Uncomplicated P. Falciparum Malaria Clinical Trial
Official title:
Efficacy and Safety of Artesunate+Sulphadoxine-Pyrimethamine for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Malaria Control Center Asadabad in Kunar Province of Afghanistan
In Afghanistan, studies over the past 15 years have shown a high degree of Plasmodium
falciparum resistance to chloroquine. In 2003 the high failure rate of chloroquine against
falciparum malaria led the national malaria treatment programme to switch its recommended
first line drug treatment for uncomplicated Plasmodium falciparum malaria to
artemisinin-based combination therapy (ACT) in the form of
Artesunate/Sulphadoxine-Pyrimethamine (AS+SP). Second line drug treatment is oral quinine (7
days).
For operational reasons, prior to recent studies (manuscript in preparation) there have been
no molecular data on P. falciparum SP resistance markers from within the borders of
Afghanistan. These studies have revealed early evidence of increasing SP resistance
(resistance polymorphisms with double DHFR & triple DHPS mutations). The aim of this study is
to conduct a focused, prospective study in Kunar for monitoring of the efficacy of the AS+SP
combination in this province, along with molecular studies of isolates from recruited
patients.
Afghanistan is a poor country that remains largely dependent on foreign aid. Life expectancy
remains in the order of 60 years, with 30% of mortality due to communicable diseases.
Malaria is a large health burden, and antimalarial drug resistance poses a considerable
threat to malaria control. Resistance to chloroquine was evident in Afghanistan by the
late-1990s, with failure rates more than 60% for the country as a whole and as high as 90%
for Jalalabad (Nangarhar province). The combination of artesunate with amodiaquine also
proved to have low efficacy. In 2004 failure rates for SP for the treatment of P. falciparum
were 10-15% consistent with comparable clinical data in Afghan refugees residing in Pakistan.
Given this efficacy, the Ministry of Public Health, in consultation with WHO and other
international partners, has implemented AS+SP as first-line treatment of slide confirmed P.
falciparum malaria in Afghanistan. Quinine (7 days po) is second line treatment. CQ+SP has
been the recommended treatment for patients with a presumptive diagnosis of malaria since
2003. Both artesunate and sulphadoxine-pyrimethamine are safe and well tolerated drugs and
there is no evidence of an interaction between them.
Artesunate (AS) has been reported to be associated with mild gastrointestinal disturbances,
dizziness and tinnitus although none of these associations are convincing. The only
potentially serious adverse effect that has been reported with the artemisinin class of drugs
in clinical trials is type I hypersensitivity reactions (about 1:3,000 patients). Transient
reticulocytopenia, neutropenia, and elevated liver enzyme values have been reported but none
have been clinically significant. The weight of evidence suggests these drugs have no
significant adverse cardiovascular effects. A variety of clinical, neurophysiological, and
pathologic studies in humans have not shown evidence of neurological toxicity. Because these
drugs have not been evaluated extensively in early pregnancy in humans, they should be
avoided in patients in the first trimester of pregnancy with uncomplicated malaria until more
information is available (WHO guidelines 2006).
Sulphadoxine-pyrimethamine (SP) is a fixed combination of a long-acting sulfonamide and the
antifolate pyrimethamine. These are synergistic against sensitive parasites. Minor adverse
effects are unusual and serious sulfonamide toxicity is very unusual with a single-dose
treatment of malaria. The anti-folate properties of pyrimethamine rarely produce toxicity.
The combination of AS + SP has been evaluated extensively in adults and children with
uncomplicated malaria and is sufficiently efficacious in areas where 28-day cure rates with
sulphadoxine-pyrimethamine alone exceed 80%. This ACT is currently being used in parts of
South America, the Middle East, and South Asia where SP susceptibility remains high. Studies
conducted between 2004-2006 to evaluate the efficacy of artesunate plus
sulphadoxine-pyrimethamine (AS+SP) against P. falciparum showed high efficacy in terms of
adequate clinical and parasitological response (Afghanistan National Malaria Strategic Plan).
The genetic determinants of in vitro resistance to the two drug components of SP individually
are shown to be point mutations at seven sites in the dihydrofolate reductase gene (dhfr)
causing resistance to pyrimethamine and five sites in the dihydropteroate synthase (dhps)
gene causing resistance to sulphadoxine. Different combinations of mutations within each gene
confer differing degrees of insensitivity. Due to administrative instability, until recently
few molecular data relating to P. falciparum SP resistance markers have been available from
within the borders of Afghanistan. However the investigators have obtained recent (submitted)
data showing that in addition to two resistance polymorphisms in DHFR (C59R and S108N) that
are well known to be at high frequency in the region, a small number of parasites in the
Kunar province have three mutations (A437G, K540E and A581G) in DHPS.
This study is a prospective, open label, single arm clinical trial to test the PCR confirmed
efficacy and tolerability of AS+SP for the treatment of uncomplicated falciparum malaria in
Afghanistan. Follow-up will be for 42 days, in order to sensitively detect recrudescence.
Recrudescence will be distinguished from re-infection by molecular techniques based on well
characterized microsatellite markers msp1, msp2 and glurp will be used. Baseline and any
recurrent parasites will be tested for DHFR and DHPS polymorphisms by RFLP as well as
sequencing if indicated. The proposed study will provide accurate data and accurate evidences
on efficacy of the current malaria treatment regimen in Afghanistan.
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