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Three-dose penicillin regimen not superior to single dose for syphilis in patients with HIV

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March 10, 2017

A three-dose regimen of intramuscular benzathine penicillin G for syphilis, compared with a single dose, did not significantly improve outcomes in patients with HIV, data published in Clinical Infectious Diseases showed.

“The CDC’s sexually transmitted disease treatment guidelines advocate treating HIVinfected patients who have primary or secondary syphilis with the same number of doses of penicillin as [those used] for HIVuninfected patients. This recommendation has remained unchanged in the last several guideline cycles,” Roberto Andrade, MD, from Baylor College of Medicine, and colleagues wrote.  “To our knowledge, there have been no randomized controlled trials comparing the efficacy of a single dose of benzathine penicillin G with that of three doses of benzathine penicillin G administered at 1-week intervals for early syphilis in HIVinfected patients.”

Andrade and colleagues performed an open-label, randomized clinical trial on 64 HIVinfected patients with syphilis. Patients were randomly assigned to either a single-dose or three-dose regimen of benzathine penicillin G, with rapid plasma reagin (RPR) titers measured every 3 months. Researchers defined successful treatment as an RPR titer decrease of 2 dilutions or more over the course of a year.

Participants were overwhelmingly male (95%) and men who have sex with men (84%).

In the intention-to-treat analysis, the single-dose group had a success rate of 80% (28 of 35 patients), whereas the three-dose group had a 93% (27 of 29) success rate, the researchers reported (95% CI, 5% to 30%). However, in the per-protocol analysis, the researchers reported that the single-dose group had a 93% success rate (27 of 29 patients) and the 3-dose group had a 100% success rate (27 of 27 patients; absolute difference, 7%; 95% CI, 7% to 22%). Factors such as CD4 count, RPR titers and stage of syphilis did not affect outcomes, Andrade and colleagues wrote.

“Larger, ideally multicenter, studies are needed to confirm our findings,” Andrade and colleagues wrote. “In the meantime, our results support the current CDC recommendations to use a single dose of benzathine penicillin G for treatment of early syphilis in HIVinfected patients.”

In an accompanying editorial, A. Clinton White, Jr., MD, from the University of Texas Medical Branch, agreed that the findings support the CDC’s treatment guidelines, but with some reservation.

“Given these results, what conclusions can be drawn? Clearly, the bulk of evidence supports current recommendations to treat early syphilis with a single injection of benzathine penicillin regardless of the patient’s HIV status,” White wrote. “At the same time, the evidence to support this recommendation is not optimal. The difference between groups in the study by Andrade and colleagues raises concerns that a single injection might not be optimal. In the meantime, careful follow-up is essential regardless of treatment, and repeated courses of therapy may be needed for those patients who have not responded.” – by Andy Polhamus

 Disclosure: The researchers report no relevant financial disclosures.

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Jodie Dionne-Odom
Early syphilis infections are on the rise, with nearly 24,000 cases of primary and secondary disease reported to CDC in 2015, which represents a 19% increase compared with the previous year. Nearly 60% of these reported infections were among men who have sex with men (MSM), and 50% had co-infection with HIV. Most health care providers who treat HIV in the United States are experienced in recognizing and screening for syphilis in clinic, and Treponema pallidum remains highly sensitive to penicillin therapy. Nonetheless, there has been some reluctance among health care providers who treat infectious disease to follow CDC Treatment Guidelines for patients with HIV with early syphilis. Since 2006, CDC guidelines have stated to treat adults with early syphilis with a single IM dose of 2.4 million units of benzathine penicillin (BPG), irrespective of HIV status. Several, but not all, observational studies in coinfected patients over the past decade have confirmed these CDC recommendations. This new study published in Clinical Infectious Diseases by Andrade et al is the first known prospective, open-label, randomized controlled trial to focus on this key question.

Researchers enrolled study subjects at three sites in Texas (n = 64, 95% men, 51% MSM), and their findings confirmed the role of single-dose BPG in HIVinfected patients with early syphilis. These findings are relevant to contemporary HIV practice in the U.S. because a majority of subjects were taking antiretroviral therapy with a mean CD4 count of 388 cells/mm3. Receipt of ART, CD4 count and HIV viral load did not predict treatment response, although few patients had a CD4 count less than200 cells/mm3. These important results are expected to change clinical practice and improve adherence to 2015 CDC treatment guidelines. They should provide reassurance to providers that additional therapy for early syphilis is not necessary in patients with HIV. Larger multi-center trials to confirm these findings would add to our confidence in the results, but funds may be better spent on developing innovative ways to promote and optimize universal syphilis screening in HIV clinics, particularly among MSM.


Centers for Disease Control and Prevention DoSP. STD Surveillance Report, 2015. 2016.

Centers for Disease Control and Prevention. STD Treatment Guidelines. 2015.

Costa-Silva M, Azevedo C, Azevedo F, Lisboa C. Early syphilis treatment in HIV-infected patients: single dose vs. three doses of benzathine penicillin G. J Eur Acad Dermatol Venereol. 2016;30(10):1805-1809.

Dionne-Odom J, Karita E, Kilembe W, et al. Syphilis treatment response among HIV-discordant couples in Zambia and Rwanda. Clin Infect Dis. 2013;56(12):1829-1837.

Dowell D, Polgreen PM, Beekmann SE, Workowski KA, Berman SM, Peterman TA. Dilemmas in the management of syphilis: a survey of infectious diseases experts. Clin Infect Dis. 2009;49(10):1526-1529.

Mattson CL, Bradley H, Beer L, Johnson C, Pearson WS, Shouse RL. Increased STD testing among sexually active persons receiving medical care for HIV infection in the United States, 2009 - 2013. Clin Infect Dis. 2017;64(5):629-634.

Yang CJ, Lee NY, Chen TC, et al. One dose versus three weekly doses of benzathine penicillin G for patients co-infected with HIV and early syphilis: a multicenter, prospective observational study. PloS One. 2014;9(10):e109667.

Jodie Dionne-Odom, MD
Assistant Professor, Division of Infectious Diseases, University of Alabama School of Medicine

HIVMA Member

Disclosure: Dionne-Odom reports no relevant financial disclosures.