Therapeutic efficacy of Artemether/Lumefantrine (Coartem^®) against Plasmodium falciparum in Kersa, South West Ethiopia

Early diagnosis and treatment of cases are the most important strategies for the control and prevention of malaria. It is crucial for proper management of the disease and to prevent further complications. P. falciparum has developed resistance to nearly all antimalarials in current use, although the geographical distribution of resistance to any single antimalarial drug varies greatly [1]. World maps that depict countries as having or not having drug-resistant malaria are potentially misleading, as there is great heterogeneity within countries and across political boundaries [1].

In Ethiopia, the increased resistance of P. falciparum to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) necessitated a change as first-line antimalarial drug for the treatment of P. falciparum. Consequently, Artemether/Lumefantrine (Coartem^®) (AL) was adopted in 2004 [2, 3]. Currently Coartem^® is being used as the first-line drug for the treatment of uncomplicated malaria [3]. A base-line study in 2004 [4] showed that AL was a highly efficacious drug with a treatment success of 99.1% and with no report of adverse effects [4].

However, the trend of malaria changes over time, and thus the cure rate, tolerance, compliance and safety of AL (Coartem^®) need be monitored with particular emphasis to monitoring its therapeutic efficacy [2–5]. Therefore, close monitoring of resistance patterns would be required to maximize the therapeutic benefits of this drug as well as policy development and mapping of resistance areas. Based on this notion, this study set the objective to determine the efficacy of AL (Coartem^®) in the routine treatment of uncomplicated P. falciparum malaria at Serbo health center, Kersa district, south west Ethiopia.

During the study, 1628 febrile cases, clinically suspected to be infected with malaria, were screened for eligibility. Of these 428 (26.3%) had malaria-positive slides and 361 (22.2%) of them had P. falciparum mono-infections. Of the P. falciparum mono-infected patients, 236 could not be enrolled in the study for having a parasite load below 1000 parasites per microliter of blood. Of the remaining 125 patients who were eligible for the study, 35 were excluded for the following reasons: 27 were out of the reachable area, 2 were pregnant, another 4 took anti-malaria drugs before commencement of the study and the remaining 2 refused consent.

Finally 90 patients fulfilled all the criteria and enrolled in the study (Figure 2). Five were excluded for vomiting the first dose twice and having mixed infection. On day 7, 85 slides from patients were examined and one person was found to be P. falciparum positive and excluded as treatment failure and treated with quinine. On day 21, 84 slides were examined and two positive slides were found, one positive for P. falciparum and the other for P. vivax. The first was removed as treatment failure and the second withdrawn from the study and treated with chloroquine. On the final day (Day 28), slides from the remaining 82 patients were examined and one P. falciparum and three P. vivax cases were recorded. The first was considered a treatment failure and treated with quinine, and the later three were taken as negative slides for data analysis and were treated with chloroquine (Figure 2.)

In the present study 7.7%(7/90) patients (PCR uncorrected) were excluded during follow-up. And thus a total 82 patients were analyzed at the end-point (day 28) and the result was satisfactory compared with other studies. All patients completed the study properly and none of them missed the follow-up.

As shown in Figure 3, fever clearance was similar in all age groups, fever was significantly cleared on day 3 in all patients (P < 0.05). 98% of parasites were cleared on day 1 and almost all parasites where cleared on day 3. In adults and 5-14 age groups, parasites were totally cleared from blood on day 2 and 3, respectively. In under 5 patients, a small fraction (1.1%) of patients showed parasite occurrence on day 3 and total clearance occurred on Day 7 (Table 3).

	Under 5 (n = 33)		5-14 (n = 41)		Adults (n = 16)
Day	Temp	Para	Temp	Para	Temp	Para
D0	38.3	18983	38	32607	37.9	5541
D1	37.4	350.2	37	676	37	102
D2	37.3	13.3	36.6	59.8	36.5	0
D3	37	1.1	36.6	0	36.7	0
D7	36.9	0	36.5	0	36.4	0
D14	37	0	36.4	0	36.6	0
D21	36.9	0	36.5	0	36.3	0
D28	37	0	36.5	0	36.4	0

Temp: Temperature

Para: parasite load (μl)

Gametocyte clearance declined with age in the early treatment days, 72.5% were cleared on day 1. However, the remaining, about 28% of gametocyte load was maintained up to day 3 irrespective of treatment. However, total clearance was observed on day 7 (Figure 4).

Overall, there were 255 adverse events reported upon taking the drug (data not shown) of which the most common ones were cough in 46% of cases, headache in 17%, anorexia in 9%, weakness/fatigue in 7%, abdominal pain in 5%, diarrhea and sleep disorder in 3%, and vomiting in 2% of the cases. There was also a considerable occurrence of inflammation of the oral mucosa (mouth ulcer) in 7% of patients.

Most of adverse events disappeared with resolution of the disease, however cough prevailed after treatment. The occurrence of mouth ulcer (peri-oral wound) is not a commonly reported adverse effect of Coartem^®, however, it was recorded in considerable number of patients (7%) in under 5 and 5-14 age groups.

Our findings have indicated that artemether/lumefantrine (Coartem^®) has a high cure rate. The results showed very high efficacy in the very young children less than five years of age followed by middle age children and adults. Results from the present study were consistent with previous studies conducted in Ethiopia and elsewhere [4, 10–16]. The overall cure rate was 96.3% (97.5% PCR corrected). Although the results obtained in the present study are similar to the results of a study conducted in Uganda [15] the age-stratified results from Uganda showed a reversed trend i.e., 100%, 97.7% and 96.4% cure rates were obtained for adults, 5-14 and under five, age groups, respectively. This may be due to differences in malaria exposure, where adults in more endemic areas acquire immunity to enhance the drug effect.

Inclusion of all age groups in the trial was because the area showed unstable malaria of lower (hypo) endemicity where inhabitants were considered to be non-immune to malaria. In accord with this, the child splenomegally rate of the district was found to be 7.3% (data not shown) confirming the hypo-endemicity of the study site. Hence our study area being one of an unstable seasonal malarious type, no such stratified immunity acquisition was expected. However, the high cure rate among children could be due to higher milk/fat content in their diet, which facilitates the absorption and hence efficacy of Coartem^®. This is actually a known phenomenon with lipophilic antimalaria drugs given in the oral route [17]). Nevertheless, the age differences in cure rate were low.

Of the total of the three treatment failures (one LPF and two LCFs), PCR genotyping showed two of the three recurrent infections (one LPF and one LCF) were recrudescence and one of the LCF was PCR unresolved and excluded. The PCR analysis result increased the overall efficacy in to 97.5%, and the recrudescence rate with Coartem^® was found to be very low at about 2.5%.

In this study, although Coartem^® clears fever and parasitemia in a very short period of time (less than three days), the concentration of hemoglobin fails to increase within the same period of time. Increments in hemoglobin level have been noted with clearance of fever and parasitemia, especially in those patients who had a lower level of hemoglobin concentration in the baseline of treatment than others. However, the difference was statistically insignificant (p < 0.05). Similar findings were also observed in other studies [10, 14]. The high prevalence of geohelminths (especially hookworm) in the area can also be a contributing factor to the chronicity of anemia. A recent study in Asendabo, one of the nearby districts of Jima zone, showed 27.6% (102/370) of the sample population to be anemic, of which, 26.5% (27/102) had hookworm infection, 19.6% (20/102) were malaria positive and 15.8% (19/102) were physiologically anemic with no infection and 22.5% with co-infection. Anemia was significantly higher in hookworm positive individuals [18].

Fever is a manifestation of malaria that most frequently causes discomfort. Thus, it was encouraging that patients treated with Coartem^® become afebrile within the first two or three days. An antipyretic (paracetamol) was given for febrile patients (body temperature above 38°C), however the number of patients who required paracetamol during the follow up period was significantly low compared to the baseline. A similar finding was noted in other studies [4, 10–15, 17, 19]. This is due to the inherent feature of Coartem^®, as a drug with fast resolution capacity of clinical symptoms.

The study showed the decline of gametocytes with treatment. They were almost cleared from the patients after seven days. This rate of clearance was higher when compared with other studies, which reported the presence of gametocytes up to the 14^th day and beyond [19, 14]. It has been reported that artemesinin derivatives are gametocidal [10, 20, 21] and the absence of gametocytes, seven days post treatment with Coartem^® supports the report that there was some effect of the artemisinin derivative on the sexual stage of the parasite [21]. Other aretemesinin combinations (ACTs) were also reported to have the same effect [18, 14]. Coartem^® decreases gametocytes by 6-8 fold compared with SP and CQ [21]. Thus, the present finding is in line with other studies. In other studies, Coartem^® was reported to reduce gametocyte infectivity down to 40% [21] of paramount importance in the control of transmission compared with other drugs.

Studies showed that the overall toxicity of artemether combinations is very low, the drug is well-tolerated and non-compliance is very low [11, 17, 21]. A number of side effects were seen for Coartem^® most of which are similar to the symptoms of malaria itself. An adverse effect noted in 16.5% of all patients was dry, unproductive cough at baseline. This appears to be very likely a symptom associated with the disease. Interestingly, a further 45% of all patients developed this symptom after commencement of treatment. Similar results were reported in a study conducted in Uganda where, 37% and 40% of cough was observed before and after treatment, respectively [13]. However cough, headache, abdominal pain and anorexia were the most common pro-dromal complaints reported. In addition, the present study revealed the development of oral inflamation (oral ulcer) with improved clinical and parasitological signs, indicating that it is not hyper-pyrexia induced phenomena. To the best of our knowledge these side effect has not been reported for Coartem^® and its etiology is not clear. Low levels of immunity due to concurrent diseases such as HIV could be one reason. But, the problem has been noted in 7.1% (6/85) of the patients. The clinicians in the area have also reported the same side effect of the drug in the past. It is therefore, very unlikely to consider the occurrence to be due to chance.

This study has proved the excellent therapeutic efficacy profile of the combination drug, given as a three day multiple regimen of the optimized formulation for the treatment of P. falciparum in Kersa district south west, Ethiopia. Four years after its introduction as a first line drug, Coartem^® has been proved to be effective, in rapidly clearing fever and parasites within 72 h in patients suffering from uncomplicated malaria. However, the proper absorption of the drug must be ensured and monitored through controlled nutritional interventions so that the parasites are not exposed to mal-absorbed low, tolerable level of the drug.

This work also recommends further study on blood concentration of the drug and pharmaco-vigilance on the drug toxicity particularly the development of mouth ulcer in children, as drug adverse effects hamper compliance to the proper dosage which in turn enhances development of drug resistance.