The need for evidence-based strategies and tools for onchocerciasis elimination in Africa.

In a recent article we discussed the feasibility of onchocerciasis elimination in Africa by 2025. We expressed concern that elimination may be impeded by failure to build on the lessons learned in the African onchocerciasis control programmes and the introduction of strategies and tools from the Americas. Richards et al. and Cupp et al. wrote to refute our concern and described recent achievements with stopping treatment in some areas.In this response, we discuss their arguments which did not convince us. We point out several scientific flaws in the American conceptual framework of elimination which has led to longer periods of treatment than necessary, and in the use of an arbitrary threshold for stopping treatment. We show that recent achievements fall significantly short of what would be needed to achieve onchocerciasis elimination by 2025.We conclude our response by advocating for a more objective and inclusive debate on strategies and tools for onchocerciasis elimination.

Is onchocerciasis elimination in Africa feasible by 2025: a perspective based on lessons learnt from the African control programmes.

BACKGROUND: Onchocerciasis is found predominantly in Africa where large scale vector control started in 1974. Registration and donation of ivermectin by Merck & Co in 1987 enabled mass treatment with ivermectin in all endemic countries in Africa and the Americas. Although elimination of onchocerciasis with ivermectin was considered feasible only in the Americas, recently it has been shown possible in Africa too, necessitating fundamental changes in technical and operational approaches and procedures. MAIN BODY: The American programme(OEPA) operating in onchocerciasis epidemiological settings similar to the mild end of the complex epidemiology of onchocerciasis in Africa, has succeeded in eliminating onchocerciasis from 4 of its 6 endemic countries. This was achieved through biannual mass treatment with ivermectin of 85% of the eligible population, and monitoring and evaluation using serological tests in children and entomological tests. The first African programme(OCP) had a head start of nearly two decades. It employed vector control and accumulated lots of knowledge on the dynamics of onchocerciasis elimination over a wide range of epidemiological settings in the vast expanse of its core area. OCP made extensive use of modelling and operationalised elimination indicators for entomological evaluation and epidemiological evaluation using skin snip procedures. The successor African programme(APOC) employed mainly ivermectin treatment. Initially its objective was to control onchocerciasis as a public health problem but that objective was later expanded to include the elimination of onchocerciasis where feasible. Building on the experience with onchocerciasis elimination of the OCP, APOC has leveraged OCP's vast modelling experience and has developed operational procedures and indicators for evaluating progress towards elimination and stopping ivermectin mass treatment of onchocerciasis in the complex African setting. CONCLUSIONS: Following the closure of APOC in 2015, implementation of onchocerciasis elimination in Africa appears to overlook all the experience that has been accumulated by the African programmes. It is employing predominantly American processes that were developed in a dissimilar setting from the complex African onchocerciasis setting. This is impeding progress towards decisions to stop intervention in many areas that have reached the elimination point. This article summarizes lessons learned in Africa and their importance for achieving elimination in Africa by 2025.

Model-Based Geostatistical Mapping of the Prevalence of Onchocerca volvulus in West Africa.

BACKGROUND: The initial endemicity (pre-control prevalence) of onchocerciasis has been shown to be an important determinant of the feasibility of elimination by mass ivermectin distribution. We present the first geostatistical map of microfilarial prevalence in the former Onchocerciasis Control Programme in West Africa (OCP) before commencement of antivectorial and antiparasitic interventions. METHODS AND FINDINGS: Pre-control microfilarial prevalence data from 737 villages across the 11 constituent countries in the OCP epidemiological database were used as ground-truth data. These 737 data points, plus a set of statistically selected environmental covariates, were used in a Bayesian model-based geostatistical (B-MBG) approach to generate a continuous surface (at pixel resolution of 5 km x 5km) of microfilarial prevalence in West Africa prior to the commencement of the OCP. Uncertainty in model predictions was measured using a suite of validation statistics, performed on bootstrap samples of held-out validation data. The mean Pearson's correlation between observed and estimated prevalence at validation locations was 0.693; the mean prediction error (average difference between observed and estimated values) was 0.77%, and the mean absolute prediction error (average magnitude of difference between observed and estimated values) was 12.2%. Within OCP boundaries, 17.8 million people were deemed to have been at risk, 7.55 million to have been infected, and mean microfilarial prevalence to have been 45% (range: 2-90%) in 1975. CONCLUSIONS AND SIGNIFICANCE: This is the first map of initial onchocerciasis prevalence in West Africa using B-MBG. Important environmental predictors of infection prevalence were identified and used in a model out-performing those without spatial random effects or environmental covariates. Results may be compared with recent epidemiological mapping efforts to find areas of persisting transmission. These methods may be extended to areas where data are sparse, and may be used to help inform the feasibility of elimination with current and novel tools.

Wuchereria bancrofti transmission pattern in southern Mali prior to and following the institution of mass drug administration.

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched in 2000 with the goal of stopping transmission of lymphatic filariasis (LF) through yearly mass drug administration (MDA). Although preliminary surveys of the human population in Mali suggested that Wuchereria bancrofti infection was highly endemic in the Sikasso district, baseline entomological data were required to confirm high levels of transmission prior to the selection of villages in this region for a study of the impact of MDA on transmission of LF by anopheline vectors. METHODS: W. bancrofti transmission was assessed in 2001 (pre-MDA) and 2002 (post-MDA) in the Central District of Sikasso in southern Mali by dissection of Anopheles mosquitoes caught using the human landing catch (HLC) method. The relative frequencies and molecular forms of An. gambiae complex were determined. RESULTS: The majority (86%) of the anopheline vectors captured were identified as An. gambiae complex, and these accounted for >90% of the entomological inoculation rate (EIR) during both years of the study. There was a dramatic decrease in the number of An. gambiae complex mosquitoes captured and in the An. gambiae complex infectivity rates following MDA, accounting for the observed decrease in EIR in 2002 (from 12.55 to 3.79 infective bites per person during the transmission season). An. funestus complex mosquitoes were responsible for a low level of transmission, which was similar during both years of the study (1.2 infective bites per person during the transmission season in 2001 and 1.03 in 2002). CONCLUSIONS: Based on the entomological data from this study, the district of Sikasso was confirmed as an area of high W. bancrofti transmission. This led to the selection of this area for a multi-national study on the effects of MDA on LF transmission by anopheline vectors. Comparison of vector transmission parameters prior to and immediately following the first round of MDA demonstrated a significant decrease in overall transmission. Importantly, the dramatic variability in EIR over the transmission season suggests that the efficacy of MDA can be maximized by delivering drug at the beginning of the rainy season (just prior to the peak of transmission).

A research agenda for helminth diseases of humans: towards control and elimination.

Human helminthiases are of considerable public health importance in sub-Saharan Africa, Asia, and Latin America. The acknowledgement of the disease burden due to helminth infections, the availability of donated or affordable drugs that are mostly safe and moderately efficacious, and the implementation of viable mass drug administration (MDA) interventions have prompted the establishment of various large-scale control and elimination programmes. These programmes have benefited from improved epidemiological mapping of the infections, better understanding of the scope and limitations of currently available diagnostics and of the relationship between infection and morbidity, feasibility of community-directed or school-based interventions, and advances in the design of monitoring and evaluation (M&E) protocols. Considerable success has been achieved in reducing morbidity or suppressing transmission in a number of settings, whilst challenges remain in many others. Some of the obstacles include the lack of diagnostic tools appropriate to the changing requirements of ongoing interventions and elimination settings; the reliance on a handful of drugs about which not enough is known regarding modes of action, modes of resistance, and optimal dosage singly or in combination; the difficulties in sustaining adequate coverage and compliance in prolonged and/or integrated programmes; an incomplete understanding of the social, behavioural, and environmental determinants of infection; and last, but not least, very little investment in research and development (R&D). The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to undertake a comprehensive review of recent advances in helminthiases research, identify research gaps, and rank priorities for an R&D agenda for the control and elimination of these infections. This review presents the processes undertaken to identify and rank ten top research priorities; discusses the implications of realising these priorities in terms of their potential for improving global health and achieving the Millennium Development Goals (MDGs); outlines salient research funding needs; and introduces the series of reviews that follow in this PLoS Neglected Tropical Diseases collection, "A Research Agenda for Helminth Diseases of Humans."

A research agenda for helminth diseases of humans: intervention for control and elimination.

Recognising the burden helminth infections impose on human populations, and particularly the poor, major intervention programmes have been launched to control onchocerciasis, lymphatic filariasis, soil-transmitted helminthiases, schistosomiasis, and cysticercosis. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. A summary of current helminth control initiatives is presented and available tools are described. Most of these programmes are highly dependent on mass drug administration (MDA) of anthelmintic drugs (donated or available at low cost) and require annual or biannual treatment of large numbers of at-risk populations, over prolonged periods of time. The continuation of prolonged MDA with a limited number of anthelmintics greatly increases the probability that drug resistance will develop, which would raise serious problems for continuation of control and the achievement of elimination. Most initiatives have focussed on a single type of helminth infection, but recognition of co-endemicity and polyparasitism is leading to more integration of control. An understanding of the implications of control integration for implementation, treatment coverage, combination of pharmaceuticals, and monitoring is needed. To achieve the goals of morbidity reduction or elimination of infection, novel tools need to be developed, including more efficacious drugs, vaccines, and/or antivectorial agents, new diagnostics for infection and assessment of drug efficacy, and markers for possible anthelmintic resistance. In addition, there is a need for the development of new formulations of some existing anthelmintics (e.g., paediatric formulations). To achieve ultimate elimination of helminth parasites, treatments for the above mentioned helminthiases, and for taeniasis and food-borne trematodiases, will need to be integrated with monitoring, education, sanitation, access to health services, and where appropriate, vector control or reduction of the parasite reservoir in alternative hosts. Based on an analysis of current knowledge gaps and identification of priorities, a research and development agenda for intervention tools considered necessary for control and elimination of human helminthiases is presented, and the challenges to be confronted are discussed.

A research agenda for helminth diseases of humans: the problem of helminthiases.

A disproportionate burden of helminthiases in human populations occurs in marginalised, low-income, and resource-constrained regions of the world, with over 1 billion people in developing areas of sub-Saharan Africa, Asia, and the Americas infected with one or more helminth species. The morbidity caused by such infections imposes a substantial burden of disease, contributing to a vicious circle of infection, poverty, decreased productivity, and inadequate socioeconomic development. Furthermore, helminth infection accentuates the morbidity of malaria and HIV/AIDS, and impairs vaccine efficacy. Polyparasitism is the norm in these populations, and infections tend to be persistent. Hence, there is a great need to reduce morbidity caused by helminth infections. However, major deficiencies exist in diagnostics and interventions, including vector control, drugs, and vaccines. Overcoming these deficiencies is hampered by major gaps in knowledge of helminth biology and transmission dynamics, platforms from which to help develop such tools. The Disease Reference Group on Helminths Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. In this review, we provide an overview of the forces driving the persistence of helminthiases as a public health problem despite the many control initiatives that have been put in place; identify the main obstacles that impede progress towards their control and elimination; and discuss recent advances, opportunities, and challenges for the understanding of the biology, epidemiology, and control of these infections. The helminth infections that will be discussed include: onchocerciasis, lymphatic filariasis, soil-transmitted helminthiases, schistosomiasis, food-borne trematodiases, and taeniasis/cysticercosis.

A research agenda for helminth diseases of humans: health research and capacity building in disease-endemic countries for helminthiases control.

Capacity building in health research generally, and helminthiasis research particularly, is pivotal to the implementation of the research and development agenda for the control and elimination of human helminthiases that has been proposed thematically in the preceding reviews of this collection. Since helminth infections affect human populations particularly in marginalised and low-income regions of the world, they belong to the group of poverty-related infectious diseases, and their alleviation through research, policy, and practice is a sine qua non condition for the achievement of the United Nations Millennium Development Goals. Current efforts supporting research capacity building specifically for the control of helminthiases have been devised and funded, almost in their entirety, by international donor agencies, major funding bodies, and academic institutions from the developed world, contributing to the creation of (not always equitable) North-South "partnerships". There is an urgent need to shift this paradigm in disease-endemic countries (DECs) by refocusing political will, and harnessing unshakeable commitment by the countries' governments, towards health research and capacity building policies to ensure long-term investment in combating and sustaining the control and eventual elimination of infectious diseases of poverty. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. This paper discusses the challenges confronting capacity building for parasitic disease research in DECs, describes current capacity building strategies with particular reference to neglected tropical diseases and human helminthiases, and outlines recommendations to redress the balance of alliances and partnerships for health research between the developed countries of the "North" and the developing countries of the "South". We argue that investing in South-South collaborative research policies and capacity is as important as their North-South counterparts and is essential for scaled-up and improved control of helminthic diseases and ultimately for regional elimination.

A research agenda for helminth diseases of humans: social ecology, environmental determinants, and health systems.

In this paper, the Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), with the mandate to review helminthiases research and identify research priorities and gaps, focuses on the environmental, social, behavioural, and political determinants of human helminth infections and outlines a research and development agenda for the socioeconomic and health systems research required for the development of sustainable control programmes. Using Stockols' social-ecological approach, we describe the role of various social (poverty, policy, stigma, culture, and migration) and environmental determinants (the home environment, water resources development, and climate change) in the perpetuation of helminthic diseases, as well as their impact as contextual factors on health promotion interventions through both the regular and community-based health systems. We examine these interactions in regard to community participation, intersectoral collaboration, gender, and possibilities for upscaling helminthic disease control and elimination programmes within the context of integrated and interdisciplinary approaches. The research agenda summarises major gaps that need to be addressed.

Density-dependent mortality of the human host in onchocerciasis: relationships between microfilarial load and excess mortality.

BACKGROUND: The parasite Onchocerca volvulus has, until recently, been regarded as the cause of a chronic yet non-fatal condition. Recent analyses, however, have indicated that in addition to blindness, the parasite can also be directly associated with human mortality. Such analyses also suggested that the relationship between microfilarial load and excess mortality might be non-linear. Determining the functional form of such relationship would contribute to quantify the population impact of mass microfilaricidal treatment. METHODOLOGY/PRINCIPAL FINDINGS: Data from the Onchocerciasis Control Programme in West Africa (OCP) collected from 1974 through 2001 were used to determine functional relationships between microfilarial load and excess mortality of the human host. The goodness-of-fit of three candidate functional forms (a (log-) linear model and two saturating functions) were explored and a saturating (log-) sigmoid function was deemed to be statistically the best fit. The excess mortality associated with microfilarial load was also found to be greater in younger hosts. The attributable mortality risk due to onchocerciasis was estimated to be 5.9%. CONCLUSIONS/SIGNIFICANCE: Incorporation of this non-linear functional relationship between microfilarial load and excess mortality into mathematical models for the transmission and control of onchocerciasis will have important implications for our understanding of the population biology of O. volvulus, its impact on human populations, the global burden of disease due to onchocerciasis, and the projected benefits of control programmes in both human and economic terms.

Control of onchocerciasis.

Onchocerciasis is a filarial infection which causes blindness and debilitating skin lesions. The disease occurs in 37 countries, of which 30 are found in Africa (the most affected in terms of the distribution and the severity of the clinical manifestations of the disease), six in the Americas and one in the Arabian Peninsula. The latest WHO Expert Committee on Onchocerciasis estimated that in 1995 around 17.7 million persons were infected, about 270,000 of whom were blind and another 500,000 severely visually impaired. The disease is responsible for 1 million DALYs. Eye disease from onchocerciasis accounts for 40% of DALYs annually although severe skin disease is also recognized as of public health significance. Great progress has been made in the last thirty years in the control of onchocerciasis, both in Africa and the Americas, and this progress has been due largely to international public-private partnerships, sustained funding regional programmes, and new tools and technology. Landmarks in the global control of river blindness include the significant success of the Onchocerciasis Control Programme of West Africa (1975-2002), and the donation of ivermectin (Mectizan) by Merck & Co. Inc., in 1988, a medicine that is distributed to millions free of charge each year. Future major technical challenges of onchocerciasis control include ivermectin mass administration in areas co-endemic for the parasite Loa loa in the light of possible severe adverse reactions, ivermectin treatment in hypoendemic areas hitherto excluded from African control programmes, sustainability of ivermectin distribution, post-control surveillance for recrudescence detection, surveillance for emergence of resistance, and decisions of when to stop mass ivermectin treatments. There is the need to develop the appropriate information systems and diagnostic tools to help in accomplishing many of these tasks. A search for a second-line treatment or as an additional drug to ivermectin as well as a search for a macrofilaricide are issues that need to be addressed in the future.

Incidence of blindness during the Onchocerciasis control programme in western Africa, 1971-2002.

BACKGROUND: Infection with Onchocerca volvulus is associated with the prevalence of severe visual impairment and blindness. However, longitudinal studies of the incidence of blindness caused by onchocerciasis are scarce. METHODS: The relationship, at the individual level, between infection with O. volvulus microfilariae and bilateral blindness was examined, by use of data collected, during the Onchocerciasis Control Programme in western Africa (OCP), from 2315 villages in 11 countries. The data were analyzed by Poisson maximum-likelihood techniques with adjustment for overdispersion. RESULTS: A total of 297,756 persons were eligible for follow-up in the cohort, and, during 1971-2001, these persons accumulated 367,788 person-years of follow-up without blindness. A total of 673 bilateral cases of blindness occurred during this period; 29.7% were caused by onchocerciasis. After ivermectin therapy was introduced (during 1988-2001), only 19.6% of cases were caused by onchocerciasis. The incidence of blindness was significantly and positively associated with increasing microfilarial burden (P<.001). Overall, female subjects had an ~40% lower risk of becoming blind than did male subjects (P<.001). After an initially high incidence of blindness at the beginning of the OCP, the rate of blindness from causes other than onchocerciasis remained approximately constant during follow-up. CONCLUSIONS: We demonstrate, in a comprehensive data set and in both sexes, a direct relationship between microfilarial load and the incidence of blindness.

Uptake of Onchocerca volvulus (Nematoda: Onchocercidae) by Simulium (Diptera: Simuliidae) is not strongly dependent on the density of skin microfilariae in the human host.

The relation between the number of microfilariae (mf) ingested by host-seeking vectors of human onchocerciasis and skin mf load is an important component of the population biology of Onchocerca volvulus, with implications for disease control and evaluation of the risk of transmission recrudescence. The microsimulation model ONCHOSIM has been used to assess such risk in the area of the Onchocerciasis Control Program (OCP) in West Africa, based on a strongly nonlinear relation between vector mf uptake and human mf skin density previously published. However, observed levels of recrudescence have exceeded predictions, warranting a recalibration of the model. To this end, we present the results of a series of fly-feeding experiments carried out in savanna and forest localities of West Africa. Flies belonging to Simulium damnosum s.s., S. sirbanum, S. soubrense, and S. leonense were fed on mf carriers and dissected to assess the number of ingested mf escaping imprisonment by the peritrophic matrix (the number of exo-peritrophic mf), a predictor of infective larval output. The method of instrumental variables was used to obtain (nearly) unbiased estimates of the parameters of interest, taking into account error in the measurement of skin mf density. This error is often neglected in these types of studies, making it difficult to ascertain the degree of density-dependence truly present in the relation between mf uptake and skin load. We conclude that this relation is weakly (yet significantly) nonlinear in savanna settings but indistinguishable from linearity in forest vectors. Exo-peritrophic mf uptake does not account for most of the density dependence in the transmission dynamics of the parasite as previously thought. The number of exo-mf in forest simuliids is at least five times higher than in the savanna vectors. Parasite abundance in human onchocerciasis is regulated by poorly known mechanisms operating mainly on other stages of the lifecycle.

Impact of ivermectin on onchocerciasis transmission: assessing the empirical evidence that repeated ivermectin mass treatments may lead to elimination/eradication in West-Africa.

BACKGROUND: The Onchocerciasis Control Program (OCP) in West Africa has been closed down at the end of 2002. All subsequent control will be transferred to the participating countries and will almost entirely be based on periodic mass treatment with ivermectin. This makes the question whether elimination of infection or eradication of onchocerciasis can be achieved using this strategy of critical importance. This study was undertaken to explore this issue. METHODS: An empirical approach was adopted in which a comprehensive analysis was undertaken of available data on the impact of more than a decade of ivermectin treatment on onchocerciasis infection and transmission. Relevant entomological and epidemiological data from 14 river basins in the OCP and one basin in Cameroon were reviewed. Areas were distinguished by frequency of treatment (6-monthly or annually), endemicity level and additional control measures such as vector control. Assessment of results were in terms of epidemiological and entomological parameters, and as a measure of inputs, therapeutic and geographical coverage rates were used. RESULTS: In all of the river basins studied, ivermectin treatment sharply reduced prevalence and intensity of infection. Significant transmission, however, is still ongoing in some basins after 10-12 years of ivermectin treatment. In other basins, transmission may have been interrupted, but this needs to be confirmed by in-depth evaluations. In one mesoendemic basin, where 20 rounds of four-monthly treatment reduced prevalence of infection to levels as low as 2-3%, there was significant recrudescence of infection within a few years after interruption of treatment. CONCLUSIONS: Ivermectin treatment has been very successful in eliminating onchocerciasis as a public health problem. However, the results presented in this paper make it almost certain that repeated ivermectin mass treatment will not lead to the elimination of transmission of onchocerciasis from West Africa. Data on 6-monthly treatments are not sufficient to draw definitive conclusions.