Challenging Cases in HIV Medicine from Bellevue Hospital: HIV and Syphilis – Diagnostic and Therapeutic Approach

Case Patient: Presentation

In 2004, a 37-year-old man who has sex with men (MSM) presented to the Bellevue Virology/Infectious Diseases Clinic after a hospital admission. He had been admitted after painless maculopapular, purpuric mucocutaneous lesions developed on his palate, gingival area, trunk, and extremities, with marked bilateral foot involvement. A biopsy of these lesions revealed Kaposi's sarcoma (KS). This prompted an enzyme-linked immunosorbent assay (ELISA) HIV test, results of which were positive for HIV infection and confirmed with Western blot. His CD4+ cell count at that time was 50 cells/microliter (mcL) and his viral load was greater than 100,000 HIV RNA copies/mL. Routine HIV intake laboratory tests were performed, including a rapid plasma reagin (RPR), results of which were reactive with a titer of 1:2. The patient did not report any neurologic or ocular symptoms. He reported being previously diagnosed and treated for late latent syphilis at an outside institution in 2000. RPR results and titer were unavailable. Because of his low CD4+ cell count, HIV-positive status, and late latent syphilis, a lumbar puncture (LP) was performed. Cerebrospinal (CSF) analysis showed no pleocytosis and results of a Venereal Disease Research Laboratory (VDRL) test of CSF were nonreactive. He was treated for late latent syphilis without central nervous system (CNS) involvement with 3 doses of 2.4 million units of benzathine penicillin G intramuscularly (IM) at weekly intervals. No further serologic tests were performed between 2004 and 2006 to follow response. In 2004, the patient was started on trimethoprim/sulfamethoxazole; fixed dose combination of zidovudine/abacavir/lamivudine with efavirenz. His regimen was changed in 2006 to fixed dose combination of efavirenz/emtricitabine/tenofovir to lessen pill burden. Additionally, he was treated with liposomal doxorubicin 20 mg/m² every 2 weeks for KS. After 12 weeks of antiretroviral therapy, HIV viral load was undetectable and the KS was in remission. His viral load remains undetectable since he first suppressed in 2004 with a CD4+ count that has increased to 370 cells/mcL.

In December 2006, routine yearly testing for syphilis revealed an RPR titer of 1:8. Physical examination findings were negative for any oral, anal, or skin lesions, with no lymphadenopathy. Neurologic, ocular, and auditory examination results were normal.

Discussion and Case Follow-up

Case Discussion

HIV infection and syphilis. The key to syphilis recognition is a full examination with special attention to the protean manifestations of syphilis. This examination should include all of the skin, mouth, and genital region.[1,2]

Treponema pallidum, a spirochete, causes syphilis and is spread through contact with infectious lesions or body fluids. An ulcerative skin lesion, known as chancre, typically develops at the site of inoculation approximately 21 days after exposure (range, 10-90 days). Chancres may occur in the oral cavity, vaginal, or anal mucosa, making diagnosis particularly challenging. HIV infection may alter primary syphilis manifestations, leading to an atypical presentation and/or multiple ulcers that may be mistaken for genital herpes. Lesions fitting the classic descriptions of clean-based, painless, solitary ulcers with induration only occur in 31% of patients with syphilis.[3] Classic chancres may be the exception and not the rule.

Secondary syphilis may appear 4 to 10 weeks after resolution of the chancre and is characterized by a diffuse maculopapular rash that is found in more than 90% of patients on physical examination.[4] Some features of syphilis during this stage, such as fever, sore throat, malaise, and lymphadenopathy, can easily be mistaken for clinical manifestations of primary HIV infection, HIV immune reconstitution, adverse cutaneous reactions to drugs, viral exanthem, streptococcal pharyngitis, and mononucleosis-like illness, among others.

Dermatologic manifestations of secondary syphilis are varied. Although commonly a maculopapular eruption that does not spare the palms and soles, secondary syphilis may have almost any dermatologic manifestation except vesicles.[5] Biopsy is often necessary to clarify the diagnosis in complex cases.

There is some inclination among HIV providers and in the literature that HIV disease may alter the course of syphilis as well as response to therapy. Cases of persistent chancres, ulcerative skin lesions, and rapid progression to gummatous disease have been described in a review by Lynn and Lightman.[2] A greater frequency of ocular involvement, neurosyphilis, and treatment failure have also been documented.[6]

Untreated, secondary syphilis may enter an asymptomatic, latent phase. Duration of syphilis infection is critical in determining the appropriate treatment strategy during the latent phase. Early latent infection is defined as newly acquired syphilis with a negative RPR less than 1 year previously. Late latent syphilis is diagnosed more than 1 year after the last negative RPR.

Unrecognized latent infection may progress to tertiary syphilis, which is noninfectious, is characterized by cardiovascular manifestations, gummatous disease or late neurosyphilis (general paresis and tabes dorsalis). T pallidum infects the CNS in 25% to 60% of patients with syphilis. Five percent will go on to have symptomatic CNS disease (meningitis, cranial neuritis, ocular involvement, meningovascular disease).

Diagnostic testing in HIV patients. Definite diagnosis of early syphilis is made through visualization of T pallidum spirochetes on darkfield microscopy, with direct fluorescent antibody tests, or with polymerase chain reaction.[7,8] These tests usually are impractical, so patients are presumptively diagnosed on serologic testing and physical examination.

Some case reports have raised the possibility of differences in serological testing for syphilis among HIV-negative and -positive patients.[9–14] HIV patients may have a high rate of false-negative test results, may demonstrate failure to clear nontreponemal antibody after therapy (referred to as “remaining serofast”), or may have false-positive test results. Current CDC guidelines[15] recommend diagnosis and interpretation of the results of treponemal and non-treponemal serologic test for syphilis should be the same in HIV-infected and uninfected patients. Gwanzura and colleagues[16] examined 709 sera from 580 men in Zimbabwe . The prevalence of HIV in the cohort was 19.8 % and with both HIV positive and negative sea the negative predictive values of VDRL and RPR were > 99.9%.The sensitivities for the nontreponemal test are 78% to 86% in primary syphilis, 100% in secondary syphilis, and 95% to 98% in latent syphilis as reviewed in previously.[1,2] Occasional patients may present with manifestations of syphilis and have negative syphilis screening test results. Such patients must have investigations aimed at direct identification of the organism, that is, darkfield microscopy or tissue biopsies from suspicious lesions.

Risk factors for syphilis in HIV patients. From 2000 to 2004, the incidence of primary and secondary syphilis in the United States increased from 2.1 to 2.7 cases per 100,000 population. The majority of the increase was among men, a finding that is interpreted to mean increasing syphilis rates among MSM.[17]Additionally, the rate of primary and secondary syphilis among blacks was 5.1 times higher than that in whites in 2003, and 5.6 times higher in 2004. The US Centers for Disease Control and Prevention (CDC) estimated that in 2004, approximately 64% of all primary and secondary syphilis cases were among MSM.[17] Increases in the incidence of primary and secondary syphilis among MSM have been characterized by high rates of HIV coinfection, high-risk sexual behavior, Internet partner recruitment, and use of drugs such as methamphetamines.[18] HIV-infected non-gay-identified MSM who also have female partners likely contribute to primary and secondary syphilis among women.[16]

Need for lumbar puncture. The CDC Sexually Transmitted Diseases (STD) Guidelines, 2006[15] recommend CSF evaluation in any patient (HIV positive or negative) at any stage of disease, who has clinical evidence of neurologic involvement with syphilis (eg, cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis) and/or uveitis or other ocular manifestation frequently associated with syphilis (iritis, neuroretinitis, or optic neuritis). CSF analysis should be performed in HIV-infected patients who have either late latent syphilis, syphilis of unknown duration, or have failed therapy as shown by rebounding or stable RPR titers at follow-up. Others further elaborate on when to perform a lumbar puncture in HIV-infected individuals taking immune status and RPR titer into account. In addition to standard indications for CSF examination, a RPR titer ≥ 1:32 at any CD4+ cell count, or a RPR ≤ 1:32 in the setting of CD4+ cells ≤ 350 may be independent indications for a LP.[1]

Treatment in HIV patients. Primary and secondary syphilis are treated similarly in HIV-positive and -negative individuals. CDC guidelines recommend a single dose of benzathine penicillin G, 2.4 million units IM. Some experts elect to treat even early stage syphilis in an HIV-positive patient as late latent disease with 3 doses of benzathine penicillin G on 3 consecutive weeks. Neurosyphilis is treated with intravenous aqueous crystalline penicillin G 18-24 million units/day (4 million units intravenously every 4 hours or by continuous infusion) for 10 to 14 days. Penicillin-allergic people require skin testing and desensitization.[15]

Follow-up. Clinical and serological evaluation for treatment failure is critical in HIV patients. Treatment failure is considered to have occurred when signs or symptoms persist or recur or when there is not a 4-fold decrease in titer by the nontreponemal test at follow-up.

For the case of primary and secondary syphilis, follow-up evaluation should be at 3, 6, 9, 12, and 24 months after therapy. If there is treatment failure or no 4-fold decrease of titer by the nontreponemal test within 6 to 12 months, then the patient should have a LP and be retreated based on these results. In the case of latent syphilis (early and late), clinical and serological evaluation for treatment failure should be at 6, 12, 18, and 24 months after therapy. If clinical failure occurs or the nontreponemal test titer does not decline 4-fold in 12 to 24 months, an LP should be performed to guide treatment strategy.

Neurosyphilis follow-up requires CSF re-examination if pleocytosis was present at the time of diagnosis. A CSF examination should be repeated every 6 months until the cell count is normal (VDRL and protein level changes occur more slowly than cell count). If cell count has not decreased after 6 months or if CSF is not normal after 2 years, then retreatment is advised.

Case: Follow-up

In our case, an increase in the patient's RPR titer by 4-fold (from 1:2 to 1:8) was deemed to be evidence of potential recurrence or re-infection. Additionally, the absence of a stable negative previous RPR result within 1 year of the 1:8 RPR titer further categorizes the patient as being in the late latent phase of syphilis. He did not have any neurologic, auditory, or visual problems. His CD4+ cell count was 370 cells/mcL with a viral load < 50 copies/mL on fixed dose combination efavirenz/tenofovir/emtricitabine. Following the CDC STD guidelines from 2006, he fulfilled the criteria for LP as either a treatment failure or a re-infection found during the late latent phase of disease. The patient underwent LP, results of which showed no pleocytosis, normal protein level, and nonreactive VDRL. The patient is currently receiving benzathine penicillin G 2.4 million units intramuscularly once weekly for 3 consecutive weeks for late latent syphilis. Clinical and serologic follow-up will be pursued at 6, 12, 18, and 24 months after therapy is finished.