Saturday, August 22, 2009

Tamiflu-resistant H1N1 may have spread in Singapore

Tamiflu-resistant H1N1 may have spread in Singapore

SINGAPORE, Aug 22 — Resistance to Tamiflu has been detected in a patient in Singapore who was down with the pandemic Influenza A (H1N1) bug. Similar cases have also emerged in Hong Kong, China, Japan, Canada, the United States and Denmark.

When the novel strain first appeared in April, the antiviral worked well against it. The World Health Organisation (WHO) feels that these instances of it not working are isolated cases of resistance that have developed because Tamiflu had been used at lower, prophylactic doses in people who might have been exposed to the bug.

Because these so-called contacts were, in fact, already infected, the lower doses turned out to be suboptimal, which allowed resistance to emerge. There is no proof that resistance is circulating in the community at large, the WHO asserts.

Yet there is at least one documented case of a 16-year-old girl who fell ill while travelling from San Francisco to Hong Kong on June 11. Though she declined Tamiflu, an isolate from her was found to carry the H274Y mutation, which signals Tamiflu-resistance.

She was, however, not the world’s first case of such resistance, an honour belonging to a woman seen in Denmark in late June. When she got home from Britain, she was given Tamiflu prophylaxis. Yet she still fell ill on the fifth day of taking Tamiflu. H274Y was detected in her isolate.

Could she have been infected in Britain by someone carrying mainly Tamiflu-sensitive bugs but also a small population of resistant bugs? In that case, suboptimal Tamiflu dosage might have suppressed enough of the sensitive bugs to prevent any clinical symptoms. Over the five days, however, the resistant bugs could have replicated enough to predominate and thus cause clinical illness.

But if this is so, then the mutation must already have been circulating in Britain — which, however, has not reported any cases of Tamiflu resistance yet. Alternatively, she might have caught the resistant bug in Denmark itself, during the five days when she was well and ambulant.

One reason for suspecting community circulation of the resistant bug is that 98 per cent of all seasonal H1N1 bugs now carry H274Y. If patients are infected with both strains, that mutation could jump from seasonal flu to pandemic flu. But the WHO insists there is no evidence this has occurred, so all resistant cases must have emerged because of suboptimal Tamiflu dosages.

There are signs of community circulation in the US, at least. First, the genomics of the Hong Kong isolate where no Tamiflu was used suggests that the infection originated in the US.

Second, it was revealed only this month that a May 30 isolate taken from a young American woman returning to Singapore from Honolulu carried H274Y.

Flying on May 26, she fell ill on board the plane, was hospitalised here on May 27, was confirmed to be a H1N1 case on May 28, but was discharged on May 31 feeling well.

Although her May 28 sample was Tamiflu-sensitive, her May 30 sample had H274Y. Two days is probably too short an interval for resistance to develop from any suboptimal dosages of Tamiflu. At any rate, as a confirmed case, she would have been given the full dosage.

Thus it is entirely possible that she was infected in the US with both the sensitive and resistant strains, which her immune defences could have cleared quickly, so she was discharged fairly quickly.

Third, on Aug 15, the US authorities sent out an urgent report to physicians that two intensive care patients in Washington state who had been infected last month and treated aggressively with Tamiflu were found to have bugs with H274Y.

These four cases suggest that H274Y may already be circulating in the US. It is possible we are seeing relatively few of these isolates for a technical reason: All published genomes are consensus sequences of DNA. That is, the base that is considered to occupy a specific position on the genome is the one that occurs most frequently. But it needs do so 100 per cent of the time.

If a base occurs in only 10 per cent of viral particles, it isn’t likely to show up in the published sequence. It is only when a base occurs in, say, half the cases that it might appear in the consensus sequence.

If H274Y were found in, say, 10 per cent of viral particles, it won’t appear in the consensus sequence of samples taken from a patient prior to Tamiflu being used. Once Tamiflu is employed, the population of sensitive bugs would be drastically reduced. However, those with H274Y would flourish.

Thus, although it was already around prior to Tamiflu being used, the resistant bug would not be detected. After the drug is employed, however, the resistant bugs can grow to greater numbers than the sensitive ones, rendering them detectable.

Of course, if more samples are taken before Tamiflu is used, H274Y might be detected more often. Such comprehensive surveillance, however, would consume too much resources.

History suggests it was limited testing that enabled Tamiflu-resistance in seasonal Influenza A (H1N1) to creep up on the world unawares. The first instance of that was detected in Norway in spring last year.

By the 2008/2009 season, however, it was found in 98 per cent of bugs worldwide. Yet a re-testing of old samples showed that H274Y was already widespread by the autumn of 2007. This means it was circulating in the community before it was first detected in Norway last year.

Is history repeating itself? If so, Singapore should be stocking up on Relenza, the other antiviral that still works. — Straits Times

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