Lymphatic Filariasis: Transmission, Treatment and Elimination

Lymphatic filariasis (LF) is a mosquito-borne, tropical disease caused by filarial worms. Infection can lead to disabling chronic disease, characterized by swelling of extremities or external genitalia (lymphoedema, elephantiasis and hydrocele). Mass treatment with antifilarial drugs is used to reduce the parasite load in the population, in order to reduce transmission and prevent disease. This is so effective that elimination of LF seems possible. Using a mathematical for lymphatic filariasis transmission in Pondicherry, India, we predicted how long yearly mass treatment would have to be continued to achieve elimination. Six annual treatments with the recommended combination of diethylcarbamazine (DEC) and albendazole would be sufficient if population coverage is 65% per round. Only four rounds would do if coverage is 80%. The required duration of mass treatment increases with endemicity level. In a comparison of transmission efficiency for different mosquito species, we found that the relationship between infection intensity in humans and the number of infective larvae developing in mosquitoes differed markedly. Mosquito characteristics may largely influence elimination prospects and predictions for Pondicherry cannot be generalized. A further study concentrated on the role of acquired immunity. We found that existing models for such immunity, which predict a decline in infection intensity in older humans, are not valid for lymphatic filariasis. We also quantified the effects of drugs treatment on different parasite stages: DEC and ivermectin were found to affect a very large proportion of microfilariae and adult worms; these drugs were even more effective when given in combination with albendazole. In conclusion, prospects for LF elimination by mass treatment are good if population coverage is sufficiently high, but the required duration depends on local transmission dynamics, endemicity level, and the efficacy of employed treatment regimens

Predicting the risk and speed of drug resistance emerging in soil-transmitted helminths during preventive chemotherapy

Control of soil-transmitted helminths relies heavily on regular large-scale deworming of high-risk groups (e.g., children) with benzimidazole derivatives. Although drug resistance has not yet been documented in human soil-transmitted helminths, regular deworming of cattle and sheep has led to widespread benzimidazole resistance in veterinary helminths. Here we predict the population dynamics of human soil-transmitted helminth infections and drug resistance during 20 years of regular preventive chemotherapy, using an individual-based model. With the current preventive chemotherapy strategy of mainly targeting children in schools, drug resistance may evolve in soil-transmitted helminths within a decade. More intense preventive chemotherapy strategies increase the prospects of soil-transmitted helminths elimination, but also increase the speed at which drug efficacy declines, especially when implementing community-based preventive chemotherapy (population-wide deworming). If during the last decade, preventive chemotherapy against soil-transmitted helminths has led to resistance, we may not have detected it as drug efficacy has not been structurally monitored, or incorrectly so. These findings highlight the need to develop and implement strategies to monitor and mitigate the evolution of benzimidazole resistance.</p

Predicting the risk and speed of drug resistance emerging in soil-transmitted helminths during preventive chemotherapy

Control of soil-transmitted helminths relies heavily on regular large-scale deworming of high-risk groups (e.g., children) with benzimidazole derivatives. Although drug resistance has not yet been documented in human soil-transmitted helminths, regular deworming of cattle and sheep has led to widespread benzimidazole resistance in veterinary helminths. Here we predict the population dynamics of human soil-transmitted helminth infections and drug resistance during 20 years of regular preventive chemotherapy, using an individual-based model. With the current preventive chemotherapy strategy of mainly targeting children in schools, drug resistance may evolve in soil-transmitted helminths within a decade. More intense preventive chemotherapy strategies increase the prospects of soil-transmitted helminths elimination, but also increase the speed at which drug efficacy declines, especially when implementing community-based preventive chemotherapy (population-wide deworming). If during the last decade, preventive chemotherapy against soil-transmitted helminths has led to resistance, we may not have detected it as drug efficacy has not been structurally monitored, or incorrectly so. These findings highlight the need to develop and implement strategies to monitor and mitigate the evolution of benzimidazole resistance.</p

Advances and challenges in predicting the impact of lymphatic filariasis elimination programmes by mathematical modelling

Mathematical simulation models for transmission and control of lymphatic filariasis are useful tools for studying the prospects of lymphatic filariasis elimination. Two simulation models are currently being used. The first, EPIFIL, is a population-based, deterministic model that simulates average trends in infection intensity over time. The second, LYMFASIM, is an individual-based, stochastic model that simulates acquisition and loss of infection for each individual in the simulated population, taking account of individual characteristics. For settings like Pondicherry (India), where Wuchereria bancrofti infection is transmitted by Culex quinquefasciatus, the models give similar predictions of the coverage and number of treatment rounds required to bring microfilaraemia prevalence below a level of 0.5%. Nevertheless, published estimates of the duration of mass treatment required for elimination differed, due to the use of different indicators for elimination (EPIFIL: microfilaraemia prevalence < 0.5% after the last treatment; LYMFASIM: reduction of microfilaraemia prevalence to zero, within 40 years after the start of mass treatment). The two main challenges for future modelling work are: 1) quantification and validation of the models for other regions, for investigation of elimination prospects in situations with other vector-parasite combinations and endemicity levels than in Pondicherry; 2) application of the models to address a range of programmatic issues related to the monitoring and evaluation of ongoing control programmes. The models' usefulness could be enhanced by several extensions; inclusion of different diagnostic tests and natural history of disease in the models is of particular relevance

LYMFASIM, a simulation model for predicting the impact of lymphatic filariasis control: quantification for African villages.

LYMFASIM is a simulation model for lymphatic filariasis transmission and control. We quantified its parameters to simulate Wuchereria bancrofti transmission by Anopheles mosquitoes in African villages, using a wide variety of reported data. The developed model captures the general epidemiological patterns, but also the differences between communities. It was calibrated to represent the relationship between mosquito biting rate and the prevalence of microfilariae (mf) in the human population, the age-pattern in mf prevalence, and the relation between mf prevalence and geometric mean mf intensity. Explorative simulations suggest that the impact of mass treatment depends strongly on the mosquito biting rate and on the assumed coverage, compliance and efficacy. Our sensitivity analysis showed that some biological parameters strongly influence the predicted equilibrium pre-treatment mf prevalence (e.g. the lifespan of adult worms and mf). Other parameters primarily affect the post-treatment trends (e.g. severity of density dependence in the mosquito uptake of infection from the human blood, between-person variability in exposure to mosquito bites). The longitudinal data, which are being collected for evaluation of ongoing elimination programmes, can help to further validate the model. The model can help to assess when ongoing elimination activities in African populations can be stopped and to design surveillance schemes. It can be a valuable tool for decision making in the Global Programme to Eliminate Lymphatic Filariasis

Required duration of mass ivermectin treatment for onchocerciasis elimination in Africa: a comparative modelling analysis

Background: The World Health Organization (WHO) has set ambitious targets for the elimination of onchocerciasis by 2020-2025 through mass ivermectin treatment. Two different mathematical models have assessed the feasibility of reaching this goal for different settings and treatment scenarios, namely the individual-based microsimulation model ONCHOSIM and the population-based deterministic model EPIONCHO. In this study, we harmonize some crucial assumptions and compare model predictions on common outputs. Methods: Using a range of initial endemicity levels and treatment scenarios, we compared the models with respect to the following outcomes: 1) model-predicted trends in microfilarial (mf) prevalence and mean mf intensity during 25 years of (annual or biannual) mass ivermectin treatment; 2) treatment duration needed to bring mf prevalence below a provisional operational threshold for treatment interruption (pOTTIS, i.e. 1.4 %), and 3) treatment duration needed to drive the parasite population to local elimination, even in the absence of further interventions. Local elimination was judged by stochastic fade-out in ONCHOSIM and by reaching transmission breakpoints in EPIONCHO. Results: ONCHOSIM and EPIONCHO both predicted that in mesoendemic areas the pOTTIS can be reached with annual treatment, but that this strategy may be insufficient in very highly hyperendemic areas or would require prolonged continuation of treatment. For the lower endemicity levels explored, ONCHOSIM predicted that the time needed to reach the pOTTIS is longer than that needed to drive the parasite population to elimination, whereas for the higher endemicity levels the opposite was true. In EPIONCHO, the pOTTIS was reached consistently sooner than the breakpoint. Co

Predictive Value of Microfilariae-Based Stop-MDA Thresholds after Triple Drug Therapy with IDA Against Lymphatic Filariasis in Treatment-Naive Indian Settings

Mass drug administration (MDA) of antifilarial drugs is the main strategy for the elimination of lymphatic filariasis (LF). Recent clinical trials indicated that the triple-drug therapy with ivermectin, diethylcarbamazine, and albendazole (IDA) is much more effective against LF than the widely used two-drug combinations (albendazole plus either ivermectin or diethylcarbamazine). For IDA-based MDA, the stop-MDA decision is made based on microfilariae (mf) prevalence in adults. In this study, we assess how the probability of eventually reaching elimination of transmission depends on the critical threshold used in transmission assessment surveys (TAS-es) to define whether transmission was successfully suppressed and triple-drug MDA can be stopped. This analysis focuses on treatment-naive Indian settings. We do this for a range of epidemiological and programmatic contexts, using the established LYMFASIM model for transmission and control of LF. Based on our simulations, a single TAS, one year after the last MDA round, provides limited predictive value of having achieved suppressed transmission, while a higher MDA coverage increases elimination probability, thus leading to a higher predictive value. Every additional TAS, conditional on previous TAS-es being passed with the same threshold, further improves the predictive value for low values of stop-MDA thresholds. An mf prevalence threshold of 0.5% corresponding to TAS-3 results in ≥95% predictive value even when the MDA coverage is relatively low.</p

Predicting lymphatic filariasis transmission and elimination dynamics using a multi-model ensemble framework

Mathematical models of parasite transmission provide powerful tools for assessing the impacts of interventions. Owing to complexity and uncertainty, no single model may capture all features of transmission and elimination dynamics. Multi-model ensemble modelling offers a framework to help overcome biases of single models. We report on the development of a first multi-model ensemble of three lymphatic filariasis (LF) models (EPIFIL, LYMFASIM, and TRANSFIL), and evaluate its predictive performance in comparison with that of the constituents using calibration and validation data from three case study sites, one each from the three major LF endemic regions: Africa, Southeast Asia and Papua New Guinea (PNG). We assessed the performance of the respective models for predicting the outcomes of annual MDA strategies for various baseline scenarios thought to exemplify the current endemic conditions in the three regions. The results show that the constructed multi-model ensemble outperformed the single models when evaluated across all sites. Single models that best fitted calibration data tended to do less well in simulating the out-of-sample, or validation, intervention data. Scenario modelling results demonstrate that the multi-model ensemble is able to compensate for variance between single models in order to produce more plausible predictions of intervention impacts. Our results highlight the value of an ensemble approach to modelling parasite control dynamics. However, its optimal use will require further methodological improvements as well as consideration of the organizational mechanisms required to ensure that modelling results and data are shared effectively between all stakeholders

Modeling the Impact and Costs of Semiannual Mass Drug Administration for Accelerated Elimination of Lymphatic Filariasis

The Global Program to Eliminate Lymphatic Filariasis (LF) has a target date of 2020. This program is progressing well in many countries. However, progress has been slow in some countries, and others have not yet started their mass drug administration (MDA) programs. Acceleration is needed. We studied how increasing MDA frequency from once to twice per year would affect program duration and costs by using computer simulation modeling and cost projections. We used the LYMFASIM simulation model to estimate how many annual or semiannual MDA rounds would be required to eliminate LF for Indian and West African scenarios with varied pre-control endemicity and coverage levels. Results were used to estimate total program costs assuming a target population of 100,000 eligibles, a 3% discount rate, and not counting the costs of donated drugs. A sensitivity analysis was done to investigate the robustness of these results with varied assumptions for key parameters. Model predictions suggested that semiannual MDA will require the same number of MDA rounds to achieve LF elimination as annual MDA in most scenarios. Thus semiannual MDA programs should achieve this goal in half of the time required for annual programs. Due to efficiency gains, total program costs for semiannual MDA programs are projected to be lower than those for annual MDA programs in most scenarios. A sensitivity analysis showed that this conclusion is robust. Semiannual MDA is likely to shorten the time and lower the cost required for LF elimination in countries where it can be implemented. This strategy may improve prospects for global elimination of LF by the target year 2020