Knowledge of pattern and process in helminth population biology is mostly based on the endemic equilibrium state that characterises infections before control. Current large-scale intervention ...programmes aim at controlling/eliminating helminth infection, transmission and morbidity. As a result, age-infection profiles will be modified; immune responses will be affected; underlying parasite distributions may become more aggregated; density-dependent regulatory processes will relax; and the contribution to transmission and morbidity of different host population groups will shift. There is an urgent need to understand how the paradigm that has guided parasite population biology research is changing under chemotherapy-based control programmes for this research to continue supporting parasite control efforts effectively.
Concerns that annual mass administration of ivermectin, the predominant strategy for onchocerciasis control and elimination, may not lead to elimination of parasite transmission (EoT) in all endemic ...areas have increased interest in alternative treatment strategies. One such strategy is moxidectin. We performed an updated economic assessment of moxidectin- relative to ivermectin-based strategies.
We investigated annual and biannual community-directed treatment with ivermectin (aCDTI, bCDTI) and moxidectin (aCDTM, bCDTM) with minimal or enhanced coverage (65% or 80% of total population taking the drug, respectively) in intervention-naive areas with 30%, 50%, or 70% microfilarial baseline prevalence (representative of hypo-, meso-, and hyperendemic areas). We compared programmatic delivery costs for the number of treatments achieving 90% probability of EoT (EoT90), calculated with the individual-based stochastic transmission model EPIONCHO-IBM. We used the costs for 40 years of program delivery when EoT90 was not reached earlier. The delivery costs do not include drug costs.
aCDTM and bCDTM achieved EoT90 with lower programmatic delivery costs than aCDTI with 1 exception: aCDTM with minimal coverage did not achieve EoT90 in hyperendemic areas within 40 years. With minimal coverage, bCDTI delivery costs as much or more than aCDTM and bCDTM. With enhanced coverage, programmatic delivery costs for aCDTM and bCDTM were lower than for aCDTI and bCDTI.
Moxidectin-based strategies could accelerate progress toward EoT and reduce programmatic delivery costs compared with ivermectin-based strategies. The costs of moxidectin to national programs are needed to quantify whether delivery cost reductions will translate into overall program cost reduction.
Highlights • New strategies are needed to reach the WHO neglected tropical disease (NTD) control and elimination goals. • Economic evaluations using mathematical models could improve resource ...allocation. • Dynamic models are needed to account for nonlinearities in transmission. • Challenges and research needs to address this gap are outlined.
•To reduce onchocerciasis-associated morbidity, we need to focus on young children•Six-monthly ivermectin treatment may protect school children from developing epilepsy•School-based ivermectin ...distribution should be considered in addition to annual CDTI•Onchocerciasis during pregnancy may lead to “parasite tolerance” in the offspring•“Parasite tolerance” in children may lead to onchocerciasis-associated epilepsy
Efforts are being directed toward the elimination of onchocerciasis transmission in endemic areas with community-directed treatment with ivermectin (CDTI) in Africa, which greatly reduces onchocerciasis-associated disease. However, onchocerciasis remains a major public health problem in areas of South Sudan, the Democratic Republic of the Congo, Cameroon, and the Central African Republic. Strengthening onchocerciasis elimination efforts in areas with a high prevalence of disease burden is crucial to decrease transmission, morbidity, and mortality. We argue that clinical trials are needed to investigate the safety and efficacy of ivermectin treatment of Onchocerca volvulus-infected pregnant women and children younger than 5 years. Crucially, 6-monthly administration of ivermectin in school-age children at risk of onchocerciasis-associated epilepsy could be achieved by supplementing annual CDTI with an extra round of ivermectin treatment during Child Health Days in schools and/or other distribution sites every year. These strategies would help achieve the elimination of onchocerciasis and its associated disease burden.
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.
Abstract
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.
In onchocerciasis endemic areas in Africa, heterogenous biting rates by blackfly vectors on humans are assumed to partially explain age- and sex-dependent infection patterns with Onchocerca volvulus. ...To underpin these assumptions and further improve predictions made by onchocerciasis transmission models, demographic patterns in antibody responses to salivary antigens of Simulium damnosum s.l. are evaluated as a measure of blackfly exposure.
Recently developed IgG and IgM anti-saliva immunoassays for S. damnosum s.l. were applied to blood samples collected from residents in four onchocerciasis endemic villages in Ghana. Demographic patterns in antibody levels according to village, sex and age were explored by fitting generalized linear models. Antibody levels varied between villages but showed consistent patterns with age and sex. Both IgG and IgM responses declined with increasing age. IgG responses were generally lower in males than in females and exhibited a steeper decline in adult males than in adult females. No sex-specific difference was observed in IgM responses.
The decline in age-specific antibody patterns suggested development of immunotolerance or desensitization to blackfly saliva antigen in response to persistent exposure. The variation between sexes, and between adults and youngsters may reflect differences in behaviour influencing cumulative exposure. These measures of antibody acquisition and decay could be incorporated into onchocerciasis transmission models towards informing onchocerciasis control, elimination, and surveillance.
Albendazole (ABZ), a benzimidazole (BZ) anthelmintic (AH), is commonly used for treatment of soil-transmitted helminths (STHs). Its regular use increases the possibility that BZ resistance may ...develop, which, in veterinary nematodes is caused by single nucleotide polymorphisms (SNPs) in the β-tubulin gene at positions 200, 167 or 198. The relative importance of these SNPs varies among the different parasitic nematodes of animals studied to date, and it is currently unknown whether any of these are influencing BZ efficacy against STHs in humans. We assessed ABZ efficacy and SNP frequencies before and after treatment of Ascaris lumbricoides, Trichuris trichiura and hookworm infections.
Studies were performed in Haiti, Kenya, and Panama. Stool samples were examined prior to ABZ treatment and two weeks (Haiti), one week (Kenya) and three weeks (Panama) after treatment to determine egg reduction rate (ERR). Eggs were genotyped and frequencies of each SNP assessed.
In T. trichiura, polymorphism was detected at codon 200. Following treatment, there was a significant increase, from 3.1% to 55.3%, of homozygous resistance-type in Haiti, and from 51.3% to 67.8% in Kenya (ERRs were 49.7% and 10.1%, respectively). In A. lumbricoides, a SNP at position 167 was identified at high frequency, both before and after treatment, but ABZ efficacy remained high. In hookworms from Kenya we identified the resistance-associated SNP at position 200 at low frequency before and after treatment while ERR values indicated good drug efficacy.
Albendazole was effective for A. lumbricoides and hookworms. However, ABZ exerts a selection pressure on the β-tubulin gene at position 200 in T. trichiura, possibly explaining only moderate ABZ efficacy against this parasite. In A. lumbricoides, the codon 167 polymorphism seemed not to affect drug efficacy whilst the polymorphism at codon 200 in hookworms was at such low frequency that conclusions cannot be drawn.
Mass drug administration (MDA) with ivermectin is the cornerstone of efforts to eliminate human onchocerciasis by 2020 or 2025. The feasibility of elimination crucially depends on the effects of ...multiple ivermectin doses on Onchocerca volvulus. A single ivermectin (standard) dose clears the skin-dwelling microfilarial progeny of adult worms (macrofilariae) and temporarily impedes the release of such progeny by female macrofilariae, but a macrofilaricidal effect has been deemed minimal. Multiple doses of ivermectin may cumulatively and permanently reduce the fertility and shorten the lifespan of adult females. However, rigorous quantification of these effects necessitates interrogating longitudinal data on macrofilariae with suitably powerful analytical techniques.
Using a novel mathematical modeling approach, we analyzed, at an individual participant level, longitudinal data on viability and fertility of female worms from the single most comprehensive multiple-dose clinical trial of ivermectin, comparing 3-monthly with annual treatments administered for 3 years in Cameroon.
Multiple doses of ivermectin have a partial macrofilaricidal and a modest permanent sterilizing effect after 4 or more consecutive treatments, even at routine MDA doses (150 µg/kg) and frequencies (annual). The life expectancy of adult O. volvulus is reduced by approximately 50% and 70% after 3 years of annual or 3-monthly (quarterly) exposures to ivermectin.
Our quantification of macrofilaricidal and sterilizing effects of ivermectin should be incorporated into transmission models to inform onchocerciasis elimination efforts in Africa and residual foci in Latin America. It also provides a framework to assess macrofilaricidal candidate drugs currently under development.
Diagnostic tools appropriate for undertaking interventions to control helminth infections are key to their success. Many diagnostic tests for helminth infection have unsatisfactory performance ...characteristics and are not well suited for use in the parasite control programmes that are being increasingly implemented. Although the application of modern laboratory research techniques to improve diagnostics for helminth infection has resulted in some technical advances, uptake has not been uniform. Frequently, pilot or proof of concept studies of promising diagnostic technologies have not been followed by much needed product development, and in many settings diagnosis continues to rely on insensitive and unsatisfactory parasitological or serodiagnostic techniques. In contrast, PCR-based xenomonitoring of arthropod vectors, and use of parasite recombinant proteins as reagents for serodiagnostic tests, have resulted in critical advances in the control of specific helminth parasites. 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, the diagnostic technologies relevant to control of helminth infections, either available or in development, are reviewed. Critical gaps are identified and opportunities to improve needed technologies are discussed.
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