Long-Run Public Health Impact of Doxycycline Post-Exposure Prophylaxis and Behavioural Factors on Syphilis Transmission: A Modelling Study in Singapore and England

Syphilis remains a significant global public health challenge, particularly among men who have sex with men (MSM). Although penicillin is highly effective for treatment, primary prevention strategies are limited. Recent trials indicate that doxycycline post-exposure prophylaxis (doxy-PEP) has high efficacy in reducing syphilis incidence among MSM; however, its long-run population-level impact, effects on transmission dynamics, and optimal prescribing strategies remain unclear, especially when accounting for real-world behavioural factors such as screening frequency, uptake, adherence, and discontinuation. To address this gap, we developed a behavioural transmission-dynamic model calibrated with Bayesian methods using epidemiological and sexual behavioural data from Singapore and England to characterize transmission dynamics in MSM, quantify the potential long-run public health impact, efficiency, and robustness of alternative doxy-PEP prescribing strategies across different settings (e.g., schools, clinics, age, and risk groups) under varying behavioural patterns and epidemiological settings. Over a 15-year horizon, targeting high-risk MSM at diagnosis emerged as the most efficient approach, averting an estimated 2.50 (0.68 - 5.94) cases per prescription (10000 [95% Credible Interval 1100 - 53200] total cases averted) in Singapore and 4.60 (2.12 - 7.79) cases per prescription (165000 [49300 - 503700]) in England. In contrast, broader strategies such as offering doxy-PEP to all MSM attending sexual health clinics could achieve greater overall reductions (up to 24700 [6800 - 93100] cases in Singapore and 279800 [109200 - 724000] in England), but with substantially lower efficiency, averting as few as 0.02 (0.00 - 0.23) and 0.04 (0.01 - 0.46) cases per prescription, respectively. These findings suggest that untargeted strategies could substantially reduce syphilis incidence but would do so at the cost of over-prescription, increased resource burden, and unnecessary antibiotic exposure. More importantly, our findings remain robust despite variations in behavioural factors and future scenarios. In summary, our results underscore that doxy-PEP prescribing approaches aligned with behavioural risk factors can maximise population-level impact and implementation efficiency, supporting more sustainable syphilis prevention among MSM.