g., uninsured, women living in poverty, commercial sex workers, and IDUs), testing should be repeated at 28-32 weeks of gestation and at delivery. All women delivering a stillborn infant after 20 weeks of gestation also should be tested for syphilis. Syphilis screening should also be offered at sites providing episodic care to pregnant women at high risk, including emergency departments, jails, and prisons. No infant should leave the hospital without documentation of maternal syphilis-serology status during pregnancy (562Genc M, Ledger WJ. Syphilis in pregnancy. Sex Transm Infect 2000;76:73-9.).

The rate of transmission to the fetus and adverse pregnancy outcomes of untreated syphilis are highest with primary, secondary, and early-latent syphilis during pregnancy and decrease with increasing duration of infection thereafter. Pregnancy does not appear to alter the clinical course, manifestations, or diagnostic test results of syphilis infection among adults. Concurrent syphilis infection has been associated with increased risk for perinatal transmission of HIV to the infant (563Berman SM. Maternal syphilis: pathophysiology and treatment. Bull World Health Organ 2004;82:433-8., 564Tess BH, Rodrigues LC, Newell ML, et al. Breastfeeding, genetic, obstetric and other risk factors associated with mother-to-child transmission of HIV-1 in Sao Paulo State, Brazil: Sao Paulo Collaborative Study for Vertical Transmission of HIV-1. AIDS 1998;12:513-20., 565Lee MJ, Hallmark RJ, Frenkel LM, Del Priore G. Maternal syphilis and vertical perinatal transmission of human immunodeficiency virus type-1 infection. Int J Gynaecol Obstet 1998;63:247-52., 566Wendel GD, Sheffield JS, Hollier LM, et al. Treatment of syphilis in pregnancy and prevention of congenital syphilis. Clin Infect Dis 2002;35(Suppl 2):S200-9., 567Mwapasa V, Rogerson SJ, Kwiek JJ, et al. Maternal syphilis infection is associated with increased risk of mother-to-child transmission of HIV in Malawi. AIDS 2006;20:1869-77., 568Kreitchmann R, Fuchs SC, Suffert T, Preussler G. Perinatal HIV-1 transmission among low income women participants in the HIV/AIDS Control Program in Southern Brazil: a cohort study. BJOG 2004;111:579-84.).

Treatment during pregnancy should consist of the same penicillin regimen as recommended for the given disease stage among nonpregnant, HIV-infected adults. Because of treatment failures reported after single injections of benzathine penicillin G among HIV-uninfected pregnant women (569Donders GG, Desmyter J, Hooft P, Dewet GH. Apparent failure of one injection of benzathine penicillin G for syphilis during pregnancy in human immunodeficiency virus-seronegative African women. Sex Transm Dis 1997;24:94-101.), certain specialists recommend a second injection 1 week after the initial injection for pregnant women with early syphilis (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11)., 570Sheffield JS, Sanchez PJ, Morris G, et al. Congenital syphilis after maternal treatment for syphilis during pregnancy. Am J Obstet Gynecol 2002;186:569-73.). Because of additional concerns about the efficacy of standard therapy in HIV-infected persons, a second injection in 1 week for HIV-infected pregnant women should be considered (BIII).

No alternatives to penicillin have been proven effective and safe for treatment of syphilis during pregnancy or for prevention of fetal infection. Pregnant women who have a history of penicillin allergy should be referred for skin testing and desensitization and treatment with penicillin (AIII) (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11).). Erythromycin does not reliably cure fetal infection; tetracyclines should not be used during pregnancy because of hepatotoxicity and staining of fetal bones and teeth (EIII). However, because of insufficient information regarding the use of azithromycin (571Ramsey PS, Vaules MB, Vasdev GM, Andrews WW, Ramin KD. Maternal and transplacental pharmacokinetics of azithromycin. Am J Obstet Gynecol 2003;188:714-8.) or ceftriaxone (572Zhou P, Gu Z, Xu J, Wang X, Liao K. A study evaluating ceftriaxone as a treatment agent for primary and secondary syphilis in pregnancy. Sex Transm Dis 2005; 32:495-8.) treatment in pregnancy, routine use is not a recommended (DIII).

A Jarisch-Herxheimer reaction that occurs during the second half of pregnancy might precipitate preterm labor or fetal distress (573Klein VR, Cox SM, Mitchell MD, Wendel GD, Jr. The Jarisch-Herxheimer reaction complicating syphilotherapy in pregnancy. Obstet Gynecol 1990;75:375-80.). Women should be advised to seek obstetric attention after treatment if they notice contractions or a decrease in fetal movement during the first 24 hours after treatment. During the second half of pregnancy, syphilis management may be facilitated by a sonographic fetal evaluation for congenital syphilis, but this evaluation should not delay therapy. Sonographic signs of fetal or placental syphilis indicate a greater risk for fetal treatment failure. Such cases should be managed in consultation with obstetric specialists. Evidence is insufficient to recommend specific regimens for these situations. After >20 weeks of gestation, fetal and contraction monitoring for 24 hours after initiation of treatment for early syphilis should be considered when sonographic findings indicate fetal infection.

Repeat serologic titers should be performed in the third trimester and at delivery for women treated for syphilis during pregnancy. Data related to serologic response to syphilis in HIV-infected women are insufficient. Titers can be conducted monthly for women at high risk for reinfection. Clinical and antibody response should be appropriate for the stage of disease, although the majority of women will deliver before their serologic response can be definitively assessed. Maternal treatment is likely to be inadequate if delivery occurs within 30 days of therapy, if clinical signs of infection are present at delivery or if the maternal antibody titer is fourfold higher than the pretreatment titer.

Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents: Treponema pallidum infection (syphilis)
Preferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
Excerpted from Table 2
Definitions of abbreviations: PO = by mouth; IM = intramuscular; IV = intravenous; q4h = every 4 hours; qid = 4 times daily
Preferred therapy early stage (primary, secondary, & early latent syphilis)
transparent gifgrey bulletBenzathine penicillin G 2.4 million units IM for 1 dose (AII)
transparent gif
Alternative therapy early stage (primary, secondary, and early latent syphilis) (BIII)
For penicillin-allergic patients:
transparent gifgrey bulletDoxycycline 100 mg PO bid for 14 days (BIII); or
transparent gif
transparent gifgrey bulletCeftriaxone 1 g IM or IV daily for 8-10 days (BIII); or
transparent gif
transparent gifgrey bulletAzithromycin 2 g PO for 1 dose (CII)
transparent gif
The efficacy of non-penicillin alternatives has not been evaluated in HIV-infected patients and should be undertaken only with close clinical and serologic monitoring (BIII)

Combination of procaine penicillin and probenecid is not recommended for patients with history of sulfa allergy (DIII)

The Jarisch-Herxheimer reaction is an acute febrile reaction accompanied by headache and myalgias that might occur within the first 24 hours after therapy for syphilis

Preferred therapy late-latent disease (>1year or of unknown duration, CSF examination ruled out neurosyphilis)
transparent gifgrey bulletBenzathine penicillin G 2.4 million units IM weekly for 3 doses (AIII)
transparent gif
Alternative therapy late-latent disease (without CNS involvement)
For penicillin-allergic patients:
transparent gifgrey bulletDoxycycline 100 mg PO bid for 28 days (BIII)
transparent gif
Preferred therapy late-stage (tertiary - cardiovascular or gummatous disease)
transparent gifgrey bulletRule out neurosyphilis before therapy with 3 doses of benzathine penicillin and obtain infectious diseases consultation to guide management (AIII)
transparent gif
Preferred therapy neurosyphilis (including otic and ocular disease)
transparent gifgrey bulletAqueous crystalline penicillin G, 18-24 million units per day, administered as 3-4 million units IV q4h or by continuous IV infusion for 10-14 days (AII) +/- benzathine penicillin G 2.4 million units IM weekly for 3 doses after completion of IV therapy (CIII)
transparent gif
Alternative therapy neurosyphilis
transparent gifgrey bulletProcaine penicillin 2.4 million units IM daily plus probenecid 500 mg PO qid for 10-14 days (BII) +/- benzathine penicillin G 2.4 million units IM weekly for 3 doses after completion of above (CIII); or
transparent gif

For penicillin-allergic patients:
transparent gifgrey bulletDesensitization to penicillin is the preferred approach (BIII); if not feasible,
transparent gif
transparent gifgrey bulletCeftriaxone 2 grams IM or IV daily for 10-14 days (CIII)
transparent gif

References

516. Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect 1999;75:3-17.
517. Rottingen JA, Cameron DW, Garnett GP. A systematic review of the epidemiologic interactions between classic sexually transmitted diseases and HIV: how much really is known? Sex Transm Dis 2001;28:579-97.
518. Blocker ME, Levine WC, St Louis ME. HIV prevalence in patients with syphilis, United States. Sex Transm Dis 2000;7:53-9.
519. Torian LV, Makki HA, Menzies IB, Murrill CS, Weisfuse IB. HIV infection in men who have sex with men, New York City Department of Health sexually transmitted disease clinics, 1990-1999: a decade of serosurveillance finds that racial disparities and associations between HI V and gonorrhea persist. Sex Transm Dis 2002;29:73-8.
520. CDC. Outbreak of syphilis among men who have sex with men--Southern California, 2000. MMWR 2001;50:117-20.
521. Stolte IG, Dukers NH, de Wit JB, Fennema JS, Coutinho RA. Increase in sexually transmitted infections among homosexual men in Amsterdam in relation to HAART. Sex Transm Infect 2001;77:184-6.
522. Peterman TA, Heffelfinger JD, Swint EB, Groseclose SL. The changing epidemiology of syphilis. Sex Transm Dis 2005;32(10 Suppl):S4-10.
523. Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA 2003;290:1510-4.
524. Paz-Bailey G, Meyers A, Blank S, et al. A case-control study of syphilis among men who have sex with men in New York City: association With HIV infection. Sex Transm Dis 2004;31:581-7.
525. Calza L, Manfredi R, Marinacci G, et al. Efficacy of penicillin G benzathine as antimicrobial treatment of cutaneous secondary syphilis in patients with HIV infection. J Chemother 2002;14:533-4.
526. Rompalo AM, Lawlor J, Seaman P, et al. Modification of syphilitic genital ulcer manifestations by coexistent HIV infection. Sex Transm Dis 2001;28:448-54.
527. Musher DM, Hamill RJ, Baughn RE. Effect of human immunodeficiency virus (HIV) infection on the course of syphilis and on the response to treatment. Ann Intern Med 1990;113:872-81.
528. Radolf JD, Kaplan RP. Unusual manifestations of secondary syphilis and abnormal humoral immune response to Treponema pallidum antigens in a homosexual man with asymptomatic human immunodeficiency virus infection. J Am Acad Dermatol 1988;18:423-8.
529. CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11).
530. Stoner B: Current controversies in the management of adult syphilis. Clin Infect Dis 2007;44(Suppl 3):S130-46.
531. Buchacz K, Patel P, Taylor M, et al. Syphilis increases HIV viral load and decreases CD4 cell counts in HIV-infected patients with new syphilis infections. AIDS 2004;18:2075-9.
532. Koefoed K, Gerstoft J, Mathiesen LR, Benfield T. Syphilis and human immunodeficiency virus (HIV)-1 coinfection: influence on CD4 T-cell count, HIV-1 viral load, and treatment response. Sex Transm Dis 2006;33:143-8.
533. Palacios R, Jimnez-Oate F, Aguilar M, et al. Impact of syphilis infection on HIV viral load and CD4 cell counts in HIV-infected patients. J Acquir Immune Defic Syndr 2007;44:356-9.
534. Rompalo AM, Joesoef MR, O'Donnell JA, et al. Clinical manifestations of early syphilis by HIV status and gender: results of the syphilis and HIV study. Sex Transm Dis 2001;28:158-65.
535. Bayne LL, Schmidley JW, Goodin DS. Acute syphilitic meningitis: its occurrence after clinical and serologic cure of secondary syphilis with penicillin G. Arch Neurol 1986;43:137-8.
536. Berry CD, Hooton TM, Collier AC, Lukehart SA, Lukehart SA. Neurologic relapse after benzathine penicillin therapy for secondary syphilis in a patient with HIV infection. N Engl J Med 1987;316:1587-9.
537. Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis 2004;189:369-76.
538. CDC: Symptomatic early neurosyphilis among HIV-positive men who have sex with men-four cities, United States, January 2002-June 2004. MMWR 2007;56:625-8.
539. Marra CM, Maxwell CL, Tantalo L, et al. Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis 2004;38:1001-6.
540. Wicher K, Horowitz HW, Wicher V. Laboratory methods of diagnosis of syphilis for the beginning of the third millennium. Microbes Infect 1999;1:1035-49.
541. Pope V. Use of treponemal tests to screen for syphilis. Infect Med 2004;21:399-404.
542. Rompalo AM, Cannon RO, Quinn TC. Association of biologic false-positive reactions for syphilis with human immunodeficiency virus infection. J Infect Dis 1992;165:1124-6.
543. Augenbraun MH, DeHovitz JA, Feldman J, et al. Biological false-positive syphilis test results for women infected with human immunodeficiency virus. Clin Infect Dis 1994;19:1040-4.
544. Rolfs RT, Joesoef MR, Hendershot EF, et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N Engl J Med 1997;337:307-14.
545. Augenbraun M, Rolfs R, Johnson R, Joesoef R, Pope V. Treponemal specific tests for the serodiagnosis of syphilis. Sex Transm Dis 1998;25:549-52.
546. Kingston A, Vujevich J, Shapiro M, et al. Seronegative secondary syphilis in 2 patients coinfected with human immunodeficiency virus. Arch Dermatol 2005;141:431-3.
547. Hicks CB, Benson PM, Lupton GP, Tramont EC. Seronegative secondary syphilis in a patient infected with the human immunodeficiency virus (HIV) with Kaposi sarcoma: a diagnostic dilemma. Ann Intern Med 1987;107:492-5.
548. Kamb ML, Fishbein M, Douglas JM, Jr. et al. Efficacy of risk-reduction counseling to prevent human immunodeficiency virus and sexually transmitted diseases: a randomized controlled trial. JAMA 1998;280:1161-7.
549. Fisher JD, Cornman DH, Osborn CY, et al. Clinician-initiated HIV risk reduction intervention for HIV-positive persons: formative research, acceptability, and fidelity of the Options Project. J Acquir Immune Defic Syndr 2004;37(Suppl 2):S78-87.
550. Richardson JL, Milam J, Stoyanoff S, et al. Using patient risk indicators to plan prevention strategies in the clinical care setting. J Acquir Immune Defic Syndr 2004;37(Suppl 2):S88-94.
551. CDC, HRSA NIH, HIVMA/IDSA, and the HIV Prevention in Clinical Care Working Group. Recommendations for incorporating human immunodeficiency virus (HIV) prevention into the medical care of persons living with HIV. Clin Infect Dis 2004;38:104-21.
552. Kiddugavu MG, Kiwanuka N, Wawer MJ, et al. Effectiveness of syphilis treatment using azithromycin and/or benzathine penicillin in Rakai, Uganda. Sex Transm Dis 2005;32:1-6.
553. Riedner G, Rusizoka M, Todd J, et al. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med 2005;353:1236-44.
554. CDC. Azithromycin treatment failures in syphilis infections-San Francisco, California, 2002-2003. MMWR 2004;53:197-8.
555. Lukehart SA, Godornes C, Molini BJ, et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med 2004;351:154-8.
556. Mitchell SJ, Engelman J, Kent CK, et al. Azithromycin-resistant syphilis infection: San Francisco, California, 2000-2004. Clin Infect Dis 2006;42:337-45.
557. Smith NH, Musher DM, Huang DB, et al. Response of HIV-infected patients with asymptomatic syphilis to intensive intramuscular therapy with ceftriaxone or procaine penicillin. Int J STD AIDS 2004;15:328-32.
558. Long CM, Klausner JD, Leon S, et al. Syphilis treatment and HIV infection in a population-based study of persons at high risk for sexually transmitted disease/HIV infection in Lima, Peru. Sex Transm Dis 2006;33:151-5.
559. Marra CM, Longstreth WT, Jr., Maxwell CL, Lukehart SA. Resolution of serum and cerebrospinal fluid abnormalities after treatment of neurosyphilis: influence of concomitant human immunodeficiency virus infection. Sex Transm Dis 1996;23:184-9.
560. Gordon SM, Eaton ME, George R, et al. The response of symptomatic neurosyphilis to high-dose intravenous penicillin G in patients with human immunodeficiency virus infection. N Engl J Med 1994;331:1469-73.
561. Walter T, Lebouche B, Mialhes P, et al. Symptomatic relapse of neurologic syphilis after benzathine penicillin G therapy for primary or secondary syphilis in HIV-infected patients. Clin Infect Dis 2006;43:787-90.
562. Genc M, Ledger WJ. Syphilis in pregnancy. Sex Transm Infect 2000;76:73-9.
563. Berman SM. Maternal syphilis: pathophysiology and treatment. Bull World Health Organ 2004;82:433-8.
564. Tess BH, Rodrigues LC, Newell ML, et al. Breastfeeding, genetic, obstetric and other risk factors associated with mother-to-child transmission of HIV-1 in Sao Paulo State, Brazil: Sao Paulo Collaborative Study for Vertical Transmission of HIV-1. AIDS 1998;12:513-20.
565. Lee MJ, Hallmark RJ, Frenkel LM, Del Priore G. Maternal syphilis and vertical perinatal transmission of human immunodeficiency virus type-1 infection. Int J Gynaecol Obstet 1998;63:247-52.
566. Wendel GD, Sheffield JS, Hollier LM, et al. Treatment of syphilis in pregnancy and prevention of congenital syphilis. Clin Infect Dis 2002;35(Suppl 2):S200-9.
567. Mwapasa V, Rogerson SJ, Kwiek JJ, et al. Maternal syphilis infection is associated with increased risk of mother-to-child transmission of HIV in Malawi. AIDS 2006;20:1869-77.
568. Kreitchmann R, Fuchs SC, Suffert T, Preussler G. Perinatal HIV-1 transmission among low income women participants in the HIV/AIDS Control Program in Southern Brazil: a cohort study. BJOG 2004;111:579-84.
569. Donders GG, Desmyter J, Hooft P, Dewet GH. Apparent failure of one injection of benzathine penicillin G for syphilis during pregnancy in human immunodeficiency virus-seronegative African women. Sex Transm Dis 1997;24:94-101.
570. Sheffield JS, Sanchez PJ, Morris G, et al. Congenital syphilis after maternal treatment for syphilis during pregnancy. Am J Obstet Gynecol 2002;186:569-73.
571. Ramsey PS, Vaules MB, Vasdev GM, Andrews WW, Ramin KD. Maternal and transplacental pharmacokinetics of azithromycin. Am J Obstet Gynecol 2003;188:714-8.
572. Zhou P, Gu Z, Xu J, Wang X, Liao K. A study evaluating ceftriaxone as a treatment agent for primary and secondary syphilis in pregnancy. Sex Transm Dis 2005; 32:495-8.
573. Klein VR, Cox SM, Mitchell MD, Wendel GD, Jr. The Jarisch-Herxheimer reaction complicating syphilotherapy in pregnancy. Obstet Gynecol 1990;75:375-80.
transparent gif