[Kabar-indonesia] FT Feature: Indonesia: Feeling the strain of 'bird flu'

[Joyo at aol.com]

Financial Times (UK) 
Saturday, September 2, 2006

Weekend Magazine Feature

Feeling the strain

The World Health Organisation estimates that a 'bird
flu' pandemic could affect one in four people around
the globe. Governments are stockpiling the antiviral
drug Tamiflu, the best hope of a cure but can enough
be made in time - and will it work?

By ANDREW JACK

A small girl enters the single room of her
grandparents' cramped house in a suburb of the
Indonesian city of Tangerang and runs behind a
motorbike to hide. A scrawny seven-year-old in a pink
dress, Mutiara has lost her appetite and proved
irritable, fearful and difficult since she fell ill a
year ago. But at least she is alive.

I sit on a mat on the floor with her youthful mother,
Chusuaeni, sipping sweet, milky coffee while a ceiling
fan takes futile chops at the humid air. Chusuaeni is
explaining what happened after Mutiara suffered from a
high temperature and she took her to the local clinic.

"At first, the doctor said it was ordinary flu and he
gave us three types of medicine. She took them, but
after four days she began having difficulty
breathing."

Chusuaeni is a housewife, and her husband a poorly
paid driver. Like most Indonesians they do not have
faith in the limited healthcare facilities provided by
the state and did not know what to do as their
daughter's condition worsened. Only when a close
family friend insisted, and offered to pay, did they
take Mutiara to the private hospital nearby. They were
just in time.

Within a few hours, the doctors diagnosed what they
most feared. They believed she had contracted "bird
flu", the deadly virus, known as "H5N1", that had
already killed millions of chickens across the
country. It was September 2005, and two months earlier
the flu had infected humans in Indonesia for the first
time. Since then more than half of the 241 people
infected around the world have died (141), mostly in
south-east Asia. This summer Indonesia topped the
world with the largest number of human bird flu
deaths: 46, with 60 confirmed infections. Vietnam,
Thailand and China are also among the countries with
the highest levels of infection.

Mutiara was rushed to Sulianti Saroso, the main
infectious diseases hospital in Jakarta, Indonesia's
capital. "I was very, very worried," says Chusuaeni,
who stayed with her daughter in the capital city, half
a day's journey by public transport from Tangerang.
"We have no idea how she became infected. We keep no
birds or chickens."

Part of the little girl's treatment was a white and
yellow capsule taken twice a day for a week. This is a
drug called oseltamivir phosphate. Launched seven
years ago, it is better known by its brand name,
Tamiflu. Developed to combat seasonal flu by Roche,
the Swiss-based pharmaceutical company, Tamiflu was
all but written off in 2004 because, by "big pharma"
standards, it was generating so little income. Since
then, growing fears of a pandemic caused by bird flu
have triggered a huge surge in demand as governments
have set about stockpiling the drug.

Mutiara spent 15 days in intensive care, moving in and
out of an isolation unit as her condition fluctuated.
With the help of close medical supervision and
treatment, she pulled through. Her family,
accumulating growing debts, has continued to pay for
check-ups that suggest the infection has cleared up.
Mutiara was lucky.

Sulianti Saroso, where Mutiara's life was saved, is a
good place to see what would follow if the virus
spread rapidly, as many experts fear it might. Down a
concrete corridor open to the humid air on the first
floor of the hospital is the cramped office of the
doctor on the frontline of Indonesia's battle against
the pandemic.

Dr Santoso Soeroso, the hospital's director, is a
soft-spoken man with outsize glasses and an academic
air of authority. He ushers me into an adjacent
seminar room where the new chairs are still in their
plastic wrapping, in contrast to the hospital's other
facilities that are showing their age. He flicks
through a computer presentation to show me three
X-rays of one of the first infected patients he
treated last year. In the first, the lungs of a 38-
year-old man show a few white specks of infection
among the general grey hue of healthy tissue. By the
third, taken just five days later, they are almost
entirely white.

He died shortly afterwards.

Soeroso describes the typical pattern of the illness
in patients. As the virus spreads beyond the lungs,
patients cough more, their temperature rises and they
become breathless. "By then, most of them will die,"
he says. "There is infection, fluid and debris in the
lungs, blocking the oxygen. That impairs the
distribution of oxygen to the liver, heart and brain,
leading to multi-organ failure."

The doctor grimaces as he expresses frustration at
Indonesia's half-hearted efforts to improve its
primitive health system to cope and at the limited
resources available to treat infection. "No one knows
when a pandemic might occur, but I believe it may
happen within five years."

People often speak loosely when they use the word flu.
Even when we have a bad bout of the common cold, we
sometimes say we've got flu, probably because it
sounds a bit more serious. Perhaps we do not realise
how serious. In fact "ordinary" seasonal flu claims up
to half a million lives a year, many in the tropics
where it generally goes undiagnosed.

Every few decades - most recently in 1968, 1957 and
1918 - a pandemic strain emerges against which the
human body has little defence. The 1918 "Spanish flu"
(so named because the media in neutral Spain reported
it far more extensively than in the censored countries
at war) killed 50 million people around the world,
many times more than the bullets and bombs of the
Great War itself.

On past trends, the next pandemic is long overdue. In
H5N1, first identified in humans in 1997, two of the
three necessary conditions are now in place: the virus
is widespread in birds, and it is lethal.

All it needs is to evolve a little more through its
own mutation, or by swapping genes with another virus,
and it could be widespread and lethal to humans. I
heard Robert Webster, a US-based researcher who is
among the leading experts on the virus, tell a
conference in Singapore that I had attended on my way
to Indonesia: "This is the worst flu virus I have ever
seen... If it happens in humans, God help us."

It is easy to see why Indonesia is just the sort of
place where the flu virus mutation he fears could
occur. Its 220 million people are scattered across
17,000 islands poorly served by veterinary, let alone
human, health systems. The majority of families live
in close proximity to backyard chickens raised in
unhygienic conditions, and the government is reacting
slowly to the threat.

Not only has Indonesia accounted for more H5N1
infections among humans than any other country in
recent months, but whether through late diagnosis,
poor treatment or the nature of the virus itself, a
higher proportion of victims has died than anywhere
else.

Even Sulitani Saroso, the best-prepared hospital in
Indonesia, still has just a handful of isolation beds
to limit the spread of infection.

As I watch one man lying unconscious in intensive
care, supervised by half a dozen nervous nurses
through a thick glass screen, I wonder whether the
Tamiflu he is being treated with, the best hope
doctors currently have, would save us from catastrophe
if indeed it came to that.

Modern flu research began seriously in 1933, when
scientists first isolated the human influenza virus. A
virus is a microscopic particle that works a bit like
a parasite (though, unlike parasites, a virus is not,
strictly speaking, "alive") because they cannot
reproduce unless they attach themselves to the cell of
some organism. When they do so, they infect that
organism, whether it be plant, animal or human.

In the 1940s, the US researcher George Hirst found
that it was an enzyme on the virus that did the damage
to the host human organism by destroying receptors on
red blood cells. In 1948, drawing on this work in
seeking some sort of prevention or cure, MacFarlane
Burnet from the Walter and Eliza Hall Institute in
Melbourne inspired future medical scientists when he
speculated that a drug representing "an effective
competitor poison" for the virus enzyme could prevent
infection.

Burnet's proteges found that one spike- like protein
on the surface of the virus - haemogglutinin (H) -
binds to sialic acid on the surface of a cell, which
it then enters and infects. Another protein -
neuraminidase (N) - cleaves off the sialic acid, thus
allowing the multiplying virus to leave the cell to
infect others. The different types of H and N make up
all varieties of flu virus, including H5N1.

Then in the early 1970s Australian scientist Graeme
Laver, researching the connection between pandemic flu
and birds, collected and analysed samples from nesting
sites on the Great Barrier Reef. He found that
neuraminidase could be spun using a centrifuge into a
crystalline - rather than the usual amorphous - form.
That allowed Peter Colman, another Australian
researcher, to analyse their structure using X-ray
crystallography. "I provided the protein, and he
solved the structure," recalls Laver. "Nowadays you
could use a computer, but then it was done more or
less manually, very tediously drawing contour maps on
big stacks of plastic."

Colman found that each neuraminidase spike had four
identical square balloons on its head, each with a
deep cleft. Here was a possible solution: a "plug
drug" to fill the cleft could in theory block the
function of the protein to remove sialic acid, keeping
the virus glued to an infected cell and unable to
spread.

He collaborated with the Australian company Biota,
which set about developing just such a
neuraminidase-inhibiting drug. By studying the
composition of the cleft and using computer
simulations to create a plug, researchers led by Mark
von Itzstein designed the molecule that, in time,
would be named zanamivir or Relenza and licensed to
Glaxo, the pharmaceutical giant. Biota's researchers
reported their findings in an article in Nature in
1993.

This breakthrough set off a race among rival drugs
companies that spotted the research and identified
Relenza's main weakness: it had to be inhaled, making
it complicated to take. Laver began selling his
crystals to a series of companies for use in research
and nearly a dozen, including Pfizer, Abbott and Eli
Lilly, began hunting for an alternative, pill-based,
version that could be easily swallowed.

One such company was a small and struggling operation
outside San Francisco called Gilead, which had hired
Choung Kim, a brilliant chemist, just as he was
contemplating early retirement from Bristol Myers
Squibb at the age of 51. I met Kim earlier this year
in one of Gilead's conference rooms. He was about to
take a flight to a scientific conference in Seoul. An
ethnic Korean raised in Japan, Kim's calm voice and
demeanour reflected his Buddhist beliefs and a love of
mountain trekking. Nonetheless, he recalled the
excitement to find a flu drug after the publication of
the research behind Relenza.

"They did great science and showed Relenza was very
potent, but also that it couldn't be taken orally," he
says. "There was time pressure for everything. We were
losing money, and concerned if the company would make
it. It was always clear to us that flu was a
commercially interesting disease."

"Choung has a knack for molecules," Norbert
Bischofberger, Gilead's executive vice-president for
research and development, told me. "There is some
sense he has that others don't. I need to draw models
to visualise them. But he doesn't. He thinks in three
dimensions."

Kim designed a molecule, initially called GS 4071,
which found an alternative way to plug the cleft in
neuraminidase by binding tightly to a "hydrophobic"
(water-hating) pocket. He then created a "masked"
form, GS 4104, which was able, unlike Relenza, to pass
from the gut into the blood, where it became GS 4071,
reaching the lungs and offering protection to other
parts of the body too.

Tests proved that the compound worked, and in late
1996, three years after the Nature article, Gilead
filed a patent. Laver remembers the day vividly, since
he had just arrived to sell a new batch of crystals to
a rival team from Pfizer. "The tears streamed down
their faces when they handed me the patent and said:
'We've been beaten.'"

Now Gilead had to find a partner, and held talks with
a number of multinationals about licensing its patent
in exchange for royalties on sales. It did not have
the skills, resources or network to develop a drug,
steer it through regulators and manufacture, market
and distribute it around the world. A deal was reached
that year with Roche, ironically overseen by Glaxo's
former negotiator with Biota for Relenza, Franz Humer,
who left to join Roche. "I was convinced of the need
for an oral version," he told me. Humer has since been
promoted to chairman and chief executive at Roche.

Both companies meanwhile had to conduct clinical
trials in animals and humans in order to win
regulatory approval for these antiviral drugs, which
began in 1999. However, Roche and Glaxo struggled to
win endorsement from cost-conscious health systems
while at the same time having to market a drug for
which demand fluctuated wildly in line with seasonal
flu outbreaks that were sometimes mild, sometimes
harsh.

Relenza suffered the additional handicap of being
inhaled and the first decision of the National
Institute for Clinical Excellence, the UK government's
new medicines advisory body, was that the drug did not
offer sufficient value for money to justify
reimbursement by the National Health Service. In 2004,
Glaxo sold just Pounds 4m of the drug.

Things were not much better for Tamiflu. "Our
forecasts were more optimistic initially," says Humer.
"We had thought that doctors would prescribe and
governments reimburse." With a few exceptions, notably
in Japan, that assessment proved wrong.

In the spring of last year, after Asia had been
afflicted by H5N1 for two years, and with the human
death toll rising and billions of dollars in losses
caused by culling infected poultry, the west finally
began to take notice.

In February 2005, Canada became one of the first
countries to announce the purchase of a government
pandemic stockpile of Tamiflu, designed to treat
nearly 1 million people. The move reflected a small
outbreak of bird flu, but above all Canada's painful
experience in the frontline of the Sars (Severe Acute
Respiratory Syndrome) outbreak in 2003, with 438
suspected cases and 44 deaths - more than anywhere
outside Asia. It would trigger the start of
large-scale orders and a change in fortunes for Roche.

The WHO had long been tracking the progress of H5N1 as
it infected millions of birds in south-east Asia and
began to kill humans. Then, last year, it began to
spread more widely. Specialists in Asia watched in
bemusement as a few cases of H5N1 in animals reached
Europe and media attention touched hysterical levels
as a handful of human cases, and then deaths, were
later reported in Turkey.

If health specialists had long been preparing for a
pandemic, the public pressure on politicians in Europe
and elsewhere in the developed world gave new impetus
and greater funding for their plans, many of which
included the provision of antiviral drugs. In the US,
the White House had been criticised for failing to
listen to advance warnings about, and then to respond
adequately to, Hurricane Katrina.

The flu plan gave President George W. Bush the chance
to counter-attack. He took responsibility himself for
launching his country's ambitious pandemic flu plan
last autumn, backed by Dollars 7bn in funding.

The WHO stepped up technical meetings on the subject,
which tapped into a strong appetite among its member
nations for a theme far more appealing on grounds of
self-interest than the "neglected diseases" such as
malaria and tuberculosis, which largely affect the
poor. By summer, the EU's newly created European
Centre for Disease Prevention and Control, based in
Sweden, was also gearing up activities on flu.

One route medicine pursues with infectious diseases
is, of course, the development of a vaccine. However,
given that flu is constantly mutating, by the time a
pandemic strain is identified and a vaccine developed
and distributed, it is likely to be too late to save
many lives. Antivirals could at least help fill the
gap.

The WHO stopped short of making precise
recommendations on how much Tamiflu should be bought
in by health authorities, but its estimate that a
pandemic could infect one in four human beings across
the world provided a powerful reference point for
policymakers considering how to protect their
citizens. Today, more than 65 governments have ordered
stockpiles of Tamiflu, with many developed nations
buying in supplies sufficient to treat 25 to 40 per
cent of their populations.

Glaxo has received modestly increased orders for
Relenza, but the relative success of Tamiflu showed
the power of a pill over a more cumbersome inhaled
medicine.

Roche sold SFr1.6bn of the drug during 2005, the
majority for government pandemic stockpiles. In 2006
the company is predicting government stockpile sales
alone (excluding regular seasonal flu prescriptions)
of SFr1.3bn for the full year. However, at the same
time this surging demand provoked criticism that
Tamiflu was both too expensive and in short supply.

To counter this, the company said it was selling
pandemic stockpiles to governments at 215 per
treatment, a substantial discount on the regular
seasonal flu price, and 212 to developing nations.
Roche has donated 5 million treatments of Tamiflu to
the WHO for regional stockpiles. It also invested in
new plants and launched negotiations with
sub-contractors so that it could increase production,
which is set to reach 400 million treatments a year by
the end of 2006.

That did not stop a number of drug companies in the
developing world launching copycat versions that were
cheaper. Nor did it prevent individuals concerned by
the pandemic scares, and with little faith in Roche's
supplies or the capacity of their own governments,
from (illegally) ordering the drug - or counterfeit
versions of it - from unregistered pharmacies over the
internet. Indeed, before flying out of San Francisco
after visiting Gilead, I stopped off to see US
Homeland Security officials in the post office mail
hangar at the airport, where letters and packs arrive
from all over the world. Nina Grass, a supervisor,
said: "We get 3 million pieces of mail a day here, and
90 per cent of it is illegal." She held up a small
packet that she had confiscated just before I arrived,
an order from an illegal online pharmacy in Thailand
for a customer in Atlanta. Inside were two boxes of
Tamiflu.

In spite of the fact that it is in the poor world that
bird flu is most rampant, it is in a very rich
country, Japan, that Tamiflu's effects can best be
observed. On the cramped metros and busy streets,
people wearing white masks are a common sight. Some
protect hayfever sufferers, but in such a densely
populated country, many are intended to prevent
infection from colds and flu and to stop it spreading
to others.

"People live so close together, sleep in the same
room, so the contagiousness of flu was very
important," says Roche's Humer. "They immediately saw
the benefits, and the threat of the disease." The
Japanese government became one of the few countries to
agree to reimburse health services for Tamiflu.

Roche was helped by other factors. The structure of
Japanese medicine means patients can see doctors
quickly, getting prescriptions soon after their
symptoms begin, when Tamiflu is most effective. And in
2001, just as it was receiving approval in the
country, Roche took control of Chugai, an established
Japanese company with a powerful distribution network.
The result is that of the 40 million people who have
taken Tamiflu worldwide since it was launched, 25
million are Japanese. Their experiences provide the
most detailed statistics of the risks and benefits of
the drug. They include 75 patients who have died.
Twelve of those deaths raise a haunting concern among
health officials and experts, for they were suicides
by children taking Tamiflu.

Japanese regulators insist there is no causal link
between Tamiflu and suicide. The incidents are not
statistically significant, they say, and they argue
that flu itself - rather than any treatment - can
cause psychiatric complications that could provoke
such acts. This view, echoed by Roche, was supported
late last year by the US Food and Drug Administration.

In the Japanese industrial town of Chiryu I go to
visit someone who believes otherwise. Her name is
Ryuko, and she kneels in front of the shrine in the
corner of the living room in her small modern
apartment, placing the bouquet of white flowers I have
given her next to a candle beneath a photograph of her
son, Kohei. Memorabilia of Kohei's 14-year life are
also there: a baseball and bat, a hat, some toys. On
the table is a photo from the local newspaper, showing
an assembly at his school. Ryuko explains: "Each
person's name on the register was called out, and when
it came to Kohei's turn, all 194 children said 'yes'."

In February last year Kohei called his mother on his
mobile phone after a baseball game to say that he did
not feel well. The next morning, after a restless
night and with his temperature at 39 degrees, she took
him to the doctor, who prescribed Tamiflu.

"At 4pm, he ate some rice with the first capsule of
Tamiflu," she says. "His sister came home, and they
watched TV together. He was in a good mood, and I told
him to sleep while we chatted and napped. At 6pm, I
went to see Kohei but he wasn't there. The front door
was unlocked, with his shoes inside."

When the police came later, they found Kohei's
fingerprints on the railing on top of the waist-high
wall outside their ninth-floor apartment, suggesting
that he had clung on before falling to his death.

Kohei's mother draws the link between Tamiflu and his
suicide, but is strikingly measured and dignified in
her response. "We are totally dependent on the doctor
in Japan. That is not a good thing. Every drug has
side effects, and doctors and pharmacies should say
that if you take Tamiflu for your children, you have
to keep an eye on them." She also points out a
conflict of interest. The regulatory authorities are
also responsible for administering a compensation
scheme for those who suffer from drug side effects. So
far, there has been no ruling by the scheme on whether
to accept Kohei's case. "In Japan they have bought
pandemic stockpiles of Tamiflu. Because of their
policy, they probably don't want to say that it's
related."

If such extreme events are rare, there are other
concerns about Tamiflu. In Japan, 4 per cent of
children taking the drug for seasonal flu, and 0.4 per
cent of adults, proved resistant to treatment, with
the virus still present in samples and patients taking
longer to recover than expected for someone prescribed
the medication. Animal experiments using the H5N1
virus have also shown resistance to Tamiflu, and human
patients have failed to respond to the drug and died
(although this may be because treatment began too
late).

What seems to be happening is that the virus evolves
into a strain that Tamiflu is unable to counter. If
the new craze for the drug drives more people to buy
it - or poorly made counterfeit versions - and to
administer it themselves without taking the full
course, the problem will worsen. Improper use of
Tamiflu is likely to result in the virus being
imperfectly killed, fostering more widespread
evolution of drug-resistant forms.

Resistance is one of several issues that worry Tom
Jefferson, a flu specialist. A former British GP who
now lives in Italy and works with the Cochrane Centre,
an international non-profit network of researchers
providing independent assessments of the effectiveness
of medicines, he published a scathing "meta-analysis"
to examine the value of antivirals. A meta-analysis
looks at existing published trials rather than
conducting original research of its own.

"If you use Tamiflu in seasonal flu, you'll get
resistance and a huge tax bill," he told me. One of
his concerns is that in practice, doctors have no way
of reliably diagnosing flu compared with a number of
other "influenza-like" infections with similar
symptoms against which the drug has no effect.
Encouraging them to prescribe it will result in
significant costs, he believes.

As for Tamiflu's effectiveness during a pandemic, he
stresses that data on its value in treating H5N1
remain scant, while questioning the substantial
resources its purchase requires - notably in the
developing world - when it is still unclear if a
pandemic will even occur.

In an article in The Lancet, he wrote: "Over-reliance
on a pharmacological solution to the ravages of
influenza may impede the development and
implementation of broader intervention strategies
based on public health measures (such as quarantine)."

While other experts are less radical in their
criticism, many admit current evidence is thin. "If
you take reduced mortality as the outcome, then
Tamiflu has not really proved effective," Menno de
Jong told me on the telephone from the infectious
diseases department of the Hospital for Tropical
Diseases in Ho Chi Minh City in Vietnam, where he has
supervised treatment of nearly 20 of the country's 93
H5N1 patients (42 of the total have died). "Of those
we treated with Tamiflu, 60 to 70 per cent died."

But the problem with these depressing figures - and a
difficulty with using the drug in practice - is that
many H5N1 victims have so far been poor people living
in remote areas with limited access to healthcare.
Tamiflu works best when administered within 48 hours
of symptoms, which normally occur about two days after
infection. By the time many of those who fall ill have
the money, time or inclination to seek help, the flu
is already too advanced.

A second practical issue for de Jong is that his
patients typically have diarrhoea and are in poor
condition when admitted. While pills may be easier to
give than an inhaled drug, it is still difficult to
ensure that they take and absorb the prescribed dose.
"If it was up to me, I would like an intravenous
formulation," he says.

What struck me as I tried to understand Tamiflu's
effectiveness in the treatment of humans was how
little information exists. The WHO and Roche referred
repeatedly to the same handful of academic papers that
have been published, covering fewer than a quarter of
the nearly 250 infections to date. Despite their
extensive resources, neither had collected more
comprehensive data.

One hypothesis based on recent tests of H5N1 in
animals given Tamiflu is that the drug will work
better at twice the normal dose of 150mg a day for a
week. But studying its effectiveness in humans is
difficult.

The mutated pandemic strain does not yet exist, and
given the danger of the existing strain of the virus,
testing it in the conventional way for new drugs is
ethically impossible.

That would entail a clinical trial that involved
giving Tamiflu to some and a placebo to others before
exposing them to H5N1 at considerable risk to their
lives. De Jong is working with the WHO and the US
National Institutes of Health on the next best option:
comparing the normal dose with the double dose of
Tamiflu in patients who contract H5N1 and are admitted
to a network of hospitals in the most affected areas
in south-east Asia. Given the small number of cases to
date, however, it is likely to take many months to
analyse a significantly large number.

For now, those on the frontline treating H5N1
infections in humans are placing their hopes on
Tamiflu while waiting for more data on its dosing,
alternative formulations or the emergence of better
medicines and vaccines. "I think it has to be given
the benefit of the doubt," says de Jong. "It's the
best drug we have."

There is a final logistical issue. Even in the
unlikely event that the developing world could afford
- or was subsidised - to buy Tamiflu at 212 per pack,
it would take Roche another decade to supply a single
week-long treatment for everyone in the world. The
more studies argue for higher doses, or prophylactic
use over many weeks, the less attainable protection
and treatment seems.

For the next few years, Tamiflu is likely to remain
the best first- line of defence for those that can
afford it. It may save many lives and protect others
from becoming infected, in which case Roche and
Gilead's profits would be justified. But if fear of a
global pandemic has saved Tamiflu, Tamiflu can only
have a limited role in saving the world.

------------------------------------------ 
Joyo Indonesia News Service
------------------------------------------