Modelling the elimination of river blindness using long-term epidemiological and programmatic data from Mali and Senegal.
ABSTRACT: The onchocerciasis transmission models EPIONCHO and ONCHOSIM have been independently developed and used to explore the feasibility of eliminating onchocerciasis from Africa with mass (annual or biannual) distribution of ivermectin within the timeframes proposed by the World Health Organization (WHO) and endorsed by the 2012 London Declaration on Neglected Tropical Diseases (i.e. by 2020/2025). Based on the findings of our previous model comparison, we implemented technical refinements and tested the projections of EPIONCHO and ONCHOSIM against long-term epidemiological data from two West African transmission foci in Mali and Senegal where the observed prevalence of infection was brought to zero circa 2007-2009 after 15-17 years of mass ivermectin treatment. We simulated these interventions using programmatic information on the frequency and coverage of mass treatments and trained the model projections using longitudinal parasitological data from 27 communities, evaluating the projected outcome of elimination (local parasite extinction) or resurgence. We found that EPIONCHO and ONCHOSIM captured adequately the epidemiological trends during mass treatment but that resurgence, while never predicted by ONCHOSIM, was predicted by EPIONCHO in some communities with the highest (inferred) vector biting rates and associated pre-intervention endemicities. Resurgence can be extremely protracted such that low (microfilarial) prevalence between 1% and 5% can be maintained for 3-5 years before manifesting more prominently. We highlight that post-treatment and post-elimination surveillance protocols must be implemented for long enough and with high enough sensitivity to detect possible residual latent infections potentially indicative of resurgence. We also discuss uncertainty and differences between EPIONCHO and ONCHOSIM projections, the potential importance of vector control in high-transmission settings as a complementary intervention strategy, and the short remaining timeline for African countries to be ready to stop treatment safely and begin surveillance in order to meet the impending 2020/2025 elimination targets.
Project description:<h4>Background</h4>Great strides have been made toward onchocerciasis elimination by mass drug administration (MDA) of ivermectin. Focusing on MDA-eligible areas, we investigated where the elimination goal can be achieved by 2025 by continuation of current practice (annual MDA with ivermectin) and where intensification or additional vector control is required. We did not consider areas hypoendemic for onchocerciasis with loiasis coendemicity where MDA is contraindicated.<h4>Methods</h4>We used 2 previously published mathematical models, ONCHOSIM and EPIONCHO, to simulate future trends in microfilarial prevalence for 80 different settings (defined by precontrol endemicity and past MDA frequency and coverage) under different future treatment scenarios (annual, biannual, or quarterly MDA with different treatment coverage through 2025, with or without vector control strategies), assessing for each strategy whether it eventually leads to elimination.<h4>Results</h4>Areas with 40%-50% precontrol microfilarial prevalence and ?10 years of annual MDA may achieve elimination with a further 7 years of annual MDA, if not achieved already, according to both models. For most areas with 70%-80% precontrol prevalence, ONCHOSIM predicts that either annual or biannual MDA is sufficient to achieve elimination by 2025, whereas EPIONCHO predicts that elimination will not be achieved even with complementary vector control.<h4>Conclusions</h4>Whether elimination will be reached by 2025 depends on precontrol endemicity, control history, and strategies chosen from now until 2025. Biannual or quarterly MDA will accelerate progress toward elimination but cannot guarantee it by 2025 in high-endemicity areas. Long-term concomitant MDA and vector control for high-endemicity areas might be useful.
Project description:<h4>Background</h4>Mass drug administration (MDA) of ivermectin for onchocerciasis has been disrupted by the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modelling can help predict how missed/delayed MDA will affect short-term epidemiological trends and elimination prospects by 2030.<h4>Methods</h4>Two onchocerciasis transmission models (EPIONCHO-IBM and ONCHOSIM) are used to simulate microfilarial prevalence trends, elimination probabilities and age profiles of Onchocerca volvulus microfilarial prevalence and intensity for different treatment histories and transmission settings, assuming no interruption, a 1-y (2020) interruption or a 2-y (2020-2021) interruption. Biannual MDA or increased coverage upon MDA resumption are investigated as remedial strategies.<h4>Results</h4>Programmes with shorter MDA histories and settings with high pre-intervention endemicity will be the most affected. Biannual MDA is more effective than increasing coverage for mitigating COVID-19's impact on MDA. Programmes that had already switched to biannual MDA should be minimally affected. In high-transmission settings with short treatment history, a 2-y interruption could lead to increased microfilarial load in children (EPIONCHO-IBM) and adults (ONCHOSIM).<h4>Conclusions</h4>Programmes with shorter (annual MDA) treatment histories should be prioritised for remedial biannual MDA. Increases in microfilarial load could have short- and long-term morbidity and mortality repercussions. These results can guide decision-making to mitigate the impact of COVID-19 on onchocerciasis elimination.
Project description:The African Programme for Onchocerciasis Control (APOC) has refocused its goals on the elimination of infection where possible, seemingly achievable by 15-17 years of annual mass distribution of ivermectin in some African foci. Previously, APOC had focused on the elimination of onchocerciasis as a public health problem. Timeframes have been set by the World Health Organization, the London Declaration on Neglected Tropical Diseases and the World Bank to achieve these goals by 2020-2025.A novel mathematical model of the dynamics of onchocercal disease is presented which links documented associations between Onchocerca volvulus infection and the prevalence and incidence of morbidity and mortality to model outputs from our host age- and sex-structured onchocerciasis transmission framework (EpiOncho). The model is calibrated for African savannah settings, and used to assess the impact of long-term annual mass administration of ivermectin on infection and ocular and skin disease and to explore how this depends on epidemiological and programmatic variables.Current onchocerciasis disease projections, which do not account for excess mortality of sighted individuals with heavy microfilarial loads, underestimate disease burden. Long-term annual ivermectin treatment is highly effective at reducing both the morbidity and mortality associated with onchocerciasis, and this result is not greatly influenced by treatment coverage and compliance. By contrast, impact on microfilarial prevalence and intensity is highly dependent on baseline endemicity, treatment coverage and systematic non-compliance.The goals of eliminating morbidity and infection with ivermectin alone are distinctly influenced by epidemiological and programmatic factors. Whilst the former goal is most certainly achievable, reaching the latter will strongly depend on initial endemicity (the higher the endemicity, the greater the magnitude of inter-treatment transmission), advising caution when generalising the applicability of successful elimination outcomes to other areas. The proportion of systematic non-compliers will become far more influential in terms of overall success in achieving elimination goals.
Project description:BACKGROUND:The World Health Organization recommends monitoring Onchocerca volvulus Ov16 serology in children aged <10 years for stopping mass ivermectin administration. Transmission models can help to identify the most informative age groups for serological monitoring and investigate the discriminatory power of serology-based elimination thresholds. Model predictions depend on assumed age-exposure patterns and transmission efficiency at low infection levels. METHODS:The individual-based transmission model, EPIONCHO-IBM, was used to assess (1) the most informative age groups for serological monitoring using receiver operating characteristic curves for different elimination thresholds under various age-dependent exposure assumptions, including those of ONCHOSIM (another widely used model), and (2) the influence of within-human density-dependent parasite establishment (included in EPIONCHO-IBM but not ONCHOSIM) on positive predictive values for different serological thresholds. RESULTS:When assuming EPIONCHO-IBM exposure patterns, children aged <10 years are the most informative for seromonitoring; when assuming ONCHOSIM exposure patterns, 5-14 year olds are the most informative (as published elsewhere). Omitting density-dependent parasite establishment results in more lenient seroprevalence thresholds, even for higher baseline infection prevalence and shorter treatment durations. CONCLUSIONS:Selecting appropriate seromonitoring age groups depends critically on age-dependent exposure patterns. The role of density dependence on elimination thresholds largely explains differing EPIONCHO-IBM and ONCHOSIM elimination predictions.
Project description:Recently, there has been a shift in onchocerciasis control policy, changing from prevention of morbidity toward elimination of infection. Switching from annual to biannual ivermectin distribution may accelerate progress toward the elimination goals. However, the settings where this strategy would be cost effective in Africa have not been described.An onchocerciasis transmission framework (EpiOncho) was coupled to a disease model in order to explore the impact on disability-adjusted life years averted, program cost, and program duration of biannual ivermectin treatment in different epidemiological and programmatic scenarios in African savannah.While biannual treatment yields only small additional health gains, its benefit is pronounced in the context of the elimination goals, shortening the time frames for and increasing the feasibility of reaching the proposed operational thresholds for stopping treatment. In settings with high precontrol endemicity (and/or poor coverage and compliance), it may not be possible to reach such thresholds even within 50 years of annual ivermectin, requiring adoption of biannual treatment. Our projections highlight the crucial role played by coverage and compliance in achieving the elimination goals.Biannual ivermectin treatment improves the chances of reaching the 2020/2025 elimination goals, potentially generating programmatic cost savings in settings with high precontrol endemicity. However, its benefit and cost are highly sensitive to levels of systematic noncompliance and, in many settings, it will lead to an increase in costs. Furthermore, it may not always be feasible to implement biannual treatment, particularly in hard-to-reach populations. This highlights the continued need for a macrofilaricide.
Project description:BACKGROUND:Currently, the predominant onchocerciasis control strategy in Africa is annual mass drug administration (MDA) with ivermectin. However, there is a consensus among the global health community, supported by mathematical modelling, that onchocerciasis in Africa will not be eliminated within proposed time frameworks in all endemic foci with only annual MDA, and novel and alternative strategies are urgently needed. Furthermore, use of MDA with ivermectin is already compromised in large areas of central Africa co-endemic with Loa loa, and there are areas where suboptimal or atypical responses to ivermectin have been documented. An onchocerciasis vaccine would be highly advantageous in these areas. METHODOLOGY/PRINCIPAL FINDINGS:We used a previously developed onchocerciasis transmission model (EPIONCHO) to investigate the impact of vaccination in areas where loiasis and onchocerciasis are co-endemic and ivermectin is contraindicated. We also explore the potential influence of a vaccination programme on infection resurgence in areas where local elimination has been successfully achieved. Based on the age range included in the Expanded Programme on Immunization (EPI), the vaccine was assumed to target 1 to 5 year olds. Our modelling results indicate that the deployment of an onchocerciasis vaccine would have a beneficial impact in onchocerciasis-loiasis co-endemic areas, markedly reducing microfilarial load in the young (under 20 yr) age groups. CONCLUSIONS/SIGNIFICANCE:An onchocerciasis prophylactic vaccine would reduce the onchocerciasis disease burden in populations where ivermectin cannot be administered safely. Moreover, a vaccine could substantially decrease the chance of re-emergence of Onchocerca volvulus infection in areas where it is deemed that MDA with ivermectin can be stopped. Therefore, a vaccine would protect the substantial investments made by present and past onchocerciasis control programmes, decreasing the chance of disease recrudescence and offering an important additional tool to mitigate the potentially devastating impact of emerging ivermectin resistance.
Project description:<h4>Background</h4>Onchocerciasis elimination through mass drug administration (MDA) is hampered by coendemicity of Loa loa, as people with high L. loa microfilariae (mf) density can develop serious adverse events (SAEs) after ivermectin treatment. We assessed the geographical overlap of onchocerciasis and loiasis prevalence and estimated the number of coinfected individuals at risk of post-ivermectin SAEs in West and Central Africa from 1995 to 2025.<h4>Methods</h4>Focusing on regions with suspected loiasis transmission in 14 countries, we overlaid precontrol maps of loiasis and onchocerciasis prevalence to calculate precontrol prevalence of coinfection by 5 km2 × 5 km2 pixel, distinguishing different categories of L. loa mf intensity. Using statistical and mathematical models, we predicted prevalence of both infections and coinfection for 2015 and 2025, accounting for the impact of MDA with ivermectin.<h4>Results</h4>The number of people infected with onchocerciasis was predicted to decline from almost 19 million in 1995 to 4 million in 2025. Of these, 137 000 people were estimated to also have L. loa hypermicrofilaremia (?20 000 L. loa mf/mL) in 1995, declining to 31 000 in 2025. In 2025, 92.8% of coinfected cases with loiasis hypermicrofilaremia are predicted to live in hypoendemic areas currently not targeted for MDA.<h4>Conclusions</h4>Loiasis coinfection is a major concern for onchocerciasis elimination in Africa. We predict that under current strategies, at least 31 000 coinfected people still require treatment for onchocerciasis in 2025 while being at risk of SAEs, justifying continued efforts in research and development for safer drugs and control strategies.
Project description:Recent studies in Mali, Nigeria, and Senegal have indicated that annual (or biannual) ivermectin distribution may lead to local elimination of human onchocerciasis in certain African foci. Modelling-based projections have been used to estimate the required duration of ivermectin distribution to reach elimination. A crucial assumption has been that microfilarial production by Onchocerca volvulus is reduced irreversibly by 30-35% with each (annual) ivermectin round. However, other modelling-based analyses suggest that ivermectin may not have such a cumulative effect. Uncertainty in this (biological) and other (programmatic) assumptions would affect projected outcomes of long-term ivermectin treatment.We modify a deterministic age- and sex-structured onchocerciasis transmission model, parameterised for savannah O. volvulus-Simulium damnosum, to explore the impact of assumptions regarding the effect of ivermectin on worm fertility and the patterns of treatment coverage compliance, and frequency on projections of parasitological outcomes due to long-term, mass ivermectin administration in hyperendemic areas. The projected impact of ivermectin distribution on onchocerciasis and the benefits of switching from annual to biannual distribution are strongly dependent on assumptions regarding the drug's effect on worm fertility and on treatment compliance. If ivermectin does not have a cumulative impact on microfilarial production, elimination of onchocerciasis in hyperendemic areas may not be feasible with annual ivermectin distribution.There is substantial (biological and programmatic) uncertainty surrounding modelling projections of onchocerciasis elimination. These uncertainties need to be acknowledged for mathematical models to inform control policy reliably. Further research is needed to elucidate the effect of ivermectin on O. volvulus reproductive biology and quantify the patterns of coverage and compliance in treated communities.
Project description:Spurred by success in several foci, onchocerciasis control policy in Africa has shifted from morbidity control to elimination of infection. Clinical trials have demonstrated that moxidectin is substantially more efficacious than ivermectin in effecting sustained reductions in skin microfilarial load and, therefore, may accelerate progress towards elimination. We compare the potential cost-effectiveness of annual moxidectin with annual and biannual ivermectin treatment.Data from the first clinical study of moxidectin were used to parameterise the onchocerciasis transmission model EPIONCHO to investigate, for different epidemiological and programmatic scenarios in African savannah settings, the number of years and in-country costs necessary to reach the operational thresholds for cessation of treatment, comparing annual and biannual ivermectin with annual moxidectin treatment.Annual moxidectin and biannual ivermectin treatment would achieve similar reductions in programme duration relative to annual ivermectin treatment. Unlike biannual ivermectin treatment, annual moxidectin treatment would not incur a considerable increase in programmatic costs and, therefore, would generate sizeable in-country cost savings (assuming the drug is donated). Furthermore, the impact of moxidectin, unlike ivermectin, was not substantively influenced by the timing of treatment relative to seasonal patterns of transmission.Moxidectin is a promising new drug for the control and elimination of onchocerciasis. It has high programmatic value particularly when resource limitation prevents a biannual treatment strategy, or optimal timing of treatment relative to peak transmission season is not feasible.
Project description:BACKGROUND:In response to the recent publication "Is onchocerciasis elimination in Africa feasible by 2025: a perspective based on lessons learnt from the African control programmes" by Dadzie et al., it is important to clarify and highlight the positive and unequivocal research and operational contributions from the American experience towards the worldwide elimination of human onchocerciasis (river blindness). MAIN TEXT:The strategies of twice or more rounds of mass drug administration (MDA) of ivermectin per year, as well as the use of OV-16 serology have allowed four American countries to be verified by World Health Organization to have eliminated transmission of Onchocerca volvulus, the etiological agent. These advances were also implemented in Sudan and Uganda; currently, both are the only African countries where ivermectin MDA was safely stopped in several transmission zones. CONCLUSIONS:Programmatic treatment and evaluation approaches, pioneered in the Americas, are the most efficient among the existing tools for elimination, and their broader use could catalyze the successful elimination of this disease in Africa.