Adherence to a six-dose regimen of artemether-lumefantrine among uncomplicated Plasmodium falciparum patients in the Tigray Region, Ethiopia

Despite the current surge of global efforts to scale up malaria control interventions, the disease is still the leading cause of morbidity, mortality and economic losses in sub-Saharan African (SSA) countries [1, 2]. Ethiopia is among the countries which contribute most to this burden. It is estimated that three quarters of the country's total area is malarious and an approximated 54 million (68%) of the total population of 80 million (projected from 2007 census for 2010) live in areas where they are at risk for the disease [3, 4]. Unlike most parts of SSA where most, if not all, malaria infections are attributed to Plasmodium falciparum, the parasite pool in Ethiopia is co-dominated by both P. falciparum and Plasmodium vivax, sharing approximately 60% and 40% of the cases, respectively [3, 5].

In fighting this deadly disease, provision of early diagnosis and prompt and effective treatment is the core of malaria control strategies in the country [5]. However, wide emergence of drug resistance to P. falciparum has been one of the main barriers to the effectiveness of this strategy. As result of the 2003 nationwide anti-malarial in vivo therapeutic efficacy assessment, the country switched its first-line treatment of uncomplicated P. falciparum malaria from sulphadoxine-pyrimethamine (SP) to a fixed artemisinin-based combination therapy (ACT), artemether-lumefantrine (AL).

Clinical trials have shown that AL is a highly efficacious and safe anti-malarial drug [6‐11]. However, several issues need to be addressed in order to achieve its desired therapeutic outcome [12]. Among many, patient adherence to the treatment regimen is a major determining factor [13, 14]. Poor adherence results in sub-therapeutic drug concentrations which fail to provide a successful cure. Furthermore, the presence of sub-curative concentrations of the anti-malarial drug in the blood will only eliminate the most sensitive parasites, allowing those that are less sensitive to survive [15]. This contributes to the spread of drug resistant mutant strains of the malaria parasite [16‐18], thus complicating the treatment scenario.

The need to take unsupervised AL twice daily for three successive days at the right dose and correct time interval is challenging and might increase the risk for poor adherence. Thus, understanding the patient adherence level to this six-dose regimen of AL for the treatment of P. falciparum and identifying its possible determinant factors is crucial in the provision of effective malaria treatment. However, despite the fact that AL is the most widely deployed anti-malarial [1, 19], studies on this treatment are limited, and even the available studies not only demonstrate different levels of adherence, but also account for different risk factors[20‐23]. While high levels of adherence (74-98%) have been found in most African studies [2, 22, 24, 25], lower levels have been reported in a study from southern Sudan (40%) [20]. A literature review on adherence to various types of anti-malarial drugs identified different definitions, methods, criteria and results. The review also revealed that the quality and quantity of information were inadequate and the results varied depending on the local setting [23]. These variations highlight the need for local evidence, which is practically lacking in the Ethiopian context.

Adherence to AL is a capital issue in achieving effective implementation of the malaria case management strategy. The poor results obtained in this study population (26.5% were definitely non-adherers) raises great concern. Taking into consideration the probable non-adherent patients, the level of non-adherence could increase up to 61.3%. Few studies, mostly from African countries, have specifically assessed the level of adherence to the six-dose regimen of AL. The level of adherence in these studies ranged between 74% in Ghana to 98.3% in Tanzania [2, 22, 24, 25, 32]. However, low levels of adherence to AL similar to our study (40%) have also been reported in children aged less than 5 years in southern Sudan[20]. The only non-African study assessing adherence to AL comes from Bangladesh. This randomized controlled trial comparing directly observed vs. non-directly observed treatment (NDOT) obtained 93% adherence rate in the NDOT group [33]. While the enormous gap between these studies and ours could be real, several issues need to be taken into account that might partly explain these discrepancies.

One first issue relates to the type of context where the studies were carried out. For instance, in the Ugandan study [22], the sample was an educated semi-urban population living in a high endemic malaria area, whereas our study was placed in a rural setting with a predominantly illiterate population living in a low transmission setting where cases were managed at rural health facilities. Populations in high endemic areas are more aware of malaria and its consequences [34], and semi-urban populations are also more likely to have better access to health information than in rural settlements

A second issue to consider is the design of the study. In a study conducted in Tanzania, a level of adherence to AL of approximately 90% was reported. However, patients or caregivers were informed that there would be a follow-up visit, which could influence patient/caregiver behaviour. In another study from Ghana, patient follow-up took place between 4 and 14 days after the initial dose. In such cases, blister pack inspection for leftover tablets with this lag of time might not show real adherence. In addition, the close supervision carried out by the research team could have contributed to the high level of compliance reported [24].

A third aspect relates to the definition of adherence. In this study, a very strict definition was used, including patients who reported taking all doses at the given time interval (on the correct day and correct timing), at the correct amount and with no spitting or vomiting within the first 30 min, or such spat/vomited dose was re-administered. In some previous studies, the inter-dose time interval was either not clearly described [22, 25, 32, 33] or very broadly defined [2]. For instance, in the study from Ghana (adherence level 92.5%), adherence was based on the description of how AL was given by the caregivers but no specific information about the time interval or the correct dose seems to have been collected [24]. In the study from Zambia, the inter-dose timing (+/-4 h) was wide compared to this one (+/-2 h), thus increasing the number of probably adherent patients [2]. In fact, three fourths of the probably non-adherent classifications in our study were due to incorrect timing.

Several reasons were presented by patients/caregivers on why they did not finish the treatment course. The most common reason was "too many tablets" (37.3%). This concern was mainly expressed by caregivers of children less than 15 years old. Parents/caregivers might be fearful to give many tablets to their small child. Thus, they might have modified either the dosing or timing or both and were ultimately found to be non-adherent. The rapid fever clearance and clinical recovery under AL treatment seemed to encourage patients to give up the regimen. "Felt better before finishing the regimen" was the second reason (25.5%) for not taking all the tablets. Different studies have also pointed to an improvement in the condition as the main reason for treatment discontinuation [14, 22, 24, 33]. Reasons such as "refused to take", "bitter", and "too big to swallow" were restricted to children aged less than 5 years. This indicated that the AL tablets were inconvenient for caregivers to administer. The current introduction of a dispersible paediatric formulation of AL might contribute to overcoming this problem [35].

One commonly reported reason for lack of adherence in many other studies was misunderstanding the instructions provided by the health care personnel [31, 36]. In the present study, this was low (2.4%). One potential explanation of this finding might be that the HEWs were native residents from the area, which could increase the communication confidence of the patient. In addition, the pictogram and clustering of the doses within the blister packet might have contributed to understand dosing and inter-dose spacing. On the other hand, given that the HEWs were in this study providers and data collectors at the same time, patients might have been reluctant to report misunderstandings. Although side-effects have been reported with other drugs as a reason for not completing the treatment course [37], this was not the case with AL in the current study.

Three risk factors were strongly associated with being adherent: owning a radio, the belief that malaria cannot be treated traditionally and a delay in treatment seeking. The Tigray Health Bureau has made an effort to communicate health messages on malaria prevention and control strategies via posters, leaflets, community gatherings and radio messages. Radio broadcasting health messages is a well-known health promotion tool. A previous study in the area has shown that the ownership of a radio also increases the knowledge about malaria and the practice of prevention measures, such as the use of long-lasting insecticidal nets [34]. Those who sought treatment more than 1 day after the onset of fever were 5.4 times more likely to adhere to the treatment regimen than those who sought treatment earlier. This could be because the more a patient delays the visit, the more they suffer and the likelihood of treatment-seeking increases with the severity of symptoms [14]. The delay in treatment-seeking as promoting factor for adherence should be interpreted with some caution. Though it increased adherence, this should be discouraged since it contradicts with the national and regional goal of 100% of suspected malaria cases diagnosed and treated within 24 h of the onset of illness [3]. The belief that malaria can be treated traditionally supported the possibility of interrupting AL treatment in favour of traditional medicine. Education has been found to be an important risk factor for adherence in some studies [22, 31, 33]. However, in agreement with research from Bangladesh, education did not play any role in this study. A probable explanation would be the high proportion of uneducated people in this rural area.

This study has also identified some issues of concern. First, although few, patients reported borrowing/sharing tablets for replacing vomited doses or keeping them for future episodes. Second, protocol violations (prescription did not match the subject's age), which was seen only in children, indicated that the fear of "too many tablets" occurred not only among caregivers, but also among care providers. Third, despite the recommendation for early diagnosis and prompt treatment and improved formal health care access as the result of the HEP, only one-quarter of the patients sought treatment within 1 day of the onset of fever.

Adherence to recommended malaria drug regimens is a key determinant of the success of any malaria control programme. The current study in Tigray has shown very low adherence to AL. This brought about three serious concerns: i) the inadequate cure of the patient, ii) the risk of transmission due to parasite survivors in non-adherent patients and iii) the development of parasite resistance. This study has identified some aspects which the malaria control programme in Tigray should concentrate on. The use of radios should be promoted and radio-health messages regarding the importance of adherence to AL should be intensified. Specific training on communicating treatment instructions should be carried out with the HEWs. The implementation of a monitoring adherence system is essential to ensure long-term treatment efficacy.