Jarisch-Herxheimer Reaction After Benzathine Penicillin G Treatment in Adults With Early Syphilis: Secondary Analysis of a Randomized Clinical Trial

Importance Syphilis rates have been increasing in the US for the past decade. The incidence of the Jarisch-Herxheimer reaction (JHR) after penicillin treatment for early syphilis is reported to range from 8% to 56%. Objectives To prospectively assess the incidence of JHR signs and symptoms among adults with early syphilis treated with benzathine penicillin G and to document factors associated with JHR and benzathine penicillin G treatment response outcomes. Design, Setting, and Participants The main study was designed as a phase 4 randomized clinical trial to compare the treatment efficacy of 1 vs 3 doses of benzathine penicillin G in adults with early syphilis, measured as serologic response at 6 months. A total of 249 adults with or without HIV were screened and enrolled between October 31, 2018, and March 3, 2020. Participants were screened and enrolled at 10 US study sites in the Sexually Transmitted Infections Clinical Trials Group. Statistical analysis for this secondary analysis took place between March 2023 and August 2024. Intervention Participants received a first dose of benzathine penicillin G, 2.4 million units intramuscularly, at the enrollment visit. The JHR assessment window was day 1 to day 7 after the first dose of benzathine penicillin G. Main Outcomes and Measures Primary outcomes in this study were the incidence of symptoms consistent with JHR within 7 days after benzathine penicillin G treatment. Unelicited and elicited symptoms were assessed by participant self-report using a standardized checklist during contact made by a study clinician. Factors associated with JHR were collected at baseline, and serologic treatment response was assessed at 6 months. Posttreatment incident JHR symptoms were captured as safety outcomes for this trial. Analysis was performed on an intention-to-treat basis. Results Of 249 participants, the median age was 32 years (IQR, 27-41 years), 242 (97.2%) were men, and 153 (61.4%) were living with HIV. One or more JHR symptoms occurred in 59 participants (23.7%) treated for early syphilis, with a median symptom onset at 4.9 hours (IQR, 3.0-9.2 hours) and a median duration of 12.8 hours (IQR, 5.0-24.0 hours). Symptom onset was within 12 hours of treatment for 49 of 57 participants (86.0%). Among 59 symptomatic participants, myalgias (30 [50.8%]), chills (27 [45.8%]), weakness (23 [39.0%]), and feverishness (21 [35.6%]) were most common. In adjusted models, JHR was associated with secondary syphilis (adjusted odds ratio [AOR], 2.91 [95% CI, 1.51-5.61]) and the absence of HIV (AOR for living with HIV, 0.49 [95% CI, 0.26-0.94]). The proportion of participants with a serologic treatment response to benzathine penicillin G at 6 months was higher among participants with JHR (84.7% [50 of 59] vs 68.9% [131 of 190] without JHR). Conclusions and Relevance In this prespecified secondary analysis of a randomized clinical trial of early syphilis treatment wtih benzathine penicillin G in adults, approximately 1 in 4 participants experienced short-lived JHR symptoms, which were associated with secondary syphilis stage, lack of HIV, and successful treatment outcomes at 6 months. These messages could be used in patient counseling. Trial Registration ClinicalTrials.gov Identifier: NCT03637660