New drugs, drug combinations and improved diagnostics for the control of helminthic infections

Neglected Tropical Diseases (NTDs) represent one of the biggest health challenges in tropical and subtropical countries. They are most commonly caused by helminths, including the soil-transmitted helminths (STH) (Ascaris lumbricoides, Trichuris trichiura, Ancylostoma duodenale and Necator americanus), Schistosoma spp (S. haematobium, S. mansoni, S. japonicum being the most common) and Strongyloides stercoralis. Helminth infections are widely distributed but prevalence is highest in low-resource settings in subSaharan Africa, the Americas and Asia. Helminthic infections are more common in children, and, when chronic may be responsible for severe morbidities that interfere with normal growth and cognitive development. Preventive chemotherapy (PC) is the main strategy promoted by the World Health Organization to control morbidities linked to NTDs. This intervention is based on regular anthelminthic treatment of in-need populations in endemic areas. Diagnostic methods for the detection of these infections suffer from low sensitivity and new approaches, such as molecular techniques, that may improve sensitivity, often are not applicable in field laboratories where expensive tools are not affordable. The treatment of NTDs relies on few drugs: benzimidazoles (albendazole and mebendazole) for STH, praziquantel for schistosomiasis and ivermectin for onchocerciasis, lymphatic filariasis and strongyloidiasis. PC programs are highly effective but the regular use of the few available drugs in a vast population raises concern regarding development of resistance. Although confirmed resistance has not yet been proved, a lower sensitivity to praziquantel has been reported in populations who received several rounds of PC. Additionally, benzimidazoles are scarcely effective against T. trichiura. Therefore, there is a great need of new effective drugs to tackle these infections. In the frame of my PhD program, I addressed the need of developing new drugs against helminthic infections by testing the efficacy of moxidectin, a macrocyclic lactone used in veterinary medicine, against STH, S. haematobium, S. mansoni, and S. stercoralis in exploratory randomized Phase 2 trials. We confirmed its good efficacy against S. stercoralis but not against Schistosoma spp. In our randomized non-inferiority Phase 2 clinical trial conducted with different drug combinations, moxidectin in co-administration with albendazole showed a good efficacy against STH infections. From a diagnostic point of view, we assessed the sensitivity of two DNA extraction methods for the detection of S. stercoralis using PCR; this technique showed a good potential but further studies are still necessary to improve its standardization. We also conducted an ultrasound assessment of the impact of different doses of praziquantel on urinary tract morbidity in S. haematobium infected children versus placebo. We found that light and moderate bladder morbidity has an early onset, and is present in pre-school-aged children. Six months after treatment we registered 90% of regression of morbidity in treated children and only 10% in the placebo group. Our findings contribute to the development of moxidectin against helminthic infections. Our findings indicate that this drug is worth further evaluations before it can be promoted for public health campaigns. Furthermore, our data might foster the development of new potential diagnostics for NTDs such as S. stercoralis. Eventually, we confirmed the relevance of PC for the control of morbidity due to urogenital schistosomiasis that can be assessed in the field by relatively simple tools such as ultrasound