Background: After an animal-associated injury (AAI) in rabies-endemic regions, post-exposure prophylaxis (PEP) is needed to prevent infection.(1,2) PEP consists of rabies vaccinations (RV) and in... Show moreBackground: After an animal-associated injury (AAI) in rabies-endemic regions, post-exposure prophylaxis (PEP) is needed to prevent infection.(1,2) PEP consists of rabies vaccinations (RV) and in some cases also additional rabies immune globulins (RIG). Not always PEP medication, and RIG in particular, is accessible. Along with an increased number of exposure notifications among Dutch travellers, this might lead to treatment delay and thus to increased health risks. Until now, research mainly focused on factors associated with exposition, but none on which factors are associated with PEP delay. This study aimed to identify which general sample characteristics are associated with PEP delay while being abroad.Methods: A quantitative retrospective observational study was conducted. The study population consisted of insured Dutch international travellers who actively contacted their medical assistance company (2015-2019) because of an animal-associated injury (AAI) (N = 691). The association between general sample characteristics and delay of different PEP treatments was studied using survival analysis.Results: Travellers without pre-exposure prophylaxis (PrEP) had an increased hazard, and therefore a shorter delay, for receiving their first RV as compared to travellers with PrEP (HR:1.11, 95%CI:1.01-1.22). The travellers needing both RV and RIG had a decreased hazard, and therefore a longer delay, as compared to travellers only needing RV (HR:0.81, 95%CI:0.67-0.96). General sample characteristic associated with RIG administration delay was travel destination. Travellers to Central and South America, East Mediterranean and Europe had a decreased hazard, and therefore a longer delay, for receiving RIG treatments relative to travellers to South East Asia (HR:0.31, 95%CI:0.130.70; HR:0.34, 95%CI:0.19-0.61; HR:0.46, 95%CI:0.24-0.89; HR:0.48, 95%CI:0.12-0.81, respectively).Conclusions: Our results suggest that the advice for PrEP should be given based on travel destination, as this was found to be the main factor for PEP delay, among travellers going to rabies-endemic countries. Show less
Geloven, N. van; Balan, T.A.; Putter, H.; Cessie, S. le 2020
We study the effect of delaying treatment in the presence of (unobserved) heterogeneity. In a homogeneous population and assuming a proportional treatment effect, a treatment delay period will... Show moreWe study the effect of delaying treatment in the presence of (unobserved) heterogeneity. In a homogeneous population and assuming a proportional treatment effect, a treatment delay period will result in notably lower cumulative recovery percentages. We show in theoretical scenarios using frailty models that if the population is heterogeneous, the effect of a delay period is much smaller. This can be explained by the selection process that is induced by the frailty. Patient groups that start treatment later have already undergone more selection. The marginal hazard ratio for the treatment will act differently in such a more homogeneous patient group. We further discuss modeling approaches for estimating the effect of treatment delay in the presence of heterogeneity, and compare their performance in a simulation study. The conventional Cox model that fails to account for heterogeneity overestimates the effect of treatment delay. Including interaction terms between treatment and starting time of treatment or between treatment and follow up time gave no improvement. Estimating a frailty term can improve the estimation, but is sensitive to misspecification of the frailty distribution. Therefore, multiple frailty distributions should be used and the results should be compared using the Akaike Information Criterion. Non-parametric estimation of the cumulative recovery percentages can be considered if the dataset contains sufficient long term follow up for each of the delay strategies. The methods are demonstrated on a motivating application evaluating the effect of delaying the start of treatment with assisted reproductive techniques on time-to-pregnancy in couples with unexplained subfertility. Show less
