Making the Switch

Ensuring access to improved treatment
for severe malaria in Africa

Cover design and layout: Daniel Jaquet
Cover photos: Brendan Bannon, Bruno De Cock
April 2011

Making the Switch • 1

Making the Switch
Malaria continues to be the leading cause of death in African
children. Of an estimated 781,000 malaria-related deaths
reported in 2009, 91% occurred on the African continent, and
85% were among children under the age of five1.
The majority of the 225 million cases of malaria reported
worldwide in 2009 were uncomplicated (or simple) malaria,
and while this represents a significant burden of illness,these cases are, for the most part, non-fatal. However,around eight million simple malaria cases will progress tosevere malaria annually2.
Patients who have severe malaria show clinical signs oforgan damage, which may involve the brain, lungs, kidneys
or blood vessels. By definition, all malaria deaths are theresult of severe malaria. Uncomplicated malaria is most
likely to progress to severe malaria in patients who have notrepeatedly been exposed to malaria in the past, and so have
not had a chance to develop an immune response against theparasite. For this reason, children are the most vulnerable3.
Severe malaria has been described as a life-threatening
medical emergency and a neglected disease that poses a
significant economic burden on most African countries4.

Severe malaria has traditionally been treated with quinine.
Today, the latest scientific evidence clearly shows thatmany more children’s lives can be saved by switchingtreatment from quinine to a more effective drug, artesunate.
However, making this switch will require a concerted effort
and dedicated support from the international community.
Médecins Sans Frontières (MSF) has long been an
important provider for malaria diagnosis and treatment
and treated over one million cases of malaria in Africa in2009. In response to the latest evidence, MSF has revised
its treatment guidelines for all projects to replace quininewith artesunate, and is working with national ministries ofhealth to be able to introduce artesunate in all countries
where MSF works.
This report, based on a review of the latest scientificevidence, coupled with information from MSF’s malaria
programmes across Africa, highlights some of theimportant challenges in making this life-saving switch toartesunate for the treatment of severe malaria especiallyin children, and provides some recommendations for theway forward.

Niger: “The real difficulty is that treating children with severe malaria with quinine is too complex”
During the rainy season in Niger when the risk of getting
malaria is highest, over 75% of the children admitted in MSF
projects test positive for malaria. Last year, over 200,000
children under five were treated for the disease by MSF in
the country. Young children are particularly susceptible toprogressing to severe malaria which is often fatal as theirimmune systems are less developed. This vulnerability
is particularly heightened in Niger, where children are
already in a weakened state due to malnutrition. Dr. Yvonne
Nzomukunda, MSF’s deputy medical coordinator in Niger,
explains the difficulties in dealing with the seasonal peak ofmalaria cases, and why a change in protocol to treating thedisease with artesunate would make a real difference to thequality of care children receive.
“The real difficulty is that treating children with severe
malaria with quinine is too complex. With quinine, we rely on
infusions of the drug delivered in a glucose solution througha vein. Each child needs a succession of separate infusions,each lasting four hours and each time checks have to be
carried out – is the drip placed correctly? Is it flowing at theright speed? Has the child moved and does the infusion need
to be reset? When there’s a spike in admissions during thepeak malarial seasons, this places a lot of pressure on thestaff and makes it extremely difficult to ensure each childis getting the right treatment at the right time in the rightdoses.”
Quinine is the first choice in the country’s protocols for thetreatment of severe malaria in children, although intramuscular

injections of artemether, another antimalarial drug derived
from the Chinese plant, artemisin, are allowed in the caseof quinine stock outs, or if a child shows an intolerance
to quinine. Dr. Nzomukunda explains that in a context like
Niger where many of the children are malnourished, this canhappen all too often:“Large volume infusions are risky for malnourished children,
who are often in a fragile metabolic state and therefore
must be carefully monitored when given fluids. Plus quinine
carries the risk of severe side effects, such as hypoglycaemia
and irregular heart beat that can be fatal. If we could use
artesunate to treat children, we would have the ability todeliver a dose of the drug through injection in just over four
minutes, rather than the four hour period taken currently todeliver quinine, so this would obviously be an advantage andthat’s why we are really hoping that we will be able to switch
away from quinine and use injectable artesunate instead.”
Moves are now underway to work with the health authorities
so that artesunate can be used in the treatment of severe
malaria in children.
However, any moves in Niger or elsewhere on the continent
are likely to be aided by enhanced guidance from theWorld Health Organization; with both the revision of its
own guidelines setting out artesunate as the preferredtreatment for severe malaria in children and also providing
countries with the necessary medical guidance and training
to implement.

2 • Making the Switch

The science

Artesunate saves more lives than quinine
According to a nine-country trial done in Africa in 2010, forevery 41 children treated for severe malaria with artesunate
instead of quinine, one life would be saved. This study
found that treatment with artesunate reduces the risk ofdeath by 39% in adults and 24% in children; this translates
into many thousands of children’s lives saved by making
the switch12. The benefits are likely to be even greater inprogramme settings, where the difficulties of using quinine
are more burdensome than in trial conditions (see below).
Overall, it has been estimated that if all cases of severe
malaria were treated with artesunate instead of quinine,around 195,000 additional lives would be saved2.
Artesunate is safer than quinine
In addition to reducing mortality, artesunate is safer to use
than quinine. The most common side effect experienced
by patients with severe malaria is low blood sugar(hypoglycemia), which is particulary dangerous for pregnant
women. Quinine can worsen low blood sugar in severe
malaria patients; this risk is reduced by more than half if
artesunate is used instead13. Other significant side effectsof quinine include dizziness, anaemia and, in some cases,
cardiotoxicity and death15.

Artesunate is easier to use than quinine
Quinine is a difficult drug to administer for many reasons.
Doses must be calculated precisely according to thepatient’s body weight and administered as slow infusions
over four hours that must be repeated every eight hours
until the patient can tolerate oral therapy. In addition, thefirst dose needs to be adjusted in cases where the patient
has taken quinine treatment prior to admission to avoid
toxicity. However, it is not always possible to establish aclear history, so some patients will risk being overdosed.
These difficulties in administering quinine, particularly inrural areas of Africa where health workers may lack thenecessary training or equipment, can lead to overdosingof quinine, which has resulted in instances of permanent
blindness, convulsions, cardiotoxicity and coma16. A recent
study examining malaria deaths in healthcare facilities inthree provinces of South Africa found that almost one infour patients were not given quinine doses as prescribed;
four patients received excessive amounts and at least
one patient was thought to have died as a result of rapid
quinine infusion17. A study from Uganda reported similarfindings, with 12.7% of patients being underdosed and12.3% being overdosed with quinine4.
For these reasons, intravenous quinine treatment requires
trained professionals for accurate dosing, slow infusion,and continuous monitoring for side effects. The lack ofavailable skilled professionals may contribute to a delay instarting quinine infusions, and this can lead to avoidable
suffering and death. In the African trial comparing quinine
and artesunate, children assigned to receive quinine
were almost four times more likely to die before everreceiving treatment compared to children assigned toreceive artesunate12.

© Brendan Bannon

Quinine has been the mainstay of malaria treatment for
hundreds of years and currently almost all African countries
rely on quinine for the treatment of severe malaria1. However,
several large clinical trials conducted over the past decadein Asia and Africa show that artesunate saves more lives,is safer, and is easier to use compared to quinine. Taken
together, an overwhelming body of evidence supports thesuperiority of artesunate over quinine for the treatment ofsevere malaria in both adults and children across the world.

Making the Switch • 3

Evidence supporting the switch from quinine to artesunate
1980s Following the rediscovery of qinghaosu (artemisinin)
in China and subsequent synthesis of artemether
and artesunate, both are found to be highly effective
alternatives to quinine5.
1992-2003 Evidence from small trials done in Myanmar,
Thailand, and Vietnam suggest a benefit of artesunate
over quinine, but studies are too small to be definitive6,7.
2005 A large clinical trial involving nearly 1,400 patients(mostly adults) with severe malaria in Asia shows that
artesunate (administered intravenously) reduces deaths bya third compared to quinine8. The study is stopped earlybecause of the very large mortality difference between
patients receiving artesunate and quinine.
2006 The WHO recommends artesunate (delivered
intravenously) as the treatment of choice for adults withsevere malaria, although the guidelines state that quinine
would be an acceptable alternative in situations whereartesunate is unavailable9.
2007 A systematic review of existing trials comparing
artesunate and quinine lends further support to the benefit ofartesunate in terms of reduced side effects and mortality10.

March 2010 The WHO issues stronger guidelines in favourof artesunate treatment for adults with severe malaria.
However, these guidelines state that there is insufficientevidence to recommend artemisinin derivatives overquinine for treating children, especially in endemic areas
in Africa11.
November 2010 A trial involving more than 5,000 children
from 11 centres in nine African countries reports that
artesunate is more effective at reducing mortality compared
to quinine. The study concludes that for every 41 children
given artesunate instead of quinine, one life is saved12.
March 2011 Updated review of available data concludes
that treating severe malaria with artesunate instead ofquinine reduces the risk of death by 39% in adults and
24% in children13.
April 2011 WHO guidelines are revised to recommend
artesunate (to be delivered intravenously) as the first-line
treatment for severe malaria in both adults and children14.
Several African countries, including Guinea, Niger andUganda, indicate that they are preparing to revise
their malaria treatment guidelines to reflect the latest
recommendations.

Guinea: “The challenge that will need to be met is ensuring that these new medicines are made available”
In December 2010, MSF with the active support of the Ministryof Health, began using a new protocol to treat children forsevere malaria in rural health centres in the Guéckédou areain Guinea’s eastern, forested uplands. Instead of quinine
infusions, children now receive artemether injections, andin a few months’ time artesunate will be introduced as thetreatment of choice. MSF Field Coordinator Divin Barutwanayo
explains what pushed MSF and the health authorities tomake the switch as he looks back on the first months of
implementation.
“With the eventual introduction of artesunate injections andthe phasing out of quinine, we’re really hoping to ease theburden of severe malaria on the population here. Until now all
the complicated cases of severe malaria had to be referred tohospitals and this creates real difficulties for people from thevillages. There are no ambulances, very few vehicles around andthe roads are bad so if you’re sent to hospital it’s very hard to getfood or for family members to come for support. But the problem
has been that local health clinics don’t have the capacity to treat
the illness using quinine which is tricky to administer.
We first started using artemether to treat severe malaria inthe local health clinics around here in December last year. To
start with, the health workers, some of the nurses and thedoctors, were a little reticent about using the new treatment,
because quinine has been used for years, so it’s not so easy tochange overnight. And the patients too – everyone is familiar
with infusions when a child has severe malaria, so when theyreceived an injection instead, many at first thought they hadn’t
received proper treatment, and they wanted the infusions.
So we’re working to familiarise health workers with the new
medication and reaching out to the local population with radio
spots, through posters in waiting rooms and through a networkof local organisations and community officers who go out andspread the information in the villages.
And attitudes are changing: in January we treated only six casesof severe malaria with the new treatment, in February we had
27 and in March 46. We’re hopeful that we can replicate thissuccess when we introduce artesunate, sometime during thecourse of the year, with the support of the Ministry of Health.
The challenge that will need to be met is ensuring that these
new medicines are made available throughout the healthstructure of Guinea and not just MSF-supported clinics. Currently
some health centres in Guinea sometimes lack even basic
medicines and obviously, this presents a big hurdle that needs
to be addressed by the government and the donors.”4 • Making the Switch

Challenges to making the switch
In response to the latest evidence, the WHO has publishedrevised treatment guidelines to recommend artesunate
as first-line treatment for children and adults with severe
malaria everywhere14. However, there are a number ofimportant barriers that can be anticipated in making thisswitch.
Translating evidence into policy
The latest WHO guidelines will need to be rapidly
disseminated to all relevant malaria actors so that national
protocols can be revised, and these new protocols mustthen be distributed to healthcare providers throughout
the country. The reality today is that almost no Africancountries even recommend artesunate as treatment forsevere malaria in adults, even though this has been therecommendation by WHO since 20069.
Translating policy into practice
Health providers and managers – both in the public andprivate sector – are generally not aware of the latest
evidence. To date, there are no international plans in place
to finance or provide technical support for such training at
the scale required. Similarly, caregivers and patients have
yet to be made aware that a new, more effective treatment
exists. Healthcare workers may be reluctant to switch toa new and unfamiliar treatment, or may hold a personalconviction that, in spite of the evidence, quinine remains
the best treatment available. MSF teams in Niger havereported that, despite a willingness to change practice atthe national level, many local doctors remain convinced thatquinine is the best treatment for severe malaria. However,while quinine has been used to treat severe malaria for
hundreds of years, this does not mean it is easy to use.
Even in well-resourced clinical trial conditions, quinine use
has been shown to be difficult to administer and can havelife-threatening side effects. In contrast, artesunate can begiven intravenously over just a few minutes, and has far
fewer side effects. (This is followed by a full course of oral
treatment (ACTs) to achieve complete parasite clearance
and minimise the risk of development of resistance.)
Replacing quinine production
Switching to artesunate may prove particularly difficultin areas where this is seen as a threat to local quinine
production, which is an important economic activity ina number of malaria-endemic countries. In Burundi, forexample, quinine is the most frequently available drug inboth the public and private sector. It has been available
in Burundi since the 1940s and is one of the few drugs
manufactured in the country, making it more popularand more easily accessible than imported antimalarials20.
However, countries may balance the interests of local quinine
producers with the fact that producers of artemisinin, theraw material for artesunate, are today located in several
African countries in addition to traditional production sites
in Asia21.

Lessons to be learnt from slow malaria policy change in the past
For most of the twentieth century, chloroquine was thestandard malaria treatment throughout Asia and Africa. In
the 1960s and 1970s, however, it became apparent that theuse of a single drug (or monotherapy) leads to resistanceand, as a result, chloroquine was becoming less and lesseffective throughout Africa. Another drug, sulphadoxinepyrimethamine, was introduced in the 1970s, but thisdrug combination rapidly suffered a similar fate, becoming
ineffective due to resistance. By the 1990s, widespread
resistance to both chloroquine and sulphadoxinepyrimethamine had been documented across the continent.
Largely as a result of the reduced treatment effectiveness,malaria deaths began to soar, with deaths reported in the
period 1982 - 97 four times higher than deaths in thepreceeding two decades. In 2000, a ministerial meetingin Abuja issued a declaration that artemisinin-based
treatments should become the first-line therapy for simple
malaria. MSF and other providers began advocating for theswitch to artemisinin-based combination therapy (ACT) for
simple malaria in 2001, and WHO recommended switching
to ACT for all cases of simple malaria the following year18.

But the road from policy change to implementation islong, and it took several years and considerable efforts totranslate the WHO recommendations into practice.
Between 1996 and 2004, MSF teams undertook 43
resistance studies in 18 countries to provide evidence thata move away from chloroquine to ACT was necessary19.
By 2006, close to 40 countries in Africa had changed
their national treatment protocols to recommend ACT
for simple malaria treatment, but still chloroquine use
persisted in health centres across Africa. Limited ACT
supplies, the higher cost of ACT compared to chloroquine,
and an enduring conviction among health providers thatchloroquine was still the drug of choice, meant that ACTs
were still not reaching the patients who needed them
most.
Even today, ten years after international policy change,
there are reports that health workers in high-burdencountries continue to provide chloroquine because they
believe it is the better drug.

Making the Switch • 5

The long shelf life of quinine (five years) means that large
quinine stocks exist in many countries. Reports frommalaria programmes in Guinea suggest that programmemanagers would be reluctant to purchase artesunate when
they have already paid a lot of money for quinine. This
may result in a lag-time during which quinine is phased
out. This may make economic sense, but it means thatchildren will continue to receive what is now known to be
sub-optimal treatment.
Improving quality supply
A WHO prequalified source of artesunate is now available
to support the switch22. As demand increases, additional
manufacturers should be encouraged to enter this market,
increase supply security and reduce the price for quality
assured artesunate.
Decreasing drug costs
The higher cost per dose of artesunate compared toquinine is likely to be an important concern. Currently,
the cost of drugs to treat a child with severe malaria
are around $3.3 for artesunate compared to $1.3 forquinine23. It can be expected that some governments will
be reluctant to switch to artesunate as long as it remains
more expensive than quinine. While the unit price ofartesunate is currently higher than that of quinine, overall
costs are found to be equivalent. Cost analyses from thetrials in Asia24 and Africa23 show that if total costs are
considered (in particular the costs of administering the
drugs and the management of side effects), artesunate isfound to be cost-effective.
Supporting acceptance of the evidence
Finally, calls for local evidence are often made by national
governments out of concern that studies done in othercontexts may not apply to their setting. It should be
noted that two large trials were done in more than nine
African and four Asian countries, and their results are
considered to be widely generaliseable. For this reason,
the latest review of the evidence to date concluded thatfurther research to examine the efficacy of artesunate
versus quinine in children and adults is unnecessary13.
International ethical standards clearly state that patientsshould only be subjected to experimental trials if there isreal uncertainty about which drug is better25. Thus, while
operational research may help provide practical lessons
for the implementation of artesunate, it would clearly beunethical to delay implementation by insisting on further
drug effectiveness studies and to subject patients toclinical research where there is already enough evidence.

The difference between artemether and artesunate
There are two commonly used artemisinin derivatives forthe treatment of severe malaria: artesunate and artemether.
Artesunate is a water-based preparation and can beadministered via intravenous or intramuscular injection.
Artemether, on the other hand, is an oil-based preparation
and as such can only be used intramuscularly. Intravenous
treatment is most effective in treating severe malaria.
During the 1980s, two parenteral formulations were
produced (artesunate and artemether) in China and initially,
the oil-based intramuscular formulation of artemether waspreferred and pursued in studies that compared artemether
against quinine5. Data from these trials found that there
was an overall mortality benefit in favour of artemether,and the fact in programme settings artemether was more
likely to be administered correctly than quinine meant that
it was more effective.
We now know that artesunate is more effective thanartemether; a recent randomised trial comparing both drugsdelivered through intramuscular injection found a 47%

mortality reduction among patients receiving artesunate(although the trial was not large enough to be statisticallysignificant)26.
A number of African countries have already included
intramuscular artemether in their national guidelines,
and this may act as an additional barrier to introducing
artesunate14. Health staff may prefer artemether because
it is provided ready for injection once drawn up in asyringe, whereas artesunate requires prior mixing with aninjection solution. However, artemether cannot be seen as
equivalent to artesunate. Artesunate is almost immediately
absorbed and fully converted to the active form of thedrug, whereas artemether is slowly, erratically absorbed
and only partially converted to an active form27. There isplenty of evidence that delays in treatment kill. This is why
the latest WHO guidelines recommend artesunate, and notartemether, for severe malaria. In resource-limited settings
where intravenous administration is impractical, WHOrecommends intramuscular or rectal artesunate.

6 • Making the Switch

Democratic Republic of Congo: “Let’s not forget, current treatment is hard on the patient”
In addition to years of violence and conflict, the people of
the North Kivu region of the Democratic Republic of Congoare burdened with high rates of malaria – one in every three
consultations carried out in MSF clinics in January this year
were due to the disease. MSF supports many health clinics
throughout the area and, in 2010, treated tens of thousandsof people for malaria. Around one-third of those are, like
Colette, children under the age of five.
When little Colette arrived at the Mpety health centre,
her life hung in the balance. With a high fever, she washaving difficulty breathing and was experiencing seizures, allsymptoms that she was clearly suffering from severe malaria.
Nurses battled to save the two year old’s life by setting up
the first of many drip infusions, where quinine is administeredin a glucose solution through a vein over a number of hours.
The drug has been the mainstay of malaria treatment in the
DRC for many years as set out by government regulations,but it’s not that easy a treatment to administer as MSF’s
medical coordinator, Dr. Martins Dada explains:© J.B. Russell / Framework“Staff in clinics based in very remote areas run by the Ministryof Health often have great difficulties with setting up thethrice daily infusions with quinine. Sometimes this is because
they lack basic medical supplies such as glucose solutions,infusion lines and intravenous catheters. Other times, placing
the infusion in a child can be tricky because they cannot
find a good enough vein or because the infusion needs toremain in place for four hours at a time, multiple times andmovement can disturb this. Also, treatment isn’t standardisedand each treatment has to be adapted specifically to eachchild, and this makes things complex for medical staff too.”
Quinine is also a difficult treatment for patients to tolerate:
because of both the nature of quinine and the challenges inadministering it in the correct dosage, patients can suffer awide range of side effects - including short-term dizziness,hearing loss, or ringing in the ears - and progress into
far more serious, life-threatening ones such as irregularheartbeat and even coma.
Despite recent studies that have shown that artesunate could
save many more lives, quinine remains the main plank oftreatment in DRC. Many at the health centre express hopefor a switch to a medication like artesunate, which would not
only be safer with fewer side-effects, but also more effective.
“Let’s not forget, current treatment is hard on the patient. The
real benefit [of switching to artesunate] to me as a doctor
would be the knowledge that I can treat patients faster andwith less side effects,” Dr. Dada explains.
Colette pulled through after seven days of treatment andwent on to make a full recovery at the nearby Pinga hospital.
Her mother, aunt and baby brother who were by her side
during her entire treatment were overjoyed with her recovery.
Although Colette won her battle with severe malaria today,
there are many who aren’t so lucky.

Making the Switch • 7What needs to happen
The evidence is clear: switching from quinine to artesunate
will simplify the management of severe malaria and has
the potential to save hundreds of thousands of children’s
lives each year. Policy change does not happen overnight,
and making the switch will require a dedicated effort by
the international community and governments of malariaendemic countries.
The World Health Organization’s updated guidelines shouldbe rapidly disseminated to affected country governments,
supported by programme guidance and appropriate training
materials. WHO should also prioritise the prequalification of
additional sources of injectable artesunate.
National ministries of health should begin the process ofchanging their guidelines based on the existing evidence.
Specific activities to support implementation of thetreatment switch are needed. This includes establishingprocurement and supply chains, staff trainings, as well as
community education to ensure that patients understand
why their care is being changed from a drip infusion to an
injection.

© Brendan Bannon

Manufacturers should prepare for increased demand of
injectable artesunate. Additional manufacturers should begiven a clear message that the market exists to encouragethem to start production of injectable artesunate and obtain
WHO prequalification. Market forecasting will be essential
to convince manufacturers that artesunate productionneeds to increase and to support market diversificationthat will contribute to a more stable drug supply andsubsequently, lower prices. Manufacturers should also
work to improve the preparation and dosing presentationof artesunate.

Malaria partnerships and initiatives should help withawareness raising of the benefits of changing treatment
for severe malaria, as well as provide technical support
to countries to change treatment protocols, to apply forfunding where needed, and to implement the switch. Roll
Back Malaria could be well placed to establish and championa multi-stakeholder strategy to support the switch. Country
co-ordinating mechanisms and their supporters in the Roll
Back Malaria network should be encouraged to include
specific requests for funding to support severe malaria
treatment in their applications to the Global Fund.
Donors should act now to support efforts to revise nationalguidelines and replace drug supplies. Multilateral donors
such as UNITAID, the Global Fund, and the World Bank,as well as bilateral donors with a major commitment
to malaria control such as USAID and DFID all have an
important role to play. International donors have not
traditionally supported severe malaria treatment due to the
low cost of quinine. The challenges ahead in the short term
require specific donor support in order to switch to a drug
that, in terms of unit costs, is more expensive.
The cost of making the switch is well within reach of theinternational community. To treat all cases of severe malaria
world-wide with artesunate instead of quinine represents
an additional annual drug cost of $31.8 million and a total
drug cost of $49.2 million in order to save around 195,000
lives each year*.
An international plan is needed to support the switch
without delay.
* Calculation based on reported number of cases of severe malaria2, reported
costs of drugs for adults23 and children24, and reported proportion of severe
malaria cases in children4.

8 • Making the Switch

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