Moxidectin is a milbemycin endectocide recently approved for the treatment of human onchocerciasis. Onchocerciasis, earmarked for elimination of transmission, is a filarial infection endemic in ...Africa, Yemen, and the Amazonian focus straddling Venezuela and Brazil. Concerns over whether the predominant treatment strategy (yearly mass drug administration (MDA) of ivermectin) is sufficient to achieve elimination in all endemic foci have refocussed attention upon alternative treatments. Moxidectin's stronger and longer microfilarial suppression compared to ivermectin in both phase II and III clinical trials indicates its potential as a novel powerful drug for onchocerciasis elimination.
This work summarizes the chemistry and pharmacology of moxidectin, reviews the phase II and III clinical trials evidence on tolerability, safety, and efficacy of moxidectin versus ivermectin, and discusses the implications of moxidectin's current regulatory status.
Moxidectin's superior clinical performance has the potential to substantially reduce times to elimination compared to ivermectin. If donated, moxidectin could mitigate the additional programmatic costs of biannual ivermectin distribution because, unlike other alternatives, it can use the existing community-directed treatment infrastructure. A pediatric indication (for children <12 years) and determination of its usefulness in onchocerciasis-loiasis co-endemic areas will greatly help fulfill the potential of moxidectin for the treatment and elimination of onchocerciasis.
Background. Onchocerca volvulus and lymphatic filariae, causing river blindness and elephantiasis, depend on endosymbiotic Wolbachia bacteria for growth, development, fertility, and survival. ...Clinical trials have shown that doxycycline treatment eliminates Wolbachia, causing long-term sterilization of adult female filariae and effecting potent macrofilaricidal activity. The continual reinfection by drug-naive worms that occurs in these trial settings dilutes observable anti-Wolbachia and antifilarial effects, making it difficult to estimate therapeutic efficacy and compare different doxycycline regimens, evaluated at different times after treatment. Methods. A meta-analytical modeling framework is developed to link all usable data collected from clinical trials measuring the Wolbachia status and viability of individual female adult worms collected at various times after treatment with 4, 5, or 6 weeks of daily 100 or 200 mg oral doxycycline. The framework is used to estimate efficacy parameters that are not directly measurable as trial outcomes. Results. The estimated efficacy of doxycycline (the maximum proportional reduction in the percentage of adult female O. volvulus positive for Wolbachia) is 91%–94% on average, irrespective of the treatment regimen. Efficacy is >95% in the majority of trial participants. The life span of Wolbachia-depleted worms is reduced by 70%–80%, from approximately 10 years to 2–3 years. Conclusions. The efficacy parameters are pertinent to the prospects of using doxycycline on a "test and treat" basis for onchocerciasis control and confirm doxycycline as a potent macrofilaricidal therapy. The modeling approach is more generally relevant to the design and evaluation of clinical trials for antifilarial drugs conducted in endemic settings.
Understanding disease transmission dynamics in multihost parasite systems is a research priority for control and potential elimination of many infectious diseases. In China, despite decades of ...multifaceted control efforts against schistosomiasis, the indirectly transmitted helminth Schistosoma japonicum remains endemic, partly because of the presence of zoonotic reservoirs. We used mathematical modeling and conceptual frameworks of multihost transmission ecology to assess the relative importance of various definitive host species for S. japonicum transmission in contrasting hilly and marshland areas of China. We examine whether directing control interventions against zoonotic reservoirs could further reduce incidence of infection in humans or even eliminate transmission. Results suggest that, under current control programs, infections in humans result from spillover of transmission among zoonotic reservoirs. Estimates of the basic reproduction number within each species suggest that bovines (water buffalo and cattle) maintained transmission in the marshland area and that the recent removal of bovines from this area could achieve local elimination of transmission. However, the sole use of antifecundity S. japonicum vaccines for bovines, at least at current efficacies, may not achieve elimination in areas of comparable endemicity where removal of bovines is not a feasible option. The results also suggest that rodents drive transmission in the hilly area. Therefore, although targeting bovines could further reduce and potentially interrupt transmission in marshland regions of China, elimination of S. japonicum could prove more challenging in areas where rodents might maintain transmission. In conclusion, we show how mathematical modeling can give important insights into multihost transmission of indirectly transmitted pathogens.
Summary The broad-spectrum antiparasitic drug ivermectin was licensed for use against onchocerciasis in 1987, yet the mechanisms by which it exerts a fast decrease and long-lasting suppression of ...Onchocerca volvulus microfilaridermia, and inhibition of microfilarial release by female worms remain largely unknown. A better understanding of the effects of ivermectin on O volvulus microfilariae and macrofilariae is crucial to improve our ability to predict the long-term effect of treatment. We did a systematic review of individual and population-based ivermectin trials to investigate the temporal dynamics of the drug's microfilaricidal and embryostatic efficacy after administration of a single, standard dose (150 μg/kg). Meta-analyses on data from 26 microfilarial and 15 macrofilarial studies were linked by a mathematical model describing the dynamics of potentially fertile female parasites to skin microfilariae. The model predicts that after treatment, microfilaridermia would be reduced by half after 24 h, by 85% after 72 h, by 94% after 1 week, and by 98–99% after 1–2 months, the latter also corresponding to the time when the fraction of females harbouring live microfilariae is at its lowest (reduced by around 70% from its original value). Our results provide a baseline microfilarial skin repopulation curve against which to compare studies done after long-term treatment.
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.
Mass drug administration (MDA) of ivermectin is currently the main strategy to achieve elimination of transmission (EoT) of onchocerciasis. Modelling suggests that EoT may not be reached in all ...endemic foci using annual MDA alone. Onchocerciasis and loiasis are coendemic in forest areas of Central Africa where ivermectin treatment can lead to severe adverse events in individuals with heavy loiasis load, rendering MDA inappropriate. Vector control has been proposed as a complementary intervention strategy. Here, we discuss (i) achievements and pitfalls of previous interventions; (ii) epidemiological impact, feasibility, and combination with MDA to accelerate and/or protect EoT; (iii) role of modelling; (iv) opportunities for innovative methods of vector monitoring and control; and (v) strengthening entomological capacity in endemic countries.
Modelling studies have suggested that elimination of transmission (EoT) of onchocerciasis may not be achieved by relying solely on mass drug administration (MDA) of ivermectin, particularly in hyperendemic areas and in those areas where onchocerciasis and loiasis are coendemic.In onchocerciasis-loiasis coendemic areas, vector control methods could provide complementary strategies to accelerate elimination.Study of host-seeking behaviour could inform the development of new control/monitoring tools against vectors. These new tools could be used against vectors of onchocerciasis, vectors of loiasis, or both.Control and monitoring tools, exploiting the natural attraction of hosts, could be implemented by communities and enhance country ownership.To ensure vector control capacity, well-trained, motivated, and appropriately funded local entomologists are essential to lead vector research and entomological operations.
BACKGROUND: Intensive anti-malaria campaigns targeting the Anopheles population have demonstrated substantial reductions in adult mosquito density. Understanding the population dynamics of Anopheles ...mosquitoes throughout their whole lifecycle is important to assess the likely impact of vector control interventions alone and in combination as well as to aid the design of novel interventions. METHODS: An ecological model of Anopheles gambiae sensu lato populations incorporating a rainfall-dependent carrying capacity and density-dependent regulation of mosquito larvae in breeding sites is developed. The model is fitted to adult mosquito catch and rainfall data from 8 villages in the Garki District of Nigeria (the 'Garki Project') using Bayesian Markov Chain Monte Carlo methods and prior estimates of parameters derived from the literature. The model is used to compare the impact of vector control interventions directed against adult mosquito stages - long-lasting insecticide treated nets (LLIN), indoor residual spraying (IRS) - and directed against aquatic mosquito stages, alone and in combination on adult mosquito density. RESULTS: A model in which density-dependent regulation occurs in the larval stages via a linear association between larval density and larval death rates provided a good fit to seasonal adult mosquito catches. The effective mosquito reproduction number in the presence of density-dependent regulation is dependent on seasonal rainfall patterns and peaks at the start of the rainy season. In addition to killing adult mosquitoes during the extrinsic incubation period, LLINs and IRS also result in less eggs being oviposited in breeding sites leading to further reductions in adult mosquito density. Combining interventions such as the application of larvicidal or pupacidal agents that target the aquatic stages of the mosquito lifecycle with LLINs or IRS can lead to substantial reductions in adult mosquito density. CONCLUSIONS: Density-dependent regulation of anopheline larvae in breeding sites ensures robust, stable mosquito populations that can persist in the face of intensive vector control interventions. Selecting combinations of interventions that target different stages in the vector's lifecycle will result in maximum reductions in mosquito density.
In 2012, the World Health Organization (WHO) set the elimination of Chagas disease intradomiciliary vectorial transmission as a goal by 2020. After a decade, some progress has been made, but the new ...2021-2030 WHO roadmap has set even more ambitious targets. Innovative and robust modelling methods are required to monitor progress towards these goals. We present a modelling pipeline using local seroprevalence data to obtain national disease burden estimates by disease stage. Firstly, local seroprevalence information is used to estimate spatio-temporal trends in the Force-of-Infection (FoI). FoI estimates are then used to predict such trends across larger and fine-scale geographical areas. Finally, predicted FoI values are used to estimate disease burden based on a disease progression model. Using Colombia as a case study, we estimated that the number of infected people would reach 506 000 (95% credible interval (CrI) = 395 000-648 000) in 2020 with a 1.0% (95%CrI = 0.8-1.3%) prevalence in the general population and 2400 (95%CrI = 1900-3400) deaths (approx. 0.5% of those infected). The interplay between a decrease in infection exposure (FoI and relative proportion of acute cases) was overcompensated by a large increase in population size and gradual population ageing, leading to an increase in the absolute number of Chagas disease cases over time. This article is part of the theme issue 'Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs'.
Limited access to Chagas disease diagnosis and treatment is a major obstacle to reaching the 2020 World Health Organization milestones of delivering care to all infected and ill patients. Colombia ...has been identified as a health system in transition, reporting one of the highest levels of health insurance coverage in Latin America. We explore if and how this high level of coverage extends to those with Chagas disease, a traditionally marginalised population. Using a mixed methods approach, we calculate coverage for screening, diagnosis and treatment of Chagas. We then identify supply-side constraints both quantitatively and qualitatively. A review of official registries of tests and treatments for Chagas disease delivered between 2008 and 2014 is compared to estimates of infected people. Using the Flagship Framework, we explore barriers limiting access to care. Screening coverage is estimated at 1.2% of the population at risk. Aetiological treatment with either benznidazol or nifurtimox covered 0.3–0.4% of the infected population. Barriers to accessing screening, diagnosis and treatment are identified for each of the Flagship Framework's five dimensions of interest: financing, payment, regulation, organization and persuasion. The main challenges identified were: a lack of clarity in terms of financial responsibilities in a segmented health system, claims of limited resources for undertaking activities particularly in primary care, non-inclusion of confirmatory test(s) in the basic package of diagnosis and care, poor logistics in the distribution and supply chain of medicines, and lack of awareness of medical personnel. Very low screening coverage emerges as a key obstacle hindering access to care for Chagas disease. Findings suggest serious shortcomings in this health system for Chagas disease, despite the success of universal health insurance scale-up in Colombia. Whether these shortcomings exist in relation to other neglected tropical diseases needs investigating. We identify opportunities for improvement that can inform additional planned health reforms.
•Serious health system shortcomings exist for diagnosing and treating Chagas disease.•Access to Chagas care is low despite Colombia's celebrated universal health insurance.•Care involves a complex and ambiguous pathway with many actors and institutions.•Low levels of screening are a major limiting factor in accessing care for Chagas.•Global efforts need to ensure reliable and sufficient access to Chagas treatment.
Countering the Zika epidemic in Latin America Ferguson, Neil M.; Cucunubá, Zulma M.; Dorigatti, Ilaria ...
Science (American Association for the Advancement of Science),
07/2016, Letnik:
353, Številka:
6297
Journal Article
Recenzirano
Odprti dostop
Epidemic dynamics are key and data gaps must be addressed
As evidence grew for a causal link between Zika infection and microcephaly and other serious congenital anomalies (
1
), the World Health ...Organization (WHO) declared the Latin American Zika epidemic a public health emergency of international concern in February 2016 (
2
). The speed of spread see the figure, top, and the supplementary materials (SM) has made effective public health responses challenging. Immediate responses have included vector control (
3
) and advice to delay pregnancy in a few countries (
4
), followed by an extended recommendation to all affected countries by WHO in June 2016. These have merits but are likely to have limited effectiveness (
5
) and may interact antagonistically. Fuller understanding of dynamics and drivers of the epidemic is needed to assess longer-term risks to prioritize interventions.
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