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Therapeutic Advances

OI Update: Syphilis

Interpreting the 1998 CDC Treatment Guidelines for Management of HIV-Infected Patients

August 1998

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

Seismologists like to say "Earthquakes don't kill people -- buildings that are heavily damaged by earthquakes kill people." The same sort of reasoning can be applied to HIV infection: "The human immunodeficiency virus doesn't kill people -- opportunistic infections that occur in patients with heavily damaged immune systems kill people." This observation is as true today as it was at the outset of the HIV epidemic, and although the incidence and severity of AIDS-related OIs has dropped dramatically since the introduction of multidrug antiretroviral therapies that include at least one protease inhibitor, these infections continue to exact a high toll on individuals with advanced HIV disease.

Although OI rates began to drop before the advent of the protease inhibitors -- thanks to a combination of earlier intervention, more effective prophylaxis, combination nucleoside therapy, and improved clinical care -- truly dramatic reductions occurred only after the widespread adoption of protease-inhibitor-containing therapies.

Overall, the incidence of OIs has dropped a stunning 70% since the protease inhibitors became widely available some two and a half years ago. Evidence continues to accumulate that maximally suppressive antiretroviral therapy has a significant impact on AIDS-related morbidity. There have been multiple anecdotal reports that such therapy can sometimes have a positive therapeutic impact on previously untreatable OIs like progressive multifocal leukoencephalopathy, cryptosporidiosis, and microsporidiosis.

More recently there have been reports that highly active therapy can restore sufficient immune competence to permit the successful withdrawal of long-term suppressive therapy for CMV retinitis, Mycobacterium avium complex, and fluconazole-resistant candidiasis. These are early reports, however, and we cannot yet gauge how durable these effects will be or how many patients can expect a similar response. Until we understand a good deal more about the effects of immune reconstitution, providers should err on the side of extreme caution when it comes to taking patients off OI prophylaxis and/or long-term suppressive regimens.

To keep clinicians abreast of new developments in the treatment of these old threats to their patients, the editors of HIV Newsline have inaugurated "OI Update," a series of succinct and timely reports on the current standard of care for a wide range of opportunistic infections. Although syphilis is not technically an opportunistic infection, it does present particular problems in HIV-infected individuals. As Drs. Marrazzo and Marra point out in the ensuing article, coinfection with HIV can complicate the clinical presentation, diagnosis, and management of syphilis.

In these patients syphilis can be highly aggressive -- as evidenced by the fact that seropositive patients can progress from primary to tertiary syphilis in just a few years, a progression that occurs over decades in HIV-negative individuals. For this reason we have chosen to publish their recommendations for diagnosing and treating this common STD under the rubric "OI Update."

-- The Editors

Syphilis, caused by the bacterium Treponema pallidum, is well known for the diversity of its clinical manifestations -- a feature that often contributes to delayed recognition of this common STD. Coinfection with HIV can complicate the clinical presentation, diagnosis, and management of syphilis. For this reason, among others, the Centers for Disease Control and Prevention (C.D.C.) periodically convene a panel of experts for the purpose of revising the centers' treatment guidelines for sexually transmitted diseases. This article reviews the 1998 C.D.C. guidelines for clinical management of syphilis in the HIV-infected patient.

A major unresolved issue is whether HIV infection confers an increased propensity for treatment failure and for the development of neurosyphilis. We know that T. pallidum invades the central nervous system during the early stages of infection. Studies from the pre-antibiotic era documented cerebrospinal fluid abnormalities -- including the presence of T. pallidum -- in 20% of patients with primary syphilis and up to 70% of patients with secondary syphilis. More recent studies suggest that CNS invasion by T. pallidum is no more common in HIV-infected patients than in uninfected individuals. Nonetheless, several recent studies suggest that ocular syphilis and neurosyphilis, particularly the meningeal and meningovascular forms, are more likely to occur in HIV-infected persons.

The definitive diagnosis of syphilis requires the visualization of treponemes in lesion exudate or tissue by dark-field microscopy or by special stains. A presumptive diagnosis may be made serologically. A reactive non-treponemal serologic test (RPR or VDRL) is confirmed with a specific treponemal test (MHA-TP or FTA-ABS). While high serum titers, fluctuating titers, and false-negative titers have been reported in HIV-infected persons, syphilis serology appears to be fairly reliable in this group, and therefore serology in seropositive patients should be interpreted as it is for HIV-negative individuals. However, clinicians will want to avoid repeat serology and/or more aggressive pursuit of other diagnostic options (such as biopsy of lesions or rash) in the HIV-infected patient in whom syphilis is suspected but serology is negative.

At present there is considerable debate about whether all HIV-infected patients with syphilis, regardless of stage, should have a routine CSF examination to rule out neurosyphilis. The C.D.C. recommends that neurosyphilis be considered in the differential diagnosis of neurologic disease in HIV-infected persons, but the new guidelines stop short of recommending a routine CSF examination in early syphilis, stating only that "some experts" recommend a CSF examination before initiating treatment.

The diagnosis of neurosyphilis is confirmed by a reactive CSF-VDRL, but a negative CSF-VDRL does not exclude the diagnosis. CSF abnormalities other than a reactive CSF-VDRL do occur in early syphilis. Their interpretation in HIV-infected persons is complicated by the fact that HIV infection itself may cause CSF abnormalities. Because the prognostic significance of CSF abnormalities in HIV-infected persons is uncertain, the diagnostic and therapeutic value of a routine CSF examination for all HIV-infected persons with syphilis is not defined.

A careful neurologic history and examination are essential, of course, and the workup should include questions regarding visual and auditory symptoms. Any indication that the patient has visual symptoms of infection should prompt a full ophthalmologic examination. Furthermore, a high serum VDRL titer (<1:32) may be more likely to predict CSF abnormalities in early syphilis. Special consideration should therefore be given to CSF examination in such patients, even in the absence of neurologic findings. For late latent syphilis or syphilis of unknown duration in HIV-infected persons, routine CSF examination is strongly recommended.

"In a recent multicenter trial, HIV-infected patients with primary and secondary syphilis were more likely to fail treatment than uninfected patients, but more aggressive treatment was not associated with an improved response. Treatment failure was not associated with identification of T. pallidum in CSF before therapy was initiated."

Treatment recommendations

The main question with regard to treatment in HIV-infected persons is whether the usual therapy for early syphilis needs to be extended or intensified to account for a potential increase in the risk of serologic treatment failure or neurologic complications. In part, the answer to the question is unclear because the magnitude of these risks is not well defined. In a recent multicenter trial, HIV-infected patients with primary and secondary syphilis were more likely to fail treatment than uninfected patients, but more aggressive treatment was not associated with an improved response. Treatment failure was not associated with identification of T. pallidum in CSF before therapy was initiated.

The C.D.C. recommends that HIV-infected persons with early syphilis receive the same therapy that an HIV-seronegative individual would receive -- a single dose of benzathine penicillin (Table). However, some experts do recommend a more aggressive approach: three weekly injections of BZN-PCN, which is the course of treatment usually reserved for late syphilis. There are no comparative data to recommend one of these regimens over the other.

Treatment of late syphilis depends in part on the results of the CSF examination. If no CSF abnormalities are found, treatment is the same as for HIV-negative persons: 2.4 million units of BZN-PCN weekly for three successive weeks. It should be noted here that if a patient misses even one dose of penicillin on this treatment schedule, the entire three-week cycle must be restarted.

Table: Treatment of Syphilis in the HIV-Infected Person, 1998
Disease Stage
PrimaryBenzathine PCN G 2.4 million units IM as a single dose1
SecondaryBenzathine PCN G 2.4 million units IM as a single dose1
Early LatentBenzathine PCN G 2.4 million units IM as a single dose2
Late LatentBenzathine PCN G 2.4 million units IM weekly for three weeks2
Tertiary3Benzathine PCN G 2.4 million units IM weekly for three weeks2
Neurosyphilis4Aqueous PCN G 3-4 million units IV every 4 hr for 10-14 days; or
Procaine PCN 2.4 million units IM daily plus
Probenecid 500 mg PO 4 times daily for 10-14 days

1. For the PCN-allergic patient, 2 weeks of doxycycline (100 mg PO twice daily) or tetracycline (500 mg PO 4 times daily) may be substituted. See text for details.

2. For the PCN-allergic patient with early latent or late latent syphilis, desensitization to and treatment with PCN is recommended. The efficacy of alternative treatment (2 weeks of doxycycline or tetracycline at the dosages above, given for 2 weeks for early latent and 4 weeks for late latent disease) is not assured.

3. Refers to gummatous or cardiovascular syphilis; does not include neurosyphilis. Some experts treat cardiovascular syphilis with the regimen recommended for neurosyphilis.

4. Non-penicillin regimens are not recommended for neurosyphilis.

Follow-up of patients with syphilis

Serologic response to treatment is assessed by changes in the non-treponemal test titers. Ideally, follow-up testing should be performed using the same test (either RPR or VDRL) performed by the same laboratory. The time to appropriate serologic response may be longer in HIV-infected persons than in uninfected individuals.

For HIV-infected persons with early syphilis (primary, secondary, or early latent), clinical and serologic assessments should occur at 3, 6, 9, 12, and 24 months after treatment is completed. Some experts recommend an annual assessment thereafter, even in patients who have a good serologic response, because cases of serologic relapse have been reported in HIV-infected persons more than a year after treatment.

Treatment failure in early syphilis is defined as failure of the non-treponemal test to decline fourfold (equivalent to 2 dilutions; for example, from 1:16 to <1:4, or 1:64 to <1:16) within 6 to 12 months after treatment, or a fourfold increase in titer at any time. Treatment failure mandates that CSF be examined; identification of pleocytosis or reactive CSF-VDRL warrants treatment for neurosyphilis. If the only abnormality is an elevated CSF protein, treatment should be considered on an individual basis. If the CSF is normal, the patient should be retreated with three weekly injections of 2.4 million units of BZN-PCN.

HIV-infected persons with late latent syphilis should undergo serologic follow-up at 6, 12, 18, and 24 months after the completion of treatment. Treatment failure, defined as failure of the non-treponemal titer to decline at least fourfold between 12 and 24 months after treatment -- or a fourfold increase in titer at any time -- warrants CSF examination.

Patients with syphilis who are allergic to penicillin present a special dilemma for care providers. For primary and secondary syphilis without neurosyphilis, some HIV-infected penicillin-allergic patients can be successfully treated with doxycycline or tetracycline, although some experts contend that non-penicillin regimens should not be used in HIV-infected patients with any stage of syphilis. For late latent syphilis -- and especially for neurosyphilis -- penicillin is always the recommended treatment, and penicillin-allergic individuals should therefore undergo desensitization.

The recommended treatment of neurosyphilis in the HIV-infected patient is the same as that for uninfected individuals (Table). However, the C.D.C. acknowledges that some experts advise adding three successive weekly injections of 2.4 million units of BZN-PCN after the completion of IV therapy. All patients should have repeat CSF examinations every six months until the CSF cell count is normal, and some experts also recommend CSF examination at three months after therapy. The CSF cell count should decrease within six months after completion of therapy, and the CSF should be entirely normal within two years. If the patient's CSF profile does not improve, providers should consider the possibility of treatment failure and the advisability of retreatment.

Management of the sexual partners of patients with syphilis

It is essential that the sexual partners of all persons diagnosed with syphilis be treated. The C.D.C. recommends that partners exposed to an infected person within 90 days prior to a diagnosis of early syphilis be presumptively treated with 2.4 million units of BZN-PCN, regardless of serology. For persons outside of this 90-day window -- including long-term sexual partners -- treatment should be initiated if either clinical or serologic examination indicates the presence of infection. If the index case has a high titer (<1:32) and syphilis of unknown duration, all of the patient's sexual partners should be treated presumptively for early syphilis.

Jeanne M. Marrazzo, M.D., M.P.H., and Christina M. Marra, M.D., are from the Department of Medicine, University of Washington, Division of Allergy and Infectious Diseases, Seattle, Washington.

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.
See Also
Syphilis -- a Dreadful Disease on the Move
Syphilis Fact Sheet
Basic Questions and Answers About Syphilis and Men Who Have Sex With Men (MSM)
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