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COMPARISON OF THE EFFECTIVENESS OF ARTEMETHER/LUMEFANTRINE (COARTEM) WITH CHLOROQUINE PLUS SULFADOXINE/PYRIMETHAMINE IN THE TREATMENT OF UNCOMPLICATED MALARIA IN CHILDREN
SUMMARY
The choice of artemisinin based combination recommended by WHO for the treatment of uncomplicated malaria may depend on several factors. These include cost, efficacy, side effects and simplicity of administration. However, sulfadoxine/pyrimethamine (SP) and chloroquine are still being used in some parts of Nigeria despite increasing resistance of Plasmodium falciparum to these cheap and affordable antimalarial agents.
A comparative trial of Artemether/Lumefantrine (Coartem), an artemisinin based combination with Sulfadoxine/Pyrimethamine plus Chloroquine for the treatment of uncomplicated malaria in children at Plateau Specialist Hospital Jos was done.
Children aged 6 months to 12 years with uncomplicated P. falciparum infection and parasite density of 2,000/µL and above were enrolled following informed consent by parents. Eligible children were randomly assigned to receive a six dose regimen of artemether-Lumefantrine (20/120mg tablet) or a single dose of sulfadoxine/pyrimethamine (500/25mg tablet) plus a 3 day regimen of chloroquine
(150mg base tablet).
Patients were followed up with clinical and Laboratory assessments until day 14 using standard WHO in-vivo antimalarial drug test protocol. A total of 294 eligible children were enrolled but only 266 completed the study. One hundred and thirty-one in the Coartem group and 135 in the SP+CQ group.
Adequate clinical responses (ACR) were 93.9% and 70.4% for Coartem and SP + CQ group respectively. Early treatment failures were 2.3% and 11.9% for Coartem and SP + CQ respectively, while late treatment failure (LTF) were 3.8% for
Coartem and 17.8% for SP +CQ.
The sensitivity of the parasite to SP + CQ was 70.1% while that to Coartem was 93.1%. The R1, RII and RIII resistance were 14.1%, 3.7% and 11:9% respectively for SP + CQ while that of Coartem were 4.5%, 0% and 2.3% for RI, RII and RIII, respectively.
Based on these findings, artemether/lumefantrine is considered very effective and is recommended for the treatment of uncomplicated falciparum malaria in children. Sulfadoxine/Pyrimethamine + CQ on the other hand should be
considered obsolete.
TABLE OF CONTENTS
Title page - - - - - - - - - i
Declaration - - - - - - - - - ii
Certification - - - - - - - - - iii
Dedication - - - - - - - - - iv
Acknowledgement - - - - - - - - v
Table of content - - - - - - - - vi
List of figures - - - - - - - - ix
Abbreviations - - - - - - - - - x
Summary - - - - - - - - - 1
CHAPTER ONE
1.0 Introduction - - - - - - - - 3
1.1.0 Preamble - - - - - - - - 3
1.1.1 Historical background - - - - - - - 4
1.1.2. Epidemiology - - - - - - - 6
1.1.3 Transmission of malaria - - - - - - 6
1.1.4 Natural protection and acquired immunity against malaria - - 8
1.2 Statement of the problem - - - - - - 9
1.3 Rationale of study - - - - - - 11
1.4 Hypothesis - - - - - - - - 13
1.5 Objectives - - - - - - - - 14
CHAPTER TWO
2.0 Review of Literature - - - - - - - 15
2.1 Overview of drug combination in malaria treatment - - - 15
2.2 The life cycle of malaria parasite - - - - - 15
2.3 Effect of combination therapy on drug resistance - - - 18
2.4 Pharmacology of Artemether Lumefantrine - - - - 18
2.5 Pharmacology of sulfadoxine/pyrimethamine - - - 22
2.6 Pharmacology of chloroquine - - - - - - 23
2.7 The efficacy of sulfadoxine/pyrimethamine alone
and when combined with chloroquine - - - - 25
2.8 Resistance of falciparum malaria to chloroquine and -
Sulfadoxine/Pyrimethamine - - - - - - 31
2.9 The efficacy of artemether –Lumefantrine and other artemisinin
based combination therapy - - - - - - 37
CHAPTER THREE
3.0 Materials and methods - - - - - - 45
3.1 Study environment - - - - - - 45
3.2 Study site - - - - - - - - 46
3.3 Study design - - - - - - - - 47
3.4 Ethical clearance - - - - - - - 48
3.5 Inclusion criteria - - - - - - - 48
3.6 Exclusion criteria - - - - - - - 48
3.7 Drug administration - - - - - - - 49
3.8 Follow up - - - - - - - - 50
3.9 Laboratory Examination - - - - - - 51
3.10 Measurement of outcome - - - - - - 52
3.11 Definitions of clinical and parasitological outcome - - - 52
3.12 Sample size - - - - - - - - 54
3.13 Data analysis and statistical method - - - - - 54
CHAPTER FOUR
4.0 Results - - - - - - - - 55
4.1 Characteristic of patients at enrolment using clinical and
Laboratory parameters - - - - - - 58
4.2 Distribution of the treatment groups by age - - - - 59
4.3 Symptoms and signs resolution for the treatment groups - - 61
4.4 Parasite clearance - - - - - - - 66
4.5 Clinical outcome and assessment - - - - - 67
4.6 Sensitivity and resistance to treatment - - - - 68
CHAPTER FIVE
5.0 Discussion - - - - - - - - 70
5.1 Limitations - - - - - - - - 83
5.2 Conclusion and Recommendation - - - - - 84
References - - - - - - - - - 87
CHAPTER ONE
1.0 INTRODUCTION
1.1.0. Preamble
WHO estimated that malaria kills between 1.5 and 2.7 million people every year1. An additional 300 to 560 million people suffer annually from malaria attack. It is the leading cause of infant mortality and morbidity in subSaharan African along with HIV/AIDS2. Malaria also presents major obstacles to social and economic development. Malaria has been estimated to cost Africa more than $12 billion every year, even though it could be controlled for a fraction of that sum2.
There are several reasons why Africa bears an overwhelming proportion of the malaria burden. Most malaria infections in Africa South of the Sahara are caused by plasmodium falciparum, the most severe and life threatening form of the disease. This region is also home to the most efficient, and therefore deadly, species of the mosquitoes which transmit the disease.
Moreover, many countries in Africa lacked the infrastructures and resources necessary to mount sustainable campaigns against malaria and as a result few benefited from efforts to eradicate malaria3.
Growing political commitment by African leaders for action on malaria was given a boost by the founding of the Roll Back malaria global partnership in 1998. Less than two years later, African Heads of States and their representatives met in Abuja, Nigeria to translate RBM goals of reducing the malaria burden by 2010 into tangible political action. However, not much had been achieved in this regard3.
1.1.1. Historical Background
The symptoms of malaria were described in ancient Chinese medical writings. In 2700 BC, several characteristics symptom of what would later be named malaria were described in Nei Ching (the Canon medicine)4. Malaria became widely recognized in Greece by the 4th Century, and it was responsible for the decline of many of the city State Populations. Hippocrates noted the principal symptoms4. The symptoms of malarial fever were described as attributed to the bites of certain insects. A number of Roman writers attributed Malaria diseases to the swamps4,5.
Charles Louis Aphonse Laveran, a French Army surgeon stationed in
Constantine, Algeria was the first to notice parasites in the blood of a
patient suffering from malaria. This occurred on the 6th of November 1880.
For this discovery, Leveran was awarded the noble prize in 19071.
Camillo Golgi, an Italian neurophysiologist (1880), established that there were at least, two forms of the disease, one with tertian periodicity (fever every other day) and one with quartan periodicity (fever every third day). He also observed that the forms produced differing number of merozoites upon maturity and that fever coincided with the rupture and release of merozoite in the blood stream on August 20th, 18975.
Ronal Ross, a British Officer in the Indian Medical Service, was the first to demonstrate that malaria parasite could be transmitted from infected patients to mosquitoes5. In further work with malaria birds, Ross showed that mosquitoes could transmit malaria parasites from bird to bird. Ross was also awarded a noble prize for this in 19021
In 1898, a team of Italian investigators, led by Giovanni Batista Grassi collected anopheles claviger mosquitoes and fed them on malaria patients. The complete sporogonic cycle of plasmodium falciparum, P. vivax and
- malariae was demonstrated. In 1899, mosquitoes infected by feeding on
a patient in Rome were sent to London where they fed on two volunteers, both of whom developed benign tertian malaria1,3.
1.1.2. Epidemiology
Malaria is a disease of wide distribution and has been reported in 100 countries; fifty of which are in sub-Saharan Africa with Nigeria having a very high endemicity5. The risk of malaria exists throughout the country, but is more in the rural areas. Globally, countries between Latitude 32o South and 64o North have high incidence and prevalence of Malaria1. In the forest belt malaria is prevalent all year round but in the dry Savannah, it is relatively low, between the months of November and March6.
1.1.3. Transmission of malaria
Malaria transmission is favored by the following; temperature range from 20oC to 28oC, mean monthly rainfall of greater than 100mm, relative humidity greater than 60% and topography with altitudes of below 2000 meters above sea level7.
The parasites plasmodium species exhibit a heterogeneous life cycle involving a vertebrate host and an arthropod vector1. Vertebrate host include reptiles, birds, rodents, monkeys and humans. Plasmodium species are quite host specific and there are no zoonoses. Four distinct species infect humans; P. falciparum, P. vivax, P. ovale and P. malariae. The species differ in regard to their morphology, details of their life cycle and their clinical manifestation7. More than 80% of human malaria is caused by P. falciparum and mammalian plasmodium species are transmitted by anopheles mosquitoes7,8.
Over 40 species of Anopheles mosquitoes have been identified in Nigeria but the major vectors of human malaria are anopheles gambiae, anopheles arabiensis,anopheles funestus and Anopheles melas. Anopheles funetus has an uneven distribution while anopheles arabiensis are dominant in the savannah areas and cities. Anopheles melas is coastal specie. The most efficient vector of human malaria in the world is anopheles gambiae9. The pathology and clinical manifestation associated with malaria are almost exclusively due to the asexual erythrocytic stage parasite10. This is one of the stages in the reproductive cycle of the parasite. Tissue schizonts and gametocyte cause little, if any pathology. Plasmodium infections cause an acute febrile illness which is most notable for its periodic fever paroxysms occurring at either 48 or 72 hours intervals 11. The severity of the attack depends on plasmodium species as well as other circumstances such as state of immunity and the general health and nutritional status of the infected individual. The disease has the tendency to relapse or recrudescence over months or even years12.
Natural transmission by mosquitoes is the most common way to obtain malaria, but it can also be transmitted, via blood transfusion or sharing needle and syringe. Mechanical transmission of infected blood will result in a shorter incubation period since there will be no liver stage13. Congenital transmission has also been documented, but is believed to be relatively rare
despite the heavy infection of the placenta12,13.
The typical pre-patent and incubation period following sporozoites inoculation vary slightly according to species. The pre-patent period is defined as the time between sporozoite inoculation and appearance of the parasite in the blood. Incubation period is defined as time between sporozoite inoculation and the onset of symptoms14. Sometimes the incubation period can be prolonged for several months in P. Vivax, P.
Ovale and P. malariae13,14.
1.1.4 Natural protection and acquired immunity against malaria
Biologic characteristics present from birth can protect against certain types of malaria. Two genetic factors both associated with human red blood cells have been shown to be epidemiologically important. Persons who have the sickle cell traits (heterozygous for abnormal haemoglobin gene HbAS) are relatively protected against P.falciparum malaria and thus enjoy a biologic advantage. Persons who are negative for the Duffy blood group have red blood cells that are resistant to infection by P. vivax. Since the majority of Africans are Duffy negative, P. vivax is
rare in Africa south of Sahara, especially West Africa.5,7
Acquired immunity greatly influences how malaria affects an individual and a community. After repeated attacks of malaria a person develops a partial protective immunity. Such ‘semi-immune’ person often can still be infected by malaria parasites but do not develop severe disease and frequently lack any typical malaria symptoms.7,9
1.2 Statement of the Problem
More than forty-five percent of the world’s population is at risk of malaria. The disease affects all age group with more severe effect on children and
pregnant women.15-18. An estimated one million children die from the effect of malaria in Africa annually.19 In Nigeria, malaria has consistently been among the top three reported causes of death among children less than five years of age. In order to prevent diagnostic delays and fatal outcome of malaria in endemic zones, the world Health Organization recommended that
every febrile child must be treated for malaria until proven otherwise19,20.
This unveiled the magnitude of the problem. Economically the burden of malaria is enormous. Economic loss to malaria in African countries was $13.6 billion in 200121. Workers suffering from malaria may be incapacitated for one to four weeks and therefore, affects work on the farm. Food
production is therefore, greatly affected.
Over the years treatment of malaria has been challenging. The drugs of choice for treatment of uncomplicated malaria were chloroquine and sulphadoxine/pyrimethamine22. These drugs were very cheap affordable and effective. However, parasite resistance to the conventional treatment using these drugs has been a major problem in recent times22-26. Ever since the discovery of the first case of chloroquine resistance along the ThaiCambodian border in the late 1950s, South East Asia has played an important role as a focus for the development of drug resistance in the plasmodium falciparum27. Although the first case of Quinine resistance had been reported much earlier for South America, the onset of chloroquine resistance marked the beginning of a new chapter in the history of malaria in Southeast Asia. By 1973 chloroquine finally had to be replaced by the combination of sulphadoxine and pyrimethamine (SP) as first line drug for the treatment of uncomplicated malaria in Thailand and more than 10 African Countries have also switched their first line drugs to SP27. In 1985 SP was replaced by mefloquine in some of these countries. The rapid development of resistance to this new drug leads to the introduction of artemesinin as a combination drug in the mid-1990s. Although several studies favor the use of artemisinin based combination therapy (ACT), the drugs are either very expensive or unavailable. Besides, some take longer time to cure malaria and some are more difficult to comply with than chloroquine29. Urgent efforts are, therefore, needed to identify effective, affordable alternative anti malarial regimen.
1.3 Rationale of the study
Due to overwhelming spread of multi drug resistance to plasmodiumfalciparum malaria the search for alternative treatment becomes more urgent. This certainly entails careful evaluation of the existing anti malaria and
analyzing their cure rate, parasite clearance and clinical outcome as a guide24-
- 30. Knowledge of drug resistance is very helpful in doing this.
Drug resistance of malaria is defined as the ability of a malaria parasite to multiply and survive in the presence of drug concentration that normally
destroy or prevent the multiplication of the parasite 31,32. These drugs concentration are based on dosing for treatment not dosing for prophylaxis. Drug resistance develops when parasite with decrease sensitivities to anti malaria drugs are selected under drug pressure. Decrease drug sensitivity can be conferred by several mechanisms and reflect genetic mutation(s) or polymorphism in the parasite population. The drug resistant parasite will have selective advantage over the drug sensitive parasite in the presence of drug and will be preferentially transmitted33. Major factors in the development of drug resistance are the use of sub therapeutic doses of drugs or not completing the treatment regimen. The lower drug levels will eliminate the most susceptible parasite but those which can tolerate the drug, will continue to reproduce. Over time this will have to continue selection for parasite that can tolerate even the higher dose of drug. It is crucial to maintain an adequate concentration of the drug for sufficient time to
completely eliminate the parasite from any given individual 35-36. The use of combination therapy curbs malaria transmission by lowering both drug resistance and the rate of gametocytaemia after treatment. Toward achieving this, WHO has recommended based on some available clinical evidence, the use of artemisinin based combination therapy for the treatment of uncomplicated malaria37. These drugs are said to have; (i) rapid clinical and parasitological cure rate; (2) significant reduction of gametocyte carriage rate; (3) good safety and tolerability profiles34.
The recommended WHO ACT anti malaria drugs (in order of preference) include: artemether/Lumefantrine; artesunate/amodiaquine, and artesunate/mefloquine 38-39. However, further trials are needed to elucidate the above claim. Such attempt was made in 2004 by the Nigerian government
by conducting a nation wide trial of the combination of
artemether/Lumefantrine and artesunate/Amodiaquine, 22,40. This singular trial led to a change in the national malaria treatment policy where chloroquine and SP where dropped and above listed ACT, were adopted. Artemether/Lumefantrine was made the first line drugs of choice while artesunate/amodiaquine was considered as alternative treatment.
However, preliminary observation in the paediatric unit of Plateau State specialist hospital and other neighboring hospital showed that efficacy of these drugs is questionable. Chloroquine and SP which had been relegated to the background appeared to be more effective especially for treatment of childhood uncomplicated malaria. This therefore, necessitate a local comparative trial of the two regimens hence the rationale of this study.
1.4 Hypothesis
Combination therapy using artemether/Lumefantrine is less effective compare to that of sulfadoxine/Pyrimethamine with chloroquine in the treatment of childhood uncomplicated malaria.
1.5 Objectives
1.5.1 General objective
To determine the effectiveness of artemether/lumefantrine (Coartem) in the treatment of uncomplicated malaria in children.
1.5.2 Specific objectives
- To evaluate the clinical response and parasite clearance of children treated with Coartem.
- To compare the response to that of commonly used combination of chloroquine and SP.
COMPARISON OF THE EFFECTIVENESS OF ARTEMETHER/LUMEFANTRINE (COARTEM) WITH CHLOROQUINE PLUS SULFADOXINE/PYRIMETHAMINE IN THE TREATMENT OF UNCOMPLICATED MALARIA IN CHILDREN
