Am. J. Trop. Med. Hyg., 77(Suppl 6), 2007, pp.

181192
Copyright 2007 by The American Society of Tropical Medicine and Hygiene

Artemisinin-Based Combination Treatment of Falciparum Malaria

Franois Nosten and Nicholas J. White*
Shoklo Malaria Research Unit, Mae Sot, Thailand; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for
Tropical Medicine and Vaccinology, Churchill Hospital, Oxford, United Kingdom

Abstract. Artemisinin-based combination treatments (ACTs) are now generally accepted as the best treatments for
uncomplicated falciparum malaria. They are rapidly and reliably effective. Efficacy is determined by the drug partnering
the artemisinin derivative and, for artesunatemefloquine, artemetherlumefantrine, and dihydroartemisinin
piperaquine, this usually exceeds 95%. Artesunatesulfadoxinepyrimethamine and artesunateamodiaquine are effective in some areas, but in other areas resistance to the partner precludes their use. There is still uncertainty over the
safety of artemisinin derivatives in the first trimester of pregnancy, when they should not be used unless there are no
effective alternatives. Otherwise, except for occasional hypersensitivity reactions, the artemisinin derivatives are safe and
remarkably well tolerated. The adverse effect profiles of the artemisinin-based combination treatments are determined
by the partner drug. Most malaria endemic countries have now adopted artemisinin-based combination treatments as
first-line treatment of falciparum malaria, but in most of these only a minority of the patients that need artemisinin-based
combination treatments actually receive them.
then incidence will fall. Policy has now changed in most countries (Figure 1) but the challenge now is to deliver these drugs
to the people that need them. Donor support has increased,
there are better drugs, and there are better mechanisms for
delivery, but there is still an enormous gap between the funds
and drugs available and the global need.

INTRODUCTION
Falciparum malaria is a mass killer that went out of control.
The drug treatments for this potentially lethal infection that
have been most widely recommended and provided over the
past 50 years (i.e., chloroquine and sulfadoxinepyrimethamine) no longer work in most tropical countries. Resistance
to these drugs emerged in Asia and South America and
spread to Africa. As resistance worsened, morbidity and mortality rose as a direct consequence. But this was not appreciated because surveillance was poor, and the clinical and epidemiologic methods used to measure morbidity, mortality,
and drug resistance were insensitive. After much procrastination the seriousness of the situation was finally appreciated in
the 1990s, although antimalarial policy did not change from
ineffective to effective antimalarial drug treatment until the
past 3 years in most countries. Replacing the failing chloroquine and sulfadoxinepyrimethamine with effective drugs
required increased donor support because most endemic
countries could barely afford the failing medicines, let alone
more expensive ones. This was not forthcoming initially.
Fortunately things are changing for the better. There is now
considerably more funding available for malaria control in
endemic countries, particularly from the Global Fund
(GFATM). The treatments now recommended by the World
Health Organization and supported by the GFATM for uncomplicated falciparum malaria are artemisinin-based combination treatments (ACT); these are combinations of an artemisinin derivative and another structurally unrelated and
more slowly eliminated antimalarial. WHO has also raised
the bar recently in recommending that cure rates should be
at least 90% and preferably > 95% assessed at 28 days.1
Failure rates at 14 days of 25% (which are compatible with
true failure rates up to 60%2) are no longer considered acceptable. Provided the partner drug is effective, then ACTs
ensure prompt recovery and high cure rates, and they are
generally well tolerated. Replacing the older failing or failed
monotherapies with effective drugs will reduce morbidity and
mortality. In lower transmission settings if coverage is good,

RATIONALE
Malaria is a (eukaryotic) protozoan parasite of red blood
cells that may reach burdens as high as 1013 in the blood of the
human hostalthough most symptomatic infections are
caused by between 107 and 1012 parasites. The theory underlying combination drug treatment of tuberculosis, leprosy,
and HIV infection and many cancers is now well known, and
the same general principle is now widely accepted for malaria.
If two drugs are used with different modes of action, and
therefore different resistance mechanisms, then the perparasite probability of developing resistance to both drugs at
the same cell division is the product of their individual perparasite probabilities.36 This is of particular relevance to malaria because on any one day there are only about 1017 malaria parasites in the entire world.7,8 Most identified mechanisms of antimalarial drug resistance result from genetic
mutation. Mutation rates for eukaryotes are of the order of 1
in 106 divisions but viable resistant mutant parasites are selected at much lower frequencies. Gene duplications occur
more readily than mutations throughout the parasite genome
and may also contribute to drug resistance. Amplification of
Pfmdr, which results in increased transcription, and therefore
more of this protein pump per cell, is the main contributor
to mefloquine resistance, but at a fitness cost for the parasite.9,10 The highest frequencies documented for the de novo
emergence of mutations conferring drug resistance in acute
malaria in humans are for atovaquone and pyrimethamine at
around 1 in 1012 parasites.7 So if the per parasite probability
of developing resistance to 2 drugs (A and B) are both high at
1 in 1012, then a simultaneously resistant mutant (i.e., resistant
to both A and B) will arise spontaneously every 1 in 1024
parasites. But because there is a cumulative total of less than
1020 malaria parasites in existence each year, such a simultaneously resistant parasite would arise spontaneously roughly
once every 10,000 years, provided the drugs always con-

* Address correspondence to Nicholas White, Faculty of Tropical

Medicine, Mahidol University, 420/6 Rajvithi Rd., Bangkok 10400,
Thailand. E-mail: nickw@tropmedres.ac

181

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NOSTEN AND WHITE

FIGURE 1. The malaria affecting the world at the beginning of 2007 showing the countries that have adopted ACTs as National policy for the
first-line treatment of uncomplicated falciparum malaria. Reproduced by kind permission of the Global Malaria Program, World Health Organization.

fronted the parasites in combination.7 Thus provided the de

novo per parasite probability of developing resistance is not
much higher than 1 in 1012 cell divisions and both drugs are
present together at inhibitory concentrations, then combinations markedly delay the emergence of resistance. But for
ACTs, because the artemisinin derivatives are eliminated rapidly, and the partner drugs are eliminated slowly, there is
complete protection only for the artemisinin derivative. The
combination still provides good protection against the emergence of resistance to the partner drug, but once resistance
has developed the residual concentrations of unprotected
partner drug do provide a selective filter enhancing the
spread of resistance to the partner compound.7,8 Figure 2
shows the pharmacokineticpharmacodynamic rationale for
ACTs using artesunatemefloquine as an example.
Although parasite lines with reduced susceptibility can be
selected in the laboratory, therapeutically significant resistance to the artemisinin derivatives has not yet been identified. High-grade stable artemisinin resistance cannot be confirmed yet in the laboratory, which suggests that it may be a
rare event. The recent report that some parasites from French
Guyana with mutations in the gene encoding the putative
target PfATPase6 were highly resistant to artemether has

raised concerns,11 but these parasites have not been cultured,

and this finding must be confirmed. Treatment failure rates
are higher and parasite clearance times longer with ACTs in
Western Cambodia than elsewhere, the epicentre of drug resistance in Southeast Asia. Even if reduced susceptibility to
artemisinin derivatives is not substantiated, and despite the
reassuring laboratory studies, it would still be foolish to assume that resistance to these valuable drugs will not happen.
If high-level stable resistance to the artemisinin drugs does
arise it would be a disaster for the malaria-affected world
because they are now the cornerstone of antimalarial treatment. For mutual protection against the emergence of drug
resistance, these drugs should be used only in combination
with other antimalarials, such that no parasite sees the artemisinin component without the other drug being present.
Artemisinin derivatives are particularly effective in combinations because of their high killing rates (parasite reduction
ratios RR circa 10,000 fold per cycle),6,7 lack of adverse effects, and absence of significant resistance. In ACTs a 3-day
treatment course exposes 2 asexual cycles and so reduces the
number of parasites in the body by approximately one hundred million-fold. The gametocytocidal activity of the artemisinin compounds is an important bonus reducing transmis-

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ARTEMISININ-BASED COMBINATION TREATMENT

FIGURE 2. The pharmacokineticpharmacodynamic profile of artemisinin combination treatment in falciparum malaria.68 The individual patient parasite burden (approximating to 2% parasitemia in
an adult) is shown on the vertical axis in a logarithmic scale, and the
concomitant profile of drug concentrations is shown as a curved red
line. The total numbers of parasites exposed to the drugs are shown
as triangles, the area of which corresponds to total numbers in the
blood. In this example the ACT partner drug is mefloquine. The
treatment is given for 3 days, which covers 2 asexual cycles and the
effect of the artesunate is a 100,000,000-fold reduction in parasite
burden. This leaves approximately 10,000 parasites (dark green triangle B) remaining for residual concentrations of mefloquine (from
points m to n) to remove. If no artesunate had been given, the mefloquine would have reduced the parasite burden more slowly (light
brown large triangle), and the number of parasites corresponding to
B (i.e., B1) would have been exposed to lower mefloquine concentrations (from points p to q). In this example these concentrations
would be insufficient to inhibit growth of the most resistant parasites
prevalent (minimum inhibitory concentration; MIC R ) and so,
whereas the ACT would cure all infections provided these blood
concentrations were achieved, there would be treatment failures with
mefloquine monotherapy. MICs refers to the most sensitive MICs for
artesunate and mefloquine respectively. The time from points x to y
on the mefloquine elimination curve represents the window of selection (about 16 days in this example) during which newly acquired
infections with sensitive parasites cannot establish themselves
whereas resistant parasites can.

sibility and thus further reducing malaria incidence in lowtransmission settings.1214

Artemisinin and its derivatives are the most rapidly eliminated of all antimalarials with half-lives of approximately 1
hour. The ideal pharmacokinetic properties for an antimalarial drug have been a subject of much discussion. As described, from a resistance prevention perspective, the combination partners should have similar pharmacokinetic properties to provide optimum mutual protection. Slow elimination
of the partner drug allows 3-day regimens to be given, but at
the price of providing days or weeks of subtherapeutic blood
levels that provide a selective filter for resistant parasites acquired from elsewhere, and thereby encouraging the spread
of resistance1517 (Figure 2). On the other hand these residual
prophylactic levels18 suppress new infections giving a period of post treatment prophylaxis (PTP) which, in hightransmission settings, may improve clinical and hematological
recovery. Rapid elimination ensures that the residual concentrations do not provide a selective filter for resistant parasites,
but rapidly eliminated drugs (if used alone) do not provide
any PTP, must be given for 7 days, and adherence to 7-day
regimens is poor.6 Incomplete treatment encourages resistance. Even 7-day regimens of artemisinin derivatives (as
monotherapy) are associated with approximately 10% failure

rates.19,20 Thus to be highly effective in a 3-day regimen, the

terminal elimination half-life of at least one drug component
must exceed 24 hours (longer for less active drugs) such that
concentrations in the fourth drug-exposed asexual cycle (7 to
8 days after starting treatment) are still sufficient to suppress
multiplication of the most resistant parasites prevalent.6,7
Provided there is not high-level resistance to the partner drug,
then ACTs provide complete protection for the artemisinin
derivatives from selection of a de novo resistant mutant if
adherence is good (i.e., no parasite is exposed to artemisinin
during one asexual cycle without the partner being present),
but this does leave the partners slowly eliminated tail unprotected by the artemisinin derivative. However, because
artemisinin and its derivatives reduce parasite numbers by
approximately 10,000-fold per 2- day asexual cycle, the residual number of parasites exposed to the slowly eliminated
partner drug alone, after 2 asexual cycles of artemisinin exposure, is a tiny fraction (< 0.0001%) of those present at the
peak of the acute symptomatic infection (Figure 2). Furthermore these residual parasites are exposed to relatively high
levels of partner drug and, even if susceptibility was reduced,
these levels are usually sufficient to eradicate the infection.
But the long elimination phase tail of the partner drug does
provide a selective filter for resistant parasites acquired from
elsewhere, and thereby contributes to the spread of resistance
once it has developed. Although the greatest use of antimalarials is in high-transmission areas, historically resistance has
emerged and spread most rapidly in low-transmission settings. This illustrates the important role of host immunity in
delaying the emergence and spread of resistance.

DEPLOYMENT
The main obstacles to the success of combination treatment
in preventing the emergence of resistance will be inadequate
treatment (e.g., substandard drugs, incorrect dosing, unusual
pharmacokinetics, poor adherence) and, as for antituberculous drugs, use of one of the combination partners alone. This
is why blister packing has been encouraged and fixed dose
combinations are now being developed and recommended.
Cost is a major obstacle to ensuring adequate treatment because patients may not have enough money to purchase a full
course of treatment or, once they feel better, will keep the
remaining prescribed drugs for themselves or a family member when they next fall ill. Poor quality drugs are common in
tropical areas of the world and counterfeit medicines are a
major concern. Antimalarials are available widely in the market place, and often sold at incorrect doses or without correct
advice. Even when a correct course is obtained adherence to
antimalarial treatment regimens is often incomplete. Resistance to the artemisinins may not have happened yet, but it
would be unwise to be complacent. If artemisinin resistance
does emerge it will most likely arise in a hyperparasitemic
patient who received an inadequate dose of a single antimalarial drug (i.e., not in combination with another suitable antimalarial agent).7 Irrespective of the epidemiologic setting,
ensuring that patients with high parasitemias receive a full
course of treatment with adequate doses of ACTs would be
an effective method of slowing the de novo emergence of
antimalarial drug resistance.
Ideally, to ensure the maximum useful therapeutic life,

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NOSTEN AND WHITE

TABLE 1
Summary of pharmacokinetic properties of antimalarial drugs that have been used in artemisinin combination treatments
Drug

Absorption:
time to peak (h)

Oral dose
(mg/kg)

Plasma peak level

(mg/L)

Binding
(%)

Vd/f
(l/kg)

Clearance/f
(ml kg1 min1)

T1/2
(hrs)

Chloroquine
Piperaquine*
Amodiaquine
Dihydroartemisinin
Artesunate
Artemether
Mefloquine
Halofantrine
Lumefantrine
Pyrimethamine
Chlorproguanil
Atovaquone
Sulfadoxine
Dapsone

5
47
4

1.5
2
17
15
6
9
4
6
24
4

10
32
10
4
4
4
25
8
9
1.25
2
15
25
2.5

0.12
0.75
0.37
0.36
0.5
1.5
1.2
0.9
3.5
0.28
0.1
5
64
0.9

55
> 99

93

95
> 98
> 98
> 98
94

99.5
88
73

101000
574

0.15
2.7
20

2.7
6.3
37
6
41
1.5

2.0
15
46

50
54
0.35
7.5
3.0
1.2
17
2.5
0.04
0.7

7201440
> 550
240
0.75
0.75
1
336
113
86
65
35
30
100
27

Vd/f is the total apparent volume of distribution divided by f, the fraction of drug absorbed.
T1/2 is the terminal phase elimination half-life.
* Given in combination with dihydroartemisinin and taken with food.
t1/2 of the active metabolites; desethyl amodiaquine for amodiaquire and dihydroartemisinin for artesurate and artemethes.
Absorption increased significantly by fats.
Binds to lipoproteins.
Pregnancy is usually associated with lower drug concentrations.

there should be no resistance to the partner drug in an ACT,

yet on the Northwestern border of Thailand, an area of low
transmission where mefloquine resistance had developed already, systematic deployment of artesunatemefloquine combination therapy was dramatically effective both in stopping
resistance, and also in reducing the incidence of malaria.14,21
In fact mefloquine resistance declined after widespread deployment of artesunatemefloquine.22 In this setting before
ACTs were introduced when mefloquine monotherapy was
used, resistant parasites had a survival and transmission advantagewhich was negated by the artesunatemefloquine
combination treatment. Mefloquine resistance develops rapidly because gene amplification is a relatively frequent mitotic
event in P. falciparum, but it may also go rapidly as deamplification is also frequent, and Pfmdr amplification carries a
fitness cost. But for the other drugs and resistance mechanisms involving mutations, deploying an ACT containing a
failing drug may not lead to a reversal of resistance, and could
eventually leave the artemisinin component inadequately
protected as resistance to the partner worsens. Four ACTs
are currently recommended by WHO: artesunatemefloquine, artesunatesulfadoxinepyrimethamine (SP), artesunateamodiaquine, and artemetherlumefantrine. The combinations containing SP and amodiaquine are both threatened
by resistance.1

ACCESS
Artemisinin-based combination treatments are highly effective and really could make a major contribution to global
malaria control, but despite the recent changes in policy in
most malaria endemic countries (Figure 1) only a minority of
people who need these drugs actually receive them. Cost and
access remain formidable obstacles. Few public health structures reach out far enough or efficiently enough to provide
good coverage of effective and affordable drugs to rural communities. The Institute of Medicine reviewed and assessed the
various deployment options available.23 The review recog-

nized that the private sector still played a major role in antimalarial drug delivery in most tropical countries, and concluded that existing frameworks for antimalarial drug delivery
would not provide sufficient ACT coverage to make a major
impact on malaria, would not provide sufficient protection
against the emergence of artemisinin resistance, and would
continue to provide incentives to fake or substandard drugs.
The IOM committee recognized the potential contribution
ACTs could make to global malaria control and recommended subsidizing the cost of ACTs both to the public and
to the private sectors such that these new effective treatments
would cost no more than chloroquine to the end user. Thus
market forces would drive the ICT distribution. They noted
that antimalarial drug resistance has usually arisen in Asia
and therefore preventing resistance arising in Asia should
benefit Africa. There is increasing support for this initiative,
but there is much work to do. The current challenge is to raise
sufficient funds, to work out how best to operate such a subsidy, and how to put in place all the necessary monitoring and
evaluation mechanisms necessary.
PHARMACOLOGY
Artemisinin, the parent drug, has now largely given way to
the more potent dihydroartemisinin and its derivatives, artemether, artemotil, and artesunate. The 3 derivatives are all
converted back in vivo to dihydroartemisinin. Oral absorption is good (bioavailability > 60%) with peak concentrations
usually achieved within 4 hours. Dihydroartemisinin has more
variable oral bioavailability dependent on the excipients in
the oral formulation.2430 All are eliminated rapidly by metabolic biotransformation with half-lives of 1 hour or less (Table
1). Artesunate is readily hydrolyzed at neutral and acidic pH,
and deesterification is accelerated by red cell and plasma esterases. Artemether and artemotil are biotransformed more
slowly, being demethylated by metabolic transformation
(principally by CYP 3A4).31 These drugs are highly active
against all Plasmodium species. The artemisinin derivatives
are the most rapidly acting of all antimalarial drugs and pro-

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duce the fastest clinical responses to treatment. They are noticeably better than other antimalarial drugs. They have a
broad spectrum of antimalarial activity acting against the
young ring form parasites and preventing their development
to the more mature pathogenic stages.6 This explains the
rapid therapeutic responses obtained with the artemisinin derivatives. This effect is particularly important in the management of severe malaria, where artesunate has been shown to
reduce mortality. Artemether and artemotil have slightly less
antimalarial activity than artesunate in vitro but all 3 compounds are readily converted in vivo to dihydroartemisinin,
which contributes the majority of antimalarial effect in treatment. Dose regimens of the drugs are similar. In combination
with more slowly eliminated antimalarials, the addition of
artesunate, artemether, or dihydroartemisinin consistently
improves cure rates (unless they were 100% already) and has
the advantage of producing a more rapid clinical response to
treatment, reduction in gametocyte carriage, and thus malaria
transmission, and, when deployed extensively in lowtransmission areas, a reduction in malaria incidence.1214 A
3-day course of the artemisinin derivative in combination with
a slowly eliminated partner drug (elimination half life > 1
day) is required for optimum cure rates. Two-day and 1-day
courses are insufficient because they expose only one asexual
cycle to the artemisinin derivative. If the partner drug is effective then such regimens will still give high cure rates, but
they will not provide sufficient protection against the emergence of resistance. There has been some investigation of the
optimum dose with in-vivo dose response studies suggesting
that at least 2 mg/kg/d for 3 days of artesunate is required for
maximal effect.32 Current ACTs regimens contain between
2.5 and 4 mg/kg of artemisinin derivative given daily for 3
days. They are easy to use, and are well tolerated. There are
no specific pediatric formulations, although a pediatric formulation of artemetherlumefantrine and fixed dose combinations of artesunatemefloquine and artesunateamodiaquine with pediatric tablet sizes have been developed.33

ADVERSE EFFECTS
Artemisinin and its derivatives are safe and remarkably
well tolerated. There have been reports of mild gastrointestinal disturbances, dizziness, tinnitus, and bradycardia, although none of these associations are convincing.34 The only
potentially serious adverse effect that has been reported with
this class of drugs in clinical trials is type 1 hypersensitivity
reactions in approximately 1 in 3,000 patients.35 Transient
reticulocytopenia, neutropenia, and elevated liver enzyme
values have been reported but none have been clinically significant. Electrocardiographic abnormalities, including prolongation of the QT interval, have also been reported although most studies have not found any significant electrocardiographic abnormalities. Indeed the weight of evidence
suggests these drugs have no adverse cardiovascular effects at
all.34 In severe malaria, as with quinine, blackwater fever has
been reported. In all species of animals tested, intramuscular
artemether and artemotil cause an unusual selective pattern
of neuronal damage to certain brain stem nuclei.36,37 Neurotoxicity in experimental animals is related to the sustained
blood concentrations that follow intramuscular administra-

tion of the oil-based derivatives artemether and artemotil,

because it is much less evident when the same doses are given
orally, or with similar doses of water-soluble drugs such as
artesunate, despite transiently higher blood concentrations.3841 With the single exception of one much disputed
report,42,43 extensive clinical, neurophysiological, and pathologic studies in humans have not shown similar findings with
therapeutic use of these compounds.4448 Artemisinin and its
derivatives inhibit erythropoesis in the early fetus, and cause
fetal resorption in all experimental animals tested to date.
This can in some circumstances lead to developmental abnormalities in rodents and rabbits.4951 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 (see below).1 There is no evidence for adverse effects on the fetus exposed in the second and third
trimesters, when these drugs are recommended depending on
the safety profile of the partner drug. The safety profile of
ACTs is therefore determined by the partner drug. Largescale safety monitoring or pharmacovigilance is often talked
about in the context of antimalarial drugs, but it is difficult,
and it is not often done. As deployment increases the ACTs
will be used with increasing frequency in individuals. More
information on safety with frequent dosing is needed.

THE ACTS
Chloroquine resistance is now so widespread that it is not
included in currently recommended ACTs.52 ArtesunateSP
and artesunateamodiaquine are used in areas with drug susceptibility to these drugs. In areas where resistance to sulphonamidepyrimethamine, chloroquine, and amodiaquine is
prevalent, then artemisinin combinations with either lumefantrine or mefloquine are the current alternatives. Soon
these drugs will be joined by ACTs in fixed dose coformulations containing piperaquine, pyronaridine, or chlorproguanildapsone. In general, blister-packed oral formulations of
these drugs have shelf-lives in tropical conditions of 2 years.
Longer shelf-lives would considerably facilitate deployment.

ARTESUNATESULFADOXINEPYRIMETHAMINE
Sulfadoxine-pyrimethamine is a fixed combination of a
long-acting sulfonamide and the antifolate pyrimethamine.
These are synergistic against sensitive parasites. Minor adverse effects are unusual. Serious sulfonamide toxicity is unusual with a single-dose treatment of malaria. The anti-folate
properties of pyrimethamine rarely produce toxicity. The
combination with artesunate is available as separate scored
tablets containing 50 mg of artesunate and tablets containing
500 mg of sulfadoxine and 25 mg of pyrimethamine. There are
no plans for developing a fixed dose combination. The total
recommended treatment is 4 mg/kg BW of artesunate, given
once a day for 3 days and a single administration of sulfadoxinepyrimethamine 1.25/25 mg base/ kg BW on admission.
This SP dose was developed in adults but in the main target
group (children aged 25 years) the weight adjusted dose produced blood concentrations of both components that are ap-

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NOSTEN AND WHITE

proximately half those in adults.53 Thus the standard dose

may be sub-optimal in younger children. The combination has
been evaluated extensively in adults and children with uncomplicated malaria and is sufficiently efficacious in areas
where 28-day cure rates with sulfadoxinepyrimethamine
alone exceed 80%.52,54 This ACT is currently being used in
parts of South America, the Middle East, and South Asia
where SP susceptibility remains high. Because sulfadoxine
pyrimethamine, sulfalenepyrimethamine, and trimethoprim
sulfamethoxazole (co-trimoxazole) are still widely used as
monotherapies, resistance is likely to worsen.
ARTESUNATEAMODIAQUINE
Amodiaquine, like chloroquine, is a 4-aminoquinoline; it is
effective against chloroquine-resistant strains of P. falciparum, although there is some cross-resistance. In recent
years resistance has worsened considerably in parts of East
and Southern Africa. After oral administration amodiaquine
is largely converted to desethylamodiaquine, which contributes the majority of antimalarial activity. Amodiaquine is
generally reasonably well tolerated and slightly more palatable than chloroquine, although in some areas it has not been
a popular substitute. The serious adverse effects that have
been associated with its prophylactic use (agranulocytosis and
severe liver toxicity) are considered rare when amodiaquine is
used in malaria treatment, although more data are needed to
characterize the risks. More data are also required in pregnancy. The combination of amodiaquine with artesunate is
currently available in blister packs as separate scored tablets
containing 50 mg of artesunate and 153 mg base of amodiaquine, but co-formulated tablets have been developed recently by the Drugs for Neglected Diseases initiative (DNDi).
The total recommended treatment is 4 mg/kg BW of artesunate and 10 mg base/kg BW of amodiaquine once a day for 3
days. Artesunateamodiaquine has proved to be an efficacious combination in areas where 28-day cure rates with amodiaquine monotherapy exceed 80%.5557
ARTEMETHERLUMEFANTRINE
This was the first fixed dose combination of an artemisinin
derivative with a second unrelated antimalarial compound.
Lumefantrine (formerly benflumetol) is an aryl aminoalcohol in the same general group as mefloquine and halofantrine. It was discovered and developed in the Peoples
Republic of China. Lumefantrine is active against all the human malaria parasites, including multi-drugresistant P. falciparum (although there is some cross-resistance with halofantrine and mefloquine). Artemetherlumefantrine is dispensed as tablets containing 80/480 mg respectively. It was
introduced originally as a 4-dose regimen given at 0, 8, 24, and
48 hours. This shorter course proved insufficiently efficacious.
Pharmacokineticpharmacodynamic (PKPD) studies indicated that the principal PK determinant of cure was the area
under the plasma lumefantrine concentration time curve
(AUC), or its surrogate, the day 7 lumefantrine level.58
Lumefantrine absorption (like that of atovaquone and halofantrine) is critically dependent on co-administration with fats
and thus plasma concentrations vary markedly between patients.58 In Thailand day 7 levels over 500 ng/mL were asso-

ciated with > 90% cure rates. With the 4-dose regimen plasma
concentrations of lumefantrine during the third and fourth
post-treatment cycles (48 days) were insufficient to eradicate
all infections. To increase the AUC and thus cure rate, a
6-dose regimen (adult dose 80/480 mg at 0, 8, 24, 36, 48, and
60 hours) was then evaluated.59 This has proved highly effective and remarkably well tolerated. Against multi-drug
resistant falciparum malaria the 6-dose regimen of artemetherlumefantrine is generally as effective as and better
tolerated than artesunatemefloquine.6064 Artemether
lumefantrine is becoming increasingly available in tropical
countries. The excellent adverse effects profile and recent
price reductions (down to US $1 per adult treatment) make it
an increasingly attractive treatment option. New formulations
have also been produced but these must demonstrate comparable bioavailability with the original formulation before they
can be recommended. However, the complexity of the treatment (2 doses per day) and the required fat co-administration
(albeit small amounts; at least 1.2 g/dose) are obstacles.65
Once a day dosing is not an option because absorption is dose
limited.66 There is increasing evidence of safety for this combination in the second and third trimesters of pregnancy. But
plasma concentrations of artemether, the metabolite dihydroartemisinin, and lumefantrine are all significantly reduced
in late pregnancy, suggesting that a longer course of treatment
may be needed in this vulnerable patient group.67

ARTESUNATEMEFLOQUINE
Mefloquine is a quinoline methanol compound related to
quinine.68 Several different mefloquine formulations are now
available with different oral bioavailability. Employment of
mefloquine as monotherapy for the management of malaria
has lead to rapid spread of resistance, mediated mainly by an
increase in copy number and expression of the P. falciparum
multi-drug resistance (MDR) gene (Pfmdr1).69 There is theoretical evidence to suggest that initial deployment of the
lower dose of mefloquine encourages resistance, and that initial use of higher doses, preferably in combination with an
artemisinin derivative is less likely to lead to resistance.70
Where adherence can be assured the dose should be split at
15 mg/kg initially followed 824 hours later by a second 10
mg/kg or as 8.3 mg/kg daily for 3 days (this is approximately
the dose in the new fixed dose combination). This improves
bioavailability and reduces vomiting.71 There is no formulation of mefloquine for children. Despite earlier restrictions
there is no reason to withhold mefloquine from young children. Limited information suggested that mefloquine was
probably safe in pregnancy, although the observation in Thailand of an increased stillbirth risk when mefloquine was used
in treatment at any stage of pregnancy has cast uncertainty
over its use in pregnant women.72 This effect was not seen in
large studies conducted in Malawi.73 Mefloquine commonly
induces nausea, dysphoria, and dizziness, and in approximately 1:1,000 Asian patients, and up to 1:200 Caucasians or
African subjects, mefloquine treatment induces a self-limiting
acute neuropsychiatric syndrome manifest by encephalopathy, convulsions, or psychosis.34 Suicide has been reported.
The risks of this acute neuropsychiatric syndrome are increased if the patient has a previous history of psychiatric
illness or epilepsy. There is a considerable increase in the risk

ARTEMISININ-BASED COMBINATION TREATMENT

if mefloquine is used after severe malaria. Approximately

1:20 patients given mefloquine after recovery from cerebral
malaria will have an acute reaction and therefore mefloquine
should not be used in this group.74 Neuropsychiatric reactions
are also more common if mefloquine has been used in the
previous 2 months, and therefore mefloquine should not be
used to treat recrudescent infections occurring within 2
months of treatment. However in practice the principle adverse effect of mefloquine is vomiting. This is more likely in
young children, and even if the drug is administered again,
low blood levels and an increased risk of treatment failure
result. Combining artesunate or artemether (4 mg/kg/day for
3 days) with mefloquine has all the advantages of a combination treatment previously described,75 and the additional benefit that if mefloquine is split as 8.3mg/kg/day for 3 days or not
given until the second day of treatment then absorption is
increased and gastrointestinal adverse effects are lessened.71,76 A fixed combination of mefloquine and artesunate
has recently been developed. This is dispensed as tablets containing 200 mg of artesunate and 400 mg mefloquine (base).
Recent trials in Asia indicated that the tolerability of this new
regimen (mefloquine dose 8 mg/kg/d for 3 days) is better than
that of the standard regimen.76,77 This combination has been
evaluated and used mainly in Southeast Asia and South
America. More information on tolerability, safety, and efficacy is needed in African children so that its potential utility
in Africa can be assessed objectively.

187

metabolite cycloguanilso it remains effective against antifol-resistant parasites. Mutations in the gene encoding cytochrome b confer high level atovaquone resistance. Atovaquone absorption (like that of lumefantrine and halofantrine)
is augmented by co-administration with fats. Its elimination
half-life of 12 days provides for an effective 3- day treatment
regimen. As with many antimalarials, plasma concentrations
of both drugs are reduced in pregnancy.82 It is remarkably
well tolerated with no serious adverse effects. The main impediment to its use is the high cost of atovaquone manufacture. The drug is essentially unaffordable in malaria endemic
areas.
ARTESUNATEPYRONARIDINE
Pyronaridine is one of many synthetic antimalarials developed in China and used originally as a monotherapy. It bears
closest structural similarity to amodiaquine, although pyronaridine is much more active against resistant parasites. Pyronaridines pharmacokinetic properties have not been fully
characterized yet but like several other drugs in this general
class of antimalarials, it is extensively distributed and eliminated slowly. The mechanism of action of the drug and
mechanisms of potential resistance have not been well characterized but are likely to be related to those of the other
drugs in this general class. Pyronaridine and the ACT combination are well tolerated and effective. The fixed dose ACT
is in late-stage development.

ARTESUNATECHLORPROGUANILDAPSONE
Chlorproguanildapsone is an antifol-sulfonamide combination with a similar mode of action and synergistic properties to sulfadoxinepyrimethamine. Chlorproguanil can be
considered as a prodrug for the active antifol chlorcycloguanil
to which it is metabolized by the polymorphic CYP450 2C19.78
Activity of this enzyme is reduced in approximately 20% of
Orientals and is also reduced by estrogens (e.g., pregnancy,
oral contraceptive). The advantages of this combination are
good tolerability and rapid elimination79 providing less selective pressure on the spread of resistance and greater activity
than SP against moderately resistant Plasmodium falciparum
(although both compounds are ineffective against P. falciparum with the Ile164Leu mutation common in Asia and
South America, and recently identified in Africa). Disadvantages are resistance selected already by SP, some concerns
over the safety of dapsone (hemolytic anemia), and lack of a
post-treatment prophylactic effect. Whether this rapidly
eliminated drug will be sufficiently effective for patients with
high parasite burdens in a 3-day regimen remains to be seen.
The ACT is in the late stage development and should be
registered in the near future.80
ARTESUNATEATOVAQUONEPROGUANIL
This fixed dose combination of 2 established drugs has not
been developed as a 3-drug fixed dose ACT although it has
been evaluated and found to be well tolerated, safe, and effective.81 Atovaquoneproguanil has a different (and synergistic) mode of action to other antimalarials affecting parasite
respiration at the level of the cytochrome chain. Proguanil is
acting itself in the combination, and not via the antifol triazine

DIHYDROARTEMISININPIPERAQUINE
Piperaquine is a bisquinoline compound related to chloroquine and other 4-aminoquinolines. It was discovered in
France and developed as an antimalarial by Chinese scientists
over 30 years ago.83 Piperaquine replaced chloroquine as the
first-line treatment of falciparum malaria in China in 1978.
After over 200 metric tons were used, including in mass treatment, resistance to piperaquine developed in P. falciparum in
the late 1980s. Piperaquine was not used outside of China.
The mechanism of action of the drug and mechanism of resistance have not been well characterized but are likely to be
related to those of the other drugs in this general class. Piperaquine has a large apparent volume of distribution of > 500
L/kg and a terminal elimination half-life estimated at 2 to 3
weeks.84 With increasing sensitivity of the assay, the true terminal half-life is probably similar to that of chloroquine; 12
months.85 Oral bioavailability increases with co-administration with fat.86 The fixed dose combination formulated in
tablets containing dihydroartemisinin (40 mg) and piperaquine (320 mg) is commercially available in many countries in Asia, and also more recently in Africa. Recent clinical
trials have shown that the fixed combination given once daily
for 3 days was effective and well tolerated.8793 The most
common adverse effects are gastrointestinal (nausea, vomiting, abdominal pain, and diarrhea), but they are usually mild
and self limiting. The main determinant of the parasitological
efficacy is the slow elimination of piperaquine. This also determines the post-treatment prophylactic effect, which is
important if the drug is going to be used as Intermittent Preventive Treatment (IPT).18 The simplicity of administration,
the excellent efficacy even against multi-drugresistant strains

188

NOSTEN AND WHITE

and the favorable toxicity profile, make the DHApiperaquine combination one of the more promising of the
currently available ACTs.
ACTS IN CHILDREN
The ACTs seem to be tolerated as well or better in children
than in adults. There is no specific age-related toxicity. In
younger children vomiting or regurgitation of the administered dose are always a concern but are no more common
with ACTs than monotherapies. Recent pharmacokinetic
studies indicate that the dose regimen advocated for SP in
children for many years is probably too low.53 There are insufficient pharmacokinetic data on amodiaquine94 and more
data on the pharmacokinetics of piperaquine in children are
needed. Dose regimens for artesunatemefloquine and artemetherlumefantrine in children are justified by pharmacokinetic studies. Further work is needed to optimize dosing in
children based on weight or surface area and, where necessary, to introduce specific pediatric formulations.
ACTS IN PREGNANCY
Pregnant women are a high-risk group. They are more susceptible to malaria, more likely to develop anemia, and if
non-immune are more likely to develop complications. Birthweight is consistently reduced by malaria. Therefore, pregnant women desperately need effective and safe antimalarial
treatments. The main concern surrounding the general deployment of ACTs is their safety in the first trimester of pregnancy.4951 Work by Chinese scientists in rodents and rabbits
conducted in the 1970s indicated that early pregnancy exposure could induce fetal resorption. Recent reproductive toxicity studies have confirmed that this is a class effect of the
compounds and is seen in all experimental animal species
studied. It results from a specific inhibition of fetal erythropoeisis. Fetal resorption would result in early pregnancy loss.
Much more worrying is the potential to cause developmental
abnormality. In rodents and rabbits at doses close to human
therapeutic doses, artemisinins given in a critical window in
the early stage of gestation, may also cause limb deformation.
In primates, doses of 1230 mg/kg daily given continuously
between day 20 and day 50 pc (equivalent to 2056 days in
human pregnancy) cause fetal resorption and slight (47%)
long bone shortening, but no abnormalities. No effects were
observed at 4 mg/kg.95
Given these uncertainties the artemisinin containing drugs
are not indicated for the management of uncomplicated malaria in the first trimester of pregnancy unless there are no
effective alternatives. But it is important to emphasise that
artesunate should be used in severe malaria where it is clearly
superior in terms of life-saving efficacy to quinine. In the
second and third trimesters there is increasing evidence of
safety for these drugs, with no evidence of adverse effects in
over 1,000 prospectively followed pregnancies.96,97 Questions
on dosage remain as concentrations of artesunate, artemether, and dihydroartemisinin, and several of the partner
drugs are reduced in late pregnancy compared with nonpregnant adults.67,98,99 In the second and third trimesters, recommendations are determined more by the evidence for the
partner drug. However, there is a grave paucity of data on the

safety, the efficacy, and the pharmacokinetic properties of the

other antimalarials in pregnancy. For example there are no
published pharmacokinetic data on amodiaquine, or sulfadoxinepyrimethamine despite their extensive deployment. A
recent review on the use of antimalarials in pregnancy also
emphasizes the lack of data on the safety of some drugs that
have been used for decades.97 On the other hand, drugs that
are considered safe and for which pharmacokinetic data are
available to support current dosing recommendations are either ineffective (e.g., chloroquine) or there are safety concerns (e.g., mefloquine, quinine). Mefloquine was associated
with an increased risk of stillbirths in Thailand but not in
Malawi.72,73 Quinine is associated with a high risk of hypoglycemia in late pregnancy. Clearly more information on the
other drugs is needed urgently. The 2006 edition of the WHO
Malaria Treatment Guidelines1 recommends that ACTs
should be used in the second and third trimesters of pregnancy. These recommendations were the result of careful examination of the evidence available at the time and will be
reviewed and modified by new evidence. It is generally accepted that a drug should first be shown to be safe and effective in treatment before it can be introduced in an IPT strategy.
PLASMODIUM VIVAX
The artemisinin derivatives and the ACTs work as well or
better against Plasmodium vivax compared with Plasmodium
falciparum infections.100 The exception to this is artesunate
SP, which is ineffective in those areas with high-level antifol
resistance in P. vivax. These drugs do not affect the hypnozoites, so relapses are not prevented. The slowly eliminated
drugs (e.g., chloroquine, mefloquine, piperaquine) suppress
the emergence of the first relapse in the frequently relapsing
tropical strains of P. vivax so the first successful emergence
of a relapse (i.e., the second relapse) typically occurs about 6
weeks after treatment.
EFFECTS ON TRANSMISSION
All effective antimalarials prevent the development of gametocytes in P. vivax, P. malariae, and P. ovale infections and
the early-stage gametocytes (stages 1 to 3) of P. falciparum.
The artemisinin derivatives inhibit development of more mature P. falciparum gametocytes.12,101 Gametocytemia is
greater in recrudescent than primary infections. In lowtransmission settings this gametocytocidal effect and the high
cure rates obtained with ACTs both contribute to reducing
transmission, and thus the incidence of malaria.
CONCLUSIONS
The ACTs are now accepted as the best treatments for
uncomplicated falciparum malaria, and policy change has
taken place in most countries to make these the first-line
recommended drugs. The evidence base for efficacy and
safety has grown considerably in recent years as these have
become the most studied of all antimalarial drugs. Together
with improved diagnosis and appropriate vector control measures, the ACTs should have a significant effect in reducing
the burden of malaria throughout the tropical world, but to

ARTEMISININ-BASED COMBINATION TREATMENT

achieve this they will need to become more affordable and

more available. This would be best achieved by subsidizing
their cost both in the public and the private sectors.23 As
deployment of ACTs increases, we will need to invest more in
education, health service delivery, monitoring of rare adverse
effects, and assessment of resistance to optimize their use, and
thereby ensure they have the greatest impact on malaria.
Received February 5, 2007. Accepted for publication July 22, 2007.

15.

16.

17.

Acknowledgments: FN and NW are both supported by the Wellcome

Trust.
Authors addresses: Nicholas White, Faculty of Tropical Medicine,
Mahidol University, 420/6 Rajvithi Rd., Bangkok 10400, Thailand,
Tel: (66) 2 354 9172, Fax: (66) 2 354 9169, E-mail: nickw@
tropmedres.ac. Franois Nosten, Centre for Tropical Medicine and
Vaccinology, Churchill Hospital, Oxford, UK, E-mail: SMRU@
tropmedres.ac

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