Antiquated Tools to Fight an Ancient Foe

Syphilis is one of the oldest known diseases. Approximately 209,000 cases were reported in the United States in 2023 — the highest number of reported cases since 1950 — including nearly 4000 congenital syphilis cases, which resulted in 279 stillbirths or infant deaths.² Our ability to prevent and control this infection has been limited by relatively few advances in the diagnosis and treatment of syphilis in the past 75 years. Diagnosis continues to rely on serologic markers of infection, which do not differentiate between treated and untreated infection and are difficult even for a syphilologist to interpret. Treatment has relied on a single drug (penicillin G) since the 1950s; however, the dose and duration of treatment for various stages of syphilis continue to be debated, partly owing to the relative paucity of clinical trials.³ In addition, the lack of options for alternative treatment creates challenges to clinical management in the context of a penicillin allergy or a drug shortage. Continuing to rely on dated technology for syphilis diagnosis and a century-old drug for syphilis treatment underscores the ongoing challenges in addressing this long-stigmatized infection.

In this issue of the Journal, Hook et al.¹ lay to rest the debate on whether persons with human immunodeficiency virus (HIV) infection need more doses of benzathine penicillin G for the treatment of syphilis than persons who do not have HIV infection. In this multicenter, randomized, controlled trial, 249 persons with early syphilis (i.e., primary, secondary, or early latent syphilis) were assigned to receive either a single dose (2.4 million units) of benzathine penicillin G (the current treatment recommended by the Centers for Disease Control and Prevention [CDC] for patients with early syphilis³) or three weekly injections of 2.4 million units. The participants included 153 persons (61%) with HIV infection; the majority (92%) of those persons were receiving antiretroviral therapy, and 77% had a CD4 lymphocyte count greater than 350 cells per cubic millimeter.

In this trial, the primary end point was serologic response, defined as a decrease in the rapid plasma reagin (RPR) titer by two or more dilutions at 6 months.¹ This end point is somewhat curious. Previous studies have shown that persons who have HIV infection have a slower time to serologic response than those who do not.⁴ In addition, current CDC recommendations allow 12 months for the RPR titer to decrease by a factor of four (i.e., two dilutions) in persons with early syphilis.³ In the present trial, no significant difference in serologic response at 6 months was observed, either according to treatment regimen or HIV infection status, indicating that a single dose of benzathine penicillin G was noninferior to three doses. The overall incidence of serologic response at 6 months for participants in both groups ranged from 65 to 78% in the intention-to-treat analysis and 70 to 80% in the per-protocol analysis,¹ response rates that seem low at first blush. However, these findings are not surprising, given the results of previous clinical trials showing that 10 to 20% of persons with primary or secondary syphilis did not have a decrease in the RPR titer by a factor of four at 12 months.³

The findings from this trial should provide reassurance to clinicians, particularly those caring for patients with HIV infection, that a single dose of benzathine penicillin G is sufficient to treat early syphilis. The question remains whether persons with late latent syphilis or syphilis of unknown duration should receive the CDC-recommended regimen of three 2.4-million–unit doses of benzathine penicillin G. The data supporting the CDC recommendation are theoretical.⁵ In addition, adherence to treatment is not optimal. An analysis of surveillance data from Arizona showed that only 43% of persons with late latent syphilis or syphilis of unknown duration completed all three doses of benzathine penicillin G at adequate dosing intervals.⁶ Nonadherence to receipt of the second and third injections is probably the result of multiple factors, including injection-site pain and the strict dosing intervals that require multiple clinic visits. Missed doses (exceeding 10 to 14 days for men and nonpregnant women, respectively, and 9 days for pregnant women) mean the entire regimen must be restarted.³ At a time when the United States relies on a single manufacturer of benzathine penicillin G and consequently has seen periodic shortages and unavailability of the drug,⁷ reducing the dependence on a single drug is paramount.

In addition to studies evaluating the need for three doses of benzathine penicillin G for late latent syphilis and syphilis of unknown duration, studies of new nonpenicillin drugs for the treatment of the disease are needed. Approximately 10% of the population reports a penicillin allergy, and although less than 10% of those persons truly have an immunoglobulin E–mediated allergy, testing to determine who has a true allergy is not routinely conducted at the time of treatment in patients with syphilis.^8,9 Currently, the only acceptable alternative for men and nonpregnant women who may be allergic to penicillin is a 100-mg dose of doxycycline administered twice daily for 10 to 14 days for early syphilis and 28 days for late latent syphilis or syphilis of unknown duration. However, this treatment option can pose problems — especially during pregnancy, a context in which doxycycline, a teratogen, is contraindicated.

Nearly 100 years into the antibiotic era — an era heralded by the groundbreaking drug penicillin — syphilis continues to plague us. Although many people have forgotten about syphilis, its recent resurgence calls for renewed efforts to advance the diagnostics and therapeutics associated with this age-old infection so that we may finally control it.