Abstract
BACKGROUND: Controversy persists regarding the appropriate duration of therapy with benzathine penicillin G in persons with early (i.e., primary, secondary, or early latent) syphilis (Treponema pallidum infection). METHODS: In a multicenter, randomized, controlled, noninferiority trial, we assigned persons who had early syphilis, with or without human immunodeficiency virus (HIV) infection, to receive intramuscular injections of benzathine penicillin G in a one-time dose of 2.4 million units or in doses of 2.4 million units administered at three successive weekly intervals. The primary end point was seroreversion to nonreactive status or a decrease in the rapid plasma reagin titer by two or more dilutions at 6 months, referred to here as a serologic response (noninferiority margin, 10 percentage points). A key secondary end point was a serologic response within subgroups defined according to HIV status, also assessed in a noninferiority analysis. RESULTS: A total of 249 persons with early syphilis were enrolled. Most participants were men (97%), 62% were Black, and 153 (61%) were living with HIV infection. The distribution according to syphilis stage was 19% with primary syphilis, 47% with secondary syphilis, and 33% with early latent syphilis. The percentage of participants with a serologic response at 6 months was 76% (95% confidence interval [CI], 68 to 82) in the single-dose group and 70% (95% CI, 61 to 77) in the three-dose group (difference, -6 percentage points; 90% CI, -15 to 3, indicating noninferiority). No clinical relapse or treatment failure occurred in either group. In the one-dose group, a serologic response at 6 months was observed in 76% of participants who had HIV infection and 76% of those who did not, and in the three-dose group, a serologic response at 6 months was observed in 71% of participants who had HIV infection and 70% of those who did not. Most participants in each group had local injection-site pain and tenderness with treatment (76% with a single dose and 85% with three doses). CONCLUSIONS: Treatment with one dose of 2.4 million units of benzathine penicillin G was noninferior to treatment with three doses with regard to serologic response 6 months after treatment. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT03637660.).