Aug 1, 2005 - Humera hospitals in Tigray region and Assendabo and Nazareth in Oromia region. Subjects: Patients with body weight of more than 10 kgs, ...
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East African Medical Journal Vol. 82 No. 8 August 2005 SAFETY AND EFFICACY OF ARTEMETHER-LUMEFANTRINE IN THE TREATMENT OF UNCOMPLICATED FALCIPARUM MALARIA IN ETHIOPIA D. Jima, MD., G. Tesfaye, BSc., Malaria and Other Vector Borne Diseases Prevention and Control Unit, Federal Ministry of Health, P.O. Box 1234, Addis Ababa, Ethiopia, A. Medhin, BSc., MSc., A. Kebede, BSc., MSc., D. Argaw, MD, MPH, National Programme Office for Prevention and Control of Communicable Diseases WHO Country Office for Ethiopia, P.O Box 3069, Ethiopia and O. Babaniyi, MD, MPH, MSc, FMCPH, Country Representative, MD, MPH., MSc., FMCPH, WHO Country Office for Ethiopia, P.O. Box 3069, Addis Ababa, Ethiopia Request for reprints to: Dr. A. Medhin, P.O. Box 3069, Addis Ababa, Ethiopia
SAFETY AND EFFICACY OF ARTEMETHER-LUMEFANTRINE IN THE TREATMENT OF UNCOMPLICATED FALCIPARUM MALARIA IN ETHIOPIA D. JIMA, G. TESFAYE, A. MEDHIN, A. KEBEDE, D. ARGAW, and O. BABANIYI ABSTRACT Objective: To document baseline data on the efficacy and safety of artemetherlumefantrine for the treatment of uncomplicated falciparum malaria in Ethiopia. Design: Patients diagnosed for P. falciparum, who were treated with six doses of artemether-lumefantrine over three days, were followed for 28 days and treatment outcomes classified based on the WHO (2003) protocol. Setting: Four health facilities located in malarious areas in two regions: Alamata and Humera hospitals in Tigray region and Assendabo and Nazareth in Oromia region. Subjects: Patients with body weight of more than 10 kgs, excluding pregnant women, who or their guardians consented to participate in the study after fulfilling the inclusion criteria were enrolled in the study for a follow-up period of 28 days. Main outcome measures: Proportion of treatment success and adverse drug effects that required discontinuation of treatment and/or follow-up. Results: A total of 213 patients who fulfilled the enrolment criteria completed the 28 days follow-up after treatment with artemether-lumefantrine. A treatment success rate of 99.1% (95% confidence interval [CI] 96.9, 99.8) and no adverse effects or complaints related to the drug that required discontinuation of treatment or withdrawal from follow-up was reported. Treatment success was not achieved in 213 (0.9%) subjects for whom fever and peripheral parasitaemia was demonstrated on day 21 and 28. The day 21 and day 28 blood samples of the treatment failure cases were not PCR corrected. Conclusion: The artemisinin based combination drug artemether-lumefantrine has shown very high (99.1%) clinical and parasitological cure for the treatment of uncomplicated falciparum malaria with no reports of adverse reaction that required withdrawal of treatment or discontinuation of follow-up. In the presence of the low efficacy of sulfadoxinepyrimethamine, chloroquine and amodiaquine, the use of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria is the best choice for Ethiopia.
INTRODUCTION The malaria transmission pattern in Ethiopia is seasonal and unstable, characterised by frequent focal and large scale cyclic epidemics every five to eight years. However, some parts in the Western low land areas and river basins have malaria transmission period of more than six months (1). Plasmodium falciparum is the dominant parasite species during malaria epidemics (2). The prevalence of symptomatic malaria in areas with higher transmission shows variability with age. These variations, however, are not significant (3) indicating asymptomatic parasitaemia being not a common phenomenon. In light of the lack of immunity to diseases and the epidemic nature of malaria transmission in Ethiopia, the anti-malarial treatment goal is to ensure clinical and parasitological cure. For the achievement of this
objective, early diagnosis and prompt treatment with safe and effective drugs is one of the main strategies applied (4). The availability and use of safe and effective anti-malarial drugs that can achieve high clinical and parasitological cure, and also to contribute to reduction in malaria transmission by acting on parasite gametocytes is therefore, a pre-requisite. Sulfadoxine-pyrimethamine has been the first line anti-malarial drug for the treatment of uncomplicated falciparum malaria in Ethiopia since 1998. The drug was first introduced to Ethiopia in the mid 1980’s and has been widely used in resettlement areas and epidemic affected localities for mass treatment before it was selected as a first line drug. The therapeutic efficacy of sulfadoxinepyrimethamine for the treatment of uncomplicated falciparum malaria when it was first introduced as first line drug was 92.3% (5).
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In studies conducted to evaluate the efficacy of sulfadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in two sites in 2001, parasitological failure of up to 32.0% was reported by Kassa, et al (Proceedings of the XVth conference of the Ethiopian Public Health Association (EPHA), unpublished). A nationwide study conducted in 2003 in 10 study sites has also documented treatment failure rate as high as 35.9% (Jima D. et al, in press). The occurrence of high P. falciparum gametocyte carriage has also been shown to be associated with decline in the efficacy of sulfadoxine-pyrimethamine (6) and this phenomenon calls for the use of other safe and effective drugs with gametocytocidal properties (7) that can contribute to reduction in transmission. In preparation for a possible change in the first line anti-malarial drugs used in Ethiopia and to document information on the efficacy and safety of other treatment options for which baseline data is not available, conducting representative studies is necessary. Accordingly, a nationwide study on the safety and efficacy of the Artemisinin Based Combination Therapy (ACT) drug artemether-lumefantrine was conducted in four sites in 2003 using the WHO protocol for the assessment of efficacy of anti-malarial drugs (8). MATERIALS AND METHODS Subjects diagnosed for uncomplicated falciparum malaria were followed for 28 days after treatment with six doses of artemether-lumefantrine (Novartis Pharma AG, Base l Switzerland) for three days. The study was conducted during the major malaria transmission season months from October to December 2003. The study sites are areas with seasonal and unstable transmission typical of the country. The sites included Assendabo and Nazareth in Oromia region and Alamata and Humera in Tigray region (Figure 1). The WHO protocol (8) for the assessment of the therapeutic efficacy of anti-malarial drugs for the treatment of uncomplicated falciparum malaria in low to moderate malaria transmission areas was used. Study teams composed of a clinician, laboratory technician and a courier were assigned to each site. Team members were trained in the conduct of the study. Patients with body weight of 10 kgs and above (excluding pregnant women) with P. falciparum mono-infection and parasitaemia in the range of 1000100,000/ µ l on day zero, axillary temperature greater than or equal to 37.5°C or a history of fever during the last 24 hours, able to come for the stipulated visits and consenting to the study were enrolled. Patients were excluded from the study if they presented with general danger signs, adverse reaction to test drug, defaulting treatment regimen, mixed infections, presence of febrile conditions other than malaria or other conditions that are not in agreement with the inclusion criteria. The study drug provided by WHO/HQ was handled and used under conditions recommended by the manufacturer (Novartis Pharma AG, Basel Switzerland). The drug was administered according to body weight as per instructions of the manufacturer (Novartis Pharma AG, Basel Switzerland). First dose of each day was administered under direct observation
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while the evening dose was given to subjects or guardians to take at home. On each of the follow-up days subjects or guardians were asked if the drug was taken properly and there was no vomiting after taking the evening dose. Patients with a demonstrable fever were also given one dose of paracetamol immediately and another dose to take at home. For patients failing to respond to artemether-lumefantrine, oral or parenteral quinine was availed for rescue treatment. For cases that required referral, study teams ensured timely and appropriate follow-up. Cases excluded from the study due to P. vivax infection were given full course of chloroquine. The sample size was not calculated per site but directed towards achieving a pooled sample of a minimum of 95 subjects calculated based on an expected proportion of 50% treatment failure (for unknown proportion of treatment failure in population) in order to achieve a 10% precision at 95% confidence level. Subjects were followed on days 1, 2, 3, 7, 14, 21 and 28 or any unscheduled date for assessment. On each of these days, their clinical status and parasitaemia were assessed. Standard Giemsa stained blood films were prepared for microscopic examination and parasite density estimation (9). Body temperature measurement was done using a digital thermometer (TROGE - DIGITHERM, from 32°c to 42°c, Code No.:612114 Type CE 0123, Hamburg) and recorded to in degree Celsius. The primary outcomes were clinical and parasitological responses as described in the WHO protocol (8). Adverse drug reactions that required discontinuation of treatment and/or followup in the study were also monitored for each subject enrolled. All case record forms were collected, checked for completeness and entered on an Excel relational database developed by WHO/HQ and analysis was performed as per the WHO protocol (8). On completion of the studies, slides collected from 10% of the subjects followed were randomly selected and cross examined by a second laboratory technician for quality. Misclassification of parasite species and density estimation difference of more than 50% were subject for examination by an expatriate laboratory technician. Validation of the study data was also done by an epidemiologist assigned by the World Health Organization (WHO). Figure 1 Distribution of artemether-lumefantrine safety and therapeutic efficacy baseline study sites
Humera Atamata
Study Sites
Afar Beneshangui
Amhara
Gumuz Addis Ababa Gambella
Assendabo
Nazareth Oromiya
SNNPR
Somali
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The day 21 and 28 blood samples of the treatment failure cases were not PCR corrected. As the study was conducted during a period of a major malaria epidemic (10), the risk of re-infection is expected to be high. The PCR uncorrected treatment failure cases were both detected in the 5-15 years age group.
RESULTS A total of 219 subjects were enrolled for the study in four sites and 213 (97.3%) subjects completed the 28 days follow-up. All case record forms (CRFs) were reviewed and data were cleaned and entered on excel relational database. Blood slides from 10% of the enrolled subjects were randomly selected and submitted for cross-examination for quality control by a second laboratory technician (8). Cross-check examination results showed 100% agreement among the first and second slide examiners. After the blood film quality control checks and review of case record forms (CRFs) complete data set necessary for outcome classification was achieved for the 213 subjects while six (2.7%) were lost to follow-up. Aggregated data from four sites after 28 days follow up showed a treatment success rate of 99.1% (95 % CI 96.9, 99.8) while in 0.9% (95% CI 0.3, 3.1) treatment success was not achieved as peripheral parasitaemia and measured fever was documented on day 21 and 28. The treatment success rate was uniform in all the sites showing no significant variability.
Table 1 Baseline patient characteristics Characteristic
No.
(%)
136 77
64 36
7 83 123
3.3 39.0 57.7
213 0
100 0
Sex Male Female Age (years) 0.5-5 5-15 Above 15 Site of management Outpatient Inpatient
Table 2 Treatment outcome after 28 days follow-up Treatment Failure (%) Site
Completedl
ACPR2 (%)
TTF6(%) ETF
Alamata Asendabo Humera Nazareth
36 59 62 56
(92.3) (98.3) (96.9) (100)
Total
213 (97.3)
36 57 62 56
3
LCF
4
LPF
5
(100) (96.6) (100) (100)
0 0 0 0
0 2 (3.4) 0 0
0 0 0 0
0 2(3.4) 0 0
211 (99.1)
0
2 (0.9)
0
2(0.9)
1
Completed follow-up, 2Adequate clinical and parasitological response, Early Treatment Failure, 4Late Clinical Failure, 5Late Parasitological Failure, 6 Total Treatment Failure (ETF+LCF+LPF) 3
Table 3 Treatment outcome after 28 days of follow-up by age group Age group in years Site
Under five
5 - 15
No. (%)
TTF1 (%)
Alamata Asendabo Humera Nazareth
0 0 3 (4.8) 4 (7.1)
0 0 0 0
Total
7 (3.3)
0
1
TTF = Total Treatment Failure (ETF+LCF+LPF)
No. (%) 17 33 22 11
(47.2) (55.9) (35.5) (19.6)
83 (39)
Above 15 TTF1 (%) 0 2(6.1) 0 0 0
No. (%) 19 26 37 41
TTF1 (%)
(52.8) (44.1) (59.7) (73.2)
0 0 0 0
123 (57.7)
0
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DISCUSSION The success of malaria control programmes partly depends on the availability of safe and effective antimalarial drugs. The selection of the first line antimalaria drug should, therefore, be based on its ability to attain high clinical and parasitological cure. In addition to this, the drug should also be effective against parasite gametocytes so that it contributes to transmission reduction. In Ethiopia, the first line anti-malaria drug used for the treatment of uncomplicated falciparum malaria is sulfadoxine-pyrimethamine. The first baseline efficacy study on sulfadoxine-pyrimethamine was conducted in 1997 - 98, where a treatment failure of 7.7% was detected in a study conducted in four sites. In a nationwide study conducted in 10 sites in 2003, a mean treatment failure of 35.9% has been reported (Jima et al, in press). Treatment failure rates as high as 35% for amodiaquine and 65% for chloroquine have also been reported in previous studies (5). Therefore, making prudent preparation and selection of other anti-malarial option based on the WHO recommendations (9) is critical and should be done with sufficient lead time as experience showed that treatment guideline changes take considerable time. In light of the high incidence of treatment failure with monotherapies for the treatment of uncomplicated falciparum malaria, the use of combination therapies, especially artemisinin based combination therapies is highly recommended (9). One such Artemisinin Based Combination Therapy (ACTs) highly recommended is artemether-lumefantrine. The results obtained from the efficacy study showed high treatment success (99.1%) with no adverse effects that required discontinuation or withdrawal from study was reported. The safety and high efficacy of artemetherlumefantrine has also been reported in other studies (11) and success in the treatment of falciparum malaria in pregnancy (12) and treatment of multidrug resistant falciparum malaria (13) has been demonstrated. Report on serious adverse reactions such as cardiotoxicity was not proven (14) and reports on some manifestation of hearing loss (15) were criticized in a Roll Back Malaria (RBM) department position paper posted on the RBM website for being inference derived from improperly designed study. The repeatability of study findings on the efficacy and safety of artemether-lumefantrine was shown to be consistent as described in the Cochrane review (16). In light of the very low efficacy of amodiaquine and sulfadoxine-pyrimethamine in Ethiopia (5) the use of the ACT combination Artesunate plus amodiaquine or artesunate plus sulfadoxine-pyrimethamine is unlikely to achieve the desired treatment success. Therefore, the selection of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Ethiopia is highly recommended.
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ACKNOWLEDGEMENTS We would like to thank WHO for the technical and financial support provided to conduct this study. Special gratitude also goes to the Federal Ministry of Health, Regional Health Bureaus, the health workers who conducted the study and the subjects who participated in the study. We would also like to thank the management of the health facilities where the study was conducted for their contribution to the successful completion of the study. We appreciate the technical support provided by Dr. Nathan Bakyaita and Mrs. Farida Al Kindi in validating the study results. REFERENCES 1.
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