Modeling the effect of different drugs and treatment regimen for hookworm on cure and egg reduction rates taking into account diagnostic error

Background: Hookworm infections, caused by Ancylostoma duodenale and Necator americanus, are of considerable public health importance. The World Health Organization recommends preventive chemotherapy as the key strategy for morbidity control. Meta-analyses have been conducted to estimate treatment efficacy of available drugs and drug combinations. However, in most studies, the relation between the diagnostic error and infection intensity have not been considered, resulting in an overestimation of cure rates (CRs). Methodology: A Bayesian model was developed to compare the ‘true’ CR and egg reduction rate of different treatment regimens for hookworm infections taking into account the error of the recommended Kato-Katz thick smear diagnostic technique. It was fitted to the observed egg count data which was linked to the distribution of worms, considered the day-to-day variation of hookworm egg excretion and estimated the infection intensity-dependent sensitivity. The CR was obtained by defining the prevalence of infection at follow-up as the probability of having at least one fertilized female worm. The model was applied to individual-level egg count data available from 17 treatments and six clinical trials. Principal findings: Taking the diagnostic error into account resulted in considerably lower CRs than previously reported. Overall, of all treatments analyzed, mebendazole administered in six dosages of 100 mg each was the most efficacious treatment with a CR of 88% (95% Bayesian credible interval: 79-95%). Furthermore, diagnostic sensitivity varied with the infection intensity and sampling effort. For an infection intensity of 50 eggs per gram of stool, the sensitivity is close to 60%; for two Kato-Katz thick smears it increased to approximately 76%. Conclusions/significance: Our model-based estimates provide the true efficacy of different treatment regimens against hookworm infection taking into account the diagnostic error of the Kato-Katz method. Estimates of the diagnostic sensitivity for different number of stool samples and thick smears are obtained. To accurately assess efficacy in clinical trials with the Kato-Katz method, at least two stool samples on consecutive days should be collected. Author summary: Human hookworm infections are primarily caused by two parasitic worm species, namely Ancylostoma duodenale and Necator americanus. Already moderate infection intensities can impair cognitive and physical development of children, and reduce fertility in women of reproductive age. The World Health Organization set the global target to eliminate morbidity due to hookworm infections in preschool-age and school-age children by 2030. To reach this goal, different public health interventions are carried out. The most widely used strategy is mass drug administration. To assess the efficacy of treatments, epidemiologic studies and clinical trials usually employ the Kato-Katz thick smear technique to microscopically examine stool samples of individuals before and after treatment. Of note, this diagnostic test is not 100% accurate such that not all positive individuals are detected. We developed a mathematical model, which takes into account the diagnostic error to compare the ‘true’ efficacy of different drugs and treatment regimens against hookworm infection. Furthermore, we computed how well the test detects infected individuals in relation to infection intensity. We found that the diagnostic sensitivity of the Kato-Katz thick smear technique increases considerably if two stool specimens from different days are collected and multiple Kato-Katz thick smears are analyzed instead of one.