Bird Flu concerns raised over drug resistance

 

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 also whether through late diagnosis, poor treatment or the nature of the virus itself, a higher proportion of victims have 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 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 Layer, 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 Layer.  “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. Layer 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 shrugging 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 thug 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. Layer 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  £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 $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.Gbn 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 SFrl.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  $15 per treatment, a substantial discount on the regular seasonal flu price, and  $12 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  $12 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.