Modelling the impact of ivermectin on River Blindness and its burden of morbidity and mortality in African Savannah: EpiOncho projections

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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

Population biology of multispecies helminth infection: interspecific interactions and parasite distribution

Despite evidence for the existence of interspecific interactions between helminth species, there has been no theoretical exploration of their effect on the distribution of the parasite species in a host population. We use a deterministic model for the accumulation and loss of adult worms of 2 interacting helminth species to motivate an individual-based stochastic model. The mean worm burden and variance: mean ratio (VMR) of each species, and the correlation between the two species are used to describe the distribution within different host age classes. We find that interspecific interactions can produce convex age-intensity profiles and will impact the level of aggregation (as measured by the VMR). In the absence of correlated exposure, the correlation in older age classes may be close to zero when either intra- or interspecific synergistic effects are strong. We therefore suggest examining the correlation between species in young hosts as a possible means of identifying interspecific interaction. The presence of correlation between the rates of exposure makes the interpretation of correlations between species more difficult. Finally we show that in the absence of interaction, strong positive correlations are generated by averaging across most age classes

Modelling Anopheles gambiae s.s. Population Dynamics with Temperature- and Age-Dependent Survival

Climate change and global warming are emerging as important threats to human health, particularly through the potential increase in vector- and water-borne diseases. Environmental variables are known to affect substantially the population dynamics and abundance of the poikilothermic vectors of disease, but the exact extent of this sensitivity is not well established. Focusing on malaria and its main vector in Africa, Anopheles gambiae sensu stricto, we present a set of novel mathematical models of climate-driven mosquito population dynamics motivated by experimental data suggesting that in An. gambiae, mortality is temperature and age dependent. We compared the performance of these models to that of a “standard” model ignoring age dependence. We used a longitudinal dataset of vector abundance over 36 months in sub-Saharan Africa for comparison between models that incorporate age dependence and one that does not, and observe that age-dependent models consistently fitted the data better than the reference model. This highlights that including age dependence in the vector component of mosquito-borne disease models may be important to predict more reliably disease transmission dynamics. Further data and studies are needed to enable improved fitting, leading to more accurate and informative model predictions for the An. gambiae malaria vector as well as for other disease vectors

Assessing the impact of intervention strategies against Taenia solium cysticercosis using the EPICYST transmission model

Background The pork tapeworm, Taenia solium, and associated human infections, taeniasis, cysticercosis and neurocysticercosis, are serious public health problems, especially in developing countries. The World Health Organization (WHO) has set goals for having a validated strategy for control and elimination of T. solium taeniasis/cysticercosis by 2015 and interventions scaled-up in selected countries by 2020. Timely achievement of these internationally-endorsed targets requires that the relative benefits and effectiveness of potential interventions be explored rigorously within a quantitative framework. Methods A deterministic, compartmental transmission model (EPICYST) was developed to capture the dynamics of the taeniasis/cysticercosis disease system in the human and pig hosts. Cysticercosis prevalence in humans, an outcome of high epidemiological and clinical importance, was explicitly modelled. A next generation matrix approach was used to derive an expression for the basic reproduction number, R 0. A full sensitivity analysis was performed using a methodology based on Latin-hypercube sampling partial rank correlation coefficient index. Results EPICYST outputs indicate that chemotherapeutic intervention targeted at humans or pigs would be highly effective at reducing taeniasis and cysticercosis prevalence when applied singly, with annual chemotherapy of humans and pigs resulting, respectively, in 94 and 74% of human cysticercosis cases averted. Improved sanitation, meat inspection and animal husbandry are less effective but are still able to reduce prevalence singly or in combination. The value of R 0 for taeniasis was estimated at 1.4 (95% Credible Interval: 0.5–3.6). Conclusions Human- and pig-targeted drug-focussed interventions appear to be the most efficacious approach from the options currently available. The model presented is a forward step towards developing an informed control and elimination strategy for cysticercosis. Together with its validation against field data, EPICYST will be a valuable tool to help reach the WHO goals and to conduct economic evaluations of interventions in varying epidemiological settings

The Cost of Annual versus Biannual Community-Directed Treatment of Onchocerciasis with Ivermectin: Ghana as a Case Study

BACKGROUND: It has been proposed that switching from annual to biannual (twice yearly) mass community-directed treatment with ivermectin (CDTI) might improve the chances of onchocerciasis elimination in some African foci. However, historically, relatively few communities have received biannual treatments in Africa, and there are no cost data associated with increasing ivermectin treatment frequency at a large scale. Collecting cost data is essential for conducting economic evaluations of control programmes. Some countries, such as Ghana, have adopted a biannual treatment strategy in selected districts. We undertook a study to estimate the costs associated with annual and biannual CDTI in Ghana. METHODOLOGY: The study was conducted in the Brong-Ahafo and Northern regions of Ghana. Data collection was organized at the national, regional, district, sub-district and community levels, and involved interviewing key personnel and scrutinizing national records. Data were collected in four districts; one in which treatment is delivered annually, two in which it is delivered biannually, and one where treatment takes place biannually in some communities and annually in others. Both financial and economic costs were collected from the health care provider's perspective. PRINCIPAL FINDINGS: The estimated cost of treating annually was US Dollars (USD) 0.45 per person including the value of time donated by the community drug distributors (which was estimated at USD 0.05 per person per treatment round). The cost of CDTI was approximately 50–60% higher in those districts where treatment was biannual than in those where it was annual. Large-scale mass biannual treatment was reported as being well received and considered sustainable. CONCLUSIONS/SIGNIFICANCE: This study provides rigorous evidence of the different costs associated with annual and biannual CDTI in Ghana which can be used to inform an economic evaluation of the debate on the optimal treatment frequency required to control (or eliminate) onchocerciasis in Africa

Predicting mosquito infection from Plasmodium falciparum gametocyte density and estimating the reservoir of infection

Transmission reduction is a key component of global efforts to control and eliminate malaria; yet, it is unclear how the density of transmission stages (gametocytes) influences infection (proportion of mosquitoes infected). Human to mosquito transmission was assessed using 171 direct mosquito feeding assays conducted in Burkina Faso and Kenya. Plasmodium falciparum infects Anopheles gambiae efficiently at low densities (4% mosquitoes at 1/µl blood), although substantially more (>200/µl) are required to increase infection further. In a site in Burkina Faso, children harbour more gametocytes than adults though the non-linear relationship between gametocyte density and mosquito infection means that (per person) they only contribute slightly more to transmission. This method can be used to determine the reservoir of infection in different endemic settings. Interventions reducing gametocyte density need to be highly effective in order to halt human-mosquito transmission, although their use can be optimised by targeting those contributing the most to transmission. DOI:http://dx.doi.org/10.7554/eLife.00626.001

The potential impact of moxidectin on onchocerciasis elimination in Africa: an economic evaluation based on the Phase II clinical trial data

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13071-015-0779-4) contains supplementary material, which is available to authorized users

Uncertainty Surrounding Projections of the Long-Term Impact of Ivermectin Treatment on Human Onchocerciasis

BackgroundRecent 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.Methodology/principal findingsWe 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.Conclusions/significanceThere 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