Résumé

Objectif

Analyser les données tirées des essais contrôlés randomisés (ECR) sur la prévention et le contrôle des maladies tropicales négligées (MTN) et identifier les domaines où les données manquent.

Méthodes

Des recherches sur les ECR ont été menées dans le registre central de Cochrane des essais contrôlés (Cochrane Central Register of Controlled Trials) et PubMed, et des recherches sur les méta-analyses et les revues systématiques ont été effectuées dans la base de données de Cochrane et PubMed, depuis la date de leur création jusqu'au 31 décembre 2012.

Résultats

Globalement, 258 ECR ont été trouvés sur la trypanosomiase américaine, l'ulcère de Buruli, la dengue, les infections à géohelminthes, la leishmaniose, la lèpre, la filariose lymphatique, l'onchocercose, la rage, la schistosomiase ou le trachome. Aucun ECR n'a été trouvé sur la cysticercose, l'échinococcose, les trématodes d'origine alimentaire, la dracunculose ou la trypanosomiase humaine africaine. Les maladies les plus étudiées étaient les infections à géohelminthes (51 ECR) et la leishmaniose (46 ECR). Les vaccins, la chimioprophylaxie et les interventions ciblant les insectes vecteurs ont été évalués dans 113, 99 et 39 ECR, respectivement. Un faible nombre s'intéressait à la meilleure manière d'administrer une chimiothérapie préventive, comme le choix de l'intervalle posologique (10) ou de la population cible (4), la couverture de population nécessaire pour réduire la transmission (2) ou la méthode de distribution des médicaments (1). Trente et une publications contenant 32 revues systématiques (16 avec et 16 sans méta-analyses) ont été trouvées sur la trypanosomiase américaine, la dengue, les géohelminthes, la leishmaniose, la lèpre, la filariose lymphatique, l'onchocercose, la schistosomiase ou le trachome. Ensemble, ils comptent seulement 79 des 258 ECR publiés (30,6%). Parmi les 36 interventions évaluées, 8 ont été jugées efficaces dans plusieurs revues.

Conclusion

Nous avons trouvé peu d'ECR sur la prévention ou le contrôle des principales MTN. Les essais sur la meilleure façon d'administrer une chimiothérapie préventive ont été particulièrement rares.

Resumen

Objetivo

Analizar las evidencias procedentes de ensayos controlados aleatorios (RCT, por sus siglas en inglés) sobre la prevención y el control de enfermedades tropicales desatendidas e identificar las áreas en las que se carece de evidencias.

Métodos

Se buscaron RCT en el Registro Central Cochrane de Ensayos Controlados y en PubMed, así como metaanálisis y exámenes sistemáticos en la Base de Datos Cochrane de Revisiones Sistemáticas y en PubMed, en ambos casos, desde sus comienzos hasta el 31 de diciembre de 2012.

Resultados

En total, se hallaron 258 RCT acerca de la infección por el parásito Trypanosoma cruzi, la úlcera de Buruli, el dengue, las infecciones por geohelmintiasis, la leishmaniasis, la lepra, la filariasis linfática, la oncocercosis, las rabias, la esquistosomiasis o el tracoma. No se encontraron RCT sobre la cisticercosis, la equinococosis, las nematodiasis transmitidas por los alimentos, la dracunculosis ni la tripanosomiasis africana humana. Las enfermedades más estudiadas fueron la infección por geohelmiantiasis (51 RCT) y la leishmaniasis (46 RCT). Las vacunas, quimioprofilaxis e intervenciones cuyo objetivo eran los insectos que actúan como vectores quedaron evaluadas en 113, 99 y 39 RCT, respectivamente. Unos pocos ensayos abordaron la mejor manera de administrar quimioterapia preventiva, como la elección del intervalo de dosificación (10) o la población objetivo (4), la cobertura de la población requerida para reducir la transmisión (2) o el método de distribución de medicamentos (1). Se encontraron 31 publicaciones que incluían 32 exámenes sistemáticos (16 con metaanálisis y 16 sin metaanálisis) sobre la infección por el parásito Trypanosoma cruzi, el dengue, los geohelmintos, la leishmaniasis, la lepra, la filariasis linfática, la oncocercosis, la esquistosomiasis y el tracoma. En su conjunto, solo incluyeron 79 de los 258 RCT publicados (30,6 %). De las 36 intervenciones evaluadas, 8 se consideraron eficaces en más de un examen.

Conclusión

Se hallaron pocos RCT sobre la prevención y el control de las principales enfermedades tropicales desatendidas. Los ensayos sobre la mejor manera de administrar quimioterapia preventiva fueron especialmente escasos.

ملخص

الغرض

تحليل البيّنات من التجارب العشوائية المضبوطة حول الوقاية من أمراض المناطق المدارية المهملة ومكافحتها وتحديد المناطق التي تفتقر إلى البيّنات.

الطريقة

تم البحث في سجل كوكرين المركزي للتجارب المضبوطة وPubMed للوقوف على التجارب العشوائية المضبوطة وتم البحث في قاعدة بيانات كوكرين عن الاستعراضات المنهجية وتم البحث في PubMed للوقوف على التحليلات الوصفية والاستعراضات المنهجية، من البداية حتى 31 كانون الأول/ ديسمبر 2012.

النتائج

بشكل عام، تبين إجراء 258 تجربة عشوائية مضبوطة على داء المثقبيات الأمريكي أو قرحة بورولي أو حمى الضنك أو العدوى الديدانية المنقولة بالتربة أو داء الليشمانيات أو الجزام أو داء الفيلاريات اللمفية أو داء كلابية الذنب أو داء الكلب أو البلهارسية أو التراخوما. وتبين عدم إجراء تجارب عشوائية مضبوطة على داء الكيسات المذنبة أو داء المشوكات أو داء الديدان المثقوبة المنقولة بالأغذية أو داء التنينات أو داء المثقبيات البشري الأفريقي. وكانت الأمراض التي حظيت بأكبر قدر من الدراسة هي العدوى الديدانية المنقولة بالتربة (51 تجربة عشوائية مضبوطة) وداء الليشمانيات (46 تجربة عشوائية مضبوطة). وتم تقييم اللقاحات والوقاية الكيميائية والتدخلات التي تستهدف نواقل الحشرات في 113 و99 و39 تجربة عشوائية مضبوطة، على التوالي. وتناولت بعض التجارب أفضل الطرق لإيتاء العلاج الكيميائي الوقائي، مثل اختيار الفواصل الزمنية بين الجرعات (10) أو الفئة السكانية المستهدفة (4) أو التغطية السكانية المطلوبة لتقليل السريان (2) أو أسلوب توزيع العقار (1). وتم العثور على واحد وثلاثين نشرة تتضمن 32 استعراضاً منهجياً (يتضمن 16 منها تحليلات وصفية بينما لا يتضمن 16 منها ذلك) على داء المثقبيات الأمريكي أو حمى الضنك أو العدوى الديدانية المنقولة بالتربة أو داء الليشمانيات أو الجزام أو داء الفيلاريات اللمفية أو داء كلابية الذنب أو البلهارسية أو التراخوما. وقد اشتملا معاً على 79 تجربة عشوائية مضبوطة فقط تم نشرها من بين 258 تجربة عشوائية مضبوطة (30.6 %). وتم الحكم على نجاعة 8 تدخلات، من إجمالي 36 تدخلاً تم الوصول إليها، في أكثر من استعراض.

الاستنتاج

تبين إجراء بضعة تجارب عشوائية مضبوطة حول الوقاية من أمراض المناطق المدارية المهملة الأساسية ومكافحتها. وكانت التجارب المعنية بأفضل الطرق لإيتاء العلاج الكيميائي الوقائي على وجه الخصوص نادرة.

摘要

目的

分析来自有关预防和控制被忽视热带疾病（NTD）随机对照试验（RCT）的证据并识别缺少证据的领域。

方法

在科克伦对照试验注册中心和PubMed检索RCT，在科克伦系统评价数据库和PubMed搜索元分析和系统评价，二者时间均为最初到2012年12月31日。

结果

总计找到有关美洲锥虫病、布鲁里溃疡、登革热、土源性蠕虫感染、利什曼病、麻风病、淋巴丝虫病、盘尾丝虫病、狂犬病、血吸虫病或沙眼的258项RCT。未发现囊虫病、包虫病、食源性吸虫、麦地那龙线虫病或非洲人类锥虫病的相关RCT。大多数研究疾病是土源性蠕虫感染（51项RCT）和利什曼病（46项RCT）。分别在113、99和39项RCT中评估针对昆虫介体的疫苗、化学预防和干预措施。很少谈及如何最好地提供预防性化学疗法，例如选择给药间隔（10）或目标人群（4）、减少传播所需的人群覆盖率（2）或者药物配送方法（1）。发现有关美洲锥虫病、登革热、土源性蠕虫、利什曼病、麻风病、淋巴丝虫病、盘尾丝虫病、血吸虫病或沙眼包含32篇系统评价（16篇有元分析，16篇没有）的31份出版物。在258项已发表的RCT中加在一起仅有79项（30.6%）包括在内。在评估的36个干预措施中，不止一份评价判定8种干预是有效的。

结论

几乎未发现有关主要NTD防控的RCT。如何最好地提供预防性化学疗法的试验尤其稀少。

Резюме

Цель

Проанализировать данные рандомизированных контролируемых исследований (РКИ) по профилактике и борьбе с забытыми тропическими болезнями (ЗТБ) и определить области, в которых данные отсутствуют.

Методы

Проводился поиск РКИ в Кокрановском центральном регистре контролируемых исследований и базах данных PubMed, а также поиск мета-анализов и систематических обзоров в Кокрановской базе данных систематических обзоров и базах данных PubMed с начала создания баз данных по 31 декабря 2012 года.

Результаты

В целом, было найдено 258 РКИ по американскому трипаносомозу, язве Бурули, лихорадке денге, геогельминтной инфекции, лейшманиозу, лепре, лимфатическому филяриатозу, онхоцеркозу, бешенству, шистосомозу или трахоме. Не были найдены РКИ по цистицеркозу, эхинококкозу, трематоде пищевого происхождения, дракункулезу или африканскому трипаносомозу человека. Наиболее изученными заболеваниями являются геогельминтная инфекция (51 РКИ) и лейшманиоз (46 РКИ). Оценка вакцин, химиопрофилактики и мероприятий, направленных на борьбу с насекомыми-переносчиками инфекций, проведена соответственно в 113, 99 и 39 РКИ. Лишь в немногих РКИ рассматривался вопрос о том, как лучше всего проводить профилактическую химиотерапию, например, выбор интервала дозирования (10) или целевой группы населения (4), охвата населения для снижения количества случаев передачи инфекции (2) или методов распространения лекарств (1). Была найдена тридцать одна публикация, содержащая систематические обзоры (16 с мета-анализом и 16 без него) по американскому трипаносомозу, лихорадке денге, геогельминтам, лейшманиозу, лепре, лимфатическому филяриатозу, онхоцеркозу, шистосомозу или трахоме. Все вместе они составили только 79 из 258 опубликованных РКИ (30,6%). Из 36 оцененных мер по исправлению ситуации 8 были признаны эффективными в более чем одном обзоре.

Вывод

Было найдено незначительное количество РКИ по профилактике или контролю основных ЗТБ. Особенно редко встречаются исследования, касающиеся поиска наилучших способов проведения профилактической химиотерапии.

Introduction

More than one billion of the world’s poorest people are affected by neglected tropical diseases (NTDs), which are a group of parasitic, viral and bacterial infections that each year cause an estimated 534 000 deaths and a disease burden of 57 million disability-adjusted life–years (DALYs).¹1 Hotez PJ, Molyneux DH, Fenwick A, Ottesen E, Ehrlich Sachs S, Sachs JD. Incorporating a rapid-impact package for neglected tropical diseases with programs for HIV/AIDS, tuberculosis, and malaria. PLoS Med 2006;3:e102. doi: http://dx.doi.org/10.1371/journal.pmed.0030102 PMID:16435908
https://doi.org/10.1371/journal.pmed.003... The World Health Organization (WHO) advocates five strategies for preventing and controlling NTDs: preventive chemotherapy, intensified case management, control of disease vectors, provision of clean water and sanitation and veterinary public health measures.²2 Working to overcome the global impact of neglected tropical diseases. [Internet]. Geneva: World Health Organization; 2010. Available from: http://www.who.int/neglected_diseases/2010report [accessed 5 February 2014].
http://www.who.int/neglected_diseases/20... Historically, the development of drugs for these diseases has been limited by a lack of market incentives.³3 Trouiller P, Olliaro P, Torreele E, Orbinski J, Laing R, Ford N. Drug development for neglected diseases: a deficient market and a public-health policy failure. Lancet 2002;359:2188–94. doi: http://dx.doi.org/10.1016/S0140-6736(02)09096-7 PMID:12090998
https://doi.org/10.1016/S0140-6736(02)09... More recently, the formation of public–private partnerships for drug development has increased investment in research and development but the results have been uneven, with some diseases benefiting more than others.⁴4 Cohen J, Dibner MS, Wilson A. Development of and access to products for neglected diseases. PLoS One 2010;5:e10610. doi: http://dx.doi.org/10.1371/journal.pone.0010610 PMID:20485552
https://doi.org/10.1371/journal.pone.001... For some NTDs, such as geohelminth infection, affordable and effective treatments do exist but their availability for people living in highly endemic areas is often limited.⁴4 Cohen J, Dibner MS, Wilson A. Development of and access to products for neglected diseases. PLoS One 2010;5:e10610. doi: http://dx.doi.org/10.1371/journal.pone.0010610 PMID:20485552
https://doi.org/10.1371/journal.pone.001... For many others, treatment is inconvenient, poorly tolerated and expensive. A rational and comprehensive approach to disease control may, therefore, involve: (i) prevention strategies, including combined preventive chemotherapy (i.e. the treatment of more than one disease by the mass administration of more than one drug concurrently); (ii) improved access to clean water and sanitation; and (iii) the reduction of disease transmission by insect vectors. In addition, integrating efforts to control several NTDs into a single programme may reduce costs and streamline implementation.¹1 Hotez PJ, Molyneux DH, Fenwick A, Ottesen E, Ehrlich Sachs S, Sachs JD. Incorporating a rapid-impact package for neglected tropical diseases with programs for HIV/AIDS, tuberculosis, and malaria. PLoS Med 2006;3:e102. doi: http://dx.doi.org/10.1371/journal.pmed.0030102 PMID:16435908
https://doi.org/10.1371/journal.pmed.003... ^,55 Evans D, McFarland D, Adamani W, Eigege A, Miri E, Schulz J et al. Cost-effectiveness of triple drug administration (TDA) with praziquantel, ivermectin and albendazole for the prevention of neglected tropical diseases in Nigeria. Ann Trop Med Parasitol 2011;105:537–47. doi: http://dx.doi.org/10.1179/2047773211Y.0000000010 PMID:22325813
https://doi.org/10.1179/2047773211Y.0000... ^–88 Bill and Melinda Gates Foundation [Internet]. Leading global health organizations receive $46.7 million from Gates Foundation to integrate programs fighting neglected tropical diseases (press release). 19 December 2006. Seattle: BMGF; 2014. Available from: http://www.gatesfoundation.org/What-We-Do/Global-Health/Neglected-Infectious-Diseases/Press-Releases?page=3&perPage=8&orderBy=_searchdate&orderDir=Reverse [accessed 5 February 2014].
http://www.gatesfoundation.org/What-We-D...

Evidence from randomized controlled trials (RCTs) can provide valuable information about the relative merits of different preventive interventions. However, the evidence may be scattered across several different trials. Moreover, although several systematic reviews and meta-analyses have been carried out, typically each has considered only one or a few interventions for a single disease, thereby creating a fragmented picture of the evidence available from RCTs. To prioritize research into the control of NTDs and to make evidence-based decisions about prevention, we must know: (i) the extent to which the RCTs available and associated systematic reviews and meta-analyses address the most important questions about control and prevention; (ii) whether these studies leave modest or large gaps in evidence and (iii) whether any interventions have been found to be consistently effective.

To address these issues, we systematically collected evidence from RCTs available in the peer-reviewed literature on the prevention or control of the principal NTDs and from corresponding systematic reviews and meta-analyses. Our aims were to evaluate the evidence from RCTs, to identify interventions that were found to be effective in systematic reviews and meta-analyses, to determine whether different meta-analyses on the same topic yielded similar or conflicting conclusions and to identify gaps in the evidence available.

Methods

Randomized controlled trials

We searched PubMed and the Cochrane Central Register of Controlled Trials for RCTs published on or before 31 December 2012 that addressed the prevention or control of 16 NTDs: American trypanosomiasis (Chagas disease), Buruli ulcer, cysticercosis, dengue, dracunculiasis (guinea-worm disease), echinococcosis (hydatid cyst disease), foodborne trematode infection, geohelminth infection, human African trypanosomiasis, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, rabies, schistosomiasis and trachoma. We sought additional trials by reviewing our own literature collections, English-language systematic reviews, meta-analyses and Cochrane reviews, and the references of eligible publications we identified. The search strategy is given in detail in Table 1 (available at: http://www.who.int/bulletin/volumes/92/5/13-129601).

For several diseases, prevention, control and treatment overlap. For example, preventive chemotherapy is a disease control strategy that encompasses treatment and prevention: in highly endemic areas, periodic mass drug administration both provides treatment for infected individuals and decreases the burden of disease in the community by reducing transmission and preventing new cases.⁹9 Montresor A, Gabrielli AF, Chitsulo L, Ichimori K, Mariotti S, Engels D et al. Preventive chemotherapy and the fight against neglected tropical diseases. Expert Rev Anti Infect Ther 2012;10:237–42. doi: http://dx.doi.org/10.1586/eri.11.165 PMID:22339196
https://doi.org/10.1586/eri.11.165... Currently, preventive chemotherapy is used for schistosomiasis, lymphatic filariasis, geohelminth infection, onchocerciasis and trachoma.⁹9 Montresor A, Gabrielli AF, Chitsulo L, Ichimori K, Mariotti S, Engels D et al. Preventive chemotherapy and the fight against neglected tropical diseases. Expert Rev Anti Infect Ther 2012;10:237–42. doi: http://dx.doi.org/10.1586/eri.11.165 PMID:22339196
https://doi.org/10.1586/eri.11.165... Our study included preventive chemotherapy trials, which were defined as trials in which chemotherapy was given to a group of participants regardless of their infection status (i.e. without testing or screening for disease), either by mass drug administration to the whole population or by targeting treatment at a known high-risk group (e.g. schoolchildren). We excluded trials of individual treatment in which only infected participants were randomized. We also excluded trials of diagnostic tests, pharmacokinetic studies in healthy volunteers, trials with nonhuman subjects, non- and pseudo-randomized trials and trials that addressed the prevention of disease complications (e.g. trials of footwear for preventing foot ulcers in leprosy patients). Furthermore, we excluded trials published only as abstracts, descriptions of planned studies, subgroup or secondary analyses of previously published RCTs and trials reported in languages other than Dutch, English, French, German, Portuguese or Spanish. When we found a preliminary report of clinical trial data that were later included in a more complete publication, we included only the final publication. Trials that addressed more than one disease were included in the data set only once, although, for completeness, they are listed in each relevant disease section in Table 2.

Systematic reviews and meta-analyses

We carried out a separate search of PubMed and the Cochrane Database of Systematic Reviews to identify English-language meta-analyses and systematic reviews on the control or prevention of NTDs published on or before 31 December 2012. Eligible reviews had to contain at least one RCT that had been reported in a peer-reviewed publication and had to address the efficacy of any interventions used to prevent or control one of the 16 diseases of interest. We excluded articles on treatment, diagnosis, epidemiology, disease burden or the molecular biology, evolution or ecology of the etiological agent. We also excluded reviews that exclusively addressed animals (for example, vaccines in livestock) and protocols for planned reviews. For Cochrane reviews, we included only the most recent update. Systematic reviews had to include a methods section that described a comprehensive search strategy, with inclusion and exclusion criteria. A subset of systematic reviews included a meta-analysis that provided a formal quantitative synthesis of study results. We excluded three publications that were primarily reviews of reviews rather than of primary research data, though we read these publications to identify any additional suitable RCTs or systematic reviews. The search strategy is described in detail in Table 3 (available at: http://www.who.int/bulletin/volumes/92/5/13-129601).

Data analysis

We extracted the following information from each published RCT: first author, publication year, journal title, study country or site, study design (i.e. cluster, crossover or neither), interventions, sample size and follow-up period. We used the “unit of randomization” for calculating sample sizes: for trials in which individual participants were randomized, the sample size was the total number of individuals randomized and, for cluster randomized trials, the sample size was the total number of clusters (for example, neighbourhoods or villages). For both individually and cluster randomized trials, the sample size was taken to be the total number of individuals or clusters initially randomized rather than the number remaining after accounting for those lost to follow-up. We noted whether the trial report included a funding statement and ascribed funding to one or more of four sources: (i) a government or other public agency, including WHO and national public organizations such as the National Institutes of Health in the United States of America; (ii) industry; (iii) a charity or foundation; and (iv) a university or hospital. For each of the 10 diseases for which data were available, we calculated the Pearson correlation coefficient for the correlation between the number of RCTs performed and the annual global burden of disease, expressed in DALYs, and between the total sample size and the annual global disease burden.¹⁰10 World Health Organization [Internet]. Health statistics and health information systems. Metrics: disability-adjusted life year (DALY). Geneva: WHO; 2012. Available from: http://www.who.int/healthinfo/global_burden_disease/metrics_daly [accessed 5 February 2014].
http://www.who.int/healthinfo/global_bur... We obtained data on the disease burden of American trypanosomiasis,¹¹11 Mathers CD, Ezzati M, Lopez AD. Measuring the burden of neglected tropical diseases: the global burden of disease framework. PLoS Negl Trop Dis 2007;1:e114. doi: http://dx.doi.org/10.1371/journal.pntd.0000114 PMID:18060077
https://doi.org/10.1371/journal.pntd.000... dengue,¹¹11 Mathers CD, Ezzati M, Lopez AD. Measuring the burden of neglected tropical diseases: the global burden of disease framework. PLoS Negl Trop Dis 2007;1:e114. doi: http://dx.doi.org/10.1371/journal.pntd.0000114 PMID:18060077
https://doi.org/10.1371/journal.pntd.000... leishmaniasis,¹¹11 Mathers CD, Ezzati M, Lopez AD. Measuring the burden of neglected tropical diseases: the global burden of disease framework. PLoS Negl Trop Dis 2007;1:e114. doi: http://dx.doi.org/10.1371/journal.pntd.0000114 PMID:18060077
https://doi.org/10.1371/journal.pntd.000... leprosy,¹¹11 Mathers CD, Ezzati M, Lopez AD. Measuring the burden of neglected tropical diseases: the global burden of disease framework. PLoS Negl Trop Dis 2007;1:e114. doi: http://dx.doi.org/10.1371/journal.pntd.0000114 PMID:18060077
https://doi.org/10.1371/journal.pntd.000... lymphatic filariasis,¹¹11 Mathers CD, Ezzati M, Lopez AD. Measuring the burden of neglected tropical diseases: the global burden of disease framework. PLoS Negl Trop Dis 2007;1:e114. doi: http://dx.doi.org/10.1371/journal.pntd.0000114 PMID:18060077
https://doi.org/10.1371/journal.pntd.000... onchocerciasis,¹¹11 Mathers CD, Ezzati M, Lopez AD. Measuring the burden of neglected tropical diseases: the global burden of disease framework. PLoS Negl Trop Dis 2007;1:e114. doi: http://dx.doi.org/10.1371/journal.pntd.0000114 PMID:18060077
https://doi.org/10.1371/journal.pntd.000... rabies,¹²12 Knobel DL, Cleaveland S, Coleman PG, Fèvre EM, Meltzer MI, Miranda ME et al. Re-evaluating the burden of rabies in Africa and Asia. Bull World Health Organ 2005;83:360–8. PMID:15976877 geohelminth infections,¹¹11 Mathers CD, Ezzati M, Lopez AD. Measuring the burden of neglected tropical diseases: the global burden of disease framework. PLoS Negl Trop Dis 2007;1:e114. doi: http://dx.doi.org/10.1371/journal.pntd.0000114 PMID:18060077
https://doi.org/10.1371/journal.pntd.000... schistosomiasis¹¹11 Mathers CD, Ezzati M, Lopez AD. Measuring the burden of neglected tropical diseases: the global burden of disease framework. PLoS Negl Trop Dis 2007;1:e114. doi: http://dx.doi.org/10.1371/journal.pntd.0000114 PMID:18060077
https://doi.org/10.1371/journal.pntd.000... and trachoma.¹¹11 Mathers CD, Ezzati M, Lopez AD. Measuring the burden of neglected tropical diseases: the global burden of disease framework. PLoS Negl Trop Dis 2007;1:e114. doi: http://dx.doi.org/10.1371/journal.pntd.0000114 PMID:18060077
https://doi.org/10.1371/journal.pntd.000... No reliable estimates were available for Buruli ulcer.

For each systematic review, we extracted details of the first author, the publication year and the interventions addressed. Most meta-analyses and systematic reviews included both RCTs and nonrandomized studies. For each RCT, we extracted data on the sample size and the primary outcome. For reviews that included a meta-analysis, we recorded the effect size with 95% confidence intervals and, for all systematic reviews, we recorded the authors’ conclusions, including their views on whether the intervention could be classified as: (i) likely to be effective; (ii) likely to be ineffective or (iii) of unknown efficacy due to a lack of sufficient evidence. When two or more reviews were available on the same intervention, we recorded whether they had similar or conflicting conclusions. Finally, we determined which RCTs in our RCT data set had not been included in a systematic review.

Results

Randomized controlled trials

The initial literature search for RCTs identified 2855 publications (Fig. 1, available at: http://www.who.int/bulletin/volumes/92/5/13-129601), of which 223, containing 236 eligible RCTs, were retained for analysis. Five publications were added from our literature collection or from the bibliographies of the publications retained; 18 were added from the bibliographies of systematic reviews or meta-analyses. The final analysis included 246 publications containing details of 258 RCTs (Appendix A, available at: https://stanford.box.com/s/nm7ri7xnxq58m744gcl5).

Table 2 shows, for 11 NTDs, the number of RCTs on prevention or control performed, the total sample size and the annual global disease burden. Geohelminth infection was studied most (51 RCTs with a total sample size of 22 848), followed by leishmaniasis (46 RCTs with a total sample size of 22 758) and rabies (34 RCTs with a total sample size of 5176). No RCT had been performed on the prevention or control of five diseases: cysticercosis, dracunculiasis, echinococcosis, foodborne trematode infection and human African trypanosomiasis. There was no significant correlation between disease burden and either the number of RCTs (ρ = 0.12, P = 0.73) or the total sample size (ρ = −0.38; P = 0.28). Although the disease burden was greatest for lymphatic filariasis, only 10 RCTs had been performed.

Table 4 shows that most RCTs were conducted in the WHO Region of the Americas, the South-East Asia Region or the African Region. Only 10 RCTs (3.9%) were multicentre trials. There were 71 (27.5%) cluster randomized trials. Most trials were publicly funded (55.8%) or had no reported funding source (25.6%) and only 10.1% were funded by industry. The median sample size was 151 (interquartile range: 36 to 553).

Overall, 113 of the 258 RCTs (43.8%) involved vaccines, 99 (38.4%) involved topical or oral chemoprophylaxis and 39 (15.1%) involved interventions that targeted insect vectors, such as insecticide-treated bednets or indoor residual spraying. In addition, 80 (31.0%) had one or more preventive chemotherapy arms – either mass drug administration or targeted treatment. Few trials addressed the delivery of preventive chemotherapy: only 10 considered dosing intervals, 4 considered the choice of target population, 2 considered the population coverage needed for mass drug administration and 1 considered how best to deliver preventive chemotherapy. The other preventive chemotherapy trials either compared a drug with placebo or compared two or more drugs. Only 12 trials addressed co-treatment of more than one disease by mass drug administration. Preventive chemotherapy is the main intervention for four diseases – lymphatic filariasis, onchocerciasis, schistosomiasis and geohelminth infections – and is a key component in the control of trachoma.⁹9 Montresor A, Gabrielli AF, Chitsulo L, Ichimori K, Mariotti S, Engels D et al. Preventive chemotherapy and the fight against neglected tropical diseases. Expert Rev Anti Infect Ther 2012;10:237–42. doi: http://dx.doi.org/10.1586/eri.11.165 PMID:22339196
https://doi.org/10.1586/eri.11.165... ^,1313 Emerson PM, Burton M, Solomon AW, Bailey R, Mabey D. The SAFE strategy for trachoma control: using operational research for policy, planning and implementation. Bull World Health Organ 2006;84:613–9. doi: http://dx.doi.org/10.2471/BLT.05.28696 PMID:16917648
https://doi.org/10.2471/BLT.05.28696... Although 80 of 112 RCTs on these five diseases had a targeted treatment or mass drug administration arm, again very few addressed how best to deliver preventive chemotherapy: only 10 investigated different time intervals for drug distribution, 2 considered population coverage, 4 considered the target population and 1 considered the method of drug distribution. Moreover, of the 80 RCTs, 27 compared mass treatment and placebo, whereas 24 compared different drugs.

Systematic reviews and meta-analyses

The literature search identified 31 publications that reported one or more systematic reviews, with or without a formal meta-analysis (Fig. 2, available at: http://www.who.int/bulletin/volumes/92/5/13-129601). They addressed 36 different interventions for nine different diseases: American trypanosomiasis, dengue, geohelminths, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, schistosomiasis and trachoma. Of the 16 systematic reviews that included a meta-analysis, there were 2 on dengue,¹⁴14 Erlanger TE, Keiser J, Utzinger J. Effect of dengue vector control interventions on entomological parameters in developing countries: a systematic review and meta-analysis. Med Vet Entomol 2008;22:203–21. doi: http://dx.doi.org/10.1111/j.1365-2915.2008.00740.x PMID:18816269
https://doi.org/10.1111/j.1365-2915.2008... ^,1515 Al-Muhandis N, Hunter PR. The value of educational messages embedded in a community-based approach to combat dengue fever: a systematic review and meta regression analysis. PLoS Negl Trop Dis 2011;5:e1278. doi: http://dx.doi.org/10.1371/journal.pntd.0001278 PMID:21886848
https://doi.org/10.1371/journal.pntd.000... 1 on leishmaniasis,¹⁶16 Noazin S, Khamesipour A, Moulton LH, Tanner M, Nasseri K, Modabber F et al. Efficacy of killed whole-parasite vaccines in the prevention of leishmaniasis: a meta-analysis. Vaccine 2009;27:4747–53. doi: http://dx.doi.org/10.1016/j.vaccine.2009.05.084 PMID:19540273
https://doi.org/10.1016/j.vaccine.2009.0... 5 on leprosy (3 on the bacillus Calmette–Guérin [BCG] vaccine¹⁷17 Merle CS, Cunha SS, Rodrigues LC. BCG vaccination and leprosy protection: review of current evidence and status of BCG in leprosy control. Expert Rev Vaccines 2010;9:209–22. doi: http://dx.doi.org/10.1586/erv.09.161 PMID:20109030
https://doi.org/10.1586/erv.09.161... ^–1919 Zodpey SP. Protective effect of bacillus Calmette Guerin (BCG) vaccine in the prevention of leprosy: a meta-analysis. Indian J Dermatol Venereol Leprol 2007;73:86–93. doi: http://dx.doi.org/10.4103/0378-6323.31891 PMID:17456912
https://doi.org/10.4103/0378-6323.31891... and two on chemoprophylaxis²⁰20 Reveiz L, Buendía JA, Téllez D. Chemoprophylaxis in contacts of patients with leprosy: systematic review and meta-analysis. Rev Panam Salud Publica 2009;26:341–9. doi: http://dx.doi.org/10.1590/S1020-49892009001000009 PMID:20107683
https://doi.org/10.1590/S1020-4989200900... ^,2121 Smith CM, Smith WC. Chemoprophylaxis is effective in the prevention of leprosy in endemic countries: a systematic review and meta-analysis. MILEP2 Study Group. Mucosal immunology of leprosy. J Infect 2000;41:137–42. doi: http://dx.doi.org/10.1053/jinf.2000.0698 PMID:11023757
https://doi.org/10.1053/jinf.2000.0698... ), 2 on schistosomiasis,²²22 Liu R, Dong HF, Guo Y, Zhao QP, Jiang MS. Efficacy of praziquantel and artemisinin derivatives for the treatment and prevention of human schistosomiasis: a systematic review and meta-analysis. Parasit Vectors 2011;4:201. doi: http://dx.doi.org/10.1186/1756-3305-4-201 PMID:22004571
https://doi.org/10.1186/1756-3305-4-201... ^,2323 Pérez del Villar L, Burguillo FJ, López-Abán J, Muro A. Systematic review and meta-analysis of artemisinin based therapies for the treatment and prevention of schistosomiasis. PLoS One 2012;7:e45867. doi: http://dx.doi.org/10.1371/journal.pone.0045867 PMID:23029285
https://doi.org/10.1371/journal.pone.004... 1 on onchocerciasis,²⁴24 Basáñez MG, Pion SD, Boakes E, Filipe JA, Churcher TS, Boussinesq M. Effect of single-dose ivermectin on Onchocerca volvulus: a systematic review and meta-analysis. Lancet Infect Dis 2008;8:310–22. doi: http://dx.doi.org/10.1016/S1473-3099(08)70099-9 PMID:18471776
https://doi.org/10.1016/S1473-3099(08)70... 4 on lymphatic filariasis²⁵25 Critchley J, Addiss D, Ejere H, Gamble C, Garner P, Gelband H; International Filariasis Review Group. Albendazole for the control and elimination of lymphatic filariasis: systematic review. Trop Med Int Health 2005;10:818–25. doi: http://dx.doi.org/10.1111/j.1365-3156.2005.01458.x PMID:16135187
https://doi.org/10.1111/j.1365-3156.2005... ^–2828 Gyapong JO, Kumaraswami V, Biswas G, Ottesen EA. Treatment strategies underpinning the global programme to eliminate lymphatic filariasis. Expert Opin Pharmacother 2005;6:179–200. doi: http://dx.doi.org/10.1517/14656566.6.2.179 PMID:15757416
https://doi.org/10.1517/14656566.6.2.179... and 1 on trachoma.²⁹29 Evans JR, Solomon AW. Antibiotics for trachoma. Cochrane Database Syst Rev 2011. 3CD001860. PMID:21412875 Of the 16 systematic reviews that did not include a meta-analysis (reported in 15 publications), there were 4 on trachoma,³⁰30 Ejere HO, Alhassan MB, Rabiu M. Face washing promotion for preventing active trachoma. Cochrane Database Syst Rev 2012;4:CD003659. PMID:22513915^–3333 Emerson PM, Cairncross S, Bailey RL, Mabey DC. Review of the evidence base for the ‘F’ and ‘E’ components of the SAFE strategy for trachoma control. Trop Med Int Health 2000;5:515–27. doi: http://dx.doi.org/10.1046/j.1365-3156.2000.00603.x PMID:10995092
https://doi.org/10.1046/j.1365-3156.2000... 3 on dengue,³⁴34 Ballenger-Browning KK, Elder JP. Multi-modal Aedes aegypti mosquito reduction interventions and dengue fever prevention. Trop Med Int Health 2009;14:1542–51. doi: http://dx.doi.org/10.1111/j.1365-3156.2009.02396.x PMID:19788717
https://doi.org/10.1111/j.1365-3156.2009... ^–3636 Heintze C, Velasco Garrido M, Kroeger A. What do community-based dengue control programmes achieve? A systematic review of published evaluations. Trans R Soc Trop Med Hyg 2007;101:317–25. doi: http://dx.doi.org/10.1016/j.trstmh.2006.08.007 PMID:17084427
https://doi.org/10.1016/j.trstmh.2006.08... 1 on leprosy,³⁷37 Barreto ML, Pereira SM, Ferreira AA. BCG vaccine: efficacy and indications for vaccination and revaccination. J Pediatr (Rio J) 2006;82(Suppl):S45–54. doi: http://dx.doi.org/10.2223/JPED.1499 PMID:16826312
https://doi.org/10.2223/JPED.1499... 2 on leishmaniasis,³⁸38 Costa CH. How effective is dog culling in controlling zoonotic visceral leishmaniasis? A critical evaluation of the science, politics and ethics behind this public health policy. Rev Soc Bras Med Trop 2011;44:232–42. doi: http://dx.doi.org/10.1590/S0037-86822011005000014 PMID:21468480
https://doi.org/10.1590/S0037-8682201100... ^,3939 Romero GA, Boelaert M. Control of visceral leishmaniasis in Latin America – a systematic review. PLoS Negl Trop Dis 2010;4:e584. doi: http://dx.doi.org/10.1371/journal.pntd.0000584 PMID:20098726
https://doi.org/10.1371/journal.pntd.000... 1 on onchocerciasis,⁴⁰40 Ejere HO, Schwartz E, Wormald R, Evans JR. Ivermectin for onchocercal eye disease (river blindness). Cochrane Database Syst Rev 2012;8:CD002219. PMID:22895928 3 on schistosomiasis,⁴¹41 Bieri FA, Gray DJ, Raso G, Li YS, McManus DP. A systematic review of preventive health educational videos targeting infectious diseases in schoolchildren. Am J Trop Med Hyg 2012;87:972–8. doi: http://dx.doi.org/10.4269/ajtmh.2012.12-0375 PMID:23222138
https://doi.org/10.4269/ajtmh.2012.12-03... ^–4343 Uneke CJ. Soil transmitted helminth infections and schistosomiasis in school age children in sub-Saharan Africa: efficacy of chemotherapeutic intervention since World Health Assembly Resolution 2001. Tanzan J Health Res 2010;12:86–99. doi: http://dx.doi.org/10.4314/thrb.v12i1.56366 PMID:20737834
https://doi.org/10.4314/thrb.v12i1.56366... 1 on geohelminths⁴³43 Uneke CJ. Soil transmitted helminth infections and schistosomiasis in school age children in sub-Saharan Africa: efficacy of chemotherapeutic intervention since World Health Assembly Resolution 2001. Tanzan J Health Res 2010;12:86–99. doi: http://dx.doi.org/10.4314/thrb.v12i1.56366 PMID:20737834
https://doi.org/10.4314/thrb.v12i1.56366... and 1 on American trypanosomiasis.⁴⁴44 Abad-Franch F, Vega MC, Rolón MS, Santos WS, Rojas de Arias A. Community participation in Chagas disease vector surveillance: systematic review. PLoS Negl Trop Dis 2011;5:e1207. doi: http://dx.doi.org/10.1371/journal.pntd.0001207 PMID:21713022
https://doi.org/10.1371/journal.pntd.000... Details of the systematic reviews are given in Appendix B (available at: https://stanford.box.com/s/af4co496bynqxlfwnlgc).

Appendix C (available at: https://stanford.box.com/s/ftoxgslppc4d9qzno3j5) lists the RCTs included in each review. Overall, only 79 of the 258 RCTs (30.6%) were included in a systematic review: 31 (12.0%) were included only in a systematic review without a meta-analysis, 40 (15.5%) were included only in a systematic review with a meta-analysis and 8 (3.1%) were included in both a systematic review without a meta-analysis and one with a meta-analysis.

Nineteen interventions had been assessed by a single systematic review (Table 5). Of the 19, 14 were found to be effective, 3 were found to be ineffective and, for 2, there was insufficient evidence to judge efficacy. Another 17 interventions had been assessed by two or more systematic reviews (Table 6). Of the 17, 8 were consistently found to be effective (all had been assessed in a meta-analysis), 1 was consistently found to be ineffective and, for 8, different reviews produced conflicting conclusions. For 4 of the 8 interventions on which conclusions conflicted, different systematic reviews concluded either that the intervention was likely to be effective or that there was insufficient evidence; for 1 other intervention, different systematic reviews concluded either that the intervention was likely to be ineffective or that there was insufficient evidence; and for the remaining 3 interventions, different reviews reported all possible conclusions (i.e. likely to be effective, likely to be ineffective and insufficient evidence). Only interventions for trachoma, leprosy and schistosomiasis were consistently judged to be effective by more than one systematic review. However, interventions for American trypanosomiasis, geohelminth infection, onchocerciasis and lymphatic filariasis were judged effective by the one systematic review in which each had been assessed.

For Buruli ulcer and rabies, no systematic review of a prevention or control intervention containing a peer-reviewed RCT had been performed, though RCTs had been carried out. For cysticercosis, dracunculiasis, echinococcosis, foodborne trematode infection and human African trypanosomiasis, neither a systematic review nor an RCT had been performed.

Discussion

Our analysis of 258 RCTs and 32 systematic reviews provides a summary of the evidence available on the prevention and control of NTDs and identifies gaps in that evidence. Although prevention is likely to be more cost-effective than treatment for these diseases,⁴⁵45 Brady MA, Hooper PJ, Ottesen EA. Projected benefits from integrating NTD programs in sub-Saharan Africa. Trends Parasitol 2006;22:285–91. doi: http://dx.doi.org/10.1016/j.pt.2006.05.007 PMID:16730230
https://doi.org/10.1016/j.pt.2006.05.007... ^,4646 Conteh L, Engels T, Molyneux DH. Socioeconomic aspects of neglected tropical diseases. Lancet 2010;375:239–47. doi: http://dx.doi.org/10.1016/S0140-6736(09)61422-7 PMID:20109925
https://doi.org/10.1016/S0140-6736(09)61... far fewer trials of prevention than treatment have been carried out.⁴⁷47 Kappagoda S, Ioannidis JP. Neglected tropical diseases: survey and geometry of randomised evidence. BMJ 2012;345(oct22 2):e6512. doi: http://dx.doi.org/10.1136/bmj.e6512 PMID:23089149
https://doi.org/10.1136/bmj.e6512... We found that RCTs on prevention or control had been performed for only 11 of the 16 principal NTDs and that systematic reviews had been performed for only 9. Most RCTs had not been included in a systematic review. We identified 8 interventions that were consistently found to be effective in two or more systematic reviews: topical tetracycline and oral azithromycin chemotherapy for the prevention of trachoma; BCG vaccination, dapsone and acedapsone chemoprophylaxis for the prevention of leprosy; and artesunate, artemether and praziquantel chemoprophylaxis for schistosomiasis (Table 6). For another 14 interventions, a single review concluded that they were effective (Table 5). However, for 8 interventions for which two or more reviews were available, conclusions were conflicting (Table 6).

A range of nonpharmacological interventions for disease control was reported. Future meta-analyses would be made easier by standardizing the design of trials on vector control strategies, including habitat modification, the use of insecticide-impregnated materials and spraying for dengue and leishmaniasis. Furthermore, most vector control trials for leishmaniasis and dengue did not consider human disease as an outcome and there is a need for more research on the relationship between vector control and human disease to justify such interventions. In particular, research on leishmaniasis and dengue is very different from that on trachoma: the recent literature on trachoma reports that collaborative, large-scale studies have been carried out, study designs and protocols have been published and efforts have been made to standardize definitions and outcome measures.¹³13 Emerson PM, Burton M, Solomon AW, Bailey R, Mabey D. The SAFE strategy for trachoma control: using operational research for policy, planning and implementation. Bull World Health Organ 2006;84:613–9. doi: http://dx.doi.org/10.2471/BLT.05.28696 PMID:16917648
https://doi.org/10.2471/BLT.05.28696... ^,4848 Emerson PM, Lindsay SW, Walraven GE, Dibba SM, Lowe KO, Bailey RL. The Flies and Eyes project: design and methods of a cluster-randomised intervention study to confirm the importance of flies as trachoma vectors in The Gambia and to test a sustainable method of fly control using pit latrines. Ophthalmic Epidemiol 2002;9:105–17. doi: http://dx.doi.org/10.1076/opep.9.2.105.1522 PMID:11821976
https://doi.org/10.1076/opep.9.2.105.152... ^,4949 King JD, Ngondi J, Kasten J, Diallo MO, Zhu H, Cromwell EA et al. Randomised trial of face-washing to develop a standard definition of a clean face for monitoring trachoma control programmes. Trans R Soc Trop Med Hyg 2011;105:7–16. doi: http://dx.doi.org/10.1016/j.trstmh.2010.09.008 PMID:21036378
https://doi.org/10.1016/j.trstmh.2010.09...

There was either limited evidence that trachoma could be prevented by environmental improvements, such as increased access to sanitation, or conflicting conclusions in meta-analyses and systematic reviews. However, since such interventions may have broader benefits for other conditions, such as childhood diarrhoea⁵⁰50 Jasper C, Le TT, Bartram J. Water and sanitation in schools: a systematic review of the health and educational outcomes. Int J Environ Res Public Health 2012;9:2772–87. doi: http://dx.doi.org/10.3390/ijerph9082772 PMID:23066396
https://doi.org/10.3390/ijerph9082772... ^,5151 Bartram J, Cairncross S. Hygiene, sanitation, and water: forgotten foundations of health. PLoS Med 2010;7:e1000367. doi: http://dx.doi.org/10.1371/journal.pmed.1000367 PMID:21085694
https://doi.org/10.1371/journal.pmed.100... and geohelminth infection,⁵²52 Ziegelbauer K, Speich B, Mäusezahl D, Bos R, Keiser J, Utzinger J. Effect of sanitation on soil-transmitted helminth infection: systematic review and meta-analysis. PLoS Med 2012;9:e1001162. doi: http://dx.doi.org/10.1371/journal.pmed.1001162 PMID:22291577
https://doi.org/10.1371/journal.pmed.100... and may reduce overall childhood mortality,⁵³53 Cheng JJ, Schuster-Wallace CJ, Watt S, Newbold BK, Mente A. An ecological quantification of the relationships between water, sanitation and infant, child, and maternal mortality. Environ Health 2012;11:4. doi: http://dx.doi.org/10.1186/1476-069X-11-4 PMID:22280473
https://doi.org/10.1186/1476-069X-11-4... it may not be a good use of resources to carry out further studies into their effect on this one disease.

Publications on the five NTDs for which no systematic review or RCT had been performed – cysticercosis, dracunculiasis, echinococcosis, foodborne trematode infections and human African trypanosomiasis – generally focused on treatment.⁴⁷47 Kappagoda S, Ioannidis JP. Neglected tropical diseases: survey and geometry of randomised evidence. BMJ 2012;345(oct22 2):e6512. doi: http://dx.doi.org/10.1136/bmj.e6512 PMID:23089149
https://doi.org/10.1136/bmj.e6512... These diseases all have a focal form of transmission, which means that controlled trials would require the collaboration of veterinary public health experts, clinical researchers and behavioural health experts. For two diseases – rabies and Buruli ulcer – RCTs had been carried out but no systematic review containing an RCT was found in the literature search. For example, the systematic reviews found on rabies prevention did not include RCTs from peer-reviewed publications.⁵⁴54 Sudarshan MK, Gangaboraiah B, Ravish HS, Narayana DH. Assessing the relationship between antigenicity and immunogenicity of human rabies vaccines when administered by intradermal route: results of a metaanalysis. Hum Vaccin 2010;6:562–5. doi: http://dx.doi.org/10.4161/hv.6.7.11934 PMID:20523131
https://doi.org/10.4161/hv.6.7.11934... ^,5555 Sudarshan MK, Mahendra BJ, Madhusudana SN, Narayana DH, Sanjay TV, Gangaboraiah et al. Assessing the relationship between antigenicity and immunogenicity of human rabies vaccines. Results of a meta-analysis. Hum Vaccin 2005;1:187–90. doi: http://dx.doi.org/10.4161/hv.1.5.2110 PMID:17033270
https://doi.org/10.4161/hv.1.5.2110...

Limitations

Our study has several limitations. First, we did not consider unpublished findings or the results of trials that were published only as abstracts because such material is difficult to identify systematically and formal peer-reviews have not been carried out. Consequently, we do not know the extent to which publication or selective reporting bias may have influenced the reliability of the evidence available. However, it is unlikely that such biases would completely invalidate the large preventive effects observed. Second, we did not conduct our own systematic review or meta-analysis because this would have been difficult to achieve for the dozens of different interventions used for 16 diseases. However, the reviews and meta-analyses we identified provide a summary of the evidence available and our analysis highlights those interventions that remain controversial and indicates those that need to be evaluated in systematic reviews and meta-analyses and those that need to be tested in RCTs. Third, we avoided adopting a specific conclusion when different systematic reviews and meta-analyses reached different conclusions. Instead, we registered the discrepancy, which may have reflected differences in eligibility criteria, data analysis or interpretation.⁵⁶56 Cook DJ, Reeve BK, Guyatt GH, Heyland DK, Griffith LE, Buckingham L et al. Stress ulcer prophylaxis in critically ill patients. Resolving discordant meta-analyses. JAMA 1996;275:308–14. doi: http://dx.doi.org/10.1001/jama.1996.03530280060038 PMID:8544272
https://doi.org/10.1001/jama.1996.035302... ^–5858 Vamvakas EC. Why have meta-analyses of randomized controlled trials of the association between non-white-blood-cell-reduced allogeneic blood transfusion and postoperative infection produced discordant results? Vox Sang 2007;93:196–207. doi: http://dx.doi.org/10.1111/j.1423-0410.2007.00959.x PMID:17845256
https://doi.org/10.1111/j.1423-0410.2007... For example, different eligibility criteria were used in the reviews of chemical vector control for dengue,¹⁴14 Erlanger TE, Keiser J, Utzinger J. Effect of dengue vector control interventions on entomological parameters in developing countries: a systematic review and meta-analysis. Med Vet Entomol 2008;22:203–21. doi: http://dx.doi.org/10.1111/j.1365-2915.2008.00740.x PMID:18816269
https://doi.org/10.1111/j.1365-2915.2008... ^,3434 Ballenger-Browning KK, Elder JP. Multi-modal Aedes aegypti mosquito reduction interventions and dengue fever prevention. Trop Med Int Health 2009;14:1542–51. doi: http://dx.doi.org/10.1111/j.1365-3156.2009.02396.x PMID:19788717
https://doi.org/10.1111/j.1365-3156.2009... ^,3535 Esu E, Lenhart A, Smith L, Horstick O. Effectiveness of peridomestic space spraying with insecticide on dengue transmission; systematic review. Trop Med Int Health 2010;15:619–31. PMID:20214764 different eligibility criteria and different methods for calculating summary effect measures were used in the meta-analyses of albendazole for lymphatic filariasis,²⁷27 Tisch DJ, Michael E, Kazura JW. Mass chemotherapy options to control lymphatic filariasis: a systematic review. Lancet Infect Dis 2005;5:514–23. doi: http://dx.doi.org/10.1016/S1473-3099(05)70192-4 PMID:16048720
https://doi.org/10.1016/S1473-3099(05)70... ^,2828 Gyapong JO, Kumaraswami V, Biswas G, Ottesen EA. Treatment strategies underpinning the global programme to eliminate lymphatic filariasis. Expert Opin Pharmacother 2005;6:179–200. doi: http://dx.doi.org/10.1517/14656566.6.2.179 PMID:15757416
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Although trials of individual treatments can help in selecting drugs for use in mass drug administration programmes, such trials are not usually designed to address rare but serious side-effects or drug resistance, both of which are concerns in large-scale programmes. In addition, these trials rarely include nursing or pregnant women, who could also benefit from preventive chemotherapy.⁵⁹59 Brooker S, Hotez PJ, Bundy DA. Hookworm-related anaemia among pregnant women: a systematic review. PLoS Negl Trop Dis 2008;2:e291. doi: http://dx.doi.org/10.1371/journal.pntd.0000291 PMID:18820740
https://doi.org/10.1371/journal.pntd.000... ^–6161 Passerini L, Casey GJ, Biggs BA, Cong DT, Phu LB, Phuc TQ et al. Increased birth weight associated with regular pre-pregnancy deworming and weekly iron-folic acid supplementation for Vietnamese women. PLoS Negl Trop Dis 2012;6:e1608. Furthermore, while the evidence supporting the use of individual drugs included in mass drug administration programmes may be adequate, there are few reports of prevention or treatment trials involving combinations of drugs for several diseases, which are essential for evaluating integrated preventive chemotherapy.⁴⁷47 Kappagoda S, Ioannidis JP. Neglected tropical diseases: survey and geometry of randomised evidence. BMJ 2012;345(oct22 2):e6512. doi: http://dx.doi.org/10.1136/bmj.e6512 PMID:23089149
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In conclusion, our study provides an overview of what is and is not known about the effectiveness of prevention and control measures for the principal NTDs. Where strong evidence is available, it can be used to guide the introduction and scale-up of prevention and control programmes; where gaps in evidence have been identified, the result should be new RCTs on prevention and control measures, although carrying out such trials in endemic areas is challenging. Moreover, these trials may have to be large to detect significant effects in the population and the costs may be prohibitive. However, a considerable amount of money has already been invested in, for example, mass drug administration programmes. Such programmes could only become more acceptable and financially viable if the most effective and cost-effective ways of delivering preventive chemotherapy were identified.

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