Promising Drug Combination Treatment Against Parasitic Worm Infections

Soil-transmitted helminths (STH) affect one in five people in the world causing numerous health problems, including abdominal pain, diarrhea, blood and protein loss and both physical and cognitive growth retardation. According to WHO, over 260 million preschool-age children and over 560 million school-age children are at risk and it is highly prevalent in impoverished, rural areas with poor sanitation and inadequate access to safe water. STH infections are caused by the roundworm Ascaris lumbricoides, two hookworm species and the whipworm Trichuris trichiura.  

Only very few drugs are registered for treatment and control of STH infections in humans, all of which have limitations. To date, periodic mass administration of benzimidazoles is done within preventive chemotherapy schemes. The usage of albendazole is the cornerstone of STH control and primarily aims to reduce morbidity from high intensity infections. However, benzimidazoles show limited efficacy against Trichuris trichiura at single doses. To reduce the disease burden in endemic countries, more efficacious and safe drugs are urgently needed. One way to overcome the currently low availability of novel, potent and approved drugs is to administer combinations of already registered anthelminthics.

Co-administered ivermectin-albendazole enhances efficacy

The combination of ivermectin and albendazole has been identified as a priority to be tested as a potential improved deworming therapy. Evidence points towards a potential synergy in drug efficacy in this combination. Additionally, the individual drugs are known to have an excellent safety profile from their wide use in other neglected tropical disease control programmes.

Swiss TPH conducted the first multi-country randomized controlled clinical trial to generate robust evidence from a broader age range and distinct epidemiological settings on the superiority of co-administered ivermectin-albendazole over the current standard treatment (albendazole monotherapy). The trial involved community members aged 6-60 years from Côte d’Ivoire, Laos and Pemba Island, Tanzania, infected with Trichuris trichiura. Primary outcome was efficacy in terms of cure rates (proportion of subjects no longer shedding T. trichiura eggs 14-21 days after treatment). Ivermectin-albendazole showed higher efficacy against trichuriasis in the study groups in Laos (66% vs 8%) and on Pemba Island (49% vs 6%). Findings from Côte d’Ivoire, however, showed no benefit from ivermectin co-administration with cure rates of 14% in the ivermectin-albendazole group compared to 10% in the albendazole monotherapy group. This difference in drug efficacy could not be explained by the cohort characteristics; the two African cohorts recruited were similar with regard to their age distribution and baseline infection intensities.

The low efficacy of ivermectin-albendazole drug combination treatment against trichuriasis in Côte d’Ivoire calls for further investigation. “There are several possible reasons for the low efficacy; one of them might be the parasite itself. It is conceivable that strains of T. trichiura vary in different geographical settings and related to this, their susceptibility to drugs”, said Eveline Hürlimann, Swiss TPH Senior Scientific Collaborator and first author of this publication. “Patient factors such as differences in the intestinal microbiome or the metabolism in each subject might play a role in influencing the efficacy of the treatment as well”, she added. Nonetheless, having a long history of community-wide usage of ivermectin to fight filarial diseases, potential emergence of acquired drug resistance in Côte d’Ivoire should be examined.

Paving the path for accessibility and implementation

Having over two decades of proven success in the control of lymphatic filariasis, it was paramount to leverage on this established success of ivermectin-albendazole therapy and assess its efficacy against other STH diseases. Following these promising findings specifically against trichuriasis, making this drug accessible to endemic countries is the next reasonable step.

Before this drug combination can be implemented in countries in dire need of helminthiasis disease intervention, there are challenges that need to be addressed. These include the insufficiency in supply due to high cost and lack of donation. Furthermore, there are complications in community-wide implementation due to the yet to be approved usage of the drug in preschool-age children and that the dosage of ivermectin involves either weight or height utilities that was not needed before for STH mass drug administration.

“With no anthelminthic drug in the pipeline, the usage of drug combinations of already approved products with different modes of action could not only enhance efficacy but also delay the onset of resistance and help to eliminate this disease as a public health problem”, said Jennifer Keiser, Head of the Helminth Drug Development unit at Swiss TPH and last author of the publication.