Participatory development of a target policy profile to support soil-transmitted helminth elimination

IntroductionSoil-transmitted helminths (STH) are parasitic worms that infect nearly a quarter of the world's population, particularly those living in communities without access to adequate water, sanitation, and housing. Emerging evidence suggests that it may be possible to interrupt transmission of STH by deworming individuals of all ages via community-wide MDA (cMDA), as opposed to only treating children and other focal populations. Transitioning from a policy of STH control to STH elimination in targeted areas would require a fundamental shift in STH policy and programming. This policy change would require updated guidance to support countries as they adapt their current approaches for STH surveillance, supply chain management, community mobilization, and core programmatic activities in pursuit of STH elimination. There is an opportunity to engage with key stakeholders, such as program implementers and implementation partners, to understand what evidence they need to confidently adopt a new policy guideline and to deliver guideline adherent management at scale.MethodsWe aimed to engage with STH stakeholders to develop a Target Policy Profile (TPoP), a single document that describes optimal characteristics and evidence requirements that STH stakeholders prioritized in future potential STH transmission interruption efforts. Steps in TPoP development included a scoping review and key informant interviews (KIIs), which were used to design a two-stage Delphi technique to identify and verify TPoP components.ResultsThe scoping review resulted in 25 articles, and 8 experts participated in KII's. Twenty respondents completed the first Delphi survey and 10 respondents completed the second. This systematic effort resulted in a net of 3 key information domains (background/context, clinical considerations, and implementation considerations) encompassing 24 evidence categories (examples include evidence regarding safety and adverse events, implementation feasibility, or evidence dissemination). For each evidence category, STH stakeholders reviewed, endorsed, or revised a range of options for how the evidence could be presented.DiscussionThis information can be used by guideline committees or global policy makers prior to convening guideline advisory groups. The TPoP tool may also speed the process of stakeholder consensus building around guidelines, accelerating progress towards implementing evidence-based policy at scale

Are long-lasting insecticide-treated bednets and water filters cost-effective tools for delaying HIV disease progression in Kenya?

Background: Co-infection with malaria and other infectious diseases has been shown to increase viral load and accelerate HIV disease progression. A recent study in Kenya demonstrated that providing long-lasting insecticide-treated bednets (LLIN) and water filters (WF) to HIV-positive adults with CD4 >350 cells/mm3 significantly reduced HIV progression. Design: We conducted a cost analysis to estimate the potential net financial savings gained by delaying HIV progression and increasing the time to antiretroviral therapy (ART) eligibility through delivering LLIN and WF to 10% of HIV-positive adults with CD4 >350 cells/mm3 in Kenya. Results: Given a 3-year duration of intervention benefit, intervention unit cost of US$32 and patient-year ART cost of US$757 (2011 US$), over the lifetime of ART patients, in Kenya, we estimated the intervention could yield a return on investment (ROI) of 11 (95$2 million and savings in ART costs of about US$26 million (95$14 million, decreasing the ROI to 6. Conclusions: Provision of LLIN and WF could be a cost-saving and practical method to defer time to ART eligibility in the context of highly resource-constrained environments experiencing donor fatigue for HIV/AIDS programs

Use of anti-retroviral therapy in tuberculosis patients on second-line anti-TB regimens: a systematic review

Introduction: Use of antiretroviral therapy (ART) during treatment of drug susceptible tuberculosis (TB) improves survival. However, data from HIV infected individuals with drug resistant TB are lacking. Second line TB drugs when combined with ART may increase drug interactions and lead to higher rates of toxicity and greater noncompliance. This systematic review sought to determine the benefit of ART in the setting of second line drug therapy for drug resistant TB. Methods: We included individual patient data from studies that evaluated treatment of drug-resistant tuberculosis in HIV-1 infected individuals published between January 1980 and December of 2009. We evaluated the effect of ART on treatment outcomes, time to smear and culture conversion, and adverse events. Results: Ten observational studies, including data from 217 subjects, were analyzed. Patients using ART during TB treatment had increased likelihood of cure (hazard ratio (HR) 3.4, 95% CI 1.6–7.4) and decreased likelihood of death (HR 0.4, 95% CI 0.3–0.6) during treatment for drug resistant TB. These associations remained significant in patients with a CD4 less than 200 cells/mm3 and less than 50 cells/mm3, and when correcting for drug resistance pattern. Limitations: We identified only observational studies from which individual patient data could be drawn. Limitations in study design, and heterogeneity in a number of the outcomes of interest had the potential to introduce bias. Discussion: While there are insufficient data to determine if ART use increases adverse drug interactions when used with second line TB drugs, ART use during treatment of drug resistant TB appears to improve cure rates and decrease risk of death. All individuals with HIV appear to benefit from ART use during treatment for TB

Detecting albendazole metabolites in serum and urine: a first step in developing an indicator of MDA compliance in humans

The neglected tropical diseases (NTDs) are a group of pathogens affecting individuals in the poorest regions of the world. Among them, Soil Transmitted Helminth (STH) infections directly impact nutritional status, educational development, individual productivity, and physical and mental development in human populations. Currently, these infections are controlled through mass drug administration (MDA) programs using albendazole (ABZ) or mebendazole. However, not all programs have demonstrated expected impact on prevalence or intensity of infections. These failures may be related to poor programmatic coverage, suboptimal adherence or the exposure of parasites to sub-therapeutic drug concentrations due to poor drug dissolution, insufficient gastrointestinal absorption and/or systemic availability of the active ingredient. Accordingly, improved knowledge of the basic pharmaco-kinetics of ABZ in treated people is critical. As part of the DeWorm3 project, we sought to characterize the serum disposition kinetics and pattern of urinary excretion of ABZ and its main metabolites (ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO2)) in non-infected human volunteers. In addition, we sought to determine the duration and optimal timepoint where ABZ and/or its metabolites can be measured in urine as an indirect assessment of an individual?s adherence to treatment. Consecutive venous blood and urine samples were collected from eight (8) healthy volunteers between 2 and 72 h (serum) and 4 and 72 h (urine) for HPLC analysis of ABZ/metabolites following administration of a single postprandial oral dose of ABZ (400 mg Glaxo SmithKline).The ABZSO metabolite was the main analyte recovered either in serum and urine samples from ABZ-treated human. ABZSO serum concentrations reached its peak concentration (Cmax= 1.20 ± 0.44 μg/mL) at 4.75 h post-treatment. In urine ABZSO Cmax value was 3.24 ± 1.51 μg/mL, reached at 6.50 h post ABZ administration. The urinary AUC value, resulted higher (2.3 fold) compared to that measured in serum. The overall, PK-based information reported here demonstrates that the measurement of ABZSO concentrations both in serum and urine could be useful to confirm compliance to ABZ treatment and an objective measurement of program coverage.Fil: Ceballos, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Cimino, Rubén Oscar. Universidad Nacional de Salta. Sede Regional Orán. Instituto de Investigación de Enfermedades Tropicales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Juarez, Marisa del Valle. Universidad Nacional de Salta. Sede Regional Orán. Instituto de Investigación de Enfermedades Tropicales; ArgentinaFil: Moreno Torrejon, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Banal, Juan Pablo. Universidad Nacional de Salta. Sede Regional Orán. Instituto de Investigación de Enfermedades Tropicales; ArgentinaFil: Alvarez, Luis Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Krolewiecki, Alejandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Salta. Sede Regional Orán. Instituto de Investigación de Enfermedades Tropicales; ArgentinaFil: Walson, Judd. Natural History Museum; Reino UnidoFil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina66° Annual Meeting of American Society of Tropical Medicine and HygieneBaltimoreEstados UnidosAmerican Society of Tropical Medicine and Hygien

Intestinal disturbances associated with mortality of children with complicated severe malnutrition

Background: Children admitted to hospital with complicated severe malnutrition (CSM) have high mortality despite compliance with standard WHO management guidelines. Limited data suggests a relationship between intestinal dysfunction and poor prognosis in CSM, but this has not been explicitly studied. This study aimed to evaluate the role of intestinal disturbances in CSM mortality. Methods: A case-control study nested within a randomized control trial was conducted among children hospitalized with CSM in Kenya and Malawi. Children who died (cases, n = 68) were compared with those who were discharged, propensity matched to the cases on age, HIV and nutritional status (controls, n = 68) on fecal metabolomics that targeted about 70 commonly measured metabolites, and enteropathy markers: fecal myeloperoxidase (MPO), fecal calprotectin, and circulating intestinal fatty acid binding protein (I-FABP). Results: The fecal metabolomes of cases show specific reductions in amino acids, monosaccharides, and microbial fermentation products, when compared to controls. SCFA levels did not differ between groups. The overall fecal metabolomics signature moderately differentiates cases from controls (AUC = 0.72). Enteropathy markers do not differ between groups overall, although serum I-FABP is elevated in cases in a sensitivity analysis among non-edematous children. Integrative analysis with systemic data suggests an indirect role of intestinal inflammation in the causal path of mortality. Conclusions: Intestinal disturbances appear to have an indirect association with acute mortality. Findings of the study improve our understanding of pathophysiological pathways underlying mortality of children with CSM

Tebipenem as an oral alternative for the treatment of typhoid caused by XDR salmonella typhi

Background: Antimicrobial therapy is essential for the treatment of enteric fever, the infection caused by Salmonella serovars Typhi and Paratyphi A. However, an increase in resistance to key antimicrobials and the emergence of MDR and XDR in Salmonella Typhi poses a major threat for efficacious outpatient treatments.Objectives: We recently identified tebipenem, an oral carbapenem licensed for use for respiratory tract infections in Japan, as a potential alternative treatment for MDR/XDR Shigella spp. Here, we aimed to test the in vitro antibacterial efficacy of this drug against MDR and XDR typhoidal Salmonella.Methods: We determined the in vitro activity of tebipenem in time-kill assays against a collection of non-XDR and XDR Salmonella Typhi and Salmonella Paratyphi A (non-XDR) isolated in Nepal and Bangladesh. We also tested the efficacy of tebipenem in combination with other antimicrobials.Results: We found that both XDR and non-XDR Salmonella Typhi and Salmonella Paratyphi A are susceptible to tebipenem, exhibiting low MICs, and were killed within 8-24 h at 2-4×MIC. Additionally, tebipenem demonstrated synergy with two other antimicrobials and could efficiently induce bacterial killing.Conclusions: Salmonella Paratyphi A and XDR Salmonella Typhi display in vitro susceptibility to the oral carbapenem tebipenem, while synergistic activity with other antimicrobials may limit the emergence of resistance. The broad-spectrum activity of this drug against MDR/XDR organisms renders tebipenem a good candidate for clinical trials

Pooling as a Strategy for the Timely Diagnosis of Soil-Transmitted Helminths in Stool: Value and Reproducibility

Background: The strategy of pooling stool specimens has been extensively used in the field of parasitology in order to facilitate the screening of large numbers of samples whilst minimizing the prohibitive cost of single sample analysis. The aim of this study was to develop a standardized reproducible pooling protocol for stool samples, validated between two different laboratories, without jeopardizing the sensitivity of the quantitative polymerase chain reaction (qPCR) assays employed for the detection of soil-transmitted helminths (STHs). Two distinct experimental phases were recruited. First, the sensitivity and specificity of the established protocol was assessed by real-time PCR for each one of the STHs. Secondly, agreement and reproducibility of the protocol between the two different laboratories were tested. The need for multiple stool sampling to avoid false negative results was also assessed. Finally, a cost exercise was conducted which included labour cost in low- and high-wage settings, consumable cost, prevalence of a single STH species, and a simple distribution pattern of the positive samples in pools to estimate time and money savings suggested by the strategy. Results: The sensitivity of the pooling method was variable among the STH species but consistent between the two laboratories. Estimates of specificity indicate a \u27pooling approach\u27 can yield a low frequency of \u27missed\u27 infections. There were no significant differences regarding the execution of the protocol and the subsequent STH detection between the two laboratories, which suggests in most cases the protocol is reproducible by adequately trained staff. Finally, given the high degree of agreement, there appears to be little or no need for multiple sampling of either individuals or pools. Conclusions: Our results suggest that the pooling protocol developed herein is a robust and efficient strategy for the detection of STHs in \u27pools-of-five\u27. There is notable complexity of the pool preparation to ensure even distribution of helminth DNA throughout. Therefore, at a given setting, cost of labour among other logistical and epidemiological factors, is the more concerning and determining factor when choosing pooling strategies, rather than losing sensitivity and/or specificity of the molecular assay or the method

What Does Soil-Transmitted Helminth Elimination Look Like? Results From a Targeted Molecular Detection Survey in Japan

Background: Japan is one of the few countries believed to have eliminated soil-transmitted helminths (STHs). In 1949, the national prevalence of Ascaris lumbricoides was 62.9%, which decreased to 0.6% in 1973 due to improvements in infrastructure, socioeconomic status, and the implementation of national STH control measures. The Parasitosis Prevention Law ended in 1994 and population-level screening ceased in Japan; therefore, current transmission status of STH in Japan is not well characterized. Sporadic cases of STH infections continue to be reported, raising the possibility of a larger-scale recrudescence of STH infections. Given that traditional microscopic detection methods are not sensitive to low-intensity STH infections, we conducted targeted prevalence surveys using sensitive PCR-based assays to evaluate the current STH-transmission status and to describe epidemiological characteristics of areas of Japan believed to have achieved historical elimination of STHs. Methods: Stool samples were collected from 682 preschool- and school-aged children from six localities of Japan with previously high prevalence of STH. Caregivers of participants completed a questionnaire to ascertain access to water, sanitation and hygiene (WASH), and potential exposures to environmental contamination. For fecal testing, multi-parallel real-time PCR assays were used to detect infections of Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale and Trichuris trichiura. Results: Among the 682 children, no positive samples were identified, and participants reported high standards of WASH. Conclusions: To our knowledge, this is the first STH-surveillance study in Japan to use sensitive molecular techniques for STH detection. The results suggest that recrudescence of STH infections has not occurred, and that declines in prevalence have been sustained in the sampled areas. These findings suggest that reductions in prevalence below the elimination thresholds, suggestive of transmission interruption, are possible. Additionally, this study provides circumstantial evidence that multi-parallel real-time PCR methods are applicable for evaluating elimination status in areas where STH prevalence is extremely low.[Figure not available: see fulltext.