Monitoring Response to Early Syphilis Therapy
As T. pallidum cannot be cultured, serologic testing remains the mainstay for diagnosis and follow-up of persons with syphilis. While follow-up of persons with early syphilis should include repeat clinical evaluation, serologic testing utilizing the same non-treponemal test (i.e., rapid plasma reagin [RPR], Venereal Disease Research Laboratory [VDRL]) used at the time of initial diagnosis should be performed 6 and 12 months later. Serologic response to treatment (cure) is defined as a fourfold (two dilution) decline in non-treponemal test titer (RPR, VDRL) within 6 months of treatment. Diagnosis of treatment failure, however, is somewhat more challenging. Should symptoms recur or if there is a rise in serologic test titer of greater than two dilutions either following treatment or shortly (within 6 months) following an initial decline in titers, treatment failure and/or reinfection are likely. However, there is a large subset (approximately 20% at 6 months) of persons with syphilis for whom treatment does not result in either serologic cure or failure.
This group of serofast patients with unchanging serologic test titers are a source of anxiety and concern for clinicians, who are often uncertain as to the most appropriate next step: CSF evaluation? retreatment? or watchful waiting? In cases where continued clinical follow-up can be assured, watchful waiting with repeated serologic testing is often an appropriate plan, reserving further evaluation (i.e., lumbar puncture) or retreatment for those in whom test titers increase two or more dilutions. However, for persons for whom regular follow-up may not be possible, many clinicians opt to intervene further as described above.
Two recent papers analyzed data for serofast patients from a large randomized trial which compared benzathine penicillin with azithromycin for treatment of HIV-negative persons with early syphilis. Seña et al. determined that serofast status at 6 months was more common among persons with older age, later syphilis stage, lower initial RPR titers, with more sex partners or who did not experience a Jarisch–Herxheimer reaction. In the same study, all patients who were serofast were retreated with benzathine penicillin at 6 months per protocol. A secondary analysis of these retreated patients revealed that only an additional 27% of patients went on to meet criteria for serologic cure. These data provide some guidance regarding which patients may be more likely to remain serofast, as well as demonstrate that retreatment rarely changes serologic response.
Consideration of retreatment is, in part, dependent on the goals of therapy. Since a single dose of penicillin renders patients non-infectious to sexual partners, from a public health standpoint, the issue of serologic non-response is not a major concern. Whether persons who are serofast are at risk for progression to later stages of infection, that is, neurosyphilis or cardiovascular syphilis is unclear. However, given the rarity of neurosyphilis, it is unlikely that all or even most of the 20% of patients who have serologic non-response experience progression of disease.
Two situations raise special concerns for clinicians engaged in syphilis management: patients with HIV and pregnant patients. Fueled by numerous case reports and small series,[34–36] concerns have arisen regarding whether persons with syphilis and HIV co-infection require higher dosage or prolonged therapy to assure optimal treatment outcomes. Some reports suggest that persons with HIV and syphilis have a slower serologic decline, as well.[20,34] However, in a large randomized trial, increased intensity or duration of therapy did not affect outcomes with regards to serologic response. Because of lingering concerns about treatment failure, while the CDC does not recommend different therapy for persons with HIV and syphilis co-infection, closer and longer follow-up is recommended, with additional serologic testing at 3, 9 and 24 months, along with consideration of CSF analysis, particularly in patients who develop neurologic signs/symptoms in the setting of serologic non-response following appropriate therapy.
A second focus of concern involves pregnant women with syphilis, because treatment failure is both important for the patient, and may have lifelong consequences for the unborn child. Given the potentially devastating outcomes of congenital syphilis, documentation of appropriate penicillin-based therapy in pregnant women is particularly important. While studies do not support more intensive treatment, general consensus is that treatment should occur early in pregnancy, preferably in the first trimester, but be completed at least 30 days before delivery.[17,37] Therapy initiated during or after the second trimester should be accompanied by fetal evaluation. Unfortunately, when infection is diagnosed later in the course of pregnancy, syphilis patients may not have responded to therapy by the time of delivery. If appropriate therapy (with penicillin only) is not assured prior to delivery, the neonate must be evaluated by a specialist and consideration given for syphilis treatment for the baby. Overtreatment may occur, but is preferable given the potential serious outcomes of untreated syphilis in the neonate.
Clinical management of patients with early syphilis has been, and remains a clinical challenge. Difficulties with understanding of serologic tests, treatment options and durations and follow-up continue. Serofast serologic test results often provide a source of concern. Given the rarity of syphilitic complications (i.e., neuro-, tertiary and cardiac syphilis), it is unlikely that most serofast patients progress to later stages of syphilis. Treatment and follow-up of pregnant patients and patients co-infected with HIV remain sources of concern and controversy.
Expert Rev Anti Infect Ther. 2013;11(8):839-843. © 2013 Expert Reviews Ltd.