Tamiflu resistant H1N1 from Hong Kong more worrying than earlier findings

By Helen Branswell –

TORONTO — All cases of Tamiflu resistance are not created equal. So while the first three instances of swine flu infection with Tamiflu-resistant viruses were reported in the past week, it was Number 3, not Number 1 that put influenza experts on edge.

Public health authorities in Hong Kong announced Friday they have found a case of Tamiflu resistance in a woman who hadn't taken the drug. That means she was infected with swine flu viruses that were already resistant to Tamiflu, the main weapon in most countries' and companies' pandemic drug arsenals.

The two earlier cases, reported from Denmark and Japan, involved people who had been taking the medication. While always unwelcome, that type of resistance is known to occur with seasonal strains and may be less of a threat to the long-term viability of this key flu drug.

"It was not at all surprising to see resistance in patients on treatment but seeing it in someone who was not treated, it certainly is more concerning," says Dr. Malik Peiris, a flu expert at the University of Hong Kong.

There is currently no evidence Tamiflu-resistant viruses are spreading widely. Still, some experts see the Hong Kong case as a warning Tamiflu's role in this pandemic may not be as long-lived as pandemic planners would like.

"I think it's too early to judge," says Dr. Frederick Hayden, an expert on influenza antivirals who teaches at the University of Virginia. "But I think that possibility has existed from the beginning."

"And it's something that needs to be certainly considered in making determinations about things like antiviral stockpiling, management of patients with more serious illness in hospital and how the available drugs will be used."

Some experts say this early sign of resistance should prompt a rethink of how often and in which circumstances Tamiflu is used to battle the novel H1N1 virus.

"It ... probably highlights the importance of not using these antiviral drugs indiscriminately, given that the disease is relatively mild," says Peiris, whose hospital monitored the woman who was found to be carrying the resistant virus.

"In people who don't have underlying risk factors, it probably should not be treated with Tamiflu, basically."

Others suggest countries should limit how often they use the drug to prevent infection, a regimen known as prophylaxis. In prophylaxis, people who've been exposed to the virus are given one pill a day for 10 days, compared to the treatment regime of two pills a day for five days.

Some countries, including Canada, have been reserving prophylaxis for people at high risk from this flu, such as pregnant women.

But others have taken a different approach, using Tamiflu to try to curb spread of the virus. For instance, Britain has made the drug widely available to contacts of confirmed cases, though it announced this past week it was changing that policy.

The World Health Organization is drafting guidance for countries on the use of antivirals. While the WHO advises rather than instructs, it has been stressing that saving these drugs for treatment makes the most sense, says Dr. Keiji Fukuda, the agency's top flu expert.

"In general we have been pushing the advice that using these drugs for treatment is definitely the priority use of them," says Fukuda, the acting assistant director general for health security and environment.

"And I think this is not just from a theoretical resistance perspective, but also from the fact that if you have limited amounts of antiviral drugs, then you need to make some choices about how you use them."

From their first sighting, the new H1N1 viruses have been resistant to two older flu drugs, amantadine and rimantadine. That left the only two other influenza drugs, oseltamivir (Tamiflu) and zanamivir (Relenza), as the sole options for treatment and prophylaxis.

There is a risk inherent in using the drug to prevent illness. If people who are already infected but aren't yet experiencing symptoms are put on prophylaxis, there won't be enough drug in their systems to kill all the viruses they house. Those that survive develop resistance to the drug.

And that, it appears, may be what happened in the resistance cases in Denmark and Japan. In both instances the women involved had been given Tamiflu prophylaxis after a contact developed swine flu.

But the Hong Kong case was different. A 16-year old girl travelling from San Francisco was stopped in Hong Kong's airport in mid-June after setting off a fever detection device.

She was taken to hospital where she tested positive for swine flu. She had not been taking antivirals and declined to be treated with the drug. She was kept in isolation until she recovered.

Dr. Jennifer McKimm-Breschkin, an influenza expert from Australia and a member of the team that developed Relenza, says this case shows resistant swine flu viruses can spread.

It was previously thought flu viruses that developed resistance to the drug would be crippled in the process and would not transmit to others. But that belief was shattered in 2008 when it was discovered Tamiflu-resistant versions of the seasonal H1N1 viruses were spreading rapidly around the globe. They have since all but wiped out Tamiflu-susceptible seasonal H1N1 viruses.

"This is a patient that hasn't been treated, who has gone from San Francisco to Hong Kong. What that means is that she has caught a resistant virus in San Francisco," says McKimm-Breschkin, virology project leader at the Commonwealth Science and Research Organization - known as CSIRO - in Melbourne. (McKimm-Breschkin does not receive royalties for sales of Relenza.)

"So that means this virus has been transmitted from somebody who's presumably been treated. Which means it's been fit enough to transmit. And that is of a lot more concern than just resistance in a treated patient."

Experts have worried the seasonal H1N1 viruses might reassort or swap genes with the swine H1N1. If swine flu picked up with neuraminidase gene - the N in a flu virus' name - from the seasonal H1N1, it would acquire the resistance its seasonal cousin has developed.

Authorities in Hong Kong have not yet told the WHO whether that is what has happened in this case.

But whether the Hong Kong resistance case is due to reassortment, or from the fact that some swine flu viruses have developed resistance on their own, the situation demands careful monitoring, Fukuda and others say.

"The really big question for any finding of antiviral drug resistance with these viruses is whether it's an isolated event or whether it's a tip of a larger phenomenon," he explains.

"The bottom line, as is so often the bottom line with influenza, is that the real answer to the current situation is monitoring as closely as possible - which in this instance is really being done since an extraordinary number of viruses are being collected and looked at."

- Follow Canadian Press Medical Writer Helen Branswell's flu updates on Twitter at CP-Branswell