Welsche, Sophie. Combination therapy against soil-transmitted helminthiasis: from egg excretion patterns to treatment effects. 2024, Doctoral Thesis, University of Basel, Associated Institution, Faculty of Science.
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Abstract
Soil-transmitted helminths (STHs) are parasitic nematodes dwelling in the intestinal tract of
their hosts. The four major worms infecting humans are Ascaris lumbricoides, Trichuris trichiura, hookworm and Strongyloides stercoralis. Infections with STHs belong to the group of Neglected Tropical Diseases (NTDs), which notoriously affect the most impoverished populations in subtropical and tropical regions. An estimated 1.5 billion people are infected worldwide, causing a considerable disease burden and exacerbating the vicious cycle of socio-economic struggles and disease. The World Health Organization (WHO) promotes global coordinated control efforts with preventive chemotherapy (PC) as the central strategy. This approach primarily aims at curbing heavy infections, however the ultimate goal goes beyond morbidity control to elimination of STH infections as a public health problem. Single-dose albendazole and mebendazole are the drugs of choice to treat STH infections in PC schemes. Both drugs have excellent safety profiles and work well against A. lumbricoides infections, however the efficacy against hookworm is merely moderate and neither of the drugs are sufficiently efficacious in reducing T. trichiura infections. The co-administration of two or more drugs is a promising strategy to increase the efficacy of treatments. Furthermore, re-purposing drugs applied for other pathogens may be a comparatively fast and effective way to broaden the currently available treatment options against STHs.
The core work of this PhD centered on two randomized controlled trials (RCTs) assessing the efficacy and safety of two combination treatments against infections with T. trichiura. One objective was to contribute to a multi-country trial investigating the combination treatment of ivermectin-albendazole in comparison to albendazole monotherapy in children and adults between 6 and 60 years of age in three settings: Pemba Island, Tanzania in East Africa, Côte d’Ivoire in West Africa and Lao PDR in Southeast Asia. The results found the combination treatment to be superior to albendazole on Pemba Island and in Lao PDR, with CRs of 49% vs. 6% and 66% vs. 8%, respectively. In Côte d’Ivoire however, the combination treatment did not result in a superior efficacy to albendazole alone.
A sub-study conducted within the framework of the multi-country trial in Lao PDR had the aim of determining the optimal timepoint at which to collect stool samples for the assessment of anthelminthic drug efficacies. For this, the daily egg excretion patterns of STHs during 28 days following ivermectin-albendazole and albendazole treatment were analyzed. The assessment of samples collected at 14-21 days post-treatment could be confirmed as an adequate timeframe for an accurate representation of the true efficacy.
A second RCT assessed the safety and efficacy of the combination treatment of moxidectin-albendazole in comparison to ivermectin-albendazole in adolescents infected with T. trichiura on Pemba Island, Tanzania. Non-inferiority by two percentage points in terms of egg reduction rate (ERR) could not be shown, with 96.8% (95% CI 95.8 – 97.6) for moxidectin-albendazole in comparison to 99.0% (95% CI 98.7 – 99.3) for ivermectin-albendazole. The moxidectin-albendazole combination treatment resulted in a higher CR compared to moxidectin and albendazole administered in monotherapy, with the latter difference not being statistically significant. Combined ivermectin-albendazole led to significantly higher CRs than the respective ivermectin and albendazole monotherapies.
In conclusion, the successes achieved by PC to date should be expanded in order to meet the WHO 2030 targets for STH infections and to move from morbidity control towards elimination. Improved treatment options should be incorporated into PC schemes delivered via MDA programs. The results presented in this thesis confirmed the ivermectin-albendazole combination therapy to be superior in terms of CRs against T. trichiura compared to albendazole monotherapy in two of the three settings of the multi-country study. Furthermore, even though non-inferiority could not be shown for the moxidectin-albendazole combination treatment compared to ivermectin-albendazole in terms of ERRs among adolescents infected with T. trichiura on Pemba Island, further research in different settings is warranted as adding moxidectin to the albendazole standard treatment might be a valuable option in areas in which ivermectin is not available. The NTD landscape needs to be carefully considered in order to find the optimal treatment option for each setting to potentially target various pathogens and to enhance treatment efficacy.
their hosts. The four major worms infecting humans are Ascaris lumbricoides, Trichuris trichiura, hookworm and Strongyloides stercoralis. Infections with STHs belong to the group of Neglected Tropical Diseases (NTDs), which notoriously affect the most impoverished populations in subtropical and tropical regions. An estimated 1.5 billion people are infected worldwide, causing a considerable disease burden and exacerbating the vicious cycle of socio-economic struggles and disease. The World Health Organization (WHO) promotes global coordinated control efforts with preventive chemotherapy (PC) as the central strategy. This approach primarily aims at curbing heavy infections, however the ultimate goal goes beyond morbidity control to elimination of STH infections as a public health problem. Single-dose albendazole and mebendazole are the drugs of choice to treat STH infections in PC schemes. Both drugs have excellent safety profiles and work well against A. lumbricoides infections, however the efficacy against hookworm is merely moderate and neither of the drugs are sufficiently efficacious in reducing T. trichiura infections. The co-administration of two or more drugs is a promising strategy to increase the efficacy of treatments. Furthermore, re-purposing drugs applied for other pathogens may be a comparatively fast and effective way to broaden the currently available treatment options against STHs.
The core work of this PhD centered on two randomized controlled trials (RCTs) assessing the efficacy and safety of two combination treatments against infections with T. trichiura. One objective was to contribute to a multi-country trial investigating the combination treatment of ivermectin-albendazole in comparison to albendazole monotherapy in children and adults between 6 and 60 years of age in three settings: Pemba Island, Tanzania in East Africa, Côte d’Ivoire in West Africa and Lao PDR in Southeast Asia. The results found the combination treatment to be superior to albendazole on Pemba Island and in Lao PDR, with CRs of 49% vs. 6% and 66% vs. 8%, respectively. In Côte d’Ivoire however, the combination treatment did not result in a superior efficacy to albendazole alone.
A sub-study conducted within the framework of the multi-country trial in Lao PDR had the aim of determining the optimal timepoint at which to collect stool samples for the assessment of anthelminthic drug efficacies. For this, the daily egg excretion patterns of STHs during 28 days following ivermectin-albendazole and albendazole treatment were analyzed. The assessment of samples collected at 14-21 days post-treatment could be confirmed as an adequate timeframe for an accurate representation of the true efficacy.
A second RCT assessed the safety and efficacy of the combination treatment of moxidectin-albendazole in comparison to ivermectin-albendazole in adolescents infected with T. trichiura on Pemba Island, Tanzania. Non-inferiority by two percentage points in terms of egg reduction rate (ERR) could not be shown, with 96.8% (95% CI 95.8 – 97.6) for moxidectin-albendazole in comparison to 99.0% (95% CI 98.7 – 99.3) for ivermectin-albendazole. The moxidectin-albendazole combination treatment resulted in a higher CR compared to moxidectin and albendazole administered in monotherapy, with the latter difference not being statistically significant. Combined ivermectin-albendazole led to significantly higher CRs than the respective ivermectin and albendazole monotherapies.
In conclusion, the successes achieved by PC to date should be expanded in order to meet the WHO 2030 targets for STH infections and to move from morbidity control towards elimination. Improved treatment options should be incorporated into PC schemes delivered via MDA programs. The results presented in this thesis confirmed the ivermectin-albendazole combination therapy to be superior in terms of CRs against T. trichiura compared to albendazole monotherapy in two of the three settings of the multi-country study. Furthermore, even though non-inferiority could not be shown for the moxidectin-albendazole combination treatment compared to ivermectin-albendazole in terms of ERRs among adolescents infected with T. trichiura on Pemba Island, further research in different settings is warranted as adding moxidectin to the albendazole standard treatment might be a valuable option in areas in which ivermectin is not available. The NTD landscape needs to be carefully considered in order to find the optimal treatment option for each setting to potentially target various pathogens and to enhance treatment efficacy.
Advisors: | Keiser, Jennifer |
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Committee Members: | Utzinger, Jürg and Rinaldi, Laura |
Faculties and Departments: | 09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Helminth Drug Development (Keiser) 09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Former Units within Swiss TPH > Health Impact Assessment (Utzinger) |
UniBasel Contributors: | Keiser, Jennifer and Utzinger, Jürg |
Item Type: | Thesis |
Thesis Subtype: | Doctoral Thesis |
Thesis no: | 15361 |
Thesis status: | Complete |
Number of Pages: | xx, 223 |
Language: | English |
Identification Number: |
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edoc DOI: | |
Last Modified: | 18 Jul 2024 15:09 |
Deposited On: | 28 May 2024 12:02 |
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