Correct dosing of artemether-lumefantrine for management of uncomplicated malaria in rural Tanzania: do facility and patient characteristics matter?

The World Health Organization (WHO) declared that much of ill health, disease, premature death, and suffering are needless, since efficacious and affordable interventions for prevention and treatment are available. It is further noted that these effective interventions are not matched by the strength of health systems to deliver them to those in greatest need in a comprehensive way and on an adequate scale [1]. This fact highlights the need to assess and address health systems’ bottlenecks, in order to improve health outcomes and the quality of health care services.

Following widespread resistance by malaria parasites to commonly used anti-malarials, such as chloroquine and sulphadoxine-pyrimethamine (SP), there was a global move to use artemisinin-based combination therapy (ACT) for malaria treatment [2]. This required the artemisinin derivatives with shorter half-life be combined with a longer half-life partner drug, to enhance therapeutic efficacy and reduce treatment durations [2]. Currently, the artemisinin derivatives used for malaria combination treatment include artesunate, artemether, and dihydroartemisinin (DHA). ACT, such as artemether-lumefantrine (AL), became first-line medicine for management of uncomplicated malaria in many malaria-endemic countries, including Tanzania [3].

Good quality malaria case management entails that all true malaria cases be appropriately identified, and that all identified cases be treated with efficacious anti-malarial medicines. To achieve desired treatment outcomes, sufficient blood levels of the active medical ingredient must be reached. The increased use of microscopy and malaria rapid tests for parasitological confirmation of malaria improves identification of true malaria patients. Despite the limitations of malaria rapid tests, these tests have been introduced in routine care and have resulted in better targeting of anti-malarials in endemic countries [4, 5]. Previous studies in malaria endemic countries in Sub-Saharan Africa have documented factors affecting quality malaria case management. Challenges related to under-use of malaria testing, distrust of negative results, ambiguous treatment policies and un-availability of recommended medicines are contributing factors [6, 7].

Poor adherence and inappropriate use of recommended treatment have been linked to the development and spread of drug resistance [8, 9]. Use of medicines requires a strict dosing schedule that aligns with the drug’s pharmacokinetics [10]. The current dosing of AL is based on four predefined weight bands and age groups. According to manufacturers, an eight-hour interval between the first and the second doses of AL is critical for appropriate parasite clearance and clinical cure. In addition, manufacturers recommend completing the doses at defined time intervals and taking AL with a fatty meal for better absorption of the drug to enhance its bioavailability. These recommendations, if followed thoroughly, will optimize therapeutic response. Unfortunately many studies have reported that clinical practice differs for various reasons [7, 11, 12].

Packaging of AL medicines for public sector use in Tanzania is customized for each dosing band and incorporates illustrated instructions for patients and caretakers with low literacy. Both age-based or weight-based AL dosing recommendations are included in the guidelines [3], and therefore it is at service provider’s discretion to prescribe based on either of the two dosing methods. This study was carried out to assess the quality of malaria case management, including an assessment of AL dosing, in a real world setting. Factors influencing correct AL dosing were explored to inform disease control programme and local health management teams to plan effective malaria-related supportive supervision, focusing on areas that require emphasis.

This study assessed the association of health facility and patient characteristics to correct AL dosing for the treatment of uncomplicated malaria in rural Tanzania. Malaria treatment guidelines in Tanzania follow manufacturers’ recommendations, which allow for both age- and weight-based AL dosing [3]. More than four years after the introduction of AL, correct AL dosing was suboptimal in some patient groups, especially children aged three to 12 years. Other health facility and patient factors were not associated with correct dosing.

Concerns about incorrect dosing of anti-malarial drugs have been reported in other settings [6, 7, 14]. In particular, a study from Kenya showed that infants were more likely to receive appropriate treatment than older children [11]; the authors suggested that health workers were being more careful with the younger age group, which seems a logical explanation for the observation. In this study, 35.2% of all patients receiving AL were children aged three to 12 years, many of whom did not receive correct AL dosing. Correct AL dosing is particularly important for children as they are more likely to contract malaria, more likely to progress to severe illness, and more likely to die from malaria than adults.

Although, 92.1% of patients received correct AL dosing by age or weight criteria, fewer received correct dosing by weight-based criteria alone (85.7%) or age-based criteria alone (78.5%). Our analysis of weight versus age profile of this patient population suggests that the weight-to-age profile needs to be adapted to the local population context. Although, the weight-to-age profile matches for children <3 kg (98.8% concordant with age) and persons >35 kg (95.3% concordant with age), the weight-to-age profile does not match for children 15 to <25 kg (50.7% concordant) and for children 25 to <35 kg (42.4% concordant); most of the dosing errors based on age alone would lead to overdosing compared to dosing based on weight alone. In addition, weight-based prescriptions should be better implemented to ensure appropriate dosing. In this study, almost all (95.8%) of patients had their age assessed, but only 33.8% of patients had their weight assessed. Thus, to improve weight-based dosing health workers should be encouraged to assess weight in all patients.

AL is supplied to health facilities in four different dose packs. An informal observation during the survey found that in the event that a correct AL dose pack for the appropriate age or weight group was not in stock, the provider would use any AL package to compensate for the missing package. For example, an 11 year old who needs three AL tablets dose (pink package), may receive two packs: one blue pack (toddler package with two AL tablets per dose) and one yellow pack (baby package with one tablet per dose). This strategy might not always work well and might confuse the patient about the appropriate number of pills required. More assessment of this phenomenon is needed to understand its effect in providing adequate care for malaria patients. In addition, we do not know the impact of uniform AL packaging (e.g. adults only, or loose tablets) on correct AL dosing.

During treatment policy change it is customary to train health workers on new guidelines and provide reference materials for use upon returning to the health facility. In this assessment, neither health workers’ training on AL use nor possession of reference material improved the odds of correct AL dosing. One explanation for this finding could be that it takes time and experience for trainees to be competent in new topics. This underscores the need for frequent supervision from health management teams, with possibilities of refresher training and/or on-the-job training, to complement formal training. Moreover, training content, modality, and duration could influence providers’ understanding and performance post-training; all of which were not assessed in this study.

Receipt of supervisory visits was not associated with correct dosing, and very few patients (21.8%) were seen by providers who have had a supervisory visit in the previous six months. The study did not assess the type or content of supervision, which might be important factors. The role of supervision visits in improving quality of malaria case management has provided inconsistent conclusions in other settings [11]. However, understanding predictors of appropriate care for malaria patients can assist health managers in planning resources and performing supportive supervision with emphasis on areas seem to be challenging, in order to improve the quality of services and support disease control measures.

Correct AL dosing in the study areas was generally high, but children aged three to 12 years were significantly less likely to receive correct AL dosing. Health workers should be made aware of the possibility of incorrect dosing for older children and young adults in the middle age and weight categories of the current AL formulation in use. Supportive measures to ensure availability of basic equipment and an emphasis on weight-based AL dosing should be made to improve clinical practise.