By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
Dr. Deresinski reports no financial relationships relevant to this field of study.
SYNOPSIS: The results of this randomized trial provide support for the CDC recommendation of treatment of early stages of syphilis in HIV-infected patients with a single intramuscular 2.4-million-unit dose of benzathine penicillin.
SOURCE: Andrade R, Rodriguez-Barradas MC, Yasukawa K, et al. Single dose versus 3 doses of Intramuscular benzathine penicillin for early syphilis in HIV: A randomized clinical trial. Clin Infect Dis 2017;64:759-764.
Andrade and colleagues enrolled HIV-infected patients with syphilis at three clinical sites in Houston, Texas over approximately four years ending in 2013. In an open-label trial, 35 were randomized to receive a single 2.4-million-unit intramuscular dose of benzathine penicillin and 29 to receive three weekly doses for a total of 7.2 million units. Of the 64 patients, 95% were male and 86% were men who have sex with men. The patients had primary (6%), secondary (61%), or early latent syphilis (33%). Their mean CD4 T-cell count was 388/µL and their mean RPR titer was 1:128 (range, 1:32-1:256).
Treatment success (a four-fold decrease in RPR titer by 12 months) in the intent-to-treat analysis was achieved in 28/35 (80%) of single-dose recipients and 27/29 given three doses (13% absolute difference; 95% CI, -5% to 30%; P = 0.17). In the per protocol analysis, success was achieved in 27/29 (93%) and 27/27 (100%) (P = 0.49), respectively. Of note is that two patients in the single-dose group who were scored as failures at 12 months eventually achieved a four-fold decrease in RPR titer in the absence of any further treatment, something which has been reported. There appeared to be no effect of baseline RPR titer, syphilis stage, or CD4 T-cell count.
COMMENTARY
The CDC recommends that treatment of primary syphilis consist of a single 2.4-million-unit intramuscular dose of benzathine penicillin, regardless of HIV status.1 This recommendation has been based on a single prospective randomized trial that found no evidence of benefit from the addition of a 10-day course of amoxicillin plus probenecid to the 2.4-million-unit intramuscular dose of benzathine penicillin. Andrade et al, however, had presented the results of a trial in 2007 that compared a single to three weekly 2.4-million-unit doses in HIV-infected patients found no difference overall or related to CD4 T-cell count.2 They did find that in those with primary or secondary syphilis, the failure rates were 28% vs. 6% (P = 0.07), respectively. This, plus the fact that clinicians frequently ignored the CDC recommendations and treated HIV patients with a total of 7.2 million units of benzathine penicillin divided in three doses, were likely the stimulus for this therapeutic trial.
The results of the study reviewed here provide support for the extant CDC recommendation of single-dose treatment for early stages of syphilis. The major deficit of this study is its lack of power. The investigators had calculated a need to enroll a total of 118 patients to have a power of 80% with a two-tailed comparison with a type I error of 0.05 and hypothesized failure rates of 25% and 5% in the single- and three-dose groups, respectively. However, the intent-to-treat population of this trial was only 64.
It should be noted that since completion of this trial in 2013, several other studies have found no difference in outcome when comparing treatment with one and three doses of benzathine penicillin. In the absence of a large multicenter trial that reports benefit of the three-dose regimen, the CDC recommendations should be followed.
REFERENCES
- Workowski KA. Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines. Clin Infect Dis 2015;61Suppl 8:S759-62.
- Andrade R, Villareal-Williams E, Risser J, et al. Co-infection with Treponema pallidum and HIV: Effect of the CD4 cell count and penicillin dosage in the response of syphilis to therapy. Poster exhibition: Sydney - IAS 2007: Abstract no. MOPEB104.
The results of this randomized trial provide support for the CDC recommendation of treatment of early stages of syphilis in HIV-infected patients with a single intramuscular 2.4-million-unit dose of benzathine penicillin.
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