Mathematical modelling to support the elimination of onchocerciasis transmission
File(s)
Author(s)
Milton, Philip
Type
Thesis
Abstract
Human onchocerciasis is a neglected tropical disease (NTD) caused by the filarial nematode Onchocerca volvulus (Filarioidea: Onchocercidae) and transmitted by the bites of Simulium (Diptera: Simuliidae) blackflies. The disease is or has been endemic in 37 countries, with the majority (30) in sub-Saharan Africa, 6 in Latin America and 1 in the Eastern Mediterranean region (Yemen). Large-scale mass drug administration for onchocerciasis control became possible from the late 1980s with the donation of ivermectin by Merck & Co. Inc. With the success of onchocerciasis control programmes, the primary goal of onchocerciasis treatment (in Africa specifically) shifted from morbidity control to the elimination of the infection where feasible by 2020 and in 80% of endemic countries by 2025. In the new World Health Organization roadmap on NTDs, the goals for onchocerciasis were reformulated as verification of elimination of transmission in 12 countries by 2030. However, the feasibility of achieving and maintaining the proposed elimination goals remains unclear. With the deadlines for the proposed goals rapidly approaching, and with many countries unlikely to reach the elimination goals with ivermectin alone, the focus has increasingly shifted to identifying alternative strategies aimed at accelerating progress towards elimination.
Mathematical models of onchocerciasis have been used to provide quantitative guidance on time horizons to elimination, health impact, economic cost and cost-effectiveness, and the efficacy of potentially novel treatment strategies. The central aim of this thesis is to use EPIONCHO-IBM, a recently developed stochastic individual-based transmission model of onchocerciasis transmission and control in communities of Africa, to support efforts towards the elimination of onchocerciasis in Africa.
The first half of the thesis focuses primarily on moxidectin, a milbemycin macrocyclic lactone recently approved for the treatment of human onchocerciasis. Moxidectin represents a potential tool to accelerate progress towards elimination given its superior efficacy to ivermectin in both Phase II and Phase III clinical trials. The thesis first reviews the current literature on moxidectin’s pharmacology and clinical trials, and discusses the potential of moxidectin to accelerate onchocerciasis elimination. Subsequent chapters aim to understand the potential epidemiological impact of moxidectin in the context of onchocerciasis control programmes that currently rely on mass ivermectin administration. EPIONCHO-IBM is parameterised to capture the single-dose effects of moxidectin and ivermectin. The effects of a single treatment were extended to evaluate are compare the ability of both drugs to suppress onchocerciasis transmission and achieve local elimination given multiple rounds of treatment. EPIONCHO-IBM is also used to explore potential effects that could impact control efforts with moxidectin and ivermectin but which have not been fully evaluated. This includes inter-individual variation in treatment responses to ivermectin and moxidectin using individual data from the Phase III clinical trial of moxidectin, and the potential prophylactic effects of ivermectin and moxidectin on pre-adult larvaal stages of O. volvulus by combining data on each drug’s inhibitory effect in vitro and kinetics in vivo.
The second half of the thesis focuses on re-evaluating and refining modelling assumptions to more accurately model onchocerciasis transmission and control. Accurately modelling who is treated within the population is an important factor for model dynamics. Therefore, EPIONCHO-IBM’s current compliance model, which governs who takes treatment at a given round, is evaluated and improved by using the more flexible beta-binomial distribution. The two models of compliance are compared on their ability to capture data on the number of rounds taken by individuals in onchocerciasis control programmes as well as the impact on EPIONCHO-IBM predictions.
Blackfly biting rates are a key determinant of both the intensity of onchocerciasis transmission and the likely success of interventions. Data from recently developed immunoassays to measure antibodies against blackfly saliva antigens are analysed as a potential tool to measure exposure to blackfly bites. The analysis incudes both a statistical and mechanistic analysis of the data, including the uses of antibody acquisition models designed to capture the change in antibody levels with age and sex, as a tool to identify patterns of age- and sex-specific exposure to blackfly bites under different immunological assumptions.
Finally, challenges for both onchocerciasis modelling and the development of EPIONCHO-IBM are discussed, highlighting some of the outstanding issues that should be evaluated for mathematical models of onchocerciasis to be as helpful as possible in the global fight to eliminate onchocerciasis transmission.
Mathematical models of onchocerciasis have been used to provide quantitative guidance on time horizons to elimination, health impact, economic cost and cost-effectiveness, and the efficacy of potentially novel treatment strategies. The central aim of this thesis is to use EPIONCHO-IBM, a recently developed stochastic individual-based transmission model of onchocerciasis transmission and control in communities of Africa, to support efforts towards the elimination of onchocerciasis in Africa.
The first half of the thesis focuses primarily on moxidectin, a milbemycin macrocyclic lactone recently approved for the treatment of human onchocerciasis. Moxidectin represents a potential tool to accelerate progress towards elimination given its superior efficacy to ivermectin in both Phase II and Phase III clinical trials. The thesis first reviews the current literature on moxidectin’s pharmacology and clinical trials, and discusses the potential of moxidectin to accelerate onchocerciasis elimination. Subsequent chapters aim to understand the potential epidemiological impact of moxidectin in the context of onchocerciasis control programmes that currently rely on mass ivermectin administration. EPIONCHO-IBM is parameterised to capture the single-dose effects of moxidectin and ivermectin. The effects of a single treatment were extended to evaluate are compare the ability of both drugs to suppress onchocerciasis transmission and achieve local elimination given multiple rounds of treatment. EPIONCHO-IBM is also used to explore potential effects that could impact control efforts with moxidectin and ivermectin but which have not been fully evaluated. This includes inter-individual variation in treatment responses to ivermectin and moxidectin using individual data from the Phase III clinical trial of moxidectin, and the potential prophylactic effects of ivermectin and moxidectin on pre-adult larvaal stages of O. volvulus by combining data on each drug’s inhibitory effect in vitro and kinetics in vivo.
The second half of the thesis focuses on re-evaluating and refining modelling assumptions to more accurately model onchocerciasis transmission and control. Accurately modelling who is treated within the population is an important factor for model dynamics. Therefore, EPIONCHO-IBM’s current compliance model, which governs who takes treatment at a given round, is evaluated and improved by using the more flexible beta-binomial distribution. The two models of compliance are compared on their ability to capture data on the number of rounds taken by individuals in onchocerciasis control programmes as well as the impact on EPIONCHO-IBM predictions.
Blackfly biting rates are a key determinant of both the intensity of onchocerciasis transmission and the likely success of interventions. Data from recently developed immunoassays to measure antibodies against blackfly saliva antigens are analysed as a potential tool to measure exposure to blackfly bites. The analysis incudes both a statistical and mechanistic analysis of the data, including the uses of antibody acquisition models designed to capture the change in antibody levels with age and sex, as a tool to identify patterns of age- and sex-specific exposure to blackfly bites under different immunological assumptions.
Finally, challenges for both onchocerciasis modelling and the development of EPIONCHO-IBM are discussed, highlighting some of the outstanding issues that should be evaluated for mathematical models of onchocerciasis to be as helpful as possible in the global fight to eliminate onchocerciasis transmission.
Version
Open Access
Date Issued
2021-09
Date Awarded
2022-07
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Bhatt, Samir
Basanez, Maria-Gloria
Sponsor
Medical Research Council (Great Britain)
Publisher Department
School of Public Health
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)