Improved treatment for the control of soil-transmitted helminthiases: from meta-analysis to clinical trials

Helminth infections are responsible for the largest burden of neglected tropical diseases. The most common helminth infections are caused by soil-transmitted helminths (STHs); these worms infect about 1.5 billion people worldwide. Children the at high risk of contracting these infections, particularly in regions where inadequate water supply and sanitation, crowded living conditions, difficult access to health care and low levels of education are a reality. Although light infections are mostly asymptomatic, heavier STH infections can cause irreversible damage to the host, such as physical and intellectual growth retardation. The World Health Organization (WHO) recommends preventive chemotherapy as the main control strategy against STH infections. This strategy consists of the distribution of a single dose of albendazole or mebendazole to at-risk populations with the goal of reducing the infection intensities and, consequently, reducing morbidity. However, this approach has several drawbacks that include its inability of preventing re-infections, the low efficacy of the currently distributed drugs, and the imminent threat of resistance emergence. Thus, we are at a stage when it is crucial to find more efficacious treatment options. Most of the objectives of my PhD focused on chemotherapy and, hence, were somewhat linked to preventive chemotherapy. The first objective consisted in optimizing the use of mebendazole against hookworm. For this, we implemented two clinical trials. The first trial compared the efficacy and safety of a single dose of mebendazole to a multiple dose against hookworm infections. We found that both regimens were equally safe and, importantly, that the multiple dose of mebendazole was remarkably more efficacious against hookworm and Trichuris trichiura than the currently used single dose. The second trial compared the standard tablet of mebendazole to a new chewable formulation of mebendazole. We concluded both formulations were equally efficacious and safe. Therefore, the new chewable formulation might represent an important advantage for young children who have a difficulty swallowing whole tablets. The second objective of my PhD was to conduct a literature review and meta-analysis comparing the single dose of albendazole to the combination of albendazole and ivermectin against STH infections. This study revealed that the combination of albendazole and ivermectin was significantly better at treating T. trichiura-infected subjects than albendazole alone, but had no or only marginal benefit against Ascaris lumbricoides and hookworm. The two therapies were found to be equally safe. The third objective of my PhD was to find the most efficacious dose of moxidectin alone or moxidectin combined with albendazole (400 mg) against T. trichiura infections. We found that 8 mg of moxidectin performed just as well as 16 and 24 mg, and that the combination of moxidectin and albendazole was significantly more efficacious than either one alone. In the fourth objective we focused on the consenting procedure of clinical trials. Embedded in my first clinical trial, we conducted a sub-study that aimed at testing different methods of communicating relevant information about the clinical trial to the caregivers of the participants. We found that a pamphlet was not effective, but an oral information session significantly increase their knowledge concerning our trial. Finally, the fifth objective was to assess the health status of schoolchildren in the Kibaoni ward, Tanzania. Our cross-sectional study revealed that the prevalence of most parasitic species was low, which indicates that efforts towards the control of soil-transmitted helminthiases, schistosomiasis and malaria have been quite successful. In conclusion, our findings have shown that there are available alternative therapies (such as a multiple dose of mebendazole, the combination of albendazole and XIII ivermectin) which are more efficacious against STH than a single dose of mebendazole or albendazole. The repurposing of certain drugs, such as moxidectin, is also worth considering. Moreover, we have found that replacing the current solid tablets by chewable formulations might be a valuable step towards increasing the compliance of young children. Finally, to ensure clinical trial participants’ (or their caregivers’) true comprehension of a study before agreeing to participate, we recommend researchers plan participant information sessions