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Keywords:

  • artemether;
  • lumefantrine;
  • Coartem;
  • malaria;
  • community;
  • rapid diagnostic testing
  • artéméther;
  • luméfantrine;
  • Coartem;
  • malaria;
  • communauté;
  • tests de diagnostic rapide
  • Artemeter;
  • lumefantrina;
  • Coartem;
  • malaria;
  • comunidad;
  • pruebas de diagnóstico rápido

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Sources of funding and conflicts of interest
  9. References

Objective  To assess the impact and feasibility of artemether-lumefantrine deployment at community level, combined with phased introduction of rapid diagnostic tests (RDTs), on malaria transmission, morbidity, and mortality and health service use in a remote area of Ethiopia.

Methods  Two-year pilot study in two districts: artemether-lumefantrine was prescribed after parasitological confirmation of malaria in health facilities in both districts. In the intervention district, artemether-lumefantrine was also made available through 33 community health workers (CHWs); of these, 50% were equipped with RDTs in the second year.

Results  At health facilities; 54 774 patients in the intervention and 100 535 patients in the control district were treated for malaria. In the intervention district, 75 654 patients were treated for malaria by community health workers. Use of RDTs in Year 2 excluded non-Plasmodium falciparumin 89.7% of suspected cases. During the peak of malaria transmission in 2005, the crude parasite prevalence was 7.4% (95% CI: 6.1–8.9%) in the intervention district and 20.8% (95% CI: 18.7–23.0%) in the control district. Multivariate modelling indicated no significant difference in risk of all-cause mortality between the intervention and the control districts [adjusted incidence rate ratio (aIRR) 1.03, 95%CI 0.87–1.21, P = 0.751], but risk of malaria-specific mortality was lower in the intervention district (aIRR 0.60, 95%CI 0.40–0.90, P = 0.013).

Conclusions  Artemether-lumefantrine deployment through a community-based service in a remote rural population reduced malaria transmission, lowered the malaria case burden for health facilities and reduced malaria morbidity and mortality during a 2-year period which included a major malaria epidemic.

Déploiement de l’artéméther-luméfantrine et du test rapide dans des communautés éthiopiennes: impact sur la morbidité, la mortalité et les ressources de la santé pour la malaria

Objectif:  Evaluer l’impact et la faisabilité du déploiement de l’artéméther-luméfantrine à l’échelle communautaire, combinée avec l’introduction progressive de tests rapides de diagnostic, sur la morbidité et la mortalité de la malaria et sur l’utilisation des services de santé dans une région reculée d’Éthiopie.

Méthodes:  Etude pilote de 2 ans an dans deux districts: l’artéméther-luméfantrine a été prescrit après confirmation parasitologique de la malaria dans les services de santé dans les deux districts. Dans le district d’intervention, l’artéméther-luméfantrine a été rendu disponible chez 33 agents de santé communautaires; 50% de ceux-ci étaient équipés de tests rapides de diagnostic durant la deuxième année.

Résultats:  54.774 patients atteints de malaria ont été soignés dans les services de santé dans le district d’intervention et 100.535 dans le district témoins. 75.654 patients atteints de malaria ont été traités par des agents de santé communautaires dans le district d’intervention. L’utilisation de tests rapides de diagnostic dans l’année 2 a permis d’exclure les non P. falciparum dans 89,7% des cas suspects. Durant le pic de transmission de la malaria en 2005, la prévalence parasitaire brute était de 7,4% (IC95%: 6,1-8,9%) dans le district d’intervention et de 20,8% (IC95%: 18,7-23,0%) dans le district témoins. L’analyse multivariée n’a indiqué aucune différence significative du risque de mortalité de toutes causes confondues entre les districts d’intervention et témoins (ratio ajusté des taux d’incidence [AIRr]: 1,03; IC95% : 0, 87-1,21 ; p = 0,751), mais le risque de mortalité spécifique à la malaria était plus faible dans le district d’intervention (AIRr : 0,60, IC95%: 0,40-0,90 ; p = 0, 013).

Conclusions:  Le déploiement de l’artéméther-luméfantrine à travers un service basé sur la communauté dans une population rurale a réduit la transmission de la malaria, a diminué la charge liées aux cas de malaria pour les services de santé et a réduit la morbidité et la mortalité de la malaria au cours d’une période de deux ans couvrant une épidémie majeure de malaria.

Desplegando la artemeter-lumefantrina con pruebas rápidas en comunidades Etiopes: impacto sobre la morbilidad de malaria, mortalidad y recursos sanitarios.

Objetivo:  Evaluar el impacto y la viabilidad del despliegue a nivel comunitario de artemeter-lumefantrina, combinado con la introducción por fases de pruebas de diagnóstico rápido, sobre la morbilidad de malaria, mortalidad y uso de servicios sanitarios en un área remota de Etiopía.

Métodos:  Estudio piloto de 2-años en dos distritos: se prescribió artemeter-lumefantrina después de la confirmación parasitológica de malaria en centros sanitarios de ambos distritos. En el distrito de la intervención, el artemeter-lumefantrina también estaba disponible a través de 33 trabajadores sanitarios comunitarios; de estos, 50% estaban equipados con pruebas diagnósticas rápidas en el segundo año.

Resultados:  Se trataron 54,774 pacientes con malaria en los centros sanitarios del distrito intervenido y 100,535 en el distrito control. 75,654 pacientes con malaria fueron tratados por trabajadores sanitarios comunitarios en el distrito de intervención. El uso de pruebas diagnósticas rápidas en el Año 2 excluyó no-P. falciparum en 89·7% de los casos sospechosos. Durante el pico de transmisión de la malaria en el 2005, la prevalencia parasitaria cruda era 7.4% (95% IC: 6.1-8.9%) en el distrito de la intervención y 20.8% (95% IC: 18.7-23.0%) en el distrito control. Los modelos multivariados indicaban que no había diferencias significativas en el riesgo de mortalidad por cualquier causa entre los distritos de intervención y control (razón de tasas de la incidencia ajustado [aIRR] 1·03, 95%IC 0·87-1·21, p = 0·751), pero el riesgo de mortalidad específica por malaria era menor en el distrito de la intervención (aIRR 0·60, 95%CI 0·40-0·90, p = 0·013).

Conclusiones: El despliegue de artemeter-lumefantrina mediante un servicio basado en la comunidad en una población rural remota, redujo la transmisión de malaria, disminuyó la carga por casos de malaria en los centros sanitarios, y redujo la morbilidad y mortalidad por malaria durante un periodo de dos años que incluyeron una gran epidemia de malaria.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Sources of funding and conflicts of interest
  9. References

Malaria continues to exert a high toll in terms of morbidity, mortality and health expenditure (WHO 2008a). Efforts to control the disease have been thwarted by the emergence of P. falciparum resistance to widely used antimalarial medicines such as chloroquine and sulfadoxine-pyrimethamine (WHO 2008b), which has led to a rise in malaria mortality over the last decade. Thus, WHO recommends combination therapies, preferably those including an artemisinin derivative, as treatment for uncomplicated P. falciparum malaria for achieving a rapid cure, reducing parasite infectivity (WHO 2008b) and countering the threat of resistance to P. falciparum (WHO 2006).

Artemether-lumefantrine (AL, Coartem®; Novartis Pharma AG, Basel, Switzerland) offers polymerase chain reaction (PCR)-corrected 28-day cure rates that consistently exceed 95% (Falade et al. 2005; Koram et al. 2005; Martensson et al. 2005; Mutabingwa et al. 2005; Dorsey et al. 2007; Zongo et al. 2007) even when administered unsupervised (Fogg et al. 2004; Piola et al. 2005). AL was adopted as first-line treatment for uncomplicated P. falaciparum malaria in Ethiopia in July 2004 (FMoH 2004), with initial deployment only at health facilities, where confirmation of the diagnosis by microscopy or rapid diagnostic test (RDT) was more likely to be available. Many patients with malaria have limited access to the new recommended first-line treatment because of poor communication, lack of knowledge, as well as distance and transport costs to reach the health services (Whitty et al. 2008).

In the Northern Ethiopian national state of Tigray, where poverty remains a major impediment to the expansion and use of adequate health services, access to malaria diagnosis and treatment has been extended by a well-established system of volunteer community health workers (CHWs) (WHO 1999; Ghebreyesus et al. 2000). This situation was therefore suitable for evaluating the possible administration of AL at community level. If effective, this could be a model for community-based use of AL applicable to other rural areas of Africa.

We conducted a 2-year pilot operational research project in Tigray to assess the impact and feasibility of AL deployment at community level, combined with phased introduction of RDTs, on malaria transmission and morbidity, malaria-specific mortality and health service utilization in a resource-constrained rural setting.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Sources of funding and conflicts of interest
  9. References

Study design

This was a 2-year pilot study performed from May 2005 to April 2007 in two districts with similar malaria eco-epidemiological conditions in the Raya valley of southern Tigray, Ethiopia. Alamata district was randomly selected for the intervention, consisting of deploying AL through trained CHWs and health facilities, introducing RDTs to half the CHWs in the second year of the study. In Raya Azebo, the control district, AL was only available at health facility level.

Health services in the study districts

The physician to patient ratio in Tigray is 1:111 000, with health service coverage (defined as one health post per 5000 people) of 24% in the intervention district and 36% in the control district. The intervention district has 1 hospital, 1 health centre, 5 health stations, 9 health posts and 33 CHWs involved in prevention and diagnosis and treatment of malaria. The control district has 1 health centre, 8 health stations, 9 health posts and 56 CHWs whose role was restricted to malaria prevention activities.

Malaria transmission and concurrent vector control intervention

Malaria transmission in Tigray is unstable, with the majority of the population having little or no immunity, and hypoendemic (crude parasite prevalence of 3–10% during high transmission months) (WHO 1999; Ghebreyesus et al. 2000). As in other areas of Ethiopia, P. falciparum and Plasmodium vivax co-exist. The major malaria transmission season is from September to November, after the heavy rains of June to August, the minor transmission season lasts from April to May, after the lighter rains of February and March. A major malaria epidemic (WHO 1963) occurred in both study districts from May to October 2005. Before the project started, re-impregnation of insecticide-treated nets (ITNs) led to protection of 34 578 and 46 515 people in the intervention and control districts. In response to the 2005 outbreak, widespread indoor residual spraying with dichlorodiphenyltrichloroethane (DDT) 75% water-dispersible powder protected 71 091 people in the intervention district and 106 570 people in the control district. ITNs were distributed freely in both the intervention and the control districts (population protected: 45 847 and 63 037, respectively) and existing ITNs were re-impregnated (population protected: 9276 and 9554, respectively).

Intervention

The project was in two phases: Year 1 (May 2005–April 2006) and Year 2 (May 2006–April 2007) (Figure 1). Throughout the study, AL was dispensed at health facilities in both districts after clinical assessment or microscopic or RDT confirmation of malaria diagnosis. In the intervention district, all 33 CHWs dispensed AL at village level based on clinical diagnosis of malaria (i.e. fever or recent history of fever) during Year 1. During Year 2, 50% (n = 16) of CHWs in the intervention district were equipped with RDTs to confirm P. falciparum infection and to dispense AL only to RDT-positive patients. To be consistent with the national malaria treatment policy of Ethiopia, all patients testing negative on RDT were assumed to have P. vivax malaria and received chloroquine, the first-line treatment for P. vivax infection in Ethiopia (FMoH 2004). The remaining 17 CHWs in the intervention district without RDTs continued to treat all patients suspected with malaria with AL based on clinical diagnosis alone.

image

Figure 1.  Study design. RDT, rapid diagnostic test; CHW, community health worker.

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Artemether-lumefantrine (20 mg artemether plus 120 mg lumefantrine, Coartem®; Novartis Pharma AG) tablets were administered following the standard six-dose regimen (twice a day for 3 days). Patients were advised to take the drug with food (containing fat e.g. milk) if available. The RDT used (Paracheck® Pf; Orchid Biomedical Systems, Goa, India) is a cassette immunoassay test that detects only the presence of P. falciparum antigens in whole blood samples.

In April 2005, the 33 CHWs in the intervention district received 3 days training on malaria diagnosis, adminstering AL, patient education, referral of cases, drug storage and reporting systems. The 16 CHWs selected to use RDTs in Year 2 were provided with training on RDT procedures and blood safety in April 2006. Passive and active pharmacovigilance was undertaken during the study; the methods and results are described elsewhere (WHO 2009).

Data collection

Pre-coded case recording forms and guidelines for surveys, assessment, treatment and referral were developed or adopted, then pre-tested, standardized and deployed. Patient data were collected by CHWs using weekly forms to record patient name, age, gender, address and travel history; treatment on the basis of clinical diagnosis or RDT results; drug administered; and referrals to higher institutions. Data were collected monthly from all health facilities in both districts, including total and malaria cases and deaths and plasmodium species composition from both outpatient and inpatient departments.

Serial malaria parasite prevalence surveys were undertaken in April 2005 and 2006 (low transmission season) and September 2005 and 2006 (high transmission season) in the same village using the same methodology each time and the same trained survey teams. Ten health workers visited selected households in each district, where for each household member they obtained a blood film for microscopic analysis, performed a RDT and obtained information about recent febrile illness using a standard data collection form. Blood films were examined by two independent microscopists blinded to RDT results, and discordant findings were cross-checked by senior experts at regional level. The sample size was calculated assuming that the malaria parasite prevalence was 5% in the high transmission season (FMoH 2004; FMoH 2005), with a confidence level of 95% and a precision of 2% (3–7%); the required sample size of 456 (Lwanga & Lemeshow 1991) was increased to 1368 considering a design effect of three to correct for the effect of cluster sampling and including a 10% safety margin, i.e. equivalent to 330 households. Cluster sampling was used, and 30 villages were selected for inclusion by population proportional to size sampling. A random number was chosen to identify the starting household for a cluster, continuing on the right-hand side of this starting house until the required number of individuals had been recruited.

A geo-referenced household enumeration and mortality survey was carried out for both years of the study, using a verbal autopsy (VA) questionnaire to collect data on all deaths during the specified year in both districts and documenting the sequence of events leading to death (primarily the signs and symptoms of the illness preceding death). The VA data were interpreted using the InterVA model (Fantahun et al. 2006; Umeå University 2008) to determine up to three likely causes of death in each case. Cause-specific mortality fractions (CSMF) were derived from the likelihoods of specific causes from the InterVA model.

Data management and analysis

Data were sent on a weekly and monthly basis from CHWs and health facilities via health institutions to the district health office (malaria control unit) then relayed to the regional malaria control department of the Tigray Health Bureau in Mekelle for data entry, cleaning and analysis. Mechanisms for tracing missing data, verification and correction were instituted using database management procedures established at the Bureau. Data entered to the database were cross-checked manually against data entered on case-reporting forms.

Infants were excluded from analyses of mortality data because of the absence of pregnancy records, making complete recording of infant deaths unreliable. Poisson multivariate regression models were constructed to determine incidence rate ratios (IRRs) for all-cause mortality and malaria-specific mortality over the 2-year period, including age/sex group, altitude, urban/rural residence, ITN use and distance to nearest health facility as determinant factors. The models allowed for possible clustering at the village level.

Epi-Info version 6.04 software (ImageWare® Systems, Inc., San Diego, USA, accessible at http://www.cdc.gov/epiinfo/downloads.htm) was the primary tool used for data entry and management. Excel version 8.0 was also used. Mortality analyses were performed using stata software version 10 (Stata Corporation, College Station, TX, USA).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Sources of funding and conflicts of interest
  9. References

Study population

Over the 2-year study period, two household surveys enumerated mean populations of 89 377 and 118 693 individuals ≥1 year in the intervention and control districts, respectively. The age/sex distribution was similar between years and districts, but more people lived in rural areas and at higher altitudes in the control district (Table 1). The proportion of ITN owners increased in both districts in the second year of the study.

Table 1.   Characteristics of the surveyed populations in Year 1 (2005–2006) and Year 2 (2006–2007), n (%)
 Intervention districtControl district
2005–20062006–20072005–20062006–2007
  1. ITN, insecticide-treated net.

Surveyed population ≥1 year84 184 (100.0)94 570 (100.0)108 529 (100.0)128 857 (100.0)
Age and sex
 1–4 years8056 (9.6)10 152 (10.7)12 012 (11.1)16 296 (12.6)
 5–14 years26 045 (30.9)27 374 (28.9)35 030 (32.3)40 547 (31.5)
 15–49 male18 294 (21.7)21 674 (22.9)23 717 (21.9)27 688 (21.5)
 15–49 female21 255 (25.2)23 788 (25.2)26 313 (24.2)30 970 (24.0)
 50–64 years6694 (8.0)7400 (7.8)7540 (6.9)8894 (6.9)
 ≥65 years3840 (4.6)4182 (4.4)3917 (3.6)4462 (3.5)
Area
 Urban30 823 (36.6)34 292 (36.3)28 380 (26.1)32 218 (25.0)
 Rural53 361 (63.4)60 278 (63.7)80 149 (73.9)96 639 (75.0)
ITN ownership
 No28 767 (34.2)15 239 (16.1)28 761 (26.5)13 753 (10.7)
 Yes55 417 (65.8)79 331 (83.9)79 768 (73.5)115 104 (89.3)
Altitude
 <1600 m65 131 (77.4)73 063 (77.3)19 342 (17.8)23 214 (18.0)
 ≥1600 m19 053 (22.6)21 507 (22.7)89 187 (82.2)105 643 (82.0)
Distance to health facility
 <2 km33 964 (40.3)37 491 (39.6)34 583 (31.9)43 345 (33.6)
 2–5 km35 721 (42.4)41 456 (43.8)46 477 (42.8)55 610 (43.2)
 ≥5 km14 499 (17.2)15 623 (16.5)27 469 (25.3)29 902 (23.2)

Heath facility and community health workers activity

During the 2-year study, 54 774 patients were treated for malaria at all health facilities in the intervention district compared to 100 535 patients in the control district. While the number of patients with malaria seen at health facilities during the 2005 epidemic increased in both districts, the patient load to the health facilities in the intervention district was markedly lower (Table 2). In total, 75 654 patients with malaria were treated by the 33 CHWs in the intervention district during the 2-year study period. During Year 2, the 17 CHWs without RDTs treated 10 475 patients on the basis of clinical diagnosis alone. After the introduction of RDTs in the intervention district in Year 2, the number of patients visiting CHWs equipped with RDTs was approximately halved. The 16 CHWs who were equipped with RDTs examined 5123 patients with suspected malaria using RDT. Five hundred and twenty-six patients (10.3%) were P. falciparum-positive and treated with AL. Among these 526 patients, in a very few cases excess tablets were prescribed (172 tablets) and in very few cases there was under prescription (30 tablets) i.e. a total of 202 tablets (the sum of overdosing and underdosing) were wrongly given of a total of 11 194 tablets administered to patients treated after RDT results.

Table 2.   Outpatients presenting to clinics and health posts in the intervention and control districts and percentage diagnosed with malaria based on clinical presentation and rapid diagnostic test results during May 2005–June 2007
 MayJJASONDJFMAMJJASONDJFMAMJune
  1. JJA, June, July, August; SON, September, October, Novemeber; DJF, December, January, Feburary; MAM, March, April, May.

Intervention district
 Total number of outpatients435717 78518 67514 81413 64312 73411 41111 73011 7913671
 Number of patients with malaria207196758445399931693347479029242170651
 % patients with malaria47.554.445.227.023.226.342.024.918.417.7
Control district
 Total number of outpatients186318 24814 1527488585357364795506152301021
 Number of patients with malaria91414 7088218302219301927172516191490253
 % patients with malaria49.180.658.140.433.033.636.032.028.524.8

Serial malaria prevalence surveys

Blood films were obtained from an average of 1377 patients across all four surveys (April and September, 2005 and 2006). In the high transmission season of 2005 (September), after the major epidemic in June–August 2005, the crude parasite prevalence for all species (asexual or gametocyte stages) was threefold lower in the intervention district than in the control district (7.4% [95% CI: 6.1–8.9%] vs. 20.8% [95% CI: 18.6–23.0%]) (Table 3). Similarly, P. falciparum parasite prevalence (i.e. asexual and gametocyte stages) was threefold lower in the intervention district (4.9%vs. 14.2%). Between the low and high transmission seasons of 2005, the P. falciparum gametocyte prevalence decreased by 7% in the intervention district but increased tenfold in the control district (Table 3).

Table 3.   Results of serial malaria parasite prevalence surveys. Parasite prevalence is shown as percentage of number of blood films tested (n). 95% CI values are shown in brackets
DistrictParasite prevalence20052006
Low transmission (April)High transmission (September)Low transmission (April)High transmission (September)
Intervention district (Alamata)n1416138214061303
All stages and species4.9% (3.8–6.1%)7.4% (6.1–8.9%)0.4% (0.2–1.0%)1.2% (0.7–1.9%)
P. falciparum slide positivity4.3% (3.3–5.5%)4.9% (3.9–6.2%)0.2% (0.1–0.6%)0.5% (0.2–1.1%)
P. falciparum gametocytes1.6% (1.0–2.3%)1.4% (0.9–2.1%)0.1% (0.0–0.5%)0.2% (0.1–0.6%)
Control district (Raya Ayebo)n1430137013811329
All stages and species3.4% (2.6–4.5%)20.8% (18.7–23.0%)0.4% (0.1–0.8%)0.8% (0.4–1.4)
P. falciparum slide positivity2.5% (1.7–3.4%)14.2% (12.4–16.1%)0.1% (0.0–0.4%)0.6% (0.3–1.1%)
P. falciparum gametocytes0.8% (0.4–1.3%)7.0% (5.7–8.4%)0.0% (0.0–0.2%)0.2% (0.0–0.5%)

At hospitals and health centres, the proportion of confirmed P. falciparum cases detected by microscopy over the 2-year study period was lower in the intervention district (48% of 4778 blood slides) than the control district (64% of 6778 blood slides) (Table 4). During the June–August 2005 epidemic, the proportion of positive slides with P. falciparum was 72% and 91% in the intervention and control districts, respectively, with the remainder being because of P. vivax.

Table 4.   Proportion of patients with malaria detected by microscopy at hospitals and health facilities
 MayJJASONDJFMAMJJASONDJFMAMJune
Intervention district
 Total number of outpatients tested for malaria207196758445399931693347479029242170651
 Total number of malaria positive patients 74125512729 814 473 6411226 330 129 27
 P. falciparum, n (%) 528 (71.3)1830 (71.7)1692 (62.0) 168 (20.6) 110 (23.3)  69 (10.8) 125 (10.2)  93 (28.2)  55 (42.6) 14 (51.9)
 P. vivax, n (%) 213 (28.7) 721 (28.3)1037 (38.0) 646 (79.4) 363 (76.7)572 (89.2)1101 (89.9) 237 (71.8)  74 (57.4) 13 (48.2)
Control district
 Total number of outpatients tested for malaria 91414 7088218302219301927172516191490253
 Total number of malaria positive patients 26943863011 757 541 545 516 251 101 36
 P. falciparum, n (%) 246 (91.5)3998 (91.2)1985 (65.9) 241 (31.8)  30 (5.6)  11 (2.0)  14 (2.7)  19 (7.6)  25 (24.8) 12 (33.3)
 P. vivax, n (%)  23 (8.6) 388 (8.9)1026 (34.1) 516 (68.2) 511 (94.5) 534 (97.9) 512 (97.3) 232 (92.4)  76 (75.3) 24 (66.7)

All-cause and malaria-specific mortality

In total, 991 and 1106 deaths were reported in the intervention and control districts, respectively. Based on the average populations enumerated, the crude overall mortality rate was 11.1 per 1000 in the intervention district and 9.3 per 1000 in the control district. VA interviews yielding sufficient information to determine the cause of death were successfully carried out for 2003/2097 deaths (95.5%). Probable cause of death was malaria for 24 cases in the intervention district vs. 53 in the control district, corresponding to malaria mortality rates of 0.27 per 1000 and 0.45 per 1000, respectively.

Poisson multivariate regression modelling indicated no significant difference in the rate of all-cause mortality between the two districts (adjusted IRR 1.03, 95% CI 0.87–1.21, P = 0.751, adjusted for age/sex, urban/rural residence, net ownership, altitude and distance to health facility) (Table 5). However, the similarly adjusted rate for malaria-specific mortality was significantly lower in the intervention district (adjusted IRR 0.60, 95% CI 0.40–0.90, P = 0.013).

Table 5.   Poisson regression models of incidence rate ratios (IRRs) for all-cause and malaria-specific mortality, allowing for clustering effects at the village level
 All-cause mortalityMalaria-specific mortality
Adjusted IRR 95% CIPAdjusted IRR 95% CIP
  1. ITN, insecticide-treated net.

District
 Intervention1.030.87–1.210.7510.600.40–0.900.013
 ControlReferenceReference
Age and sex
 1–4 years3.372.66–4.25<0.0014.352.35–8.05<0.001
 5–14 yearsReferenceReference
 15–49 male4.633.87–5.54<0.0011.480.74–2.940.267
 15–49 female4.643.79–5.69<0.0013.001.63–5.51<0.001
 50–64 years6.725.39–8.38<0.0012.240.97–5.200.06
 65+ years20.6716.90–25.28<0.0012.570.79–8.370.118
Area
 Urban1.110.97–1.280.1191.140.76–1.710.521
 RuralReferenceReference
ITN ownership
 NoReferenceReference
 Yes0.830.73–0.940.0040.540.35–0.840.007
Altitude
 <1600 mReferenceReference
 ≥1600 m0.930.79–1.080.3420.940.63–1.380.736
Distance to health facility
 <2 kmReferenceReference
 2–5 km0.930.82–1.050.2371.420.89–2.270.142
 ≥5 km0.910.77–1.080.2791.280.72–2.260.396

During the study period (April 2005–June 2007), 37 deaths occurred among inpatients in the control district, of which 34 (89.5%) were attributed to malaria. In the intervention district, there were 35 inpatient deaths, of which 12 (34.3%) were considered to be because of malaria i.e. approximately 2.6-fold lower than in the control district. In the same period, 4371 inpatients or severely ill patients were seen in the health centre of the control district, of whom 79% had malaria (81% of these were because of P. falciparum). The inpatient/severe cases load at the Alamata Hospital and Health Centre in the intervention district was higher (n = 6943), but the proportion found to have malaria was lower than in the control district (n = 2930; 42%), with P. falciparum in 29% of these cases.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Sources of funding and conflicts of interest
  9. References

Findings from this pilot study suggest that community-based deployment of AL lowered the risk of malaria-specific mortality significantly (by approximately 40%) during a 2-year period that included a major malaria epidemic. The local CHW service provided rapid diagnosis and treatment close to patients’ homes in almost 60% of suspected patients with malaria. This, moreover, significantly reduced the burden of malaria at health facilities, with the case load at health facilities in the intervention district being approximately 46% lower than in the control district despite the intervention district having a population only approximately 25% smaller.

Serial malaria parasite surveys performed during the study indicated that the malaria parasite reservoir during the high transmission season of 2005 and, consequently, the scale and severity of the 2005 epidemic, was threefold lower in the intervention vs. the control district based on the crude parasite and P. falciparum prevalence rate. Remarkably, the P. falciparum gametocyte prevalence fell between the low and high transmission season of 2005, whereas it increased tenfold in the control district. As other vector control activities were comparable, or even more extensive, in the control district, where altitude was also generally higher, it seems likely that this difference was at least partly because of community-based AL deployment and the gametocytocidal effect of AL against P. falciparum (Makanga et al. 2006; van Vugt et al. 2000; Lefévre et al. 2001), which contributes to reducing malaria transmission (Sutherland et al. 2005; Mens et al. 2008). Because of the intensive intervention during the epidemic of 2005, the parasite prevalence was reduced to such a low level that there was no difference between districts in 2006 (Year 2).

The ∼40% reduction in risk of death from malaria in the intervention district was observed despite no appreciable difference in all-cause mortality between the two districts, suggesting that the difference in malaria mortality was quite specific. This is a robust and statistically significant finding that included adjustments for age and gender, distance to the nearest health facility, urban vs. rural settlement, altitude and ITN ownership, and allowed for possible mortality clustering at the village level. Use of the InterVA model (Fantahun et al. 2006; Umeå University 2008) to interpret VA data to obtain CSMF is a relatively new approach. While potentially less subtle and delicate than diagnosis by well-trained physicians, as a mathematical model InterVA (Fantahun et al. 2006; Umeå University 2008) is simpler and quicker and offers the considerable advantage of complete consistency and reproducibility across patients and districts where most deaths occur at home. The malaria-specific mortality rates obtained by InterVA modelling followed the age and gender variations that might be expected, and any internal inconsistencies of the model would have applied equally across both districts.

Our findings contrast with those of Staedke et al. (2009), who reported that provision of AL for presumptive self-treatment of febrile children at home in an urban setting in Uganda had little effect on clinical outcomes. This is perhaps unsurprising, because their approach was different, involving the distribution of three packages of AL per child to each of the households enrolled in the study, replenished each month, to treat fever episodes as malaria by the family members. This resulted in fivefold increase in AL consumption compared to a cohort of children treated at health facility level on the basis of microscopically confirmed malaria. This intervention resulted in a substantial increase in the proportion of children receiving prompt and effective treatment compared to the group receiving standard care, mild improvements in haemoglobin levels and limited reduction in hospital admissions, but the sample size was small and the study not powered to detect differences in these study outcomes. The study of Staedke et al. (2009) highlights the risk of AL over prescription in case treatment is dispensed as self-treatment and without access to diagnostic tools. The successful outcomes in our study are because of the involvement of trained and experienced CHWs in early recognition and treatment of malaria and in the confirmation of malaria diagnosis with RDTs in a sizeable proportion of cases.

The design of our pilot study does not permit inference of causality. While a randomized controlled trial using the smallest possible population groups (e.g. villages) as study unit would be the most robust design, this was not considered to be ethical, or indeed feasible because of the risk of cross-contamination if patients allocated to the control arm sought access to AL at community level in the neighbouring area. Thus, large geographical districts with similar malaria eco-epidemiological conditions and operational convenience of access were selected as the study units.

Equipping CHWs with RDTs resulted in markedly improved targeting of AL. RDT use led to exclusion of non-P. falciparum infection in almost 90% of cases, reducing treatment costs and possibly the risk of development of resistance to AL. Such a community-based use of RDTs has also proved reliable in other non-Africa countries (Shirayama et al. 2008; Yeung et al. 2008). However, the partial availability of RDTs led to more patients seeking treatment by CHWs without RDTs, to avoid exclusion from treatment in the event of a negative result. This observation suggests that non-uniform introduction of RDTs should be discouraged.

Strikingly, no adverse events were reported spontaneously during the entire 2-year study. The reason for this is not clear, but it is likely that multiple factors played a role, including the known difficulties of spontaneous reporting of adverse drug reactions in poorly resourced settings, the limited training and the lack of supervision of healthcare workers, and the influence of knowledge and attitudes on people’s perception of illness and the beneficial effects of medicines. Regrettably, the pharmacovigilance study, while well designed, yielded negligible information because it was implemented in the second year of the project which coincided with a period of low malaria transmission that restricted patient enrolment.

In conclusion, AL deployment through a community-based service in a widely dispersed and hard-to-reach rural population is feasible if CHWs are appropriately trained, well equipped with simple RDTs and supported through frequent supervision. Our findings show an impact on malaria, in contrast with presumptive self-treatment of febrile children at home not supported by trained community workers and RDT confirmation of diagnosis. The approach adopted in the current 2-year pilot project impacted on malaria transmission, lowered the malaria case load for general health services and reduced both malaria morbidity and mortality during a major malaria epidemic. It is to be hoped that community-based diagnosis and treatment of malaria using AL and RDTs will be adopted in similar settings in Ethiopia and elsewhere.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Sources of funding and conflicts of interest
  9. References

We thank Dr Tedros Adhanom (Honourable Minister of Health of Ethiopia); Mr Goitom Mehari, Mr Abrha Kahsay and Mr Berhane Hailesilassie (Tigray Health Bureau, Ethiopia); Dr Wilson Were (WHO-HQ Global Malaria Programme); Mr Roberto Ferrara (Novartis Farma S.P.A, Italy); Dr Giacomo Stefanoni (San Gallicano Dermatological Institute, Rome, Italy); and Ms Appia Augustina Appiah-Danquah (University of Ghana Medical School, Accra, Ghana). Financial support was provided by Novartis Farma S.P.A. (Italy), the Italian Ministry of Labour, Health and Social Policies – Health Sector, and the World Health Organization.

Sources of funding and conflicts of interest

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Sources of funding and conflicts of interest
  9. References

Novartis Farma S.P.A. provided study drug, RDTs and other commodities, together with funding for activities including local operational costs and capacity building. The Italian Ministry of Labour, Health and Social Policies contributed to the funding of data processing and laboratory equipment, transport and operational costs via WHO. WHO funding contributed to mid-term evaluation and re-orientation of pharmacovigilance activities, as well as study design, data interpretation and analysis with specific reference to the mortality survey. PB and EF are employees of Umeå University, Sweden. ACM, NM and A. Bianchi are employees of Novartis Pharma AG, the manufacturer of artemether-lumefantrine (Coartem®); ACM and A. Bianchi hold Novartis stock. The other authors have no conflicts of interest to declare.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Sources of funding and conflicts of interest
  9. References
  • Dorsey G, Staedke S, Clark TD et al. (2007) Combination therapy for uncomplicated falciparum malaria in Ugandan children: a randomized trial. JAMA 297, 22102219.
  • Falade C, Makanga M, Premji Z et al. (2005) Efficacy and safety of artemether-lumefantrine (Coartem) tablets (six-dose regimen) in African infants and children with acute, uncomplicated falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 99, 459467.
  • Fantahun M, Fottrell E, Berhane Y et al. (2006) Assessing a new approach to verbal autopsy interpretation in a rural Ethiopian community: the InterVA model. Bulletin of the World Health Organization 84, 204210.
  • FMoH (2004) Malaria Diagnosis and Treatment Guideline for Health Workers in Ethiopia, 2nd edn. Federal Ministry of Ethiopia, Addis Ababa.
  • FMoH (2005) Health and Health-Related Indicators, 2004/05. Federal Ministry of Health, Addis Ababa.
  • Fogg C, Bajunirwe F, Piola P et al. (2004) Adherence to a six-dose regimen of artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Uganda. American Journal of Tropical Medicine and Hygiene 71, 525530.
  • Ghebreyesus TA, Witten KH, Getachew A et al. (2000) The community-based malaria control programme in Tigray, northern Ethiopia. A review of programme set-up, activities, outcomes and impact. Parassitologia 42, 255290.
  • Koram KA, Abuaku B, Duah N & Quashie N (2005) Comparative efficacy of antimalarial drugs including ACTs in the treatment of uncomplicated malaria among children under 5 years in Ghana. Acta Tropica 95, 194203.
  • Lefévre G, Looareesuwan S, Treeprasertsuk S et al. (2001) A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand. American Journal of Tropical Medicine and Hygiene 64, 247256.
  • Lwanga SK & Lemeshow S (1991) Sample Size Determination in Health Studies. A Practical Manual. WHO, Geneva, 25 p.
  • Makanga M, Premji Z, Falade C et al. (2006) Efficacy and safety of the six-dose regimen of arthemeter-lumefrantrine in pediatrics with uncomplicated plasmodium falciparum malaria: a pooled analysis of individual patient data. American Journal of Tropical Medicine and Hygiene 74, 991998.
  • Martensson A, Strömberg J, Sisowath C et al. (2005) Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania. Clinical Infectious Diseases 41, 10791086.
  • Mens PF, Sawa P, Van Amsterdam SM et al. (2008) A randomized trial to monitor the efficacy and effectiveness by QT-NASBA of artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment and transmission control of uncomplicated Plasmodium falciparum malaria in western Kenya. Malaria Journal 7, 237.
  • Mutabingwa TK, Anthony D, Heller A et al. (2005) Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial. Lancet 365, 14741480.
  • Piola P, Fogg C, Bajunirwe F et al. (2005) Supervised versus unsupervised intake of six-dose artemether-lumefantrine for treatment of acute, uncomplicated Plasmodium falciparum malaria in Mbarara, Uganda: a randomised trial. Lancet 365, 14671473.
  • Shirayama Y, Phompida S & Kuroiwa C (2008) Monitoring malaria control in Khammouane province, Laos: an active case detection survey of Plasmodium falciparum malaria using the Paracheck rapid diagnostic test. Transactions of the Royal Society of Tropical Medicine and Hygiene 102, 743750.
  • Staedke SG, Mwebaza N, Kamya MR et al. (2009) Home management of malaria with artemether-lumefantrine compared with standard care in urban Ugandan children: a randomised controlled trial. Lancet 373, 16231631.
  • Sutherland CJ, Ord R, Dunyo S et al. (2005) Reduction in malaria transmission to Anopheles mosquitoes with a six-dose regimen of co-artemether. PLoS Medicine 2, e92.
  • Umeå University (2008) InterVA. http://www.interva.net/. Accessed 12 March 2008.
  • Van Vugt M, Looareesuwan S, Wilairatana P et al. (2000) Artemether-lumefantrine for the treatment of multidrug-resistant falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 94, 545548.
  • Whitty CJM, Chandler C, Ansah E, Leslie T & Staedke SG (2008) Deployment of ACT antimalarials for treatment of malaria: challenges and opportunities. Malaria Journal 7(Suppl 1), S7.
  • World Health Organization (1963) Terminology of Malaria and of Malaria Eradication. Columbia University Press, New York.
  • World Health Organization (1999) The Community-Based Malaria Control Programme in Tigray, Ethiopia. A Review of Programme Set-up, Activities, Outcomes, and Impact. WHO, Geneva. WHO/CDS/RBM/99.12. WHO/MAL/99.1090.
  • World Health Organization (2006) Guidelines for the Treatment of Malaria. WHO, Geneva. http://www.who.int/malaria/docs/TreatmentGuidelines2006.pdf. Accessed 11 March 2009.
  • World Health Organization (2008a) World Malaria Report 2008. WHO, Geneva. http://malaria.who.int/wmr2008/malaria2008.pdf. Accessed 11 March 2009.
  • World Health Organization (2008b) Global Malaria Control and Elimination: Report of a Technical Review. WHO, Geneva. http://www.who.int/malaria/docs/elimination/MalariaControlEliminationMeeting.pdf. Accessed 11 March 2009.
  • World Health Organization (2009) Deployment at Community Level of Artemether-Lumefantrine and Rapid Diagnostic Tests. Raya Vallay, Tigray, Ethiopia. WHO, Geneva. http://apps.who.int/docs/diagnosisandtreatment/RapportTigrayLowres.pdf. Accessed 20 November 2009.
  • Yeung S, Van Damme W, Socheat D, White NJ & Mills A (2008) Access to artemisinin combination therapy for malaria in remote areas of Cambodia. Malaria Journal 7, 96.
  • Zongo I, Dorsey G, Rouamba N et al. (2007) Artemether-lumefantrine versus amodiaquine plus sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Burkina Faso: a randomised non-inferiority trial. Lancet 369, 491498.