Efficacy of artesunate-amodiaquine combination therapy for uncomplicated malaria in patients in south-eastern Nigeria.
Abstract: Context/Objective: Artemisinin combination therapy (ACT) is currently the recommended first line treatment for uncomplicated malaria. However, with a plethora of ACTs currently available in Nigeria, it is pertinent to establish the efficacy of these drugs in clinical settings. This study aimed at evaluating the efficacy of the artesunate-amodiaquine combination in a rural community of south-eastern Nigeria.

Method: This was a randomized prospective study, which employed the assessment of day 14 clinical and parasitemia responses. It was conducted in a hospital in Ibagwa, a rural community in the outskirts of Enugu State, Nigeria. Patients who consented to enrolment had detectable parasitemia, no history of prior antimalarial drug use and a history of fever. Each patient received appropriate doses of the artesunate-amodiaquine combination and on days 4 and 14, parasitemia levels were determined micro-scopically and clinical responses assessed physically.

Results: Results showed a preponderance of children (71.4%) and females (62.2%) in this study. Fever, weakness, headache and malaise were the most reported complaints on day 1. By day 14, there was complete resolution of fever, emesis, and pains in all the patients with the least effect seen on weakness, pallor and hematomegaly. Cure rate in this population on days 4 and 14 were 67% and 99% respectively. There were no significant changes in hemoglobin, electrolyte sedimentation rate and leukocyte count. Severe weakness was the only reported side effect.

Conclusion: This study showed a high efficacy of this combination in treatment of uncomplicated malaria in this population with few side effects.

KEY WORDS: Artesunate-amodiaquine, Efficacy, Parasitemia, Nigeria.
Article Type: Report
Subject: Drug therapy, Combination (Health aspects)
Drug therapy, Combination (Research)
Malaria (Drug therapy)
Malaria (Research)
Authors: Okoli, Charles Ogbonnaya
Ugwu, Edwin Chika
Ubaka, Chukwuemeka Michael
Ezike, Adaobi Chioma
Akah, Peter Achunike
Pub Date: 03/01/2010
Publication: Name: Journal of Applied Research Publisher: Therapeutic Solutions LLC Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 Therapeutic Solutions LLC ISSN: 1537-064X
Issue: Date: March, 2010 Source Volume: 10 Source Issue: 1
Topic: Event Code: 310 Science & research
Geographic: Geographic Scope: Nigeria Geographic Code: 6NIGR Nigeria
Accession Number: 227012909
Full Text: INTRODUCTION

Treatment of uncomplicated malaria continues to generate a lot of concern particularly because of the consequences of its high prevalence in the tropics and sub-Saharan parts of Africa. Globally, an estimated 400 900 million acute infections occur annually with at least one death every 30 seconds (1,2). About 85-90% of fatalities from malaria occur in sub-Saharan Africa (1). The battle against malaria continues to face daunting challenges mounted by drug resistance to most antimalarial drugs, insecticide resistance by mosquitoes and other climatic and socio-cultural factors (3). Drug resistant P. falciparum is a serious problem and contributes to the increasing malaria-related morbidity and mortality (4,5). Resistance to the classical antimalarial drugs, notably--chloroquine, sulfadoxine-pyrimethamine, mefloquine, quinine is well documented (6,7). Continued concerns of impending multi-drug resistance has caused a shift from monotherapy to combination therapy which includes drugs like the artemisinins currently recommended by WHO as a means of prolonging the effectiveness of first-line treatment regimens (8,9). In Africa, the treatment policy with regards to uncomplicated malaria advocates the first line use of artemisinin-based combination therapies (ACTs) (10). Several of these ACTs are currently available in Nigeria of which the artesunate-amodiaquine (AA) combination is common. Although this combination has been shown to be effective and safe for use in many other African settings (11), information about its efficacy in Nigerians is very scarce and it is not known if its deployment would result in the beneficial effects associated with such ACTs. Assessment of the efficacy of AA in the treatment of malaria patients in south eastern Nigeria is significantly important given the intensity of malaria transmission in this endemic region and its consequences and the possible impact of information from such studies on disease management policy. Our main objective in this study was to evaluate the efficacy of artesunate-amodiaquine (AA) combination in a rural population in the endemic regions of south-eastern Nigeria.

MATERIALS AND METHODS

Study design

This was a randomized prospective non-comparative study conducted between June and October 2009.

Study site

The study site was a hospital (St Raphael's hospital, Ibagwa-aka) located at the heart of Igbo-eze Local Council of Enugu State, Nigeria. It is a 20-bed in-patient hospital that serves towns within the Local Government Council and neighboring communities made up of natives from the east and migrants from northern and southern parts of the country. This part of the country is predisposed to heavy malaria attacks throughout the year (hyperendemic), especially during the wet seasons when this study was conducted.

Test protocol

The Medical Board of the Hospital granted a written ethical consideration. Sample size estimation was done by taking the population proportion of clinical failures (15%), a confidence interval of 95% and a precision value of 5%. An acceptable minimum of 96 patients was obtained but 105 patients were recruited to make up for any loss during follow up. Patients were informed of the study and oral consent to participate in the study was obtained from adult patients (18 years and above) and parents of children below 18 years. Patients used in this study who fulfilled the necessary criteria, detectable parasitemia levels, temperature levels above 37.5[degrees]C or a history of fever a day or two before the study, no history of prior antimalarial drug use 2 weeks prior to the study and no other diagnosable co-existing illness were included.

The enrolled patients were clerked for their age, sex, weight and presenting complaints by the attending physician. Patients' blood samples were collected and parasitemia levels evaluated by two laboratory scientists independently. Patients were then given different doses of the artesunate-amodiaquine combination drug (generics, IDI) as shown in Table 1 based on body weight measurements. The drugs were administered orally in the presence of a trained nurse and patients who vomited repeatedly were excluded from the study. Children (aged between 0-9 years) were given crushed tablets mixed with honey. Patients were encouraged to come for 2 days of treatment and again on day 4 and 14 in which their blood were collected on slides, stained and counted microscopically. Clinical response follow-up was done on alternate days and then on days 10 and 14. A fourteen day parasitemia and clinical response duration instead of the customary 28 days was done due to difficulty in establishing recrudescence or re-infection after fourteen days of treatment. Similar studies also employed this method (12,13). Hematological data were also assessed using hemoglobin count, erythrocyte sedimentation rate and leukocyte count. Side effects were also noted and taken as worsened or new events observed after treatment. Rescue treatments for severe malaria (quinine injection) and hyperthermia (antipyretics) were provided.

Outcome was measured by cure rate (adequate clinical and parasitological response-ACPR) which was defined as percentage of patients with absence of detectable parasites in blood smears after repeated counts on day 14 of the study. Also fever clearance time was checked and defined as time for body temperature to fall to or below 37.5[degrees]C after drug treatment. Improvements in other symptoms and hematological values were also noted. Treatment failures (early treatment failure, late clinical failure and late parasitological response) were also noted. Early treatment failure (ETF) was defined as any sign of severe malaria on any treatment day, parasitemia levels on day 2 is higher than day 0 and persistent parasitemia on day 4 with measured fever. Late clinical failure (LCF) was defined as any sign severe malaria on any day after treatment days and detectable parasitemia and fever on any day after treatment. Late parasitological failure (LPF) was defined as detectable parasitemia and fever on day 14 without any earlier treatment failure.

Data was analyzed as descriptive statistics using SPSS (version 13, Chicago IL) and presented as frequencies or percentages for clinical and hematological data.

RESULTS

One hundred and five patients were recruited for this study and two (2) were excluded due to undetectable parasitemia levels but with clinical signs and symptoms of malaria. Five other patients were also excluded due to poor follow-up resulting from missing one dose of the drug or not visiting for clinical assessment after drug administration. Demographic and initial clinical characteristics for the remaining 98 patients are shown in Table 2.

The clinical presentations during and after treatment are shown in Table 3. On day 2, fifty patients (44%) had fever clearance which was different from day 0 (92%) and a fever clearance rate of 100% on day 10. Chills completely resolved by day 6 in all the patients. Other notable changes included total remission of vomiting and abdominal pains by day 14. Changes in organs were not pronounced as symptoms such as hepatomegaly and splenomegaly reduced by 9% and 42% by the 10th day respectively. The parasitemia levels and hematological data are displayed in Table 4. Three days after treatment (day 4), 66 (67%) patients had a complete parasite clearance while 32 patients all had parasitemia level of 1-10 cells/100 fields. Also five (5.1%) patients had detectable parasitemia and fever simultaneously (ETF is 5). After day 4, only 2 patients had fever from the earlier five patients with detectable parasitemia (LCF is 0). However, after 14 days, all but one (99%) had no detectable parasites in the blood without fever (LPF is 0). Thus ACPR was found in 93 patients (representing 95% of all patients who completed the study).

None of the patients reportedly had anemia (defined as Hb <9 g/dl). Sixty seven patients (68%) had Hb counts higher than 13 g/dl. The number of patients with leukocytosis doubled from 7 to 15 after 14 days of follow up.

The only observed adverse effect was weakness which was reported by all the patients between the 4th and 6th day with only 18% resolving after 14 days. Three patients required admission and were placed on dextrose infusion. Severe headache persisted in 12 patients till the 10th day and only 2 on the 14th day after receiving analgesics.

DISCUSSION

This study evaluated the clinical efficacy of artesunate-amodiaqiune combination in uncomplicated malaria in a rural setting using fever and asexual parasite clearance. Data from the study showed that the associated symptoms resolved proportionally with time. Parasitaemia clearance and complete resolution of symptoms such as fever, chills and vomiting (frequent signs of malaria) in all the patients provided evidence for clinical efficacy of the regimen. However, hepatomegaly resolved poorly throughout the study. The poor resolution may be due to the duration of the study as it is likely that longer duration than that used (14 days) may be required for considerable recovery to occur. High incidence of spleen enlargement and hepatomegaly in this population (though largely from the children) reflects repeated infections in this group (14).

With a 14-day adequate clinical and parasitological response of 95%, the result of this study is comparable to others obtained in similar settings which showed a 94% efficacy in Gabonese children (15) and some other African countries (11). Studies on AA in other African countries using parasitemia clearance rates on day 14 as the primary endpoint showed 91% cure rate in Kenya; 93% in Senegal and 98% in Gabon (12). With such a remarkable fever resolution and parasitemia clearance before day 4 seen in this study, one may suggest that AA is highly effective against the Plasmodium parasite in the population studied. Though not documented, the rate of possible recrudescence/relapse was low as late parasitological failure was seen only in a patient who had no detectable parasitemia on the 2nd day of rescue treatment with quinine which is acceptable.

The increase in white blood cell (WBC) counts might have resulted from bacterial infections which may coexist with malaria 16. Changes in WBC counts were not reported in previous studies. In the Lambarene, Gabon study, white blood cell count (WBC) and neutrophils were measured on days 0 and 28 with an automated analyzer but no changes were found (17). And so, the increase in WBC of treated patients in this study may not be due to the drug combination administered.

There was no record of discontinuation of medication by any patient. The combination appeared to be well tolerated by all patients except for complaints of severe weakness by most of the patients. Three patients (all children) were placed on dextrose infusion after complaints of severe weakness. The low rates of side effects may be due to a high prevalence of older children (8-13 years) and adults unlike in other studies (17-19) that employed only children and recorded high incidences of medication-induced emesis. However, artesunate and amodiaquine are generally safe when used in treatment of malaria (20-22).

This study had some limitations in that the sample population was small and may not be reflective of the entire community and the study lasted for 14 days instead of 28 days that would have enabled assessment of recrudescence which usually indicates treatment failure.

In conclusion, this study has shown the high clinical efficacy of artesunate-amodiaquine combination in the treatment of uncomplicated malaria in a rural community in south-eastern Nigeria. It also showed a low incidence of side effects that did not warrant discontinuation of treatment. Adherence to this regimen should be strictly maintained to preserve its therapeutic life.

ACKNOWLEDGEMENTS

The authors are grateful to the entire staff and patients of St Rapheal Hospital, Ibagwa-aka, Enugu State, Nigeria, for their technical assistance, participation and cooperation during the study.

REFERENCES

(1.) Hay S, Guerra C, Tatetew A, Noor A, Slow R. The global distribution and population at risk of malaria: past, present and future. Lancet of Infect Dis. 2004; 4: 327-336.

(2.) Fletcher E. Traditional remedies-searching their natural sources for the next malarial drug. TDR news 2007; 79:8-13.

(3.) Kretti AU, Andrade-Neto VF, Brandao MG, Ferrari WM. The search for new antimalarial drugs from plants used to treat fever and malaria or plants randomly selected: a review. Mem. Inst. Oswaldo Cruz, 2001; 96(8): 1033-1042.

(4.) Trape JF, Pison G, Preziosi MP, Enel C, Desgrees du Lou A, Dluanay V, Samb B, lagarade E, Molez JF, Simondon F. Impact of chloroquine resistance on malaria morbidity. CR Acad Sci, Paris, Ser III, 1998; 321:689-697.

(5.) Snow RN, Craig M, Deichmann U, Marsh K. Estimating mortality, morbidity and disability due to malaria among Africa's non-pregnant population. Bull WHO 1999; 77: 624-40.

(6.) White NJ. Antimalarial drug resistance: the pace quickens. J Antimicrob Agents Chemother 1992; 30: 571-85.

(7.) Krogstad DJ. Malaria as a re-emerging disease. Epidemiol Rev. 1996; 18: 77-89.

(8.) World Health Organization: Antimalarial drug combination therapy: Report of WHO technical consultation. WHO/CDS/RBM/200135 2001.

(9.) Nosten F, White NJ: Artemisinin-based combination treatment of falciparum malaria. Am J Trop Med Hyg 2007, 77:181-192.

(10.) World Health Organization: Position of WHO' Roll Back Malaria Department on malaria treatment policy. Statement: WHO 2004 [http://www.who.int/malaria/docs/who_apt_position.html]. (Accessed 29 January 2006).

(11.) Adjuik M, Agnamey P, Babiker A, Borrmann S, Brasseur P, Cisse M. et al. Amodiaquine-artesunate versus amodiaquine for uncomplicated Plasmodium falciparum malaria in African children: a randomized, multicentre trial. Lancet 2002; 359: 1365-1372.

(12.) Ekanem OJ, Weisfeld JS, Salako LA et al. Sensitivity of Plasmodium falciparum to chloroquine and sulphadoxinepyrimethamine in Nigerian children. Bull WHO. 1987; 68, 45-52.

(13.) Salako LA, Ajayi FO, Sowunmi A & Walker O (1990) Malaria in Nigeria: a revisit. Ann Trop Med Parasitol 1990; 84: 435-445.

(14.) White N.J and Breman J.G. Malaria and Babesiosis: Diseases caused by red blood cell parasites. In Harrison's Principle of Internal Medicine. Kasper D.L., Braunwald E., et al (eds). Mc Grawhill. 2005. 16th edn. 1221-2.

(15.) Syahril P., Pitaloka A. P., and Panusunan L. C. Combination of Artesunate-Amodiaquine as a treatment for uncomplicated falciparum malaria in children. PEDIATRICS 2008; 121 (Suppl): 133 (dol: 10, 1542/Peds 307-2022 xxxx).

(16.) Okwara FN, Obimbo EM, Wafula EM, Murila FV. Bacteraemia, urinary tract infection and malaria in hospitalised febrile children in Nairobi: is there an association? East Afr Med J 2004; 81(1): 47-51.

(17.) Oyakhirome, S., Potschke, M., Schwarz, N. G., Dornemann, J., Laengin, M., Salazar, C. O., Leill, B., Kun, J.F.J., Kremsner, P. G., Grobusch, M. P. Artesunate-amodiaquine combination therapy for falciparum malaria in young Gabonese children. Mal J, 2007; 6: 29.

(18.) A. Sowunmi, F. A. Fehintola, A. A. Adedeji, G. O. Gbotosho, E. Tambo, B. A. Fateye, T. C. Happi and A. M. J. Oduola . Open randomized study of artesunate-amodiaquine vs. chloroquine-pyrimethamine-sulfadoxine for the treatment of uncomplicated Plasmodium falciparum malaria in Nigerian children. J Trop Med Inter Health 2005; 10:2: 1161-1170. doi:10.1111/j.1365-3156.2005.01503.x

(19.) Sowunmi A, Fateye BA, Adedeji AA, Fehintola FA & Happi TC. Risk factors for gametocyte carriage in uncomplicated falciparum malaria in children. Parasitology 2004b; 129: 255-262.

(20.) Kremsner PG, Krishna S: Antimalarial combinations. Lancet 2004, 364: 285-294.

(21.) Looareesuwan SC, Vanijanonta S, Wilairatana P, Suntharasamai P, Charoenlarp P, Arnold K, Kyle D, Canfield C, Webster K: Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. Lancet 1992; 339: 821-824.

(22.) Nosten F, Luxemburger C, Kulie FO, Woodrow C, Eh JP, Chongsuphajaisiddhi T, White NJ: Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination. J Infect Dis 1994; 170: 971-977.

Okoli Charles Ogbonnaya, BPharm, MPharm, PhD [1] Ugwu Edwin Chika, MD, Mphram [1] Ubaka Chukwuemeka Michael, BPharm, Mpharm [2] * Ezike Adaobi Chioma, BPharm, MPharm, PhD [1] Akah Peter Achunike, BSc, MSc, PhD [1]

[1] Department of Pharmacology & Toxicology,

[2] Department of Clinical Pharmacy & Pharmacy Management, University of Nigeria, Nsukka 410001 Nigeria
Table 1: Dosages of artesunte-amiodaquine for the patients according
to ages

Patient              1st day of treatment       2nd day of treatment

Children under 1     1/2 tablet of              1/2 tablet of
                       artesunate                 artesunate
year, weight less    1/2 tablet of              1/2 tablet of
than 10 kg           amodiaquine                amodiaquine

Children from        1 tablet, artesunate,      1 tablet, artesunate,
1-7 years, weight    1 tablet, amodiaquine      1 tablet, amodiaquine
10-20 kg

Children from 7      2 tablets artesunate,      2 tablets artesunate,
years to 13 years,   2 tablets amodiaquine      2 tablets amodiaquine
weight 21-40 kg

After 13 years,      4 tablets artesunate,      4 tablets artesunate,
weight more than     4 tablets amodiaquine      4 tablets amodiaquine
40 kg

Patient              3rd day of treatment

Children under 1     1/2 tablet of artesunate
year, weight less    1/2 tablet of amodiaquine
than 10 kg

Children from        1 tablet artesunate,
1-7 years, weight    1 tablet amodiaquine
10-20 kg

Children from 7      2 tablets artesunate,
years to 13 years,   2 tablets amodiaquine
weight 21-40 kg

After 13 years,      4 tablets artesunate,
weight more than     4 tablets amodiaquine
40 kg

Each tablet of artesunate contained: 50 mg artesunate

Each tablet of amodiaquine contained: 200 mg amodiaquine.

Table 2. Patient's demographic characteristics and presenting
complaints before treatment

Demographic characteristic   Frequency (n) (%)

Sex

Male                             37 (37.8)
Female                           61 (62.2)

Age range, (yrs)

2-12                             70 (71.4)
13 and above                     28 (28.6)
Mean [+ or -] SD              25 [+ or -] 9.2
Range                              2-45

Presenting complaints

Fever                               90
Vomiting                            64
Abdominal pains                     40
Malaise                             83
Headache                            85
Weakness                            96
Nausea                              70
Loss of appetite                    76
Spenomegaly                         35
Hepatomegaly                        44
Pallor                              22
Chills                              47

n represents number of occurrence; Fever represents temperatures
37.5[degrees]C and above: SD= standard deviation.

Table 3. Presenting complaints after treatment (n=98).

                       Number of patients with symptoms/signs

Symptoms/signs     Day 0   Day 2   Day 4   Day 6   Day 10   Day 14

Fever               90      50      20       2        0        0
Vomiting            64      40      24       5        1        0
Abdominal pains     40      20       9       4        2        0
Malaise             83      80      82      80       70       55
Headache            85      70      60      30       12        2
Weakness            96      96      97      98       96       80
Nausea              70      65      67      60       40       20
Loss of appetite    76      75      70      70       30       20
Splenomegaly        35      35      33      30       30       20
Hepatomegaly        44      44      44      43       43       40
Pallor              22      22      24      26       24       20
Chills              47      25      15       0        0        0

Table 4. Hematological data before and after treatment
of patients with malaria (n=98).

Analyte                   Number of patients

                       Day 0    Day 4     Day 14
Parasitemia,
(cells/100 thick
fields)
  1-10                  60        22        --
  11-100                38     10 * (5)     1 *
Hemoglobin (g/dl)
  10-11.9               12                  10
  12-13                 19                  24
13 and above            67                  64
Electrolyte
sedimentation
rate (mm/h)
  6-8                   67                  64
  9-12                  19                  24
  13-15                 12                  10
White blood cell
count
(cells/[micro]l)
  4000-5000             69                  49
  6000-8000             22                  34
  9000-11000             7                  15

* represents parasitemia level at 1-10 cells/100 thick fields.
Number in parenthesis represents ETF (patient with parasitemia
and fever)
Gale Copyright: Copyright 2010 Gale, Cengage Learning. All rights reserved.