African Journal of Biotechnology Vol. 2 (10), pp. 384-389, October 2003 Available online at http://www.academicjournals.org/AJB 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.
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.
INTRODUCTION Malaria is the second leading health problem (the first
Malaria in Africa is mainly due to a blood parasite,
being HIV/AIDS) in sub-Saharan Africa accounting for
Plasmodium falciparum. Chloroquine, which was
over 1 million deaths yearly in the region (Rathod et al.,
introduced in the 1940s, and for many decades served as
1997). These deaths are primarily among children under
a cheap and reliable drug, is becoming ineffective against
5 years of age and pregnant women (Phillips, 2001). The
P. falciparum in most tropical areas (Rathod et al., 1997;
disease can increase the risk of major problems including
Warhurst, 2001). Resistance to chloroquine developed in
anaemia, premature births, still-births, abortion and low
Southeast Asia and South America at the end of the
birth weight. Health and socio-economic problems
1950s and in Africa by the late 1970s (Warhurst, 2001).
caused by malaria in sub-Saharan Africa are enormous,
Since the emergence of chloroquine resistant strains of
and the development and spread of malaria parasite
P. falciparum, the rate of resistance has been increasing
resistance to drugs have led to global recognition and
and limiting adequate treatment of malaria (Peters, 1998;
commitment to public health problems of malaria.
Neequaye et al., 1986). Despite the growing resistance of
P. falciparum, chloroquine remains the first line
antimalarial drug in Nigeria and many other African
countries mainly on account of cost and effectiveness in
*Corresponding author; E-mail: erah@uniben.edu, Tel: +234
uncomplicated cases of malaria. Resistance to
802 336 0318; 805 526 3622, Fax: +234 52 602257.
chloroquine by P. falciparum has prompted many studies
within the last decade in different parts of Nigeria (Molta,
of Delta State and were selected because of their
1995; Umotong et al., 1991; Salako et al., 1990;
proximity to the study site. Apart from Agharho (a village
Sowunmi et al., 1990; Sowunmi and Salako, 1992). In the
whose inhabitants are mainly farmers), the communities
study carried out in northeastern Nigeria, for example,
are urban communities whose inhabitants are mainly
most strains of P. falciparum were found to be fully
petty traders, civil servants and workers in the oil
sensitive to chloroquine (Molta, 1995). However, strains
industry. They are served by the Central Hospital, Warri
with reduced sensitivity and resistant strains have
and Shell Petroleum Hospital, Warri as well as private
emerged with parasitological failure increasing from
clinics, herbal homes, pharmaceutical stores and patent
18.7% in 1988 to 24.5% in 1995 (Molta, 1995).
medicine stores. Like other parts of southern Nigeria, the
Consistently high resistance to chloroquine by malaria
climate is equatorial, with 2 seasons: rainy season from
parasite has also been reported in southeastern Nigeria
May to October and dry season from November to April.
The goal of chemotherapy in malaria therapy is often
to effect a clinical cure or parasitological clearance or to
Patients and study protocol
limit the development of drug resistance. Resistance to
chloroquine is often manifested in subtle ways which are
After ethical approval from the Delta State Ministry of
only apparent when the treatment is accompanied by
Health, Asaba, 500 males and females patients (age: 6
detailed follow-up. Accurate and effective surveillance
months and above) with history of fever (axillary
systems for monitoring antimalarial drug efficacy have
temperature ≥ 37.5oC) in the last 48 h before attending
been recognized as an essential basis for decisions on
the hospital (Central Hospital, Warri) were clinically
the use of drugs (Malaria Foundation International, 1998).
examined and screened for malaria parasites using both
Surveillance is often carried out at different levels of
clinical examination and laboratory data. Of the 500
sophistication, from basic drug efficacy tests through to
patients, 218 patients (age range, 6 months to 48 years)
more detailed in vitro characterization of drug resistant
met the criteria for inclusion in the data analysed. These
parasite strains and clinical information. The World
patients were selected from the 5 communities using
Health Organization has recognized that malaria simple random sampling as earlier described (WHO,
treatment failure rate of 5% to 14% signals an alert phase
1992). The sample was evenly distributed among the
in malaria monitoring while failure rates of 15% to 24%
communities selected and the sample size was
signals the need for action (WHO, 2002a). Among other
satisfactory in respect of the calculated sample size of
factors, reports of chloroquine resistant P. falciparum
patients based on the population of the communities at
treatment failure rate of up to 53.6% in southeastern
95% confidence interval, 5% precision, and expected
Nigeria (Umotong et al., 1991) and up to 37% in
proportion of treatment failure of 5% – 14 % (WHO,
southwestern part of Nigeria (Salako et al., 1990;
Sowunmi et al., 1990) with a drop to 15% in 1992
The criteria for inclusion in the study included the
(Sowunmi and Salako, 1992) justifies the need for
presence of P. falciparum malaria as determined by
continuous monitoring of resistance to chloroquine.
clinical examination and laboratory data (parasite count;
The main purpose of this study was to ascertain the
2,000 to 200,000 per µl blood) and informed consent.
therapeutic efficacy of treatment of uncomplicated P.
Other criteria for inclusion were: (1) ability to be followed
falciparum malaria with chloroquine in the Delta region of
up for 7 days, (2) presence of febrile conditions caused
Nigeria. Specifically, the parasitological and clinical
by P. falciparum malaria, (3) absence of general danger
responses of P. falciparum to chloroquine and the
signs or signs of severe and complicated P. falciparum
classes of resistance are evaluated. The data obtained
malaria, and (4) the fact that the patient has not taken
from this study would provide useful information for future
any antimalarial drug within 2 week period preceding the
management of uncomplicated P. falciparum malaria in
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
Study area
repeated vomiting, diarrhoea, malnutrition, pregnancy,
difficulty in complying with drug treatment, and inability to
This study was carried out in a government-owned
comply with the stipulated follow-up visits on days 3 and
Central Hospital, Warri which is a 300-bed tertiary health
care facility. It involved patients drawn from five
The 218 patients (113 males and 105 females
communities in Delta State, Southern Nigeria namely,
including 78 children below 5 years) were routinely
Agbarho, Aladja, Effurun, Ekpan and Enerhen with a
treated with chloroquine orally: adults were treated with
population of over 1 million inhabitants. These 600 mg chloroquine base stat and 24 h later followed by
communities are located in malaria endemic oil rich area
300 mg next day; children received 10 mg/kg stat and 24
386 Afr. J. Biotechnol. Table 1. Age and sex distribution of patients with P. falciparum malaria treated with chloroquine. aχ2 = 0.015, df = 1, p = 0.903
h later, then 5 mg/kg next day, as appropriate. Each
with Chi square test or Fisher’s Exact test, using a
patient was also given appropriate doses of paracetamol
computer software, Instat (GraphPad Inc., USA).
and multivitamin orally. The qualities of drugs Probability (p) was considered at 95% confidence administered were evaluated and found to have met the
interval, and 2 – tailed p-values less than or equal to 0.05
British Pharmacopoeia (BP, 1998) standard before they
were accepted to imply significant differences between
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
Age and sex distribution of patients
levels determined using standard methods (Ejov et al.,
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
Clinical and parasitological responses to chloroquine
from the study on account of convenience. There was no
significant difference between the number of males and
Clinical failure was considered to have occurred if a
females, and the number of children below 5 years when
patient had fever or history of fever (axillary temperature
compared with other patients from 5 years and above (p
≥ 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
Clinical and parasitological responses to chloroquine
occurred if parasite count in blood was ≥ 25% of count on
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
Level of resistance to chloroquine
in the patients but parasitological success was only
achieved in 45% of the patients. The proportion of
We adopted the 7-day WHO in vivo test protocol in
patients with clinical failure or parasitological failure were
determining the class of resistance to chloroquine (Bruce,
significantly higher in patients from 5 to 48 years old than
1986). Patients with marked reduction of parasitemia
patients below 5 years (p ≤ 0.001). Furthermore, the
(parasite count reduced by more than 75%) at 48 h but
proportion of patients from 5 to 48 years old with clinical
failed to clear parasites by day 7 were considered to be
failure was more than twice the proportion of patients
R2 resistant to chloroquine. Patients whose parasitemia
below 5 years with clinical failure. Also, the proportion of
did not fall by more than 75% within 48 h or occasionally
patients from 5 to 48 years years old with parasitological
increased by day 7 were considered to be R3 resistant to
failure was nearly doubled the proportion of patients
chloroquine. R1 resistance (clearance of asexual below 5 years with parasitological failure. Gender had no
parasitemia on or after day 7 followed by recrudescence)
significant effect on either the clinical response or
was not determined because the patients were only
parasitological response to chloroquine (p > 0.05).
monitored for 7 days and it is not possible to determine
recrudescence in areas of intense malaria transmission
Level of resistance to chloroquine
Class II (R2) and class III (R3) types of resistance were
Statistical Analysis of data
found to have occurred in 81 (37.2%) and 38 (17.4%) of
the patients, respectively. We found no significant
The data obtained were categorized based on sex and
differences in the levels of resistance in males when
age and reported as frequencies. Data were compared
compared to those of the females (p > 0.05).
Table 2. Clinical and parasitological response of chloroquine in patients with P. falciparum malaria. bp = 0.001; cp < 0.001
DISCUSSION
people. Malaria infections with parasite strains other than
P. falciparum have been suggested to act as natural
Drug resistance in malaria is the ability of the parasite
vaccines preventing severe manifestations of P.
strains to survive and/or multiply despite administration
falciparum infections (Williams et al., 1996). If this
and absorption of a drug given in doses equal to or
suggestion holds, clearance of P. falciparum malaria in
higher than those usually recommended but within the
the patients below 5 years of age could be enhanced, as
limits of tolerance of the subject (Bruce, 1986). The World
none of them had severe malaria. Furthermore, long-term
Health Organization (WHO) categorized resistance in
exposure to chloroquine, particularly by presumptive
malaria as S (sensitive), R1, R2 and R3 based on in vivo
chloroquine treatment or prophylaxis, are prerequisites
test (Bruce, 1986). This test was replaced in 1996 by
for the emergence of chloroquine resistance
WHO with the Therapeutic Efficacy Test based on clinical
(Mockenhaupt et al., 2000). This situation is less likely to
and parasitological criteria - a pragmatic test for National
occur in children below the age of 5 years than older
Malaria Control Programme (WHO, 1996). We have used
people. The efficacy of chloroquine is thus more likely to
these two approaches to evaluate the effectiveness of
be lower in people older than 5 years than those below 5
chloroquine in the five communities studied. Our results
years of age. Greater awareness on the need for early
have shown that chloroquine is still effective in the
and proper treatment in chlidren below 5 years of age
treatment of uncompicated P. falciparum malaria in the
may also be a contributing factor. Gender appears not to
communities despite the high prevalence of chloroquine-
play a role in therapeutic efficacy of chloroquine as we
resistant malaria in the region. This is evident in the
found no significant difference between the frequency of
clinical success of chloroquine in 74.3% of the patients.
therapeutic failures in males as compared to females.
However, parasitemia was still evident in 45% of the
Increasing resistance of P. falciparum malaria to
patients by the 7th day after the first dose of chloroquine
chloroquine has earlier been reported in some parts of
was administered, indicating resistance to chloroquine.
Nigeria (Umotong et al., 1991). Survellance network in
We recognise that a mixed population of malaria parasite
the country from mid-1987 to 1990 revealed that
strains (susceptible and resistant) can be present in the
chloroquine resistant P. falciparum (CRPF) was
blood of the patients. In this situation, the susceptible
widespread (Ekanem, 1997). In the northern part of the
strains would be killed by the chloroquine in the early part
country, parasitological failures increased from 18.7% in
of the treatment, making way for more resistant and
1988 to 24.5% in 1995 (Molta, 1995). From 1987 to 1997,
virulent strains to multiply later (Wernsdorfer et al., 1995).
resistance ranging from 33% to 72% was also reported in
Children under the age of 5 years are known to be the
the southern part of the country (Ekanem, 1997).
most susceptible group to malaria mortality (WHO,
Although the parasitological failure found in our study is
2002b). The severity and prevalence of malaria are also
similar to the 53.6% found in Calabar, southern Nigeria in
higher in this age group than older children and adults
1991 (Umotong et al., 1991), stability of resistance to
(May et al., 1999; Mockenhaupt et al., 2000). chloroquine in the area studied cannot be inferred Furthermore, at equal dosages per body weight, plasma
because the two areas (Calabar and Delta region) are in
chloroquine concentrations are lower in children below 5
different locations. Clinical failure of 25.7% recorded in
years of age than older children and adults (Maitland et
this study is also similar to the 22% reported in Ibadan,
al., 1997). These indications would suggest that the
southern Nigeria in 1997 (Ekanem, 1997; Oduola, 1997).
therapeutic failure of chloroquine in malaria treatment is
The frequencies of clinical and parasitological failures
likely to be higher in children younger than 5 years than
following chloroquine treatment are indicative of the
older people. Conversely, our results indicate that
continuous emergence of chloroquine resistance strains
children younger than 5 years had much lower
of P. falciparum in the communities studied and most
therapeutic failure rates than older people. The reason for
likely in other parts of the country. These frequencies are
this is unclear. Earlier report indicates that mixed species
at unacceptable levels having exceeded the 15 – 24% set
infections of malaria parasites are higher in children
by WHO (2002a) as action phase. Thus, the need for
below 5 years (Mockenhaupt et al., 2000) than older
action to be taken to address the problem in the
communities and other parts of the country has become
has been established as a measure to improve treatment
efficacy, delay the emergence of drug resistance, and
Based on WHO earlier categorisation of resistance to
reduce the prevalence of gametocyte carriage which
antimalarial drugs (class I, R1; class II, R2 and class III,
could, in turn, reduce transmission of malaria parasites
R3), our results have demonstrated high proportions of
(WHO, 2001a,b). Cost considerations in many parts of
R2 (37.2%) and R3 (17.4%) resistance in the the country would support the use of empirical treatment communities studied. The R3 resistance was similar to
with chloroquine or an alternative first-line drug, such as
that reported in 1991 in Calabar (Umotong et al., 1991).
sulfadoxine-pyrimethamine (Warhurst, 2001), in patients
Studies have shown that R3 resistance to chloroquine is
with uncomplicated malaria. In the case of more
not present in some areas in Congo (Carme et al., 1998)
expensive drug regimens, the cost would have to be
and Madagascar (Raharimalala et al., 1995) but present
balanced against the potential savings in the cost of
at a very low level in Coté d'Ivoire (Henry et al., 1998). R3
treatment. Reliable, microscopy-based diagnosis should
resistance in this study is lower than the 23% reported in
be mandatory in view of the financial implications when
Zimbabwe (Mohamva et al., 1996) and the 22% reported
much more expensive alternative drugs need to be used
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
Conclusion
(Hombhanje, 1997). High, rather than low, doses of
chloroquine is believed to induce R3 resistance to
Chloroquine is still effective in the treatment of most
cases of uncomplicated P. falciparum malaria in some
The mechanism of resistance to chloroquine in the
communities in Delta State, Nigeria. However, in many
communities studied is not clear, since the mechanism of
cases of uncomplicated P. falciparum malaria, resistance
resistance to antimalarial drugs is still debatable
to chloroquine is likely and intervention with alternative
(Wellems et al., 1990; Rathod et al., 1997; Phillips, 2001).
antimalarial drugs may be required for complete
However, resistance to chloroquine has been reported to
clearance of parasitemia in the patients. Despite the
be due to reduced uptake of the drug by the infected
limited communities in which this study was carried out,
erythrocyte and presumably reflects a reduction in the
our results may be used as an important indicator of the
accumulation of the drug in the parasite’s lysosome
significant level of therapeutic failure of uncomplicated P.
(Phillips, 2001; Warhurst, 2001). Association between
falciparum malaria to chloroquine in Nigeria. Additional
chloroquine resistance and mutations in an mdr-like gene
drug efficacy assessment throughout the country is
(pfmdr-1) has been reported (Warhurst, 2001). There is
needed to support national antimalarial drug policy.
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
ACKNOWLEDGEMENTS
use of a rapid and sensitive test to detect pfcrt T76 in
blood samples to ascertain the effectiveness of We are grateful to the staff and management of Central
chloroquine (Warhurst, 2001; Reed et al., 2000). A
Hospital, Warri and Calvary Medical Laboratory for their
number of factors have been identified as playing a role
support. This work was carried out with the financial
in the emergence of resistance to chloroquine. These
support from the Arienmughare family of Warri, Delta
include poor compliance to drug therapy, host immunity,
use of sub-therapeutic doses, mutation and frequency of
re-infection (Hombhanje, 1997; Phillips, 2001;
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Therapeutisches Drug Monitoring im Rahmen der systemischen antimykotischen Therapie: Invasive Pilzinfektionen werden überwiegend durch Aspergillus spp . ( A. fumigatus ) und Candida spp . hervorgerufen und stellen lebensgefährliche Komplikationen dar. Aspergillosen imponieren nach Inokulation über den Respirationstrakt initial als Pneumonie und treten vor allem bei hämatologis
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