Research for new drugs for elimination of onchocerciasis in Africa

Abstract

Onchocerciasis is a parasitic, vector borne disease caused by the filarial nematode Onchocerca volvulus. More than 99% of the population at risk of infection live in Africa. Onchocerciasis control was initiated in West Africa in 1974 with vector control, later complemented by ivermectin mass drug administration and in the other African endemic countries in 1995 with annual community directed treatment with ivermectin (CDTI.) This has significantly reduced infection prevalence. Together with proof-of-concept for onchocerciasis elimination with annual CDTI from foci in Senegal and Mali, this has resulted in targeting onchocerciasis elimination in selected African countries by 2020 and in 80% of African countries by 2025. The challenges for meeting these targets include the number of endemic countries where conflict has delayed or interrupted control programmes, cross-border foci, potential emergence of parasite strains with low susceptibility to ivermectin and co-endemicity of loiasis, another parasitic vector borne disease, which slows down or prohibits CDTI implementation. Some of these challenges could be addressed with new drugs or drug combinations with a higher effect on Onchocerca volvulus than ivermectin. This paper reviews the path from discovery of new compounds to their qualification for large scale use and the support regulatory authorities provide for development of drugs for neglected tropical diseases. The status of research for new drugs or treatment regimens for onchocerciasis along the path to regulatory approval and qualification for large scale use is reviewed. This research includes new regimens and combinations of ivermectin and albendazole, antibiotics targeting the O. volvulus endosymbiont Wolbachia, flubendazole, moxidectin and emodepside and discovery of new compounds.

Untreated villages and factors associated with the absence of Community-Directed Treatment with Ivermectin (CDTI) in DRC

“…These side effects have discouraged the population from starting/continuing the treatment. To our opinion, one of NPOC weaknesses is the lack of importance given to education and/or public awareness which are crucial aspects leading to therapy acceptance, as demonstrated by Kuesel in his study [30]. We are convinced that onchocerciasis eradication will not be achieved without the entire cooperation of the population.…”

Genome-wide analysis of ivermectin response byOnchocerca volvulusreveals that genetic drift and soft selective sweeps contribute to loss of drug sensitivity

“…With respect to SORs, genotyping assays will benefit control programs in multiple ways by (i) providing diagnostic tools to monitor changes in the frequency of SORs (e.g. genotyping infective larvae in the vector), (ii) discriminating between genetic explanations for persistence of transmission (i.e., selection for SOR) and other factors that determine CDTI success (such as host-related factors, treatment coverage and compliance, pre-control prevalence and intensity of infection and vector biting rates [48–53, 99]), and (iii) suggesting a trigger for the initiation of alternative treatment strategies, such as anti-Wolbachia treatment [101, 102], local vector control, or new treatments that may become available sooner or later like moxidectin [46, 103], or combination treatments, flubendazole or emodepside (as reviewed in [104]) in populations where persistent transmission is observed in spite of CDTI [105].…”

Modelling exposure heterogeneity and density dependence in onchocerciasis using a novel individual-based transmission model, EPIONCHO-IBM: Implications for elimination and data needs

“…We have used EPIONCHO-IBM to better understand how density-dependent processes-in particular the density-dependent establishment of newly acquired O. volvulus parasites-and heterogeneity in individual human exposure shape both the relationships between microfilarial prevalence, microfilarial intensity and ABR, and the resilience of onchocerciasis to MDA with ivermectin. In future, EPIONCHO-IBM will be used to model the control and elimination of onchocerciasis using current and alternative interventions, including the use of anti-Wolbachia therapies [81], moxidectin [82], ground-based vector control [83] and new macrofilaricidal therapies [84]. Our work also highlights the importance and uncertainty in the key and interactive population processes of density dependence and heterogeneity in exposure to blackfly vectors.…”