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\begin{document}

\title{Advances and roadblocks in the Treatment of Malaria}



\author[1]{Nicholas White}%
\author[2]{Borimas Hanboonkunupakarn}%
\affil[1]{Faculty of Tropical Medicine, Mahidol Iniversity}%
\affil[2]{Mahidol University}%


\vspace{-1em}



  
  \date{May 20, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
The deployment of artesunate for severe malaria and the artemisinin
combination therapies (ACTs) for uncomplicated malaria has been a major
advance in antimalarial therapeutics. These drugs have reduced treated
mortality, accelerated recovery, and reduced treatment failure rates and
transmission from the treated infection. These drugs remain highly
effective against falciparum malaria in most malaria endemic areas but
significant resistance has emerged in the Greater Mekong subregion of
Southeast Asia. Resistance to artemisinin was followed by resistance in
the ACT partner drugs, and fit multidrug resistant parasite lineages
have now spread widely across the region. ACTs are highly effective
against P. vivax and the other malaria species. Recent studies show that
radical curative regimens of primaquine (to prevent relapse) can be
shortened to seven days, and that the newly introduced single dose
tafenoquine is an alternative, although the currently recommended dose
is insufficient in Southeast Asia and Oceania. Targeted malaria
elimination using focal mass treatments with
dihydroartemisinin-piperaquine have proved safe and effective malaria
elimination accelerators, but progress overall towards malaria
elimination is very slow. Indeed since 2015 overall malaria case numbers
globally have risen.%
\end{abstract}%



\sloppy


\textbf{Advances and Roadblocks in the Treatment of Malaria}

Borimas Hanboonkunupakarn \textsuperscript{1}

Nicholas J White* \textsuperscript{1,2}

\begin{enumerate}
\tightlist
\item
  Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
\item
  Centre for Tropical Medicine and Global Health, Nuffield Department of
  Medicine, Oxford University, United Kingdom.
\end{enumerate}

Correspondence: nickw@tropmedres.ac

\textbf{Summary}

The deployment of artesunate for severe malaria and the artemisinin
combination therapies (ACTs) for uncomplicated malaria has been a major
advance in antimalarial therapeutics. These drugs have reduced treated
mortality, accelerated recovery, and reduced treatment failure rates and
transmission from the treated infection. These drugs remain highly
effective against falciparum malaria in most malaria endemic areas but
significant resistance has emerged in the Greater Mekong subregion of
Southeast Asia. Resistance to artemisinin was followed by resistance in
the ACT partner drugs, and fit multidrug resistant parasite lineages
have now spread widely across the region. ACTs are highly effective
against \emph{P. vivax} and the other malaria species. Recent studies
show that radical curative regimens of primaquine (to prevent relapse)
can be shortened to seven days, and that the newly introduced single
dose tafenoquine is an alternative, although the currently recommended
dose is insufficient in Southeast Asia and Oceania. Targeted malaria
elimination using focal mass treatments with
dihydroartemisinin-piperaquine have proved safe and effective malaria
elimination accelerators, but progress overall towards malaria
elimination is very slow. Indeed since 2015 overall malaria case numbers
globally have risen.

\textbf{Keywords} : malaria, antimalarial drugs, artemisinin, resistance

\textbf{Introduction}

The treatment of malaria has improved substantially in the past 15
years, and morbidity and mortality have declined as a result, but
significant challenges lie ahead (1). The major advance in antimalarial
therapeutics has been the deployment of drugs derived from artemisinin
(qinghaosu) (2). This unusual compound (a sesquiterpene lactone
peroxide) is derived from the leaves of the plant \emph{Artemesia
annua.} The derivatives of artemisinin; dihydroartemisinin (DHA),
artesunate and artemether now form the cornerstone of current
antimalarial treatment. They are the most rapidly acting of available
antimalarial drugs and they are very well tolerated, but resistance has
now emerged in Southeast Asia and it has spread, and there are worrying
early reports from other regions. These drugs are partnered in
fixed-dose combinations (artemisinin combination therapies) with more
slowly eliminated antimalarial drugs for the treatment of uncomplicated
malaria. New antimalarial drugs are on the horizon, but they are
unlikely to become generally available within the next few years, so
current treatments must rely upon the artemisinin derivatives. This
review presents some of the recent advances in antimalarial therapeutics
and some of the obstacles to progress in controlling and eliminating
malaria.

\emph{Advance 1:} \textbf{Improvements in the treatment of severe
malaria}

In the two largest randomized controlled trials conducted in patients
hospitalised with severe falciparum malaria artesunate was shown to
reduce mortality substantially. The mortality reduction (95\% confidence
interval) was 34.7\% (18\selectlanguage{ngerman}·5 to 47·6\%) in Southeast Asian adults and
children and 22.5\% (8·1 to 36·9\%) in African children (3,4) (Figure
1). In African children it can be difficult to distinguish severe
malaria from bacterial sepsis with incidental parasitaemia. In those
children with a high likelihood of having severe malaria based on
parasite biomass estimation the reduction in mortality was the same
(i.e. one third) as observed in the Asian series (5). Artesunate was
also better tolerated (less hypoglycaemia) and easier to administer
(intravenous injection rather than controlled rate infusion, and no pain
and local toxicity following intramuscular injection) than the previous
``gold-standard'' treatment quinine. Importantly there were also less
neurological sequelae in the survivors so lives were not saved at the
expense of neurological deficits. Artemether is nearly as active as
artesunate \emph{in-vitro} against \emph{P. falciparum} but, being an
oil-based intramuscular injection, is slowly and erratically absorbed
from the intramuscular injection site in-vivo (particularly in shocked
patients) (6). In contrast the water soluble artesunate is rapidly and
reliably absorbed. This probably explains why the severe malaria
mortality following artemether is higher than that following artesunate
treatment (7,8). Community based pre-referral rectal artesunate was also
shown to reduce malaria attributable mortality by 25\% in children
unable to take oral antimalarial medications (9) Since these trials
reported artesunate has become the generally recommended first line
treatment for severe malaria (1) and usage has increased substantially,
although unfortunately quinine is still the only available parenteral
antimalarial in some malaria endemic areas.

Following drug administration the DHA derivatives are rapidly and
reliably converted back to DHA in-vivo which is then very rapidly
eliminated (t\textsubscript{1/2} \textless{} 1 hour) mainly by
glucuronidation (10), yet they are highly efficacious when given once
daily (11). The main pathological process in severe falciparum malaria
is the sequestration of erythrocytes containing mature forms of the
parasite in the vascular beds of vital organs (5,12). This reduces
microcirculatory blood flow and probably markedly disturbs endothelial
function. The key pharmacodynamic effect of the artemisinin derivatives,
which mediates the life-saving advantage over quinine, is their action
in killing the younger circulating stages of \emph{P. falciparum} before
they sequester (12). Unfortunately, this property is reduced markedly in
artemisinin resistance.

Apart from the prompt initiation of renal replacement therapies
(preferably haemofiltration) in acute kidney injury (12,13), no adjuvant
therapies have proved beneficial and many (including aspirin,
corticosteroids, heparin, mannitol, high dose phenobarbitone, anti-TNF
antibody and rapid fluid loading) were found to be harmful in severe
malaria (12,14).

\emph{Advance 2}\textbf{: Better treatments for uncomplicated falciparum
malaria}

The main advance in the treatment of falciparum malaria has been the
replacement of the failing monotherapies chloroquine and
sulfadoxine-pyrimethamine by artemisinin combination therapies (ACTs)
(1). These three-day regimens combine an artemisinin derivative with a
more slowly eliminated partner drug (Figure 2A). Four ACTs were
recommended originally; artesunate combined with
sulfadoxine-pyrimethamine (SP), amodiaquine or mefloquine, and
artemether combined with lumefantrine. More recently
dihydroartemisinin-piperaquine and artesunate-pyronaridine have been
introduced (1,15). All except artesunate-SP are available in combined
formulations and all but artemether-lumefantrine are taken once daily.
These drugs are all rapidly effective and generally well tolerated (1,
10, 16). Early concerns over potential neurotoxicity and teratogenicity
have receded with increasing evidence of safety (12). Worries over
piperaquine cardiotoxicity (QT prolongation - risk of Torsade de
Pointes) have also declined with large meta-analyses showing no increase
in the rate of sudden death (17). ACTs are now recommended as first line
treatment for all patients with falciparum malaria, including in
pregnancy (1). Costs have been reduced, and generics developed. Hundreds
of millions of treatments are dispensed annually.

The main current concern is ensuring access to diagnosis and effective
treatment and emerging resistance in \emph{Plasmodium falciparum} to the
artemisinin derivatives. Artemisinin resistance manifests as slowing of
parasite clearance because of reduced ring stage (the younger asexual
forms) parasite susceptibility (18). The discovery of a parasite
molecular marker, mutations in the propeller region of the kelch gene on
chromosome 13, has greatly facilitated characterization and
epidemiological assessments. (19, 20) Reduced parasite killing in
artemisinin resistant malaria infections places greater selective
``pressure'' on the ACT partner drug, This is because the number of
parasites which remain after the artemisinin component in an ACT has
been eliminated is many orders of magnitude greater - and the
probability of selecting resistant mutants is correspondingly higher
(Figure 2A). Indeed ACT partner drug resistance has followed artemisinin
resistance in the Greater Mekong subregion of Southeast Asia (21-24).
Fortunately artemisinin resistant \emph{P. falciparum} are still largely
confined to this one region (25), although there are increasing reports
that clusters of kelch mutant parasites have been identified elsewhere
(27,27). One potential solution is to deploy triple artemisinin
combination treatments (TACTs) which combine an artemisinin derivative
with two slowly eliminated antimalarials (23). This solves the
pharmacokinetic mismatch whereby the rapidly eliminated artemisinin
component leaves the slowly eliminated partner drug ``unprotected'' for
days or weeks after the second post-treatment asexual parasite cycle
(i.e. \textgreater{}3 days after starting the ACT). With TACTs there are
now two slowly eliminated partner drugs providing mutual protection
against the selection of resistance (Figure 2B). The two TACTs under
current development artemether-lumefantrine -amodiaquine and
dihydroartemisinin-piperaquine-mefloquine exploit reciprocal
susceptibilities whereby resistance to one of the slowly eliminated
components is associated with increased susceptibility to the other. In
large scale trials TACTs have proved well tolerated, safe and highly
effective (24).

\emph{Advance 3}\textbf{: Chemoprevention in malaria endemic areas}

For many years pregnant women living in a malaria endemic region were
advised to take chloroquine chemoprophylaxis to reduce the adverse
effects of falciparum malaria on the developing foetus (mainly low
birthweight), but as chloroquine resistance worsened chemoprophylaxis
was replaced by intermittent presumptive treatment with
sulphadoxine-pyrimethamine (IPT-SP) (1). This involves giving full
treatment doses at intervals. Although preventive efficacy is much
greater than treatment efficacy against resistant \emph{P. falciparum} ,
IPT-SP is threatened by worsening resistance -- both to the antifol and
the sulphonamide components (28). There is increasing evidence that
dihydroartemisinin-piperaquine (DP) provides excellent antimalarial
chemoprevention for approximately one month, is well tolerated, and
appears safe in pregnancy (29, 30). IPT is imperfect chemoprophylaxis.
In order to provide continuous suppressive prophylaxis DP needs to be
given at least monthly, and preferably weekly (31). The IPT-SP concept
has also been advocated in infants, where treatment doses of SP are to
be given together with the routine EPI vaccines at the ages of 2, 3 and
9 months. This is not widely practiced as the benefits are relatively
small, and SP resistance is widespread. A more effective strategy, which
is now implemented widely across the Sahel region of Africa (where there
is intense malaria transmission largely confined to the 3-4 month rainy
season), is seasonal malaria chemoprevention (SMC) with monthly
administration of treatment doses of amodiaquine together with SP to all
children aged between 6 and 59 months (1, 32). SMC prevents symptomatic
reinfection and substantially reduces the malaria burden. Adding
azithromycin to amodiaquine and SP provides no additional benefit (33).
Resistance to both components of SMC is widespread in East Africa but
whether resistance is impacting on the chemoprophylactic activity of SMC
is uncertain currently -- more information is needed on this critical
point to guide policy.

\textbf{Advances 4: Mass treatment as a malaria elimination accelerator}

Where malaria transmission is low the prospects for elimination
increase. In the Greater Mekong subregion (GMS), which harbours the most
drug resistant \emph{P. falciparum} in the world, there is a general
consensus that the only way to counter multi-drug resistance effectively
is to eliminate all falciparum malaria. This is an area of low seasonal
malaria transmission and targeted malaria elimination, even in the most
remote and inaccessible areas, has been very effective (34, 35). The key
to successful elimination is the support of village health workers in
every village (usually 300-800 people) to provide diagnosis of malaria
with a rapid diagnostic test, and treatment with an effective ACT (36).
In foci of higher transmission (sometimes called ``hot spots'), where a
significant proportion of the healthy population have asymptomatic
parasitaemias, mass treatments with dihydroartemisinin-piperaquine have
proved very effective and well tolerated ``accelerators'' of elimination
(34,35).

\textbf{Obstacles 1: The emergence and spread of antimalarial drug
resistance}

There is resistance in \emph{Plasmodium falciparum} to all currently
used antimalarial drugs but there is substantial variation in the
geographic distribution and degree of reduced susuceptibility. The most
resistant parasites are found in the eastern greater Mekong subregion of
Southeast Asia. Multidrug resistant \emph{P. falciparum} is also
prevalent in parts of South America. In general \emph{P.falciparum} in
Africa is more sensitive with higher levels of resistance in East
compared with West Africa (37). Resistance is generally less in the
other malarias although antifol resistance in \emph{P.vivax} is
widespread and chloroquine resistance in \emph{P. vivax} is found
throughout Indonesia and Papua New Guinea (38). Antifol resistance in
both \emph{P.falciparum} and \emph{P.vivax} results from stepwise
accumulation of mutations in the \emph{dhfr} gene encoding the drug
target dihydrofolate reductase , (S108N, N51I, C59R) and sulphonamide
resistance results from accumulation of mutations in the \emph{dhps}gene
encoding the drug target dihydropteroate synthase (A437G,K540E, A581G).
In general, the more of these mutations there are more resistant is the
\emph{P. falciparum} infection (39). The highest level of antifol
resistance is conferred by the \emph{Pfdhfr} I164L mutation (found in
Southeast Asia and South America). This renders parasites completely
resistant to pyrimethamine. Resistance to chloroquine and the
structurally related antimalarials which interfere with haem
detoxification results from mutations in the transporter \emph{Pfcrt} ,
and to a lesser extent mutations in \emph{Pfmdr} (notably N86Y, N1042D,
S1034C, and D1246Y). Positions 72 to 76 are mutated in the
\emph{Pfcrt}of most \emph{P. falciparum} (causing 4-aminoquinoline
resistance) with K76T being consistently mutant in the five major
haplotypes (CVIET, SVMNT, SVIET, CVMNT and CVTNT) (39). Recently
downstream mutations from the chloroquine resistance locus have been
strongly associated with piperaquine resistance (23,39). Copy number
increase in wild type\emph{Pfmdr} is the main identified genetic
association with mefloquine and lumefantrine resistance (22). Atovaquone
resistance arises readily as a result of mutations in the mitochondrial
multicopy cytochrome b gene (usually at position 268; Y268S or Y268N).

From a therapeutic perspective high level resistance precludes use of
chloroquine and sulphadoxine-pyrimethamine alone in most areas (1).
Amodiaquine alone is also not sufficiently efficacious in many parts of
the tropics but still contributes significantly to efficacy in
combinations - and artesunate-amodiaquine remains efficacious in Central
and West Africa. Significant resistance to mefloquine and piperaquine is
prevalent only in the Greater Mekong subregion (GMS) of Southeast Asia.
Fortunately in these areas artemether-lumefantrine and
artesunate-pyronaridine currently remain highly effective (24, 40). It
is an ominous precedent that the eastern GMS is the same area from which
resistance to chloroquine and sulphadoxine-pyrimethamine arose and then
spread to India and Africa (at a cost of millions of lives), and it is
where resistance to the artemisinin drugs has arisen first.

\textbf{Obstacles 2: Artemisinin resistance}

Artemisinin resistance was found first near the Thailand-Cambodia
border. It manifests by slowing of parasite clearance which reflects
reduced ``ring stage'' killing (1). In falciparum malaria the young ring
stage parasites in the first third of the 48 hour asexual life cycle
circulate in the blood stream before the infected erythrocytes adhere to
vascular endothelium (cytoadherence) -- a process called sequestration.
This does not occur to a significant extent with the other human
malarias. Sequestration is considered central to the potentially lethal
pathology of falciparum malaria, and the life saving benefit of the
artemisinin derivatives (Figure 1) results from reducing sequestration
by killing the ring stage parasites (12). The pharmacodynamic effect is
best measured in-vivo from the log-linear decline in parasite densities
which follows a variable lag phase. The slope provides the parasite
clearance rate and thus a half-life. Parasite clearance half-lives over
5 hours are generally associated with artemisinin resistance (18,20)
(Figure 3). When artemisinin resistance was recognised first it was
observed there were multiple independent mutations in the \emph{Pf}
kelch gene propeller region but in recent years successful artemisinin
resistant parasite lineages have outcompeted the other parasites and
spread across large areas (37). In the Eastern GMS a parasite lineage
bearing the C580Y mutation has predominated, whereas in Myanmar a
lineage bearing the F446I mutation has spread over large distances (41,
42) (Figure 4). The F446I mutation confers a lower degree of resistance
(in terms of parasite clearance) than many of the other propeller
mutants. This may reflect a lesser fitness cost and thus greater
competitive advantage in areas of higher transmission. These artemisinin
resistant parasites have then acquired resistance to the ACT partner
drugs -piperaquine (in the Eastern GMS) and mefloquine (along the
Thailand-Myanmar border). This has resulted in increasing rates of ACT
failure (21-23) forcing Governments to change their first-line treatment
policies. There is serious concern that these resistant parasites could
spread westward, or that artemisinin resistance could emerge de-novo
elsewhere, and derail global aspirations to control and eliminate
malaria.

\textbf{Obstacles 3: Underuse of primaquine}

Primaquine is a very important antimalarial as both a single dose
gametocytocide in falciparum malaria, and in multiple dose ``radical
cure'' regimens to prevent relapse in vivax and ovale malaria (1), but
it is underused. This is because of concerns over haemolytic toxicity in
glucose-6-phosphate dehydrogenase (G6PD) deficiency (43). Gene
frequencies for X-linked G6PD deficiency average 8-10\% in tropical
areas (although prevalences are lower in vivax malaria), but screening
tests to identify G6PD deficient patients are not widely available.
Relapses are recurrences of malaria which follow complete cure of the
blood stage infection. They derive from dormant parasite forms
(hypnozoites) which persist in the liver. Hypnozoites are resistant to
all current antimalarial drugs except the 8-aminoquinolines (8-AQ) (1).
Without radical cure relapse rates vary between 20\% and 80\%. Relapse
is a major cause of morbidity and mortality in higher transmission
settings (44). Primaquine has usually been given in 7 or 14 day
``radical cure'' courses. As these cause predictable haemolysis in G6PD
deficient patients, G6PD testing is recommended (1,43). The recent
development of rapid screening tests is a significant advance which
should enable wider safe use of primaquine for radical cure, and thereby
make elimination a more achievable target. Recent very large studies
confirm that the treatment courses even for the higher dose primaquine
regimens (total 7mg/kg) can be condensed into a one week course. With
G6PD testing to exclude deficient patients these are well tolerated ,
and if these adhered to, radical curative efficacy is very high
(\textgreater{}95\%) (45, 46).

Until recently primaquine was used in a single 0.75mg base/kg dose (45mg
adult dose) as a \emph{P. falciparum} gametocytocide to reduce
transmissibility of the treated infection. This was given in addition to
the standard three day ACT for treatment. Re-evaluation of the
transmission blocking dose-response relationship for primaquine
indicates that the same gametocytocidal effect is obtained with a dose
three times lower (0.25mg base/kg) with obviously less haemolytic risk.
This obviates the need for G6PD testing- so this has now become the
recommended dose (1,47).

\textbf{Obstacle 4: Medicine quality}

Poor medicine quality is often ignored in discussions of disease control
but the problem is massive, and it affects particularly the antimalarial
drugs. In many countries the private sector is main source of
antimalarials and there is weak regulation of pharmaceuticals (48). A
recent systematic review and meta-analysis estimated that 12·4\% of
antibiotics and 19·1\% of antimalarials in low-income and middle-income
countries were substandard or falsified, with an estimated economic
impact ranging from US\$10 billion to \$200 billion (49).

\textbf{Obstacles 5: Political roadblocks and funding gaps}

Discussion of roadblocks would be incomplete without considering the
political dimension. Although malaria has a reasonable global profile in
comparison with the ``neglected tropical diseases'' it is often low in
National Health priorities, particularly in Asia and the Americas where
it is predominantly a disease of the poor or marginalized. Much of the
funding for malaria control comes from International Agencies such as
the Global Fund to fight AIDS, TB and Malaria (GFATM) and the
President's Malaria Initiative (PMI) or from bilateral donors. Whereas
the world was doing very well in reducing malaria morbidity and
mortality in the decade between 2005 and 2015, the total number of
malaria cases has increased steadily since then (50). There has been no
in-depth analysis to explain this reversal, and no clear evidence that
providing more funding without reforms will reverse this trend.

\textbf{Advances 5: Tafenoquine}

For over 60 years primaquine has been the only widely available drug in
the 8-aminoquinoline class. In the past year, after a long and difficult
gestation, the slowly eliminated 8-AQ tafenoquine was registered and
launched. Tafenoquine is a well tolerated single dose treatment which
solves the problem of potentially poor adherence (51,52). Like the other
8-aminoquinolines tafenoquine also causes oxidant haemolysis in G6PD
deficiency. However the rapidly eliminated primaquine can be stopped in
case of haemolysis in a G6PD deficient patient, thereby limiting the
consequent anaemia -- whereas tafenoquine continues to cause haemolysis
for weeks. Thus tafenoquine has the advantage of simplicity and
reliability of dosing, but at the expense of an increased risk of
serious haemolysis. Currently available rapid screening tests identify
individuals who have 30-40\% of normal erythrocyte G6PD activity which
identifies all male hemizygotes and female homozygotes, but they do not
identify the majority of female heterozygotes (whose blood contains a
mixture of G6PD deficient and normal erythrocytes). Safe use of
tafenoquine therefore requires development and deployment of simple
quantitative G6PD screening tests which can identify individuals with
\textless{}70\% of normal red G6PD activity in blood samples. These are
under development, but they are not yet ready for roll out. In East Asia
and Oceania relapse is the main cause of vivax illness, a major
contributor to morbidity and mortality, and a major obstacle to
elimination. The dose of tafenoquine currently recommended (300mg adult
dose) is too low for this populous region, where a large proportion of
the world's relapses occur. In the pre-registration clinical trials
tafenoquine 300mg proved inferior to a sub-optimal dose of primaquine
(52) (Figure 5). Unfortunately there are no plans currently to rectify
this.

\textbf{Advances 6: New antimalarials in development}

Several new antimalarial drugs are in clinical development (53). These
include

\begin{enumerate}
\tightlist
\item
  cipargamin, a spiroindolone compound that is more rapidly acting (in
  terms of accelerating parasite clearance) than artemisinins. It
  inhibits PfATPase4.
\item
  artefenomel, a synthetic peroxide which is more stable and more slowly
  eliminated arterolane.
\item
  Ganaplacide, a potent imidazolopiperazine compound with an unknown
  mode of action;
\item
  P218, a dihydrofolate reductase inhibitor with preserved activity
  against prevalent antifol resistant parasites.
\item
  DSM265, a slowly acting dihydroorotate dehydrogenase inhibitor
\item
  Ferroquine, an aminoquinoline compound with similarities to
  chloroquine but activity against chloroquine resistant parasites.
\item
  MMV390048 is a novel~aminopyridine antimalarial~compound that
  inhibits\emph{Plasmodium} ~phosphatidylinositol-4-kinase (PI4K)
\end{enumerate}

Most of these drugs are in phase 2 testing, and so if some of these
compounds do proceed successfully to phase 3 studies and regulatory
approval, likely in combinations, and these new combination therapies
are well tolerated, effective and affordable they will be a welcome
addition to the antimalarial armamentarium. But this is will not happen
in the next few years. This means that current antimalarial treatment
strategies must make use of the currently available medicines.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  World Health Organisation. Guidelines for the treatment of malaria.
  3\textsuperscript{rd} Edition. WHO, Geneva, 2015.
\item
  A Detailed Chronological Record of Project 523 and the Discovery and
  Development of Qinghaosu (Artemisinin). ed Zhan JianFang Translation
  Arnold K, Arnold M. Strategic Book Publishing \& Rights Agency, LLC.
\item
  Dondorp A, Nosten F, Stepniewska K, Day N, White NJ; South East Asian
  Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus
  quinine for treatment of severe falciparum malaria: a randomised
  trial. Lancet 2005; \textbf{366} : 717--25.
\item
  Dondorp A M, Fanello CE, Hendriksen ICE, Gomes E, Seni A, Chhaganlal
  KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K, Kivaya E,
  Agbenyega T, Nguah SB, Evans J, Gesase S, Kahabuka C, Mtove G, Nadjm
  B, Deen J, Mwanga-Amumpaire J, Nansumba M, Karema C, Umulisa N,
  Uwimana A, Mokuolu OA, Adedoyin TO, Johnson WBR, Tshefu AK, Onyamboko
  MA, Sakulthaew T, Pan-Ngum W, Silamut K, Stepniewska K, Woodrow C,
  Bethell D, Wills B, Oneko M, Peto T, von Seidlein L, Day NPJ, White
  NJ, for the AQUAMAT group. Artesunate versus quinine in the treatment
  of severe falciparum malaria in African children (AQUAMAT): an
  open-label, randomised trial. Lancet 2010; \textbf{376} : 1647-1657.
\item
  White NJ, Turner GD, Day NP, Dondorp AM. Lethal malaria: Marchiafava
  and Bignami were right. J Infect Dis. 2013; 208: 192-8.
\item
  Hien TT, Davis TM, Chuong LV, Ilett KF, Sinh DX, Phu NH, Agus C,
  Chiswell GM, White NJ, Farrar J. Comparative pharmacokinetics of
  intramuscular artesunate and artemether in patients with severe
  falciparum malaria. Antimicrob Agents Chemother. 2004;48: 4234-9.
\item
  Artemether-Quinine Meta-analysis Study Group. A meta-analysis using
  individual patient data of trials comparing artemether with quinine in
  the treatment of severe falciparum malaria. Trans R Soc Trop Med Hyg.
  2001; 95: 637-50.
\item
  Phu NH, Tuan PQ, Day N, Mai NT, Chau TT, Chuong LV, Sinh DX, White NJ,
  Farrar J, Hien TT. Randomized controlled trial of artesunate or
  artemether in Vietnamese adults with severe falciparum malaria. Malar
  J 2010; \textbf{9} : e97.
\item
  Gomes MF, Faiz MA, Gyapong JO, Warsame M, Agbenyega T, Babiker A,
  Baiden F,Yunus EB, Binka F, Clerk C, Folb P, Hassan R, Hossain MA,
  Kimbute O, Kitua A, Krishna S, Makasi C, Mensah N, Mrango Z, Olliaro
  P, Peto R, Peto TJ, Rahman MR, Ribeiro I, Samad R, White NJ; Study 13
  Research Group. Pre-referral rectal artesunate to prevent death and
  disability in severe malaria: a placebo-controlled trial.\emph{Lancet}
  2009; \textbf{373} : 557-66.
\item
  Sugiarto SR, Davis TME, Salman S. Pharmacokinetic considerations for
  use of artemisinin-based combination therapies against falciparum
  malaria in different ethnic populations. Expert Opin Drug Metab
  Toxicol. 2017; 13: 1115-1133.
\item
  White NJ, Watson J, Ashley EA. Split dosing of artemisinins does not
  improve antimalarial therapeutic efficacy. Sci Rep. 2017;7:12132.
\item
  World Health Organisation. Severe Malaria. Trop Med Int Hlth
  2014;\textbf{19} (Supplement 1): 1-131.
\item
  Phu NH, Hien TT, Mai NT, Chau TT, Chuong LV, Loc PP, Winearls C,
  Farrar J, White N, Day N. Hemofiltration and peritoneal dialysis in
  infection-associated acute renal failure in Vietnam. N Engl J Med.
  2002 Sep 19;347(12):895-902.
\item
  Maitland K. Severe Malaria in African Children - The Need for
  Continuing Investment. N Engl J Med. 2016; 375: 2416-2417.
\item
  West African Network for Clinical Trials of Antimalarial Drugs
  (WANECAM). Pyronaridine-artesunate or dihydroartemisinin-piperaquine
  versus current first-line therapies for repeated treatment of
  uncomplicated malaria: a randomised, multicentre, open-label,
  longitudinal, controlled, phase 3b/4 trial. Lancet. 2018; 391:
  1378-1390.
\item
  Smithuis F, Kyaw MK, Phe O, Win T, Aung PP, Oo AP, Naing AL, Nyo MY,
  Myint NZ, Imwong M, Ashley E, Lee SJ, White NJ. Effectiveness of five
  artemisinin combination regimens with or without primaquine in
  uncomplicated falciparum malaria: an open-label randomised trial.
  Lancet Infect Dis 2010; \textbf{10} : 673-81.
\item
  Chan XHS, Win YN, Mawer LJ, Tan JY, Brugada J, White NJ. Risk of
  sudden unexplained death after use of dihydroartemisinin-piperaquine
  for malaria: a systematic review and Bayesian meta-analysis. Lancet
  Infect Dis. 2018 Aug;18(8):913-923.
\item
  Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey
  F,Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M,
  Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day
  NP, Lindegårdh N, Socheat D, White NJ. Artemisinin resistance
  in\emph{Plasmodium falciparum} malaria. N Engl J Med 2009;
  \textbf{361} : 455-67.
\item
  Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC, Khim N,
  Kim S, Duru V, Bouchier C, Ma L, Lim P, Leang R, Duong S, Sreng S,
  Suon S, Chuor CM, Bout DM, Ménard S, Rogers WO, Genton B, Fandeur T,
  Miotto O, Ringwald P, Le Bras J, Berry A, Barale JC, Fairhurst RM,
  Benoit-Vical F, Mercereau-Puijalon O, Ménard D. A molecular marker of
  artemisinin-resistant Plasmodium falciparum malaria. Nature. 2014;
  505: 50-5.
\item
  Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, Sreng
  S, Anderson JM, Mao S, Sam B, Sopha C, Chuor CM, Nguon C, Sovannaroth
  S,Pukrittayakamee S, Jittamala P, Chotivanich K, Chutasmit K,
  Suchatsoonthorn C, Runcharoen R, Hien TT, Thuy-Nhien NT, Thanh NV, Phu
  NH, Htut Y, Han KT, Aye KH, Mokuolu OA, Olaosebikan RR, Folaranmi OO,
  Mayxay M, Khanthavong M, Hongvanthong B, Newton PN, Onyamboko MA,
  Fanello CI, Tshefu AK, Mishra N, Valecha N, Phyo AP, Nosten F, Yi P,
  Tripura R, Borrmann S, Bashraheil M, Peshu J, Faiz MA, Ghose A,
  Hossain MA, Samad R, Rahman MR, Hasan MM, Islam A, Miotto O, Amato R,
  MacInnis B, Stalker J, Kwiatkowski DP, Bozdech Z, Jeeyapant A, Cheah
  PY, Sakulthaew T, Chalk J, Intharabut B, Silamut K, Lee SJ, Vihokhern
  B, Kunasol C, Imwong M, Tarning J, Taylor WJ, Yeung S, Woodrow CJ,
  Flegg JA, Das D, Smith J, Venkatesan M, Plowe CV, Stepniewska K,
  Guerin PJ, Dondorp AM, Day NP, White NJ; Tracking Resistance to
  Artemisinin Collaboration (TRAC). Spread of artemisinin resistance
  in\emph{Plasmodium falciparum} malaria. N Engl J Med 2014;
  \textbf{371} : 411-23.
\item
  Amaratunga C, Lim P, Suon S, Sreng S, Mao S, Sopha C, Sam B, Dek D,
  Try V, Amato R, Blessborn D, Song L, Tullo GS, Fay MP, Anderson JM,
  Tarning J, Fairhurst RM. Dihydroartemisinin-piperaquine resistance
  in\emph{Plasmodium falciparum} malaria in Cambodia: a multisite
  prospective cohort study. Lancet Infect Dis. 2016;16(3):357-65.
\item
  Phyo AP, Ashley EA, Anderson TJ, Bozdech Z, Carrara VI, Sriprawat K,
  Nair S, White MM, Dziekan J, Ling C, Proux S, Konghahong K, Jeeyapant
  A, Woodrow CJ, Imwong M, McGready R, Lwin KM, Day NP, White NJ, Nosten
  F. Declining efficacy of artemisinin combination therapy
  against\emph{P. falciparum} malaria on the Thai-Myanmar Border
  (2003-2013): The role of parasite genetic factors. Clin Infect Dis
  2016;\textbf{63} : 784-91.
\item
  van der Pluijm RW, Imwong M, Chau NH, Hoa NT, Thuy-Nhien NT, Thanh NV,
  Jittamala P, Hanboonkunupakarn B, Chutasmit K, Saelow C, Runjarern R,
  Kaewmok W, Tripura R, Peto TJ, Yok S, Suon S, Sreng S, Mao S, Oun S,
  Yen S, Amaratunga C, Lek D, Huy R, Dhorda M, Chotivanich K, Ashley EA,
  Mukaka M, Waithira N, Cheah PY, Maude RJ, Amato R, Pearson RD,
  Gonçalves S, Jacob CG, Hamilton WL, Fairhurst RM, Tarning J,
  Winterberg M, Kwiatkowski DP, Pukrittayakamee S, Hien TT, Day NP,
  Miotto O, White NJ, Dondorp AM. Determinants of
  dihydroartemisinin-piperaquine treatment failure in \emph{Plasmodium
  falciparum} malaria in Cambodia, Thailand, and Vietnam: a prospective
  clinical, pharmacological, and genetic study. Lancet Infect Dis.
  2019;\textbf{19} : 952-961.
\item
  van der Pluijm RW, Tripura R, Hoglund RM, Pyae Phyo A, Lek D, Ul Islam
  A, Anvikar AR, Satpathi P, Satpathi S, Behera PK, Tripura A, Baidya S,
  Onyamboko M, Chau NH, Sovann Y, Suon S, Sreng S, Mao S, Oun S, Yen S,
  Amaratunga C, Chutasmit K, Saelow C, Runcharern R, Kaewmok W, Hoa NT,
  Thanh NV, Hanboonkunupakarn B, Callery JJ, Mohanty AK, Heaton J, Thant
  M, Gantait K, Ghosh T, Amato R, Pearson RD, Jacob CG, Gonçalves S,
  Mukaka M, Waithira N, Woodrow CJ, Grobusch MP, van Vugt M, Fairhurst
  RM, Cheah PY, Peto TJ, von Seidlein L, Dhorda M, Maude RJ, Winterberg
  M, Thuy-Nhien NT, Kwiatkowski DP, Imwong M, Jittamala P, Lin K, Hlaing
  TM, Chotivanich K, Huy R, Fanello C, Ashley E, Mayxay M, Newton PN,
  Hien TT, Valecha N, Smithuis F, Pukrittayakamee S, Faiz A, Miotto O,
  Tarning J, Day NPJ, White NJ, Dondorp AM; Tracking Resistance to
  Artemisinin Collaboration. Triple artemisinin-based combination
  therapies versus artemisinin-based combination therapies for
  uncomplicated Plasmodium falciparum malaria: a multicentre,
  open-label, randomised clinical trial. Lancet. 2020 Mar 11. pii:
  S0140-6736(20)30552-3. doi: 10.1016/S0140-6736(20)30552-3. {[}Epub
  ahead of print{]}
\item
  Ménard D, Khim N, Beghain J, Adegnika AA, Shafiul-Alam M, Amodu O,
  Rahim-Awab G, Barnadas C, Berry A, Boum Y, Bustos MD, Cao J, Chen JH,
  Collet L, Cui L, Thakur GD, Dieye A, Djallé D, Dorkenoo MA,
  Eboumbou-Moukoko CE, Espino FE, Fandeur T, Ferreira-da-Cruz MF, Fola
  AA, Fuehrer HP, Hassan AM, Herrera S, Hongvanthong B, Houzé S, Ibrahim
  ML, Jahirul-Karim M, Jiang L, Kano S, Ali-Khan W, Khanthavong M,
  Kremsner PG, Lacerda M, Leang R, Leelawong M, Li M, Lin K, Mazarati
  JB, Ménard S, Morlais I, Muhindo-Mavoko H, Musset L, Na-Bangchang K,
  Nambozi M, Niaré K, Noedl H, Ouédraogo JB, Pillai DR, Pradines B,
  Quang-Phuc B, Ramharter M, Randrianarivelojosia M, Sattabongkot J,
  Sheikh-Omar A, Silué KD, Sirima SB, Sutherland C, Syafruddin D, Tahar
  R, Tang LH, Touré OA, Tshibangu-wa-Tshibangu P, Vigan-Womas I, Warsame
  M, Wini L, Zakeri S, Kim S, Eam R, Berne L, Khean C, Chy S, Ken M,
  Loch K, Canier L, Duru V, Legrand E, Barale JC, Stokes B, Straimer J,
  Witkowski B, Fidock DA, Rogier C, Ringwald P, Ariey F,
  Mercereau-Puijalon O; KARMA Consortium. A Worldwide Map
  of\emph{Plasmodium falciparum} K13-Propeller Polymorphisms. N Engl J
  Med. 2016 Jun 23;374(25):2453-64.
\item
  Tacoli C, Gai PP, Bayingana C, Sifft K, Geus D, Ndoli J, Sendegeya A,
  Gahutu JB, Mockenhaupt FP. Artemisinin Resistance-Associated K13
  Polymorphisms of \emph{Plasmodium falciparum} in Southern Rwanda,
  2010-2015. Am J Trop Med Hyg. 2016; 95(5): 1090-1093.
\item
  Chenet SM, Akinyi Okoth S, Huber CS, Chandrabose J, Lucchi NW,
  Talundzic E, Krishnalall K, Ceron N, Musset L, Macedo de Oliveira A,
  Venkatesan M, Rahman R, Barnwell JW, Udhayakumar V. Independent
  Emergence of the \emph{Plasmodium falciparum} Kelch Propeller Domain
  Mutant Allele C580Y in Guyana. J Infect Dis. 2016; 213: 1472-5.
\item
  Taylor SM, Levitt B, Freedman B, Madanitsa M, Thwai KL, Kalilani-Phiri
  L, Khairallah C, Mwapasa V, Ter Kuile FO, Meshnick SR. Interactions
  between antenatal sulfadoxine-pyrimethamine, drug-resistant Plasmodium
  falciparum parasites and delivery outcomes in Malawi. J Infect Dis.
  2020 Mar 28. pii: jiaa145. doi: 10.1093/infdis/jiaa145.
\item
  Ahmed R, Poespoprodjo JR, Syafruddin D, Khairallah C, Pace C, Lukito
  T, Maratina SS, Asih PBS, Santana-Morales MA, Adams ER, Unwin VT,
  Williams CT, Chen T, Smedley J, Wang D, Faragher B, Price RN, ter
  Kuile FO. Efficacy and safety of intermittent preventive treatment and
  intermittent screening and treatment versus single screening and
  treatment with dihydroartemisinin-piperaquine for the control of
  malaria in pregnancy in Indonesia: a cluster-randomised, open-label,
  superiority trial. Lancet Infect Dis. 2019;19(9):973-987.
\item
  Muhindo MK, Jagannathan P, Kakuru A, Opira B, Olwoch P, Okiring J,
  Nalugo N, Clark TD, Ruel T, Charlebois E, Feeney ME, Havlir DV, Dorsey
  G, Kamya MR. Intermittent preventive treatment with
  dihydroartemisinin-piperaquine and risk of malaria following cessation
  in young Ugandan children: a double-blind, randomised, controlled
  trial. Lancet Infect Dis. 2019;19(9):962-972.
\item
  Permala J, Tarning J, Nosten F, White NJ, Karlsson MO, Bergstrand M.
  Prediction of Improved Antimalarial Chemoprevention with Weekly Dosing
  of Dihydroartemisinin-Piperaquine. Antimicrob Agents Chemother.
  2017;61.pii: e02491-16.
\item
  Ndiaye JLA, Ndiaye Y, Ba MS, Faye B, Ndiaye M, Seck A, Tine R, Thior
  PM, Atwal S, Beshir K, Sutherland C, Gaye O, Milligan P. Seasonal
  malaria chemoprevention combined with community case management of
  malaria in children under 10 years of age, over 5 months, in
  south-east Senegal: A cluster-randomised trial. PLoS Med
  2019;16:e1002762.
\item
  Chandramohan D, Dicko A, Zongo I, Sagara I, Cairns M, Kuepfer I,
  Diarra M, Barry A, Tapily A, Nikiema F, Yerbanga S, Coumare S, Thera
  I, Traore A, Milligan P, Tinto H, Doumbo O, Ouedraogo JB, Greenwood B.
  Effect of Adding Azithromycin to Seasonal Malaria Chemoprevention. N
  Engl J Med. 2019; 380: 2197-2206.
\item
  Landier J, Parker DM, Thu AM, Lwin KM, Delmas G, Nosten FH; Malaria
  Elimination Task Force Group. Effect of generalised access to early
  diagnosis and treatment and targeted mass drug administration
  on\emph{Plasmodium falciparum} malaria in Eastern Myanmar: an
  observational study of a regional elimination programme.
  \emph{Lancet}2018; \textbf{391} : 1916-1926.
\item
  von Seidlein L, Peto TJ, Landier J, Nguyen TN, Tripura R, Phommasone
  K, Pongvongsa T, Lwin KM, Keereecharoen L, Kajeechiwa L, Thwin MM,
  Parker DM, Wiladphaingern J, Nosten S, Proux S, Corbel V, Tuong-Vy N,
  Phuc-Nhi TL, Son DH, Huong Thu PN, Tuyen NTK, Tien NT, Dong LT, Hue
  DV, Quang HH, Nguon C, Davoeung C, Rekol H, Adhikari B, Henriques G,
  Phongmany P, Suangkanarat P, Jeeyapant A,Vihokhern B, van der Pluijm
  RW, Lubell Y, White LJ, Aguas R, Promnarate C, Sirithiranont P,
  Malleret B, Rénia L, Onsjö C, Chan XH, Chalk J, Miotto O, Patumrat K,
  Chotivanich K, Hanboonkunupakarn B, Jittmala P, Kaehler N, Cheah PY,
  Pell C, Dhorda M, Imwong M, Snounou G, Mukaka M, Peerawaranun P, Lee
  SJ, Simpson JA, Pukrittayakamee S, Singhasivanon P, Grobusch MP,
  Cobelens F, Smithuis F, Newton PN, Thwaites GE, Day NPJ, Mayxay M,
  Hien TT, Nosten FH, Dondorp AM, White NJ. The impact of targeted
  malaria elimination with mass drug administrations on falciparum
  malaria in Southeast Asia: A cluster randomised trial. PLoS Med
  2019;\textbf{16} : e1002745.
\item
  McLean ARD, Wai HP, Thu AM, Khant ZS, Indrasuta C, Ashley EA, Kyaw TT,
  Day NPJ, Dondorp A, White NJ, Smithuis FM. Malaria elimination in
  remote communities requires integration of malaria control activities
  into general health care: an observational study and interrupted time
  series analysis in Myanmar. BMC Med. 2018; \textbf{16} : e183.
\item
  Worldwide Antimalarial Resistance Network. https://www.wwarn.org/
\item
  Price RN, von Seidlein L, Valecha N, Nosten F, Baird JK, White NJ.
  Global extent of chloroquine-resistant Plasmodium vivax: a systematic
  review and meta-analysis. Lancet Infect Dis. 2014; 14:982-91.
\item
  Ross LS, Fidock DA. Elucidating Mechanisms of
  Drug-Resistant\emph{Plasmodium falciparum} . Cell Host Microbe. 2019;
  26: 35-47.
\item
  Leang R, Khim N, Chea H, Huy R, Mairet-Khedim M, Mey Bouth D, Dorina
  Bustos M, Ringwald P, Witkowski B. Efficacy and Safety of
  Pyronaridine-Artesunate plus Single-Dose Primaquine for the Treatment
  of Malaria in Western Cambodia. Antimicrob Agents Chemother. 2019;63.
  pii: e01273-19.
\item
  Imwong M, Suwannasin K, Kunasol C, Sutawong K, Mayxay M, Rekol H,
  Smithuis FM, Hlaing TM, Tun KM, van der Pluijm RW, Tripura R, Miotto
  O, Menard D, Dhorda M, Day NP, White NJ, Dondorp AM. The spread of
  artemisinin-resistant \emph{Plasmodium falciparum} in the Greater
  Mekong Subregion: a molecular epidemiology observational study. Lancet
  Infect Dis. 2017: 17: 491-497.
\item
  Imwong M, Dhorda M, Tun KM, Thu AM, Phyo AP, Proux S et al. Molecular
  epidemiology of resistance to current antimalarial drugs in the
  Greater Mekong Subregion: an observational study. Lancet Infect Dis,
  in press.
\item
  Recht J, Ashley EA, White NJ. Safety of 8-aminoquinoline antimalarial
  medicines. World Health Organisation, Geneva, 2014.
\item
  Dini S, Douglas NM, Poespoprodjo JR, Kenangalem E, Sugiarto P, Plumb
  ID, Price RN, Simpson JA. The risk of morbidity and mortality
  following recurrent malaria in Papua, Indonesia: a retrospective
  cohort study. BMC Med. 2020; 18: e28.
\item
  Taylor WRJ, Thriemer K, von Seidlein L, Yuentrakul P, Assawariyathipat
  T, Assefa A, Auburn S, Chand K, Chau NH, Cheah PY, Dong LT, Dhorda M,
  Degaga TS, Devine A, Ekawati LL, Fahmi F, Hailu A, Hasanzai MA, Hien
  TT, Khu H, Ley B, Lubell Y, Marfurt J, Mohammad H, Moore KA, Naddim
  MN, Pasaribu AP, Pasaribu S, Promnarate C, Rahim AG, Sirithiranont P,
  Solomon H, Sudoyo H, Sutanto I, Thanh NV, Tuyet-Trinh NT, Waithira N,
  Woyessa A, Yamin FY, Dondorp A, Simpson JA, Baird JK, White NJ, Day
  NP, Price RN. Short-course primaquine for the radical cure
  of\emph{Plasmodium vivax} malaria: a multicentre, randomised,
  placebo-controlled non-inferiority trial. Lancet. 2019; \textbf{394} :
  929-938.
\item
  Taylor AR, Watson JA, Chu CS, Puaprasert K, Duanguppama J, Day NPJ,
  Nosten F, Neafsey DE, Buckee CO, Imwong M, White NJ. Resolving the
  cause of recurrent \emph{Plasmodium vivax} malaria probabilistically.
  Nat Commun. 2019; \textbf{10} : e5595.
\item
  White NJ, Li GQ, Q Gao, Luzzatto L. Rationale for recommending a lower
  dose of primaquine (0.25mg base/kg) as a \emph{Plasmodium
  falciparum}gametocytocide in populations where G6PD deficiency is
  common. Malaria J 2012; \textbf{11} : e418.
\item
  Newton PN, Bond KC; Oxford Statement signatories. Global access to
  quality-assured medical products: the Oxford Statement and call to
  action. Lancet Glob Health. 2019; 7: e1609-e1611.
\item
  Ozawa S, Evans DR, Bessias S, Haynie DG, Yemeke TT, Laing SK,
  Herrington JE. Prevalence and Estimated Economic Burden of Substandard
  and Falsified Medicines in Low- and Middle-Income Countries: A
  Systematic Review and Meta-analysis. JAMA Netw Open. 2018; 1:
  e181662.World health Organisation. World Malaria Report 2019. Geneva.
\item
  World Health Organisation. World Malaria Report 2019.
\item
  Lacerda MVG, Llanos-Cuentas A, Krudsood S, Lon C, Saunders DL,
  Mohammed R, Yilma D, Batista Pereira D, Espino FEJ, Mia RZ,
  Chuquiyauri R, Val F, Casapía M, Monteiro WM, Brito MAM, Costa MRF,
  Buathong N, Noedl H, Diro E, Getie S, Wubie KM, Abdissa A, Zeynudin A,
  Abebe C, Tada MS, Brand F, Beck H-P, Angus B, Duparc S, Kleim J-P,
  Kellam LM, Rousell VM, Jones SW, Hardaker E, Mohamed K, Clover DD,
  Fletcher K, Breton JJ, Ugwuegbulam CO, Green JA, Koh GCKW. Single-Dose
  Tafenoquine to Prevent Relapse of \emph{Plasmodium vivax} Malaria. N
  Engl J Med. 2019; 380:215-228.
\item
  Llanos-Cuentas A, Lacerda MVG, Hien TT, Vélez ID, Namaik-larp C, Chu
  CS, Villegas MF, Val F, Monteiro WM, Brito MAM, Costa MRF, Chuquiyauri
  R, Casapía M, Nguyen CH, Aruachan S, Papwijitsil R, Nosten FH, Bancone
  G, Angus B, Duparc S, Craig G, Rousell VM, Jones SW, Hardaker E,
  Clover DD, Kendall L, Mohamed K, Koh GCKW, Wilches VM, Breton JJ,
  Green JA. Tafenoquine versus Primaquine to Prevent Relapse of
  Plasmodium vivax Malaria. N Engl J Med. 2019; 380: 229-241.
\item
  Ashley EA, Phyo AP. Drugs in Development for Malaria. Drugs. 2018; 78:
  861-879.
\end{enumerate}



\textbf{Legends to Figures}

\textbf{Figure 1:} Mortality by treatment arm in randomized comparative
controlled trials in strictly defined severe falciparum malaria (which
together enrolled 2874 adults and 7424 children). The size of the circle
is approximately proportional to the size of the trial and the error
bars are 95\% confidence intervals. The adults were enrolled mainly in
Southeast Asia and the children in Africa (4,5,7,8).

\textbf{Figure 2:} In artemisinin combination treatments (2A: left
panel) the three day artemisinin regimen in sensitive infections (AS)
results in rapid parasite killing and consequent decline in
parasitaemia. The logarithmic scale vertical axis shows the total number
of parasites in the body of an adult with approximately 2\%
parasitaemia. The ACT partner drug has only approximately 1000 parasites
to remove in this example (green triangle). In contrast in an
artemisinin resistant infection (AR) there is much less parasite killing
initially and the ACT partner drug now has approximately 100 million
parasites to remove with a substantially greater risk of treatment
failure (recrudescence) and thus selective pressure to the emergence of
partner drug resistance. In the right panel (2B) with TACTs there are
now two slowly eliminated drugs providing a potentially greater
antimalarial effect in resistant infections and ensuring mutual
protection against the emergence of resistance. The detection limit
(dashed line) is the limit for microscopy to identify a malaria
infection.

\textbf{Figure 3:} The parasite clearance half-lives associated
with\emph{Pf} kelch mutations in patients with acute falciparum malaria
studied in the TRAC1 study (20). WT= wild type (note parasite clearance
half-lives can still be much longer than 5 hours in \emph{Pf} kelch
wild-type infections). Mutations in the ``propeller ``region are usually
associated with slow parasite clearance, the phenotypic hallmark of
artemisinin resistance, although there is substantial inter-individual
variation and some mutations (A578S: pink arrow) are clearly not
associated with artemisinin resistance. In the GMS parasite lineages
associated with the F446I mutation have spread widely in Myanmar, and a
lineages associated with C580Y was common along the Thailand-Myanmar
border before targeted elimination activities. In the Eastern GMS
lineages associated with R539T and C580Y both spread but in recent years
the C580Y lineage (termed \emph{Pf} Pailin) has dominated. Modified from
Ashley et al (20) with permission.

\textbf{Figure 4}

The spread of artemisinin resistant \emph{P. falciparum} parasite
lineages across the Greater Mekong subregion (GMS). A single
long\emph{pfKelch} C580Y haplotype (from -50 to +31·5kb either side of
the Pfkelch gene), which emerged in Western Cambodia in 2008 (\emph{Pf}
Pailin), has spread across the Eastern GMS. In Myanmar C580Y parasites
of a different lineage have spread widely and a single\emph{pfKelch}
F446I haplotype which probably originated in the North of Myanmar has
spread widely across the country; modified from Imwong et al (42) with
permission.

\textbf{Figure 5}

Individual patient meta-analysis (52) of freedom from recurrence
of\emph{P. vivax} malaria (relapse prevention) in the two pivotal phase
3 studies in adults which compared tafenoquine single dose (300mg) with
a low dose primaquine regimen (15mg base day for 14 days) (46,47). The
dashed vertical line represents the prespecified noninferiority margin
of an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine). In
Southeast Asia, which has high relapse rates, tafenoquine was
significantly inferior (orange highlighting) to the low dose primaquine
regimen (which is considered inferior to a high dose (30mg base/day)
primaquine regimen); modified from Llanos-Cuentas et al (52) with
permission.

\textbf{Hosted file}

\verb`Fig 1 BJCP.pptx`  available at \url{https://authorea.com/users/312614/articles/443169-advances-and-roadblocks-in-the-treatment-of-malaria}

\textbf{Hosted file}

\verb`Fig 2 BJCP.pptx`  available at \url{https://authorea.com/users/312614/articles/443169-advances-and-roadblocks-in-the-treatment-of-malaria}

\textbf{Hosted file}

\verb`Fig 3 BJCP.pptx`  available at \url{https://authorea.com/users/312614/articles/443169-advances-and-roadblocks-in-the-treatment-of-malaria}

\textbf{Hosted file}

\verb`Fig 4 BJCP.pptx`  available at \url{https://authorea.com/users/312614/articles/443169-advances-and-roadblocks-in-the-treatment-of-malaria}

\textbf{Hosted file}

\verb`Fig 5 BJCP.pptx`  available at \url{https://authorea.com/users/312614/articles/443169-advances-and-roadblocks-in-the-treatment-of-malaria}

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