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MALARIA
Nov 18th 2004
Treating malaria
A feverish response
A Chinese herbal medicine is effective against malaria. But
there is not enough of it to go round
TAKE a walk through the countryside around Guilin, a bustling
town in the Guangxi region of southern China, and your eyes are
immediately drawn up towering limestone peaks and down
fast-flowing rivers. But one of the most remarkable things in
this dramatic landscape is one of the easiest to overlook--a
common plant which the Chinese call QINGHAO, and which western
botanists have dubbed ARTEMISIA ANNUA. ARTEMISIA holds the key
to beating malaria, a disease that strikes at least 300m people
a year, and kills around a million, mainly young children,
throughout sub-Saharan Africa and south Asia. But ARTEMISIA is
also at the centre of a storm in international public health, as
rising prices and short supplies threaten global efforts to
loosen malaria's grasp on the developing world.
ARTEMISIA has been used in Chinese medicine for more than a
thousand years, to treat everything from malaria to skin
complaints. In the 1960s, Chinese military scientists started
screening hundreds of traditional herbs, including ARTEMISIA, in
an effort to protect their soldiers from malaria. One of the
researchers, Tu Youyou, now director of the Qinghaosu Research
and Development Centre at the China Academy of Traditional
Chinese Medicine, managed to extract and characterise a chemical
called artemisinin that gives the plant's leaves their
anti-malarial punch.
Since then, scientists have developed chemical processes to
convert artemisinin into more potent derivatives. These are good
at killing malarial parasites in the blood, but their activity
wanes after a few hours. So they are best given alongside
another anti-malarial medicine, such as lumefantrine, which
attacks the parasites in a different way and over a longer
period of time--an approach called artemisinin-class combination
therapy (ACT). This double whammy has proved extraordinarily
effective at treating malaria. Trials in several African
countries, as well as in India, Vietnam, Indonesia and Peru,
have shown that at least 90% of malaria patients treated with
ACT over three days recover from the disease.
ACT has become even more important now that other anti-malarial
drugs, such as chloroquine, are losing their effectiveness
because malarial parasites have evolved resistance to them. So
far, resistance is not a problem with ACT, in part because
combining drugs makes it much less likely that mutations in the
parasite will enable it to survive. Since 2001, the World Health
Organisation (WHO) has recommended that countries where drug
resistance occurs switch to ACT. But international efforts to
make the switch were sluggish until earlier this year, when a
stinging paper published in the LANCET accused the WHO and the
Global Fund to Fight AIDS, Tuberculosis and Malaria of "medical
malpractice" for continuing to approve and fund proposals from
poor countries to treat malaria using older, cheaper drugs
instead of ACT.
While denying the charge, both agencies have now sprung into
action. Getting countries to switch to ACT is not only a
question of securing the drugs, but also of training doctors in
how to use them, and setting up surveillance systems to monitor
resistance. The WHO estimates that the world will need 132m
courses of ACT treatment (which cost up to $2.40 each) in
2005--a four-fold increase over this year--and almost double
that number in 2006. So far, the Global Fund has set aside $205m
to help finance the shift, with the promise of more to come.
The biggest problem, at the moment, is getting enough
artemisinin. ARTEMISIA grows like a weed across China and
South-East Asia, but the best plants are found only in certain
parts of China, such as Guangxi and Hunan, which produce most of
the world's supply, and in Vietnam. The supply chain starts with
local farmers, who harvest the leaves in August, when they are
richest in artemisinin, and sell then to a handful of companies,
mainly Chinese, which extract the chemical and change it into
one of the more active derivatives. The chemicals are then sold
to the likes of Novartis, a Swiss drug giant, which produce the
combination therapies.
Just meeting this year's demand is proving tricky. The problem,
says Yan Xiaohua, the president of Guilin Pharmaceuticals, one
of China's leading producers of artemisinin and its derivatives,
is not that there are too few plants, but that the price of
leaves has shot through the roof. The reason is simple, he says.
Once the WHO made its forecast of future demand public in the
spring, the news filtered through to farmers, who quickly
tripled the price of leaves, thus jacking up the price of
artemisinin and its derivatives as well. This has caused
particular headaches for Novartis, whose Chinese supplier,
Kunming Pharmaceuticals, failed to deliver the promised
quantities. That means that Novartis will only be able to fill
half its promise of 10m courses of treatment by the end of the
year.
The good news is that Mr Yan and others are optimistic that
ARTEMISIA prices will stabilise next year. But producers are far
from certain whether they can rise to the WHO's ambitious
expectations for the next two years. This week, UNICEF, the
United Nations' children's fund, and the WHO called an emergency
meeting in Copenhagen to discuss how to boost production and to
keep prices under control.
One way would be to increase the production of ARTEMISIA. In
China, firms such as Guilin Pharmaceuticals are trying to
cultivate the plant--both on their own plantations and through
contracts with local farmers--rather than relying on wild
leaves. Chongqing Holley, a sister company of Kunming's, has set
up a research laboratory in Hunan to help it identify
high-yielding plants and establish a seed bank. As Mr Yan points
out, farming ARTEMISIA not only gives firms more control over
their supply, but also helps reduce the loss of biodiversity
that comes from picking wild plants. The WHO is also keen to see
ARTEMISIA farmed elsewhere in the world. There are pilot
projects to do this in Tanzania, Kenya and Mozambique, but it
will take time before the quantity and quality of their
production can make a real dent in the supply problem.
As Jeffrey Li, the head of Novartis's Chinese operation, points
out, there is also a shortage of facilities that can produce
high quality artemisinin and its derivatives. Novartis has been
working with Kunming Pharmaceuticals and Holley Pharmaceuticals
to upgrade their production capacity. But the great hope is to
find a way of synthesising artemisinin in the laboratory,
thereby freeing drugmakers from the vagaries of nature. Jonathan
Vennerstrom, a researcher at the University of Nebraska, has
come up with a five-step chemical process to make compounds that
can mimic the action of artemisinin derivatives. One of them,
called OZ-277, has proved more effective than artemisinin itself
in both the test-tube and in animal models of malaria. It was
also shown to be safe in recent trials in human volunteers, and
a full clinical trial in Thailand is planned soon. If this trial
is successful, then further testing is planned to see how well
the new molecule performs in combination therapy. If OZ-277
lives up to expectations, then such a therapy might be ready for
market by 2008, at less than $1 a course.
In the meantime, the world will have to meet its growing demand
for artemisinin the old-fashioned way, from nature. The trouble,
according to Fatoumata Nafo-Traore, the director of the Roll
Back Malaria department at the WHO, is that without more money
up front, companies in the business of supplying artemisinin are
reluctant to make the $25m-30m investment that it would take to
start planting on a large scale. Although the Global Fund has
earmarked money for this purpose, the way it is disbursed means
that the process is too slow and too fragmented to give firms
that sort of reassurance.
What is needed, experts say, is a commitment from an
organisation such as the World Bank to provide the hundreds of
millions of dollars needed to buy ACT, and a centralised global
purchasing body to co-ordinate the orders. As the Chinese
proverb has it, "He who plants a garden, plants happiness." With
enough money, and better co-ordination, the world could have a
bumper harvest of ARTEMISIA--which would be good for poor
farmers in China and poor patients in Africa too.
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