African Journal of Biotechnology
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African Journal of Biotechnology Vol. 2 (10), pp. 384-389, October 2003 ISSN 1684–5315 © 2003 Academic Journals
Plasmodium
falciparum malaria resistance to
chloroquine in five communities in Southern Nigeria Patrick
O Erah*, Gertrude Arienmughare and Augustine O Okhamafe
Pharmacotherapy
Group, Faculty of Pharmacy, University of Benin, Benin City, Nigeria. *Corresponding
author; E-mail: erah@uniben.edu, Tel:
+234 802 336 0318; 805 526 3622, Fax: +234 52 602257. Accepted
29 September 2003 |
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Chloroquine
is still a first-line antimalarial drug in uncomplicated falciparum
malaria. Increasing resistance to chloroquine has been reported in many
parts of Nigeria. Clinical and parasitological responses and classes of
resistance to chloroquine in falciparum malaria in five communities in
Delta region, southern Nigeria were assessed. Chloroquine was administered
to 218 patients with uncomplicated P. falciparum malaria. The
levels of parasitemia, clinical response and classes of resistance were
monitored for 7 days. High levels of therapeutic failures of chloroquine
in P. falciparum malaria were recorded in the region. The
frequencies of clinical and parasitological failure of chloroquine were
25.7% and 55%, respectively. These frequencies were significantly lower in
children below 5 years than older people. R2 and R3 resistance occurred in
37.2% and 17.4% of the patients, respectively.
The therapeutic failure of chloroquine was not gender dependent. We
conclude that chloroquine is still effective in the treatment of
uncomplicated P. falciparum malaria in some communities in Delta
region of Nigeria. However, resistance to chloroquine is likely. These
results may be used as an important indicator of the significant level of
therapeutic failure of uncomplicated P. falciparum malaria to
chloroquine in Nigeria. Keywords:
Chloroquine, falciparum malaria, resistance, clinical failure,
parasitological failure.
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Malaria
is the second leading health problem (the first being HIV/AIDS) in
sub-Saharan Africa accounting for over 1 million deaths yearly in the
region (Rathod et al., 1997). These deaths are
primarily among children under 5 years of age and pregnant women
(Phillips, 2001). The disease can increase the
risk of major problems including anaemia, premature births,
still-births, abortion and low birth weight. Health and socio-economic
problems caused by malaria in sub-Saharan Africa are enormous, and the
development and spread of malaria parasite resistance to drugs have led
to global recognition and commitment to public health problems of
malaria. Malaria
in Africa is mainly due to a blood parasite, Plasmodium falciparum.
Chloroquine, which was introduced in the 1940s, and for many decades
served as a cheap and reliable drug, is becoming ineffective against P.
falciparum in most tropical areas (Rathod et al., 1997;
Warhurst, 2001). Resistance to chloroquine
developed in Southeast Asia and South America at the end of the 1950s
and in Africa by the late 1970s (Warhurst, 2001).
Since the emergence of chloroquine resistant strains of P. falciparum,
the rate of resistance has been increasing and limiting adequate
treatment of malaria (Peters, 1998; The
goal of chemotherapy in malaria therapy is often to effect a clinical
cure or parasitological clearance or to limit the development of drug
resistance. Resistance to chloroquine is often manifested in subtle ways
which are only apparent when the treatment is accompanied by detailed
follow-up. Accurate and effective surveillance systems for monitoring
antimalarial drug efficacy have been recognized as an essential basis
for decisions on the use of drugs (Malaria Foundation International, 1998).
Surveillance is often carried out at different levels of sophistication,
from basic drug efficacy tests through to more detailed in vitro
characterization of drug resistant parasite strains and clinical
information. The World Health Organization has recognized that malaria
treatment failure rate of 5% to 14% signals an alert phase in malaria
monitoring while failure rates of 15% to 24% signals the need for action
(WHO, 2002a). Among other factors, reports of
chloroquine resistant P. falciparum treatment failure rate of up
to 53.6% in southeastern Nigeria (Umotong et al., 1991)
and up to 37% in southwestern part of Nigeria (Salako et al., 1990;
Sowunmi et al., 1990) with a drop to 15% in 1992
(Sowunmi and
Salako, 1992) justifies the need for
continuous monitoring of resistance to chloroquine.
The main purpose of this study was to ascertain the therapeutic efficacy of treatment of uncomplicated P. falciparum malaria with chloroquine in the Delta region of Nigeria. Specifically, the parasitological and clinical responses of P. falciparum to chloroquine and the classes of resistance are evaluated. The data obtained from this study would provide useful information for future management of uncomplicated P. falciparum malaria in the region.
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Study
area This
study was carried out in a government-owned Central Hospital, Warri
which is a 300-bed tertiary health care facility. It involved patients
drawn from five communities in Delta State, Southern Nigeria namely,
Agbarho, Aladja, Effurun, Ekpan and Enerhen with a population of over
1 million inhabitants. These communities are located in malaria
endemic oil rich
area of Delta State and were selected because of their
proximity to the study site. Apart from Agharho (a village whose
inhabitants are mainly farmers), the communities are urban communities
whose inhabitants are mainly petty traders, civil servants and workers
in the oil industry. They are served by the Central Hospital, Warri
and Shell Petroleum Hospital, Warri as well as private clinics, herbal
homes, pharmaceutical stores and patent medicine stores. Like other
parts of southern Nigeria, the climate is equatorial, with 2 seasons:
rainy season from May to October and dry season from November to
April. Patients
and study protocol After
ethical approval from the Delta State Ministry of Health, Asaba, 500
males and females patients (age: 6 months and above) with history of
fever (axillary temperature ³
37.5oC) in the last 48 h before attending the hospital
(Central Hospital, Warri) were clinically examined and screened for
malaria parasites using both clinical examination and laboratory data.
Of the 500 patients, 218 patients (age range, 6 months to 48 years)
met the criteria for inclusion in the data analysed. These patients
were selected from the 5 communities using simple random sampling as
earlier described (WHO, 1992). The sample
was evenly distributed among the communities selected and the sample
size was satisfactory in respect of the calculated sample size of
patients based on the population of the communities at 95% confidence
interval, 5% precision, and expected proportion of treatment failure
of 5% – 14 % (WHO, 2002a). The
criteria for inclusion in the study included the presence of P.
falciparum malaria as determined by clinical examination and
laboratory data (parasite count; 2,000 to 200,000 per ml
blood) and informed consent. Other criteria for inclusion were: (1) ability to be followed up for 7 days, (2) presence of
febrile conditions caused by P. falciparum malaria, (3) absence
of general danger signs or signs of severe and complicated P.
falciparum malaria, and (4) the fact that the patient has not
taken any antimalarial drug within 2 week period preceding the study.
However, patients with clinical symptoms compatible with severe
or complicated malaria or with any other symptoms or signs of
non-malarial etiology were excluded from the study and referred to
appropriate health services. Also excluded were patients with repeated
vomiting, diarrhoea, malnutrition, pregnancy, difficulty in complying
with drug treatment, and inability to comply with the stipulated
follow-up visits on days 3 and 7. The
218 patients (113 males and 105 females including 78 children below 5
years) were routinely treated with chloroquine orally: adults were
treated with 600 mg chloroquine base stat and 24 h later followed by
300 mg next
day; children received 10 mg/kg stat and
24 h later, then 5 mg/kg next day, as appropriate. Each patient
was also given appropriate doses of paracetamol and multivitamin orally.
The qualities of drugs administered were evaluated and found to have met
the British Pharmacopoeia (BP, 1998) standard
before they were used for this study. All patients were treated as
outpatients and were appropriately followed up for 7 days with clinical
and laboratory examinations at 3 h, day 3 and day 7 following the start
of treatment with chloroquine. Blood samples were also obtained from the
patients during the follow-up days and malaria parasite levels
determined using standard methods (Ejov et al., 1999;
Hombhanje, 1997). Clinical
and parasitological responses to chloroquine Clinical
failure was considered to have occurred if a patient had fever or
history of fever (axillary temperature ³
37.5oC) by day 7 with parasitemia detected in blood or
assessed to have been ill due to no other cause than malaria.
Parasitological failure was considered to have occurred if parasite
count in blood was ³ 25% of count on day 0 by day 7. Level
of resistance to chloroquine We
adopted the 7-day WHO in vivo test protocol in determining the
class of resistance to chloroquine (Bruce, 1986).
Patients with marked reduction of parasitemia (parasite count reduced by
more than 75%) at 48 h but failed to clear parasites by day 7 were
considered to be R2 resistant to chloroquine. Patients whose parasitemia
did not fall by more than 75% within 48 h or occasionally increased by
day 7 were considered to be R3 resistant to chloroquine. R1 resistance
(clearance of asexual parasitemia on or after day 7 followed by
recrudescence) was not determined because the patients were only
monitored for 7 days and it is not possible to determine recrudescence
in areas of intense malaria transmission as in the communities studied. Statistical
Analysis of data
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Age
and sex distribution of patients The
age and sex distribution of the 218 patients who fully participated in
this study are given in Table 1. This number excluded those who either
defaulted or withdrew from the study on account of convenience. There
was no significant difference between the number of males and females,
and the number of children below 5 years when compared with other
patients from 5 years and above (p > 0.05).
Table 1. Age and sex distribution of patients with P. falciparum malaria treated with chloroquine.
ac2 = 0.015, df = 1, p = 0.903
Clinical
and parasitological responses to chloroquine The
clinical and parasitological responses to chloroquine are shown in Table
2. Chloroquine produced a
clinical success of 74.3% in the eradication of malaria parasites in the
patients but parasitological success was only achieved in 45% of the
patients. The proportion of patients with clinical failure or
parasitological failure were significantly higher in patients from 5 to
48 years old than patients below 5 years (p £
0.001). Furthermore, the proportion of patients from 5 to 48 years old
with clinical failure was more than twice the proportion of patients
below 5 years with clinical failure. Also, the proportion of patients
from 5 to 48 years years old with parasitological failure was nearly
doubled the proportion of patients below 5 years with parasitological
failure. Gender had no significant effect on either the clinical
response or parasitological response to chloroquine (p > 0.05).
Table 2. Clinical and parasitological response of chloroquine in patients with P. falciparum malaria.
bp = 0.001; cp < 0.001
Level
of resistance to chloroquine Class
II (R2) and class III (R3) types of resistance were found to have
occurred in 81 (37.2%) and 38 (17.4%) of the patients, respectively. We
found no significant differences in the levels of resistance in males
when compared to those of the females (p > 0.05). bp = 0.001; cp < 0.001
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Drug
resistance in malaria is the ability of the parasite strains to survive
and/or multiply despite administration and absorption of a drug given in
doses equal to or higher than those usually recommended but within the
limits of tolerance of the subject (Bruce, 1986). The
World Health Organization (WHO) categorized resistance in malaria as S
(sensitive), R1, R2 and R3 based on in vivo test (Bruce, 1986).
This test was replaced in 1996 by WHO with the Therapeutic Efficacy Test
based on clinical and parasitological criteria - a pragmatic test for
National Malaria Control Programme (WHO,
1996). We have used these two approaches to evaluate the
effectiveness of chloroquine in the five communities studied. Our results
have shown that chloroquine is still effective in the treatment of
uncompicated P. falciparum malaria in the communities despite the
high prevalence of chloroquine-resistant malaria in the region. This is
evident in the clinical success of chloroquine in 74.3% of the patients.
However, parasitemia was still evident in 45% of the patients by the 7th
day after the first dose of chloroquine was administered, indicating
resistance to chloroquine. We recognise that a mixed population of malaria
parasite strains (susceptible and resistant) can be present in the blood
of the patients. In this situation, the susceptible strains would be
killed by the chloroquine in the early part of the treatment, making way
for more resistant and virulent strains to multiply later (Wernsdorfer et
al., 1995). Children
under the age of 5 years are known to be the most susceptible group to malaria
mortality (WHO, 2002b). The severity and
prevalence of malaria are also higher in this age group than older
children and adults (May et al., 1999; Mockenhaupt et
al., 2000). Furthermore, at equal dosages per
body weight, plasma chloroquine concentrations are lower in children below
5 years of age than older children and adults (Maitland et al., 1997).
These indications would suggest that the therapeutic failure of
chloroquine in malaria treatment is likely to be higher in children
younger than 5 years than older people. Conversely, our results indicate that children younger
than 5 years had much lower therapeutic failure rates than older
people. The reason for this is unclear. Earlier report indicates that
mixed species infections of malaria parasites are higher in children below
5 years (Mockenhaupt et al., 2000) than older people.
Malaria infections with parasite strains other than P. falciparum
have been suggested to act as natural vaccines preventing severe
manifestations of P. falciparum infections (Williams et al., 1996).
If this suggestion holds, clearance of P. falciparum malaria in the
patients below 5 years of age could be
enhanced, as none of them had severe malaria. Furthermore, long-term
exposure to chloroquine, particularly by presumptive chloroquine treatment
or prophylaxis, are prerequisites for the emergence of chloroquine
resistance (Mockenhaupt et al., 2000). This
situation is less likely to occur in children below the age of 5 years than older people. The efficacy of chloroquine is thus more likely to be
lower in people older than 5 years than those below 5 years of age. Greater awareness on the need for early and
proper treatment in chlidren below 5 years of age may also be a contributing factor. Gender appears
not to play a role in therapeutic efficacy of chloroquine as we found no
significant difference between the frequency of therapeutic failures in
males as compared to females. Increasing
resistance of P. falciparum malaria to chloroquine has earlier been
reported in some parts of Nigeria (Umotong et al., 1991).
Survellance network in the country from mid-1987 to 1990 revealed that
chloroquine resistant P. falciparum (CRPF) was widespread (Ekanem, 1997).
In the northern part of the country, parasitological failures increased
from 18.7% in 1988 to 24.5% in 1995 (Molta, 1995).
From 1987 to 1997, resistance ranging from 33% to 72% was also reported in
the southern part of the country (Ekanem, 1997).
Although the parasitological failure found in our study is similar to the
53.6% found in Calabar, southern Nigeria in 1991 (Umotong et al., 1991),
stability of resistance to chloroquine in the area studied cannot be
inferred because the two areas (Calabar and Delta region) are
in different locations. Clinical failure of 25.7% recorded in this
study is also similar to the 22% reported in Ibadan, southern Nigeria in
1997 (Ekanem, 1997; Oduola, 1997).
The frequencies of clinical and parasitological failures following
chloroquine treatment are indicative of the continuous emergence of
chloroquine resistance strains of P. falciparum in the communities
studied and most likely in other parts of the country.
These frequencies are at unacceptable levels having exceeded the 15
– 24% set by WHO (2002a) as action phase.
Thus, the need for action to be taken
to address
the problem
in the
communities and other parts of the country has become very urgent. Based on
WHO earlier categorisation of resistance to antimalarial drugs (class I,
R1; class II, R2 and class III, R3), our results have demonstrated high
proportions of R2 (37.2%) and R3 (17.4%) resistance in the communities
studied. The R3 resistance was similar to that reported in 1991 in Calabar
(Umotong et al., 1991). Studies have shown that R3
resistance to chloroquine is not present in some areas in Congo (Carme et
al., 1998) and Madagascar (Raharimalala et al., 1995)
but present at a very low level in Coté d'Ivoire (Henry et al., 1998).
R3 resistance in this study is lower than the 23% reported in Zimbabwe (Mohamva
et al., 1996) and the 22% reported in Port Moresby,
Papua New Guinea (Hombhanje, 1997). However, the
R2 resistance in our results is much higher than the 10% reported in
Zimbabwe (Mohamva et al., 1996) and the 4% reported
in Papua New Guinea (Hombhanje, 1997). High,
rather than low, doses of chloroquine is believed to induce R3 resistance
to chlroquine (Henry et al., 1998). The
mechanism of resistance to chloroquine in the communities studied is not
clear, since the mechanism of resistance to antimalarial drugs is still
debatable (Wellems et al., 1990; Rathod et al., 1997;
Phillips, 2001).
However, resistance to chloroquine has been reported to be due to
reduced uptake of the drug by the infected erythrocyte and presumably
reflects a reduction in the accumulation of the drug in the parasite’s
lysosome (Phillips, 2001; Warhurst, 2001).
Association between chloroquine resistance and mutations in an mdr-like
gene (pfmdr-1) has been reported (Warhurst, 2001).
There is evidence to suggest that a mutation in pfcrt is required
to confer a basic level of resistance before mutations in pfmdr-1
can have an effect; the basis for the suggested use of a rapid and
sensitive test to detect pfcrt T76 in blood samples to ascertain
the effectiveness of chloroquine (Warhurst, 2001;
Reed et al., 2000). A number of factors have been
identified as playing a role in the emergence of resistance to chloroquine.
These include poor compliance to drug therapy, host immunity, use of
sub-therapeutic doses, mutation and frequency of re-infection (Hombhanje, 1997;
Phillips, 2001; Werndorfer, 1991). Treatment
of uncomplicated malaria in the Niger-Delta region (where this study was
carried out) is frequently based on the fact that as long as chloroquine
is effective enough, there is very little incentive for basing its use on
reliable diagnostic confirmation. As in the communities studied,
resistance to antimalarial drugs is proving to be a challenging problem in
malaria control in most parts of the world. A fundamental aspect of drug
usage recommendations is the impact of resistance on morbidity and
mortality and hence the impact of the timing and nature of a policy
decision on the health of the people in the community studied and the rest
of the country. The principle of combination
drug in
malaria chemotherapy
has been established as a measure to improve treatment efficacy, delay the
emergence of drug resistance, and reduce the prevalence of gametocyte
carriage which could, in turn, reduce transmission of malaria parasites
(WHO, 2001a,b). Cost
considerations in many parts of the country would support the use of
empirical treatment with chloroquine or an alternative first-line drug,
such as sulfadoxine-pyrimethamine (Warhurst, 2001),
in patients with uncomplicated malaria. In the case of more expensive drug
regimens, the cost would have to be balanced against the potential savings
in the cost of treatment. Reliable, microscopy-based diagnosis should be
mandatory in view of the financial implications when much more expensive
alternative drugs need to be used when resistance to chloroquine occurs. Conclusion Chloroquine
is still effective in the treatment of most cases of uncomplicated P.
falciparum malaria in some communities in Delta State, Nigeria.
However, in many cases of uncomplicated P. falciparum malaria,
resistance to chloroquine is likely and intervention with alternative
antimalarial drugs may be required for complete clearance of parasitemia
in the patients. Despite the limited communities in which this study was
carried out, our results may be used as an important indicator of the
significant level of therapeutic failure of uncomplicated P. falciparum
malaria to chloroquine in Nigeria. Additional drug efficacy assessment
throughout the country is needed to support national antimalarial drug
policy. ACKNOWLEDGEMENTS |
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