Résumé

Objectif

Évaluer l'impact (sur le diagnostic et le traitement du paludisme) de l'introduction de tests diagnostiques rapides dans les pharmacies dans l'est de l'Ouganda.

Méthodes

Au total, 2 193 ménages vivant dans 79 villages de l'étude disposant d'au moins 1 pharmacie homologuée ont été recrutés et suivis pendant 12 mois. Après 3 mois de suivi, les pharmaciens de 67 villages, choisis aléatoirement pour l'intervention, se sont vus proposer une formation leur permettant d'utiliser des tests diagnostiques rapides du paludisme et, une fois formés, un accès à ces tests à un prix subventionné. Les 12 villages restants de l'étude ont servi de villages témoins. Un modèle de régression des doubles différences a été utilisé pour estimer l'impact de l'intervention.

Résultats

Les pharmaciens de 92 pharmacies ont terminé leur formation avec succès et 50 d'entre eux ont stocké et réalisé activement les tests rapides. En 9 mois, les pharmaciens formés ont réalisé une moyenne de 146 tests par officine. Les ménages ont signalé 22 697 épisodes de maladie fébrile. La disponibilité des tests rapides dans les pharmacies locales a augmenté significativement la probabilité qu'une maladie fébrile soit testée pour le paludisme de 23,15% (P = 0,015) et traitée par un médicament antipaludéen de 8,84% (P = 0,056). La probabilité que la polythérapie à base d'artémisinine soit achetée, a augmenté, de manière statistiquement non significative, de 5,48% (P = 0,574).

Conclusion

Dans la zone de notre étude, le dépistage du paludisme a été augmenté en formant les pharmaciens à l'utilisation de tests rapides et en leur fournissant l’accès à ces tests à un prix subventionné. Des interventions supplémentaires peuvent être nécessaires pour atteindre une couverture plus élevée du dépistage et un taux plus élevé de réponses appropriées aux résultats de tests.

Resumen

Objetivo

Evaluar la repercusión en el diagnóstico y el tratamiento de la malaria de la introducción de pruebas de diagnóstico rápido en farmacias del este de Uganda.

Métodos

En general, se inscribieron y vigilaron durante 12 meses 2193 hogares de 79 aldeas de estudio con al menos una farmacia autorizada. Después de tres meses de seguimiento, se ofreció capacitación en el uso de pruebas de diagnóstico rápido de la malaria a vendedores de farmacias de 67 aldeas seleccionados al azar para la intervención. Si estos ya contaban con una formación al respecto, se les ofreció acceso a este tipo de pruebas a un precio subvencionado. Las otras 12 aldeas de estudio sirvieron como controles. Se utilizó un modelo de regresión de diferencia en diferencias para estimar el efecto de la intervención.

Resultados

Los vendedores de 92 farmacias completaron correctamente la capacitación y 50 proveyeron y realizaron activamente las pruebas de diagnóstico rápido. En 9 meses, los vendedores capacitados realizaron, en promedio, 146 pruebas por farmacia. Los hogares comunicaron 22 697 episodios de enfermedad febril. La disponibilidad de pruebas rápidas en farmacias locales aumentó considerablemente la probabilidad de analizar cualquier enfermedad febril en un 23,15 % para la malaria (P = 0,015) y de recibir tratamiento con un fármaco antipalúdico en un 8,84 % (P = 0,056). La probabilidad de comprar el tratamiento combinado basado en la artemisinina aumentó un 5,48 %, lo cual es estadísticamente insignificante (P = 0,574).

Conclusión

En nuestra área de estudio, la realización de pruebas para la malaria aumentó por medio de la capacitación de los vendedores de farmacias en el uso de pruebas rápidas y la facilitación del acceso a este tipo de pruebas a un precio subvencionado. Es posible que se requieran más intervenciones para lograr una mayor cobertura de las pruebas, así como una tasa más alta de respuestas adecuadas a los resultados de las pruebas.

ملخص

الغرض

تقييم أثر تقديم الاختبارات التشخيصية السريعة إلى مخازن الأدوية في شرق أوغندا على تشخيص الملاريا وعلاجها.

الطريقة

بشكل عام، تم تسجيل 2193 أسرة في 79 قرية من قرى الدراسة التي اشتملت على الأقل على مخزن أدوية مرخص وتم رصدها لمدة 12 شهراً. وبعد 3 أشهر من الرصد، تم عرض التدريب على بائعي مخازن الأدوية في 67 قرية تم اختيارها عشوائياً للتدخل وذلك في مجال استخدام الاختبارات التشخيصية السريعة للملاريا وعُرض عليهم - في حالة تلقيهم التدريب - إتاحة هذه الاختبارات بسعر مدعم. وتم استخدام قرى الدراسة الاثنتي عشرة المتبقية كمجموعات ضابطة. وتم استخدام نموذج ارتداد الفرق في الاختلافات لتقدير أثر التدخل.

النتائج

أكمل البائعون من 92 مخزناً للأدوية التدريب بنجاح وقام 50 بائعاً بتخزين الاختبارات السريعة وإجرائها. وعلى مدار 9 أشهر، أجرى البائعون المدربون 146 اختباراً في المتوسط لكل مخزن. وقامت الأسر بالتبليغ عن 22697 نوبة من الأمراض الحموية. وأدى إتاحة الاختبارات السريعة في مخازن الأدوية المحلية إلى زيادة كبيرة في احتمالية اختبار أي مرض حموي للملاريا بنسبة 23.15 % (الاحتمال = 0.015) وعلاجه بأحد الأدوية المضادة للملاريا بنسبة 8.84 % (الاحتمال = 0.056). وازدادت احتمالية شراء العلاج التوليفي بالآرتيميسينين بنسبة كبيرة إحصائياً هي 5.48 % (الاحتمال = 0.574).

الاستنتاج

ازداد إجراء اختبارات الملاريا في منطقة الدراسة عن طريق تدريب بائعي مخازن الأدوية في مجال استخدام الاختبارات السريعة وإتاحة هذه الاختبارات لهم بسعر مدعم. وقد تكون هناك حاجة إلى تدخلات إضافية لتحقيق تغطية أعلى للاختبارات ومعدل أعلى للاستجابات المناسبة لنتائج الاختبارات.

摘要

目的

评估在乌干达东部药店引入快速诊断测试对疟疾诊断和治疗的影响。

方法

整体而言，在79个接受研究的村庄（至少有一家执照药店）有2193户家庭纳入调查，并接受12个月的观察。经过3个月的观察，向67个乡村中随机选择进行干预的药店供应商提供使用疟疾快速诊断测试的培训，如果已经培训过，则以补贴价格为其提供此类测试的使用。剩余的12个研究村庄作为对照。使用双重差分回归模型评估干预的影响。

结果

来自92家药店的供应商成功完成培训，50家积极储备和执行快速测试。在9个多月中经过培训的供应商完成了平均每间商店146次的测试。家庭报告22697起发热性疾病。当地药店快速测试的可用性让任何发热性疾病接受疟疾检测的概率显著提高23.15%（P = 0.015），接受抗疟药物治疗的概率也提高了8.84%（P = 0.056）。青蒿素联合疗法的概率有统计上不显著的5.48%的提高（P = 0.574）。

结论

在我们的研究区域，培训药店供应商使用快速检测以及以补贴价格为其提供此类测试的使用提高了疟疾测试的概率。可能需要额外的干预来实现测试的更高覆盖率和对测试结果更高比例的正确反应。

Резюме

Цель

Оценить влияние на диагностику и лечение малярии внедрения в аптеки восточной Уганды диагностических экспресс-тестов.

Методы

В общей сложности в исследование были включены и проходили мониторинг в течение 12 месяцев 2193 домохозяйства в 79 исследуемых деревнях по крайней мере с одной лицензированной аптекой. После 3 месяцев мониторинга фармацевтам аптек в 67 деревнях, случайным образом отобранных для внедрения экспресс-тестов, было предложено обучение использованию диагностических экспресс-тестов на малярию и, при условии успешного обучения, доступ к таким тестам по субсидированной цене. Остальные 12 исследуемых деревень служили в качестве контрольных. Для оценки внедрения использовалась регрессионная модель «разность разностей».

Результаты

Фармацевты из 92 аптек успешно прошли обучение и 50 активно формировали запасы и выполняли экспресс-тесты. За девятимесячный период на одну аптеку приходилось в среднем 146 тестов, выполненных обученными фармацевтами. Домохозяйства сообщали о 22 697 случаях лихорадочного заболевания. Наличие экспресс-тестов в местных аптеках значительно увеличило вероятность проверки любого лихорадочного заболевания на малярию на 23,15% (P = 0,015) и его лечения противомалярийными препаратами на 8,84% (P = 0,056). Вероятность приобретения комбинированных препаратов на основе артемизинина увеличилась на статистически незначительный показатель 5,48% (P = 0,574).

Вывод

В нашей области исследования частота тестирования на малярию была увеличена путем обучения фармацевтов аптек использованию экспресс-тестов и предоставления им доступа к подобным тестам по субсидированной цене. Для достижения более ширового охвата тестированием и более высокого процента принятия соответствующих мер по результатам тестов могут потребоваться дополнительные мероприятия.

Introduction

In areas where malaria is endemic, the appropriate management of febrile illness and the effective use of resources for malaria control rely on the availability and use of diagnostic tests.¹1 Perkins MD, Bell DR. Working without a blindfold: the critical role of diagnostics in malaria control. Malar J. 2008;7 Suppl 1:S5. doi: http://dx.doi.org/10.1186/1475-2875-7-S1-S5 PMID: 19091039
https://doi.org/10.1186/1475-2875-7-S1-S... In the absence of diagnostic tests, antimalarial drugs are often taken for illnesses that have similar symptoms to those of malaria.²2 O’Connell KA, Samandari G, Phok S, Phou M, Dysoley L, Yeung S, et al. “Souls of the ancestor that knock us out” and other tales. A qualitative study to identify demand-side factors influencing malaria case management in Cambodia. Malar J. 2012;11(1):335. doi: http://dx.doi.org/10.1186/1475-2875-11-335 PMID: 23039260
https://doi.org/10.1186/1475-2875-11-335... ^–55 Masanja IM, Selemani M, Amuri B, Kajungu D, Khatib R, Kachur SP, et al. Increased use of malaria rapid diagnostic tests improves targeting of anti-malarial treatment in rural Tanzania: implications for nationwide rollout of malaria rapid diagnostic tests. Malar J. 2012;11(1):221. doi: http://dx.doi.org/10.1186/1475-2875-11-221 PMID: 22747655
https://doi.org/10.1186/1475-2875-11-221... Failure to diagnose malaria can lead to poor case management, a waste of scarce health resources and increased risk of antimalarial resistance.¹1 Perkins MD, Bell DR. Working without a blindfold: the critical role of diagnostics in malaria control. Malar J. 2008;7 Suppl 1:S5. doi: http://dx.doi.org/10.1186/1475-2875-7-S1-S5 PMID: 19091039
https://doi.org/10.1186/1475-2875-7-S1-S... ^,66 White NJ. Antimalarial drug resistance. J Clin Invest. 2004 Apr;113(8):1084–92. doi: http://dx.doi.org/10.1172/JCI21682 PMID: 15085184
https://doi.org/10.1172/JCI21682... The non-treatment or delayed treatment of malaria contribute substantially to malaria-attributable child mortality.⁷7 Getahun A, Deribe K, Deribew A. Determinants of delay in malaria treatment-seeking behaviour for under-five children in south-west Ethiopia: a case control study. Malar J. 2010;9(1):320. doi: http://dx.doi.org/10.1186/1475-2875-9-320 PMID: 21070644
https://doi.org/10.1186/1475-2875-9-320... ^,88 Stauffer W, Fischer PR. Diagnosis and treatment of malaria in children. Clin Infect Dis. 2003 Nov 15;37(10):1340–8. doi: http://dx.doi.org/10.1086/379074 PMID: 14583868
https://doi.org/10.1086/379074... In Uganda, only a minority of febrile illnesses are treated with artemisinin combination therapy – i.e. the recommended first-line treatment for malaria – and many of such episodes go untreated.⁹9 Littrell M, Gatakaa H, Evance I, Poyer S, Njogu J, Solomon T, et al. Monitoring fever treatment behaviour and equitable access to effective medicines in the context of initiatives to improve ACT access: baseline results and implications for programming in six African countries. Malar J. 2011;10(1):327. doi: http://dx.doi.org/10.1186/1475-2875-10-327 PMID: 22039892
https://doi.org/10.1186/1475-2875-10-327... Similar observations have been made in Kenya, the United Republic of Tanzania and other African countries.¹⁰10 Results & publications [Internet]. Nairobi: ACTwatch; 2013. Available from: http://www.actwatch.info/publications [cited 2014 Dec 15].
http://www.actwatch.info/publications... ^–1313 Cohen JL, Yadav P, Moucheraud C, Alphs S, Larson PS, Arkedis J, et al. Do price subsidies on artemisinin combination therapy for malaria increase household use? Evidence from a repeated cross-sectional study in remote regions of Tanzania. PLoS One. 2013;8(7):e70713. doi: http://dx.doi.org/10.1371/journal.pone.0070713 PMID: 23923018
https://doi.org/10.1371/journal.pone.007...

The World Health Organization (WHO) recommends parasitological confirmation of malaria before antimalarial drug use.¹⁴14 Guidelines for the treatment of malaria. 2nd edition. Geneva: World Health Organization; 2010. Available from: http://whqlibdoc.who.int/publications/2010/9789241547925_eng.pdf?ua=9789241547921 [cited 2014 Dec 2].
http://whqlibdoc.who.int/publications/20... Although the current Global malaria action plan of the Roll Back Malaria Initiative calls for universal access to malaria testing,¹⁵15 The global malaria action plan for a malaria-free world [Internet]. Geneva: Roll Back Malaria Partnership; 2008. Available from: http://www.rollbackmalaria.org/gmap/index.html [cited 2014 Dec 2].
http://www.rollbackmalaria.org/gmap/inde... such access remains a distant goal in most countries with endemic malaria. A study in six African countries found that only 4–31% of children with febrile illnesses were tested for malaria.⁹9 Littrell M, Gatakaa H, Evance I, Poyer S, Njogu J, Solomon T, et al. Monitoring fever treatment behaviour and equitable access to effective medicines in the context of initiatives to improve ACT access: baseline results and implications for programming in six African countries. Malar J. 2011;10(1):327. doi: http://dx.doi.org/10.1186/1475-2875-10-327 PMID: 22039892
https://doi.org/10.1186/1475-2875-10-327... In many countries, patients and caregivers rely heavily on a loosely regulated private sector for malaria treatment.¹⁶16 Nabyonga Orem J, Mugisha F, Okui AP, Musango L, Kirigia JM. Health care seeking patterns and determinants of out-of-pocket expenditure for malaria for the children under-five in Uganda. Malar J. 2013;12(1):175. doi: http://dx.doi.org/10.1186/1475-2875-12-175 PMID: 23721217
https://doi.org/10.1186/1475-2875-12-175... ^,1717 McCombie SC. Treatment seeking for malaria: a review of recent research. Soc Sci Med. 1996 Sep;43(6):933–45. doi: http://dx.doi.org/10.1016/0277-9536(95)00446-7 PMID: 8888463
https://doi.org/10.1016/0277-9536(95)004... In consequence, the engagement of the private sector has become an increasingly common strategy in malaria control programmes – as reflected, for example, in the pilot Affordable Medicines Facility–malaria (AMFm).¹⁸18 Tougher S, Ye Y, Amuasi JH, Kourgueni IA, Thomson R, Goodman C, et al.; ACTwatch Group. Effect of the Affordable Medicines Facility—malaria (AMFm) on the availability, price, and market share of quality-assured artemisinin-based combination therapies in seven countries: a before-and-after analysis of outlet survey data. Lancet. 2012 Dec 1;380(9857):1916–26. doi: http://dx.doi.org/10.1016/S0140-6736(12)61732-2 PMID: 23122217
https://doi.org/10.1016/S0140-6736(12)61...

The development of inexpensive and simple rapid diagnostic tests for malaria has opened the possibility of widespread access to malaria diagnosis. These antigen detection tests have been shown to be as effective as routine microscopy in malaria diagnosis¹⁹19 White NJ, Pukrittayakamee S, Hien TT, Faiz MA, Mokuolu OA, Dondorp AM. Malaria. Lancet. 2014 Feb 22;383(9918):723–35. doi: http://dx.doi.org/10.1016/S0140-6736(13)60024-0 PMID: 23953767
https://doi.org/10.1016/S0140-6736(13)60... and can be safely performed by individuals with only basic training.²⁰20 Hamer DH, Brooks ET, Semrau K, Pilingana P, MacLeod WB, Siazeele K, et al. Quality and safety of integrated community case management of malaria using rapid diagnostic tests and pneumonia by community health workers. Pathog Glob Health. 2012 Mar;106(1):32–9. doi: http://dx.doi.org/10.1179/1364859411Y.0000000042 PMID: 22595272
https://doi.org/10.1179/1364859411Y.0000... Although research from Cambodia,²¹21 Yeung S, Patouillard E, Allen H, Socheat D. Socially-marketed rapid diagnostic tests and ACT in the private sector: ten years of experience in Cambodia. Malar J. 2011;10(1):243. doi: http://dx.doi.org/10.1186/1475-2875-10-243 PMID: 21851625
https://doi.org/10.1186/1475-2875-10-243... Somalia²²22 Noor AM, Rage IA, Moonen B, Snow RW. Health service providers in Somalia: their readiness to provide malaria case-management. Malar J. 2009;8(1):100. doi: http://dx.doi.org/10.1186/1475-2875-8-100 PMID: 19439097
https://doi.org/10.1186/1475-2875-8-100... and Uganda²³23 Cohen J, Fink G, Berg K, Aber F, Jordan M, Maloney K, et al. Feasibility of distributing rapid diagnostic tests for malaria in the retail sector: evidence from an implementation study in Uganda. PLoS One. 2012;7(11):e48296. doi: http://dx.doi.org/10.1371/journal.pone.0048296 PMID: 23152766
https://doi.org/10.1371/journal.pone.004... has shown that the distribution of rapid diagnostic tests by the private sector is feasible, we know very little of the impact of this approach on population-level rates of malaria diagnosis and purchase of antimalarial drugs. We therefore conducted a trial in eastern Uganda to investigate the impact – on malaria diagnosis and the purchase of antimalarial drugs – of training the vendors from licensed drug shops to test patients with a rapid diagnostic test for malaria. The trained vendors were also encouraged to buy the test, at a subsidized price, from local wholesale providers. The study took place in Uganda’s eastern region, where the annual transmission rates for malaria exceed 100 infective bites per person²⁴24 Uganda malaria indicator survey 2009. Calverton: Macro International; 2010. and presumptive symptom-based treatment remains common – especially when, as commonly occurs, treatment is sought outside the higher level public-health facilities.²⁵25 Batwala V, Magnussen P, Nuwaha F. Comparative feasibility of implementing rapid diagnostic test and microscopy for parasitological diagnosis of malaria in Uganda. Malar J. 2011;10(1):373. doi: http://dx.doi.org/10.1186/1475-2875-10-373 PMID: 22182758
https://doi.org/10.1186/1475-2875-10-373... ^–2727 Nuwaha F. People’s perception of malaria in Mbarara, Uganda. Trop Med Int Health. 2002 May;7(5):462–70. doi: http://dx.doi.org/10.1046/j.1365-3156.2002.00877.x PMID: 12000657
https://doi.org/10.1046/j.1365-3156.2002... Malaria is responsible for 30–50% of outpatient visits and 9–14% of inpatient deaths in Uganda.²⁸28 Uganda national malaria control policy. Kampala: Ministry of Health; 2010.

Methods

The study was designed as a cluster-randomized controlled trial, with extensive monitoring of the health behaviour of households before and after a rapid diagnostic test was made available in local drug shops. Since the study was designed to explore both cross-sectional and pre-post differences, 67 (85%) of the study villages were randomly selected to receive the intervention while the remaining 12 (15%) were used as a control group. The study was implemented between March 2011 and April 2012. Training in the use of the diagnostic test occurred between 21 June and 6 July, 2011. A simple random number draw – generated by Stata/SE version 11.0 (StataCorp. LP, College Station, United States of America) – was used for the selection of study villages and households and the assignment of villages to the intervention or control arm.

Villages

The sampling frame for the study included all of the villages in the districts of Budaka, Bukedea, Kibuku, Kumi, Ngora and Pallisa that had at least one drug shop licensed and registered with the ministry of health. Although the district health office initially identified 92 such villages, only 79 still had at least one licensed drug shop at the time the main study was launched. These 79 villages were included in the cluster randomization (Fig. 1).

Households

The households in all 92 target villages were listed before the launch of the study. Subsequently, 25 households in each target village were randomly selected, visited for a baseline survey to record basic demographic characteristics and health behaviours, and re-visited every month for 9 months (Fig. 1) to monitor their health problems and treatment seeking. During the tenth and final follow-up survey – i.e. the so-called endline survey – all consenting adults and – if their caregivers gave consent – the children in the study households were tested for malaria using the rapid diagnostic test.

Drug shops

Each licensed drug shop listed by the ministry of health in the 79 villages and included in the randomization was visited for a baseline survey in April 2011 and an endline survey in March 2012.

Intervention

Vendors from 108 drug shops in the 67 intervention villages were invited for 2 days of training in the use of a rapid diagnostic test for malaria – i.e. the CareStart Malaria HRP2 (Pf) test (Access Bio, Somerset, USA). The training, described previously,²³23 Cohen J, Fink G, Berg K, Aber F, Jordan M, Maloney K, et al. Feasibility of distributing rapid diagnostic tests for malaria in the retail sector: evidence from an implementation study in Uganda. PLoS One. 2012;7(11):e48296. doi: http://dx.doi.org/10.1371/journal.pone.0048296 PMID: 23152766
https://doi.org/10.1371/journal.pone.004... was facilitated by trainers approved by the national ministry of health. These trainers reviewed the signs and symptoms of uncomplicated malaria and severe illness and instructed the trainees on how to perform the diagnostic test and on the recommended first-line treatment for malaria. The first day of training was classroom-based while the second day involved practical experience in a health facility. Trainees were not given specific instructions on when to recommend testing and – apart from the promotion of artemisinin combination therapy – were not given treatment algorithms. No retail price for the test was suggested. Our main objective was to observe whether and how the trainees chose to integrate the test into their normal practice. Upon successful completion of the training, each trainee was given a free box of 40 test kits, gloves, an instruction leaflet, results slips and a sharps disposal box. Any new staff employed by the drug shops in the intervention villages after the initial training were invited to a similar training course that was run in October 2011.

Trained drug shop vendors were visited monthly to track their stocking and usage of the rapid diagnostic test and compliance with the recommended protocols for testing. Test kit storage, administration and post-use disposal were monitored using a 17-point checklist. Information on the shop’s stock of the test kits and price of the test for patients was recorded. At the same time, any questions the vendors had about the test’s administration were answered. Every 3 months, four unused test kits were collected from each shop holding the kits and sent for lot testing at the Foundation for Innovative Diagnostics Laboratory at the Pasteur Institute of Cambodia, in Phnom Penh. Every kit investigated in this way passed lot testing.

Test kits

According to WHO, the test investigated has a panel detection score of 98.7%, a false-negative rate of < 1% and a total false-positive rate of 2.4%.²⁹29 Malaria rapid diagnostic test performance – results of WHO product testing of malaria RDTs: round 3 (2010-2011). Geneva: World Health Organization; 2011. Because this test, like other tests based on the detection of histidine-rich protein II, can remain positive for up to 5 weeks after a cured infection, a higher false-positive rate may occur in settings where malaria is highly endemic.³⁰30 Laurent A, Schellenberg J, Shirima K, Ketende SC, Alonso PL, Mshinda H, et al. Performance of HRP-2 based rapid diagnostic test for malaria and its variation with age in an area of intense malaria transmission in southern Tanzania. Malar J. 2010;9(1):294. doi: http://dx.doi.org/10.1186/1475-2875-9-294 PMID: 20974009
https://doi.org/10.1186/1475-2875-9-294... Trainees were told that any patient who tested positive who had also taken antimalarial drugs in the previous 4 weeks should be referred to a facility where they could be checked for malarial infection by microscopy.

The test kits were purchased and imported, at a cost of 0.70 United States dollar (US$) per kit, by the study team. They were then sold to a prominent pharmaceutical wholesaler in Kampala at a subsidized price of US$ 0.12 per kit. The wholesaler’s regional pharmacy in the city of Mbale subsequently sold the kits – exclusively to our trainees – at a price of US$ 0.19 per kit.²³23 Cohen J, Fink G, Berg K, Aber F, Jordan M, Maloney K, et al. Feasibility of distributing rapid diagnostic tests for malaria in the retail sector: evidence from an implementation study in Uganda. PLoS One. 2012;7(11):e48296. doi: http://dx.doi.org/10.1371/journal.pone.0048296 PMID: 23152766
https://doi.org/10.1371/journal.pone.004...

Data entry and analysis

Data were entered using the CSPro 4.0 package (United States Census Bureau, Suitland, USA) and mainly analysed, using Stata version 11.0, in a multivariate linear probability difference-in-differences model. A P-value of 0.05 or less was considered statistically significant. The primary outcome was whether a household member with febrile illness was tested for malaria. Secondary outcomes included the medication taken to treat febrile illness – if any – and where treatment – if any – was sought. The main independent variable was whether the illness occurred in a village in our intervention or control arm. As vendors from 15% of the drug shops targeted for training did not complete their training, intention-to-treat effects were estimated.

To control for seasonal effects and for village characteristics, a full set of village and monthly fixed effects were included in the fully adjusted model. Estimated robust standard errors were clustered at the village level.³¹31 Moulton BR. An illustration of a pitfall in estimating the effects of aggregate variables on micro units. Rev Econ Stat. 1990;72(2):334–8. doi: http://dx.doi.org/10.2307/2109724
https://doi.org/10.2307/2109724... ^,3232 Bertrand M, Duflo E, Mullainathan S. How much should we trust differences-in-differences estimates? Q J Econ. 2004;119(1):249–75. doi: http://dx.doi.org/10.1162/003355304772839588
https://doi.org/10.1162/0033553047728395... Although adjustments were also made to remove the potential effects of a behaviour change campaign that was rolled out in the later stages of our intervention, the roll-out of the campaign was orthogonal to the main treatment and did not affect our main results.

Our study was powered to detect an increase in the fraction of fever cases seeking health care at drug shops using the rapid diagnostic kit from 10% to 20%. Assuming an incidence of one episode of febrile illness per person-year, a mean household size of five individuals, 40% of households seeking treatment at a drug shop and an intra-class correlation of 0.05, the study was powered to detect the targeted 10% difference in the 9-month intervention period with a probability of 0.92.

Ethics

Ethical approval for this study was given by the Harvard School of Public Health (protocol # P19371–106) and the Uganda National Council for Science and Technology (protocol # HS805).

Trial registry

The trial was registered as clinical trial NCT01652365 at clinicaltrials.gov.

Results

Drug shops

Out of the 108 registered drug shops, 92 shops completed training. Fourteen vendors declined to be trained, one shop was relocated outside our study area and the vendor from another shop was considered to have failed the training. Each of the 92 shops had at least one staff member who successfully completed training (Fig. 1).

Over the monitoring period from July 2011 to March 2012, shops run by successful trainees bought a mean of 146 (median: 40) diagnostic kits from the local wholesaler (Table 1). Overall, 13 440 test kits were bought and the shops investigated 10 412 patients using the test kits that they had been given or bought. However, 37 such shops (40%) did not purchase any of the test kits and most of the others bought only small numbers of the kits (Table 2). Together, just three shops accounted for 32% (3346) of all of the rapid diagnostic tests performed on patients.

The mean price paid by a patient assessed with the rapid diagnostic kit was US$ 0.43 – representing a 125% markup on the kit’s wholesale price. According to the data collected in our household surveys, the median prices paid for artemisinin combination therapy for individuals younger and older than 5 years were US$ 0.57 and US$ 0.76, respectively. The corresponding costs of quinine – which accounted for 72% of purchases of antimalarial drugs other than artemisinin combination therapies – were US$ 0.57 and US$ 0.38, respectively.¹²12 Fink G, Dickens WT, Jordan M, Cohen JL. Access to subsidized ACT and malaria treatment–evidence from the first year of the AMFm program in six districts in Uganda. Health Policy Plan. 2014 Jul;29(4):517–27. doi: http://dx.doi.org/10.1093/heapol/czt041 PMID: 23783833
https://doi.org/10.1093/heapol/czt041...

Households

Fig. 2 illustrates the households investigated and illnesses captured over the study period. In total, 25 758 episodes of illness were reported by study households across the 10 survey rounds. Respondents reported the presence of fever in 22 697 (88.1%) of these episodes and we focused on these episodes of febrile illness in our analysis. For 4364 of the reported episodes of illness – including 3908 episodes of febrile illness – treatment was sought at one of the study drug shops.

The study households in the intervention and control villages appeared similar in terms of their baseline demographic characteristics (Table 3). The estimated prevalence of malaria at the time of the endline survey was 43% in both arms of the study. Table 4 presents the characteristics of the episodes of febrile illness recorded pre-intervention, in monthly morbidity surveys. Most individuals (4448) with febrile illness sought treatment in the public sector, at a private-sector drug shop or pharmacy, or at a private-sector clinic or hospital. However, 21.5% (1218/5666) of such individuals sought no care. Roughly half (1039/2322) of the reported visits to drug shops for the treatment of febrile illness were to a shop that was involved in our study.

During the pre-intervention period, malaria testing and antimalarial drug use among cases of febrile illness were significantly less likely in the intervention villages than in the control villages – 25.9% (1258/4861) versus 38% (306/805; P = 0.002) and 54.3% (2641/4861) versus 68.2% (549/805; P = 0.003), respectively. This difference appears to be a reflection of a relatively larger fraction of patients from the control villages seeking treatment at a public facility. In the pre-intervention period, the percentage of febrile patients seeking care in the private sector who were tested for malaria was similar across the two study arms (40% [54/135] versus 33.6% [235/700]; P = 0.565).

Table 5 shows the population-level crude estimates and the corresponding – and, generally very similar – adjusted estimates of the intervention’s impact on testing, medication choice and treatment seeking. Among all cases of febrile illness and among cases of febrile illness in children younger than 5 years, according to the crude model, the intervention significantly increased the probabilities of being tested for malaria, by 6.0 (P = 0.015) and 7.6 percentage points (P = 0.015), respectively. According to the same model, the intervention increased the likelihood of taking any antimalarial drug or artemisinin combination therapy by 4.8 and 1.6 percentage points and reduced antibiotic usage by 0.3 of a percentage point – but none of these differences reached statistical significance. Appendix A (available at: https://cdn1.sph.harvard.edu/wp-content/uploads/sites/358/2012/08/AppendixA.pdf) demonstrates the robustness of these main results, which remained similar if we (i) used patient-reported episodes of suspected malaria rather than all fever episodes, (ii) confined our analysis to the episodes of illnesses that occurred before the roll-out of the behaviour change campaign, or (iii) used logistic regression instead of linear probability models.

Fig. 3 shows the fractions of patients visiting the drug shops in intervention and control villages who were tested for malaria before and after roll-out of the intervention. Prior to the first training course about the rapid diagnostic test, the fraction of patients tested for malaria in a study drug shop was similar in the intervention and control villages, 8.9% (70/786) and 10.6% (12/113), respectively. After the first training course, the fraction of patients tested for malaria in a study drug shop in the control arm remained almost unchanged (33/334) but the corresponding value in the intervention arm almost doubled (390/3011; P < 0.001). Nearly 90% (3112/3458) of patients investigated using the rapid diagnostic test gave a positive result. The reliability of the test results is discussed in Appendix A.

Fig. 4 summarizes our data on the patients who, during the intervention period, visited and were tested at the study drug shops in the intervention villages. Although over 80% (285/342) of such patients who tested positive for malaria purchased an antimalarial drug of some kind, nearly 45% (21/48) of those who tested negative did the same. Test-positive patients were more than twice as likely to purchase artemisinin combination therapy as test-negative patients (40.9% [140/342] versus 16.7% [8/48]; P < 0.001). However, less than half of the test-positive patients – and 31.5% (590/1871) of the untested patients – purchased artemisinin combination therapy. We found no differences in antibiotic purchases according to testing status or test result.

Discussion

In countries where malaria is highly endemic, many episodes of febrile illnesses are treated at drug shops. Our results indicate that, by offering training and access to subsidized rapid diagnostic tests to private drug shops, it is possible to increase malaria testing rates significantly. Three of the most commonly voiced concerns regarding use of rapid tests for malaria diagnosis by the private sector are poor adherence to protocols, the potential crowding out of public-sector treatment and increased antibiotic purchases by patients who have a negative result. We found no evidence to support any of these concerns. In addition, as we previously reported, our monthly monitoring of the drug shops indicated generally high levels of compliance with recommended treatment, storage, waste management and test-kit administration protocols.²³23 Cohen J, Fink G, Berg K, Aber F, Jordan M, Maloney K, et al. Feasibility of distributing rapid diagnostic tests for malaria in the retail sector: evidence from an implementation study in Uganda. PLoS One. 2012;7(11):e48296. doi: http://dx.doi.org/10.1371/journal.pone.0048296 PMID: 23152766
https://doi.org/10.1371/journal.pone.004...

From a policy perspective, a major challenge for any health initiative in the private sector is the achievement of adequate uptake and coverage. In our study setting, the potential impact of the intervention was limited by the need to work only with drug shops that were licensed by the Ugandan Ministry of Health. Inclusion of unlicensed outlets would have substantially increased the reach of our programme but may also have complicated monitoring and quality control. Even among the licensed shops with trained staff, however, uptake was limited. Only about 60% (55/92) of such shops chose to stock the test kits and fewer than 20% (390/2261) of the febrile patients who visited a drug shop that had a trainee were actually tested for malaria. While no detailed information on the reasons for the relatively weak uptake of the rapid tests was collected, higher rates of uptake could probably be achieved by combining behavioural change efforts with stronger financial incentives. The price subsidies for the test kits could be increased, drug shops could be paid incentives to perform tests and provide appropriate treatment to the test-positive patients, and the level of any subsidy could be correlated with the quality of the testing provided by each shop. Greater impact could potentially also be achieved if the test-related training and subsidy could be combined with training on the appropriate treatment of non-malarial illnesses – although this would require policy-makers to support the movement of non-medical professionals further into formal case management.

A second main challenge, from a policy perspective, is the remarkably low uptake of artemisinin combination therapies that we observed. Only 40.9% of the patients who tested positive for malaria actually purchased such therapies. This modest amount of uptake does not appear to have been driven by lack of access, given that 84.2% (96/114) of our study drug shops reported having artemisinin combination therapies in stock at the time of our endline survey.¹²12 Fink G, Dickens WT, Jordan M, Cohen JL. Access to subsidized ACT and malaria treatment–evidence from the first year of the AMFm program in six districts in Uganda. Health Policy Plan. 2014 Jul;29(4):517–27. doi: http://dx.doi.org/10.1093/heapol/czt041 PMID: 23783833
https://doi.org/10.1093/heapol/czt041... It is possible that patients perceived the prices of such therapies to be too high – compared with those of other antimalarial treatments – even though, in Uganda at the time of our study, the prices of such therapies had been substantially lowered by subsidies from the Affordable Medicines Facility–malaria programme.¹²12 Fink G, Dickens WT, Jordan M, Cohen JL. Access to subsidized ACT and malaria treatment–evidence from the first year of the AMFm program in six districts in Uganda. Health Policy Plan. 2014 Jul;29(4):517–27. doi: http://dx.doi.org/10.1093/heapol/czt041 PMID: 23783833
https://doi.org/10.1093/heapol/czt041... ^,1818 Tougher S, Ye Y, Amuasi JH, Kourgueni IA, Thomson R, Goodman C, et al.; ACTwatch Group. Effect of the Affordable Medicines Facility—malaria (AMFm) on the availability, price, and market share of quality-assured artemisinin-based combination therapies in seven countries: a before-and-after analysis of outlet survey data. Lancet. 2012 Dec 1;380(9857):1916–26. doi: http://dx.doi.org/10.1016/S0140-6736(12)61732-2 PMID: 23122217
https://doi.org/10.1016/S0140-6736(12)61...

Furthermore, use of rapid tests for malaria diagnosis in the private sector appears to be a feasible and potentially effective way to increase testing rates and improve overall case management. As discussed in greater detail elsewhere,³³33 Cohen JM, Woolsey AM, Sabot OJ, Gething PW, Tatem AJ, Moonen B. Public health. Optimizing investments in malaria treatment and diagnosis. Science. 2012 Nov 2;338(6107):612–4. doi: http://dx.doi.org/10.1126/science.1229045 PMID: 23118172
https://doi.org/10.1126/science.1229045... the subsidizing of such tests for use in the private sector is likely to yield highest returns in settings where malaria prevalence is low and treatment seeking in the private sector is common. The accurate diagnosis of malaria could eliminate the wasteful use of antimalarial drugs for non-malarial illness and improve the management of malaria and other febrile illnesses – particularly if the private sector is properly incentivized and equipped to treat the true causes of non-malarial illness appropriately.

References

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