Efficacy of One versus Three Doses of Benzathine Penicillin G in Early Syphilis

Syphilis is a sexually transmitted infection caused by Treponema pallidum that remains a major public health concern due to its high transmissibility, potential neurologic and cardiovascular complications, increased risk of HIV coinfection, and adverse pregnancy outcomes. In recent decades, syphilis rates have risen globally, including cases of congenital syphilis, underscoring the need for effective and accessible therapeutic strategies.

Since the 1950s, benzathine penicillin G has been the treatment of choice. Although the standard recommendation has long been a single intramuscular dose of 2.4 million units for early syphilis, concerns persist about whether multiple doses may be necessary in people living with HIV. Moreover, recurrent global shortages of benzathine penicillin highlight the importance of rational and efficient use.

In this multicenter, randomized, open-label, noninferiority trial, 249 adults with early syphilis (primary, secondary, or early latent), 61% of whom were living with HIV, were assigned to receive either a single dose of benzathine penicillin G (2.4 million units) or three consecutive weekly doses (2.4 million units each). The primary endpoint was a serologic response at 6 months, defined as seroreversion or a decline of at least two dilutions in rapid plasma reagin (RPR) titers.

Results showed that 76% of patients in the single-dose group and 70% in the three-dose group achieved a serologic response, confirming noninferiority of the simplified regimen. No clinical relapses or treatment failures were observed, and outcomes were consistent regardless of HIV status. Adverse events were common, mainly injection-site pain, which was more frequent in the three-dose group.

The study concludes that a single dose of benzathine penicillin G is sufficient for treating early syphilis, including in patients with HIV infection, offering comparable efficacy to three weekly doses while improving convenience, reducing costs, clinic visits, and patient discomfort from multiple injections.

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