Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 6: Disease-Specific Treatment

Syphilis

Background

Syphilis is a sexually transmitted infection (STI) caused by the spirochete Treponema pallidum. It is a complex disease with protean variations that can mimic many common infections or illnesses. HIV infection may alter the natural history and management of syphilis, causing a more rapid course of illness, higher risk of neurologic complications, and greater risk of treatment failure with standard regimens. Because many individuals with syphilis have no symptoms, or have symptoms that subside without treatment, sexually active individuals at risk for syphilis should receive regular screening for syphilis as well as for other STIs. Many clinicians strongly recommend routine syphilis testing every 3-6 months in patients at risk for syphilis.

In recent years, increasing numbers of syphilis cases have been reported in HIV-infected men who have sex with men (MSM), predominantly in major metropolitan areas. This trend reflects reduced use of safer sex practices, and is concerning both because syphilis can have major health consequences if it is undetected and untreated, and because it is associated with increased risk of new HIV infections. Risk assessment should be conducted at each patient visit for unprotected sex (including oral sex), multiple sexual partners, and use of recreational drugs (methamphetamine and cocaine, in particular, are associated with high-risk sexual practices in MSM). Asymptomatic persons at risk of acquiring syphilis should be screened at regular intervals (with rapid plasma reagin [RPR] or Venereal Diseases Research Laboratory [VDRL] testing, as below), depending on their risk factors. MSM with multiple partners should be tested every 3-6 months.

The natural history of untreated syphilis infection is divided into several different stages based on length of infection.

Primary Syphilis

Primary syphilis usually manifests after an incubation period of 1-3 weeks from exposure and is characterized by a painless self-limiting ulcer (chancre) at the site of sexual contact. HIV-infected individuals may have multiple or atypical chancres that might be misidentified. Some patients have no primary lesion, or have a primary lesion that is not visible. Associated regional lymphadenopathy can occur. HIV-infected individuals sometimes have a chancre concurrently with rash typical of secondary syphilis.

Secondary Syphilis

Secondary syphilis usually develops 2-8 weeks after initial infection and is caused by ongoing replication of the spirochete, with disseminated infection that may involve multiple systems. Rash is the most common presenting symptom; skin lesions may be macular, maculopapular, papular, or pustular, or may appear as condyloma lata. The rash often appears on the trunk and extremities and may involve the palms and soles of feet. Constitutional symptoms, lymphadenopathy, arthralgias, and myalgias are common and neurologic or other symptoms may occur. In the absence of treatment, the manifestations of secondary syphilis last days to weeks, then usually resolve to the latent stages.

Latent Syphilis

Latent syphilis follows resolution of secondary syphilis. As in HIV-uninfected individuals, latent syphilis is asymptomatic and the diagnosis is determined by positive serologic tests. Latent syphilis is further classified as "early latent" if the infection is known to be less than 1 year in duration, "late latent" if the infection is known to be greater than 1 year in duration, or "latent syphilis of unknown duration" if the duration of infection is not known.

Late or Tertiary Syphilis

Late or tertiary syphilis is due to chronic infection with progressive disease in any system causing serious illness and death in untreated patients. The most common manifestations include neurosyphilis, cardiovascular syphilis, and gummatous syphilis.

Neurosyphilis

Neurosyphilis can occur at any time after initial infection, due to spread of the spirochete to the central nervous system (CNS). In HIV-infected individuals, neurosyphilis may occur more commonly early in the course of infection, during secondary or latent syphilis. It is associated with neurologic symptoms, including cranial nerve abnormalities (particularly extraocular or facial muscle palsies, tinnitus or hearing loss) or symptoms of meningitis. Uveitis or other eye disease may occur in conjunction with neurosyphilis.

S: Subjective

Symptoms will depend on the site of initial infection, the stage of disease, and whether neurosyphilis is present. Symptoms are not present in all patients.

If symptoms are present, the patient may complain of:

• Painless sore(s) or ulcer(s) in the genital area, vagina, anus, or oral cavity
• New rash, usually on the trunk, soles, and/or palms; patchy hair loss
• Fever, malaise, swollen glands, arthralgias, myalgias
• Altered mental status, weakness, paralysis
• Neurosyphilis: vision changes, eye pain, hearing loss, headaches, dizziness, generalized weakness, seizures, confusion, changes in personality or affect

Conduct a targeted history, asking the patient about symptoms listed above, including duration; inquire about other or associated symptoms Ascertain the following:

• Previous diagnosis of syphilis
• New sex partner(s) in past 90 days (for primary or secondary syphilis)
• Unprotected sex (oral, vaginal, anal)
• Date of last syphilis test
• Possible pregnancy

O: Objective

Check for fever, document other vital signs

Perform a complete examination including:

• Skin and mucosal areas (including the genitals, palm, and soles): rash, gummas, granulomas, patchy hair loss
• Oropharynx: chancres, mucous patches, condyloma lata
• Lymph nodes
• Heart: murmurs
• Ophthalmic examination
• Neurologic examination (mental status, cranial nerves [including visual acuity], sensory, motor, reflexes, coordination, gait): abnormal mental status, visual acuity changes, extraocular movement abnormalities, neurosensory hearing loss, facial palsy, paraesthesias, paralysis, hemiplegia, hyperactive reflexes, ataxia

A: Assessment

Because syphilis has a wide range of manifestations, the differential diagnosis is broad. It is important to consider syphilis as a possible cause of many presenting illnesses. A partial differential diagnosis includes:

• Other causes of maculopapular rashes: pityriasis, drug eruption, condyloma, folliculitis, psoriasis, acute HIV infection
• Other causes of genital ulcerative disease: herpes simplex virus (HSV), chancroid
• Other causes of ocular disease; glaucoma, cytomegalovirus (CMV) retinitis, CMV immune reconstitution uveitis, HSV keratitis
• Other causes of neurologic disease: stroke, Bell's palsy, CNS lymphoma, toxoplasmosis, meningitis
• Other causes of cardiac murmurs: bacterial endocarditis, congenital abnormalities
• Other causes of systemic symptoms (eg, fever, malaise, adenopathy): acute HIV infection, acute hepatitis, other infections or malignancies

P: Plan

Diagnostic Evaluation

Darkfield examination and direct fluorescent antibody

Darkfield examination and direct fluorescent antibody (DFA) testing of a sample from suspicious genital or anal chancres or moist dermatologic lesions (not oral lesions) are definitive tests for syphilis.

Serologic tests

Nontreponemal tests (RPR or VDRL) are most sensitive in primary and secondary syphilis when titers are high, though the response may be delayed in HIV-infected patients (typically nontreponemal tests are positive within 3 months after infection). Because false-positive results may occur, positive nontreponemal test results must be confirmed with a treponemal test. Titers may be used to follow response to treatment; a fourfold change in titer is considered a significant change. Note that the same nontreponemal test should be used consistently for a single patient; RPR titers cannot be compared with VDRL titers.

Treponemal antibody tests (TP-PA [T pallidum particle agglutination] or FTA-ABS [fluorescent treponemal antibody absorption]) confirm a positive nontreponemal test.

A false-negative RPR or VDRL test may occur, usually when the test is performed in early infection, before a sufficient antibody response has developed. Another possible cause of a false-negative nontreponemal test is the prozone phenomenon, seen when antibody concentrations are very high (usually in secondary syphilis) and the specimen is not diluted sufficiently. If serologic tests are negative and suspicion of syphilis is high, perform other diagnostic tests (biopsy, etc) and/or request that the laboratory perform additional dilutions on nontreponemal test specimens.

Cerebrospinal fluid (CSF) evaluation

HIV-infected patients with clinical evidence of neurologic or ocular syphilis, late latent syphilis, syphilis of unknown duration, or tertiary syphilis should receive lumbar puncture (LP) and CSF analysis. LP also is indicated for patients in whom treatment for early syphilis fails (see below). Some specialists recommend CSF evaluation for all HIV-infected patients with syphilis of any stage. CSF analysis should include:

• CSF-VDRL: this test is specific but is not very sensitive.
• Leukocytes: elevated white blood cell count (>10 cells/µL) is suggestive but is not specific. Note that mononuclear pleocytosis (up to 5-20 cells/µL) is not uncommon in patients with HIV infection, particularly those with higher CD4 cell counts.

Other testing

All patients who test positive for syphilis should be tested for gonorrhea and chlamydia, with sampling sites based on sexual practices and exposures (oropharyngeal, urethral, vaginal, or anorectal testing). Patients not known to be HIV-infected also should be tested for HIV.

Treatment

Treatment of syphilis in HIV-infected individuals essentially is the same as in HIV-uninfected individuals, and depends on stage and the presence or absence of neurosyphilis. It is important to follow patients closely to assure the success of treatment. For further information, see the Centers for Disease Control and Prevention (CDC) Sexually Transmitted Diseases Treatment Guidelines (reference below).

Early syphilis

Less than 1 year duration, ie, primary, secondary, and early latent; nonneurologic

• Preferred: benzathine penicillin G, 2.4 million units intramuscularly (IM) (single dose).
• Alternatives: In penicillin-allergic, nonpregnant patients, consider the following. Note that these therapies are not as well proven in HIV-infected individuals; close monitoring for treatment response is recommended.
  • Doxycycline, 100 mg orally twice daily for 14 days
  • Tetracycline, 500 mg orally 4 times daily for 14 days
  • Ceftriaxone, 1 gm IM or intravenously (IV) daily for 8-10 days
  • High rates of treatment failure have been reported in patients treated with azithromycin (2 grams, single dose); this regimen should be used only if other options are contraindicated and close follow-up is possible

Late latent syphilis

More than 1 year duration or of unknown duration; nonneurologic

• CSF examination to rule out neurosyphilis should be done on all patients with a history of syphilis of more than 1 year or of unknown duration.
• If CSF examination is negative, treat with benzathine penicillin G, 2.4 million units IM weekly for 3 consecutive weeks (7.2 million units total).
• In penicillin-allergic clients, refer for desensitization to penicillin. As an alternative, some consider doxycycline 100 mg orally twice daily for 28 days. Referral to infectious disease specialist and close clinical monitoring are required, as treatment is not proven in HIV-infected individuals.

Tertiary syphilis

Consult with specialists.

Neurosyphilis

Syphilis at any stage with neurologic or ocular symptoms or CSF findings of neurosyphilis

Ideally, patients should be hospitalized and given 2 weeks of penicillin IV under close observation. Penicillin-allergic patients should be referred for desensitization, if possible.

• Preferred: aqueous crystalline penicillin G, 18-24 million units IV per day (3-4 million units every 4 hours [or continuous infusion] for 10-14 days).
• Alternatives (require strict adherence with therapy):
  • Procaine penicillin 2.4 million units IM per day, plus probenecid 500 mg orally 4 times daily, both for 10-14 days.
  • Some consider use of ceftriaxone, 2 gm IM or IV once daily for 10-14 days with close clinical monitoring.
• Some specialists recommend administration of benzathine penicillin, 2.4 million units IM weekly for 3 weeks, after completion of the standard 10- to 14-day course of therapy for neurosyphilis.
• Recheck CSF leukocyte count every 6 months until the cell count normalizes (if CSF pleocytosis was present at initial evaluation). If the leukocyte count is not lower at 6 months, consider retreatment (consult with a specialist).

Note that a Jarisch-Herxheimer reaction may occur after initial syphilis treatment, especially in primary, secondary, or even latent syphilis. This self-limited treatment effect should not be confused with an allergic reaction to penicillin. It usually begins 2-8 hours after the first dose of penicillin and consists of fever, chills, arthralgias, malaise, tender lymphadenopathy, and intensification of rash. It resolves within 24 hours and is best treated with rest and acetaminophen. Patients should be warned about the possibility of Jarisch-Herxheimer reaction.

Pregnancy

Pregnant women should be treated with penicillin, if possible, using a regimen appropriate to the stage of infection (see above). Penicillin-allergic pregnant women should be referred for desensitization to penicillin. Doxycycline and tetracycline may cause fetal toxicity and should not be used during pregnancy; erythromycin is not sufficiently effective in treating syphilis in the fetus. The efficacy of azithromycin and ceftriaxone in pregnancy is uncertain.

Women treated during the second half of pregnancy are at risk of contractions, early labor, and fetal distress if they develop a Jarisch-Herxheimer reaction; thus, they should be monitored carefully.

Sex partners

Syphilis is transmitted sexually only when mucocutaneous lesions of syphilis are present; this is uncommon after the first year of infection. Nevertheless, sex partners of a patient who has syphilis in any stage should be evaluated.

• Persons exposed within 90 days preceding the diagnosis of primary, secondary, or early latent syphilis should be treated presumptively, as they might be infected with syphilis even if they are seronegative.
• Persons exposed more than 90 days before the diagnosis of primary, secondary, or early latent syphilis should be treated presumptively if serologic test results are not available immediately and the patient's follow-up is in doubt. Otherwise, they should receive serologic testing and be treated appropriately if the test result is positive. Note that some experts recommend presumptive treatment of all persons potentially exposed to syphilis. For patients with primary syphilis, this means partners within the previous 3 months; for secondary, within 6 months; for early latent, within 1 year.

Follow-up

All HIV-infected patients treated for syphilis should be evaluated clinically and serologically at 3, 6, 9, 12, and 24 months (at 6, 12, 18, and 24 months for late syphilis) to rule out treatment failure. Treatment success is determined by a fourfold decrease in RPR or VDRL titer by 6-12 months (for early syphilis) or 12-24 months (for late syphilis) after treatment. Patients whose titers do not decrease appropriately probably either experienced treatment failure or were reinfected. Any patient with apparent treatment failure should undergo an LP for CSF analysis and be re-treated as appropriate. If, at any time, symptoms develop or nontreponemal test titers increase fourfold, CSF examination should be performed and appropriate treatment should be given.

Some patients retain reactive (low-titer) nontreponemal test results after successful treatment for syphilis. In these "serofast" individuals, reinfection with syphilis is indicated by a rise in test titer of at least 4-fold.

Risk-reduction counseling

All patients with syphilis should receive risk evaluation and risk-reduction counseling. Evaluate each patient's sexual practices with regard to risk of acquiring STIs and of transmitting HIV. Work with the patient to reduce sexual risks.

Patient Education

• Instruct patients to go to clinic for treatment at the intervals recommended. If patients are given oral antibiotics (penicillin-allergic individuals), instruct them to take their medications exactly as prescribed.
• Warn patients about the possibility of Jarisch-Herxheimer reaction and advise them about self-management of associated symptoms (eg, acetaminophen or aspirin at usual doses, fluids, and rest).
• Instruct patients about the required follow-up laboratory and clinical evaluations necessary to document adequate treatment. Emphasize the need for regular evaluation of treatment efficacy.
• Sexual partners from the previous 3-6 months (sometimes longer, depending on the stage of syphilis) need to be evaluated and treated as soon as possible, even if they have no symptoms. Advise patients to inform their partner(s) that they need to be tested and treated.
• Syphilis is a reportable communicable disease in the United States. Patients will be contacted to assist with partner tracing and to ensure appropriate treatment.
• Provide education about sexual risk reduction. Review sexual practices and support patients in using condoms with every sexual contact to prevent becoming reinfected with syphilis or infected with other STIs, and to prevent passing HIV to sexual partners.

References

• Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR Recomm Rep. 2002 May 10;51(RR-6):1-78.
• Centers for Disease Control and Prevention. Trends in primary and secondary syphilis and HIV infections in men who have sex with men--San Francisco and Los Angeles, California, 1998-2002. MMWR Morb Mortal Wkly Rep. 2004 Jul 9;53(26):575-8.
• Centers for Disease Control and Prevention, National Institutes of Health, HIV Medicine Association/Infectious Diseases Society of America. Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents. December 17, 2004.
• Colven R, Spach DH. Generalized Cutaneous Manifestations of STD/HIV Infection. In: Holmes KK, Mardh PA, Sparling PF, et al, eds. Sexually Transmitted Diseases, 3rd Edition. New York: McGraw-Hill; 1999:875-876.
• Mitchell SJ, Engelman J, Kent CK, et al. Azithromycin-resistant syphilis infection: San Francisco, California, 2000-2004. Clin Infect Dis. 2006 Feb 1;42(3):337-45.
• Musher DM. Early Syphilis. In: Holmes KK, Mardh PA, Sparling PF, et al, eds. Sexually Transmitted Diseases, 3rd Edition. New York: McGraw-Hill; 1999:48.