Seeking an optimal dosing regimen for OZ439/DSM265 combination therapy for treating uncomplicated falciparum malaria.

BACKGROUND: The efficacy of artemisinin-based combination therapies (ACTs), the first-line treatments for uncomplicated falciparum malaria, has been declining in malaria-endemic countries due to the emergence of malaria parasites resistant to these compounds. Novel alternative therapies are needed urgently to prevent the likely surge in morbidity and mortality due to failing ACTs. OBJECTIVES: This study investigates the efficacy of the combination of two novel drugs, OZ439 and DSM265, using a biologically informed within-host mathematical model. METHODS: A within-host model was developed, which accounts for the differential killing of these compounds against different stages of the parasite's life cycle and accommodates the pharmacodynamic interaction between the drugs. Data of healthy volunteers infected with falciparum malaria collected from four trials (three that administered OZ439 and DSM265 alone, and the fourth a combination of OZ439 and DSM265) were analysed. Model parameters were estimated in a hierarchical Bayesian framework. RESULTS: The posterior predictive simulations of our model predicted that 800 mg of OZ439 combined with 450 mg of DSM265, which are within the safe and tolerable dose range, can provide above 90% cure rates 42 days after drug administration. CONCLUSIONS: Our results show that the combination of OZ439 and DSM265 can be a promising alternative to replace ACTs. Our model can be used to inform future Phase 2 and 3 clinical trials of OZ439/DSM265, fast-tracking the deployment of this combination therapy in the regions where ACTs are failing. The dosing regimens that are shown to be efficacious and within safe and tolerable limits are suggested for future investigations.

Use of quantitative PCR to assess the efficacy of albendazole against Necator americanus and Ascaris spp. in Manufahi District, Timor-Leste.

BACKGROUND: Soil-transmitted helminths (STHs) including Ascaris lumbricoides, Necator americanus, Ancylostoma spp. and Trichuris trichiura are cause of significant global morbidity. To mitigate their disease burden, at-risk groups in endemic regions receive periodic mass drug administration using anthelmintics, most commonly albendazole and mebendazole. Assessing the efficacy of anthelmintic drugs is important for confirming that these regimens are working effectively and that drug resistance has not emerged. In this study we aimed to characterise the therapeutic efficacy of albendazole against Ascaris spp. and N. americanus in Timor-Leste, using a quantitative polymerase chain reaction (qPCR) method for parasite detection and quantification. RESULTS: A total of 314 participants from 8 communities in Timor-Leste provided stool samples before and 10-14 days after the administration of a single 400 mg dose of albendazole. Helminth infection status and infection intensity (measured in Ct-values and relative fluorescence units) were determined using qPCR. Efficacy was determined by examining the cure rates and infection intensity reduction rates. Albendazole was found to be highly efficacious against Ascaris spp., with a cure rate of 91.4% (95% CI: 85.9-95.2%) and infection intensity reduction rate of 95.6% (95% CI: 88.3-100%). The drug was less efficacious against N. americanus with a cure rate of 58.3% (95% CI: 51.4-64.9%) and infection intensity reduction rate of 88.9% (95% CI: 84.0-97.0%). CONCLUSIONS: The observed cure rates and infection intensity reduction rates obtained for Ascaris spp. and to a lower extent N. americanus, demonstrate the continued efficacy of albendazole against these species and its utility as a mass chemotherapy agent in Timor-Leste. Furthermore, this study demonstrates the usefulness of qPCR as a method to measure the efficacy of anthelminthic drugs. Additional research is necessary to translate Ct-values into eggs per gram in a systematic way. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry 12614000680662 (registered 27 June 2014).

Investigations into the association between soil-transmitted helminth infections, haemoglobin and child development indices in Manufahi District, Timor-Leste.

BACKGROUND: Timor-Leste has a high prevalence of soil-transmitted helminth (STH) infections. High proportions of the population have been reported as being anaemic, and extremely high proportions of children as stunted or wasted. There have been no published analyses of the contributions of STH to these morbidity outcomes in Timor-Leste. METHODS: Using baseline cross-sectional data from 24 communities (18 communities enrolled in a cluster randomised controlled trial, and identically-collected data from six additional communities), analyses of the association between STH infections and community haemoglobin and child development indices were undertaken. Stool samples were assessed for STH using qPCR and participant haemoglobin, heights and weights were measured. Questionnaires were administered to collect demographic and socioeconomic data. Intensity of infection was categorised using correlational analysis between qPCR quantification cycle values and eggs per gram of faeces equivalents, with algorithms generated from seeding experiments. Mixed-effects logistic and multinomial regression were used to assess the association between STH infection intensity classes and anaemia, and child stunting, wasting and underweight. RESULTS: Very high stunting (60%), underweight (60%), and wasting (20%) in children, but low anaemia prevalence (15%), were found in the study communities. STH were not significantly associated with morbidity outcomes. Male children and those in the poorest socioeconomic quintile were significantly more likely to be moderately and severely stunted. Male children were significantly more likely than female children to be severely underweight. Increasing age was also a risk factor for being underweight. Few risk factors emerged for wasting in these analyses. CONCLUSIONS: According to World Health Organization international reference standards, levels of child morbidity in this population constitute a public health emergency, although the international reference standards need to be critically evaluated for their applicability in Timor-Leste. Strategies to improve child development and morbidity outcomes, for example via nutrition and iron supplementation programmes, are recommended for these communities. Despite the apparent lack of an association from STH in driving anaemia, stunting, wasting and underweight, high endemicity suggests a need for STH control strategies. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12614000680662 ; retrospectively registered.

A cluster-randomised controlled trial integrating a community-based water, sanitation and hygiene programme, with mass distribution of albendazole to reduce intestinal parasites in Timor-Leste: the WASH for WORMS research protocol.

INTRODUCTION: There is limited evidence demonstrating the benefits of community-based water, sanitation and hygiene (WASH) programmes on infections with soil-transmitted helminths (STH) and intestinal protozoa. Our study aims to contribute to that evidence base by investigating the effectiveness of combining two complementary approaches for control of STH: periodic mass administration of albendazole, and delivery of a community-based WASH programme. METHODS AND ANALYSIS: WASH for WORMS is a cluster-randomised controlled trial to test the hypothesis that a community-based WASH intervention integrated with periodic mass distribution of albendazole will be more effective in reducing infections with STH and protozoa than mass deworming alone. All 18 participating rural communities in Timor-Leste receive mass chemotherapy every 6 months. Half the communities also receive the community-based WASH programme. Primary outcomes are the cumulative incidence of infection with STH. Secondary outcomes include the prevalence of protozoa; intensity of infection with STH; as well as morbidity indicators (anaemia, stunting and wasting). Each of the trial outcomes will be compared between control and intervention communities. End points will be measured 2 years after the first albendazole distribution; and midpoints are measured at 6 months intervals (12 months for haemoglobin and anthropometric indexes). Mixed-methods research will also be conducted in order to identify barriers and enablers associated with the acceptability and uptake of the WASH programme. ETHICS AND DISSEMINATION: Ethics approval was obtained from the human ethics committees at the University of Queensland, Australian National University, Timorese Ministry of Health, and University of Melbourne. The results of the trial will be published in peer-reviewed journals presented at national and international conferences, and disseminated to relevant stakeholders in health and WASH programmes. This study is funded by a Partnership for Better Health--Project grant from the National Health and Research Council (NHMRC), Australia. TRIAL REGISTRATION NUMBER: ACTRN12614000680662; Pre-results.

A novel high throughput assay for anthelmintic drug screening and resistance diagnosis by real-time monitoring of parasite motility.

BACKGROUND: Helminth parasites cause untold morbidity and mortality to billions of people and livestock. Anthelmintic drugs are available but resistance is a problem in livestock parasites, and is a looming threat for human helminths. Testing the efficacy of available anthelmintic drugs and development of new drugs is hindered by the lack of objective high-throughput screening methods. Currently, drug effect is assessed by observing motility or development of parasites using laborious, subjective, low-throughput methods. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe a novel application for a real-time cell monitoring device (xCELLigence) that can simply and objectively assess anthelmintic effects by measuring parasite motility in real time in a fully automated high-throughput fashion. We quantitatively assessed motility and determined real time IC(50) values of different anthelmintic drugs against several developmental stages of major helminth pathogens of humans and livestock, including larval Haemonchus contortus and Strongyloides ratti, and adult hookworms and blood flukes. The assay enabled quantification of the onset of egg hatching in real time, and the impact of drugs on hatch rate, as well as discriminating between the effects of drugs on motility of drug-susceptible and -resistant isolates of H. contortus. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that this technique will be suitable for discovery and development of new anthelmintic drugs as well as for detection of phenotypic resistance to existing drugs for the majority of helminths and other pathogens where motility is a measure of pathogen viability. The method is also amenable to use for other purposes where motility is assessed, such as gene silencing or antibody-mediated killing.