Predictors of Serological Cure and Serofast State After Treatment in HIV-Negative Persons With Early Syphilis

During the past century, medications for syphilis have evolved from mercury-based compounds to penicillin, which has been the therapy of choice for >60 years [1]. Although syphilis treatment recommendations have advanced since the prepenicillin era, the basis for evaluating therapeutic response remains serological testing. Clinical management relies upon interpretation of nontreponemal antibody test titers to assess treatment response, despite their inherent flaws including false-positive results and day-to-day variation in performance between assays. The Centers for Disease Control and Prevention (CDC) recommends obtaining nontreponemal test titers to evaluate serological response at 6 and 12 months after treatment for primary and secondary syphilis and, additionally, at 24 months for early latent (EL) syphilis among persons without human immunodeficiency virus (HIV) infection [2]. Patients with nontreponemal titers that decline 4-fold or more are regarded as having an appropriate serological response, whereas those with a ≥4-fold increase are considered as having possible treatment failure or reinfection [2]. However, in a substantial proportion (15%–20%) of persons with early syphilis, nontreponemal titers neither increase nor decrease 4-fold after treatment and are referred to as being “serofast” [2–5]. The factors that predict serological response after syphilis treatment have not been well-defined, and the optimal management of serofast patients is unclear. We conducted a large, randomized, multicenter study to compare the efficacy of benzathine penicillin with azithromycin for the treatment of early syphilis (defined as primary, secondary, or EL syphilis) in persons without HIV infection [4]. We found that both drugs had comparable efficacy with similar serological cure rates at 6 months, supporting other studies evaluating azithromycin as a potential therapy for Treponema pallidum infections [5, 6]. To begin to address the conundrum of serofast status, we examined the data collected from this study and assessed baseline factors associated with serological response.