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Tamiflu Resistance in Swine Flu No Cause for Concern—Yet

by Martin Enserink on 30 June 2009, 3:05 PM | 1 Comments

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A Danish swine flu patient has developed resistance against the most widely used influenza drug, oseltamivir. But public health experts say there is no reason to be alarmed, because resistance developed while the patient was being treated—which suggests the resistant virus isn’t circulating yet—and she appears not to have infected other people. In a “threat assessment”  issued today, the European Centre for Disease Control and Prevention (ECDC) says that the finding “does not represent a public health threat.”

The specter of a pandemic strain that’s resistant to oseltamivir—also known as Tamiflu—worries flu experts because it could render countries’ massive stockpiles of the drug useless. They have seen this happen before: In the seasonal H1N1 strain, resistance has become rampant the past few years, thanks to a mutation in the virus’s neuraminidase gene called H274Y.

The emergence of that strain is a complex story. For many years, researchers occasionally saw H274Y appear in seasonal flu patients while they were being treated, but those viruses tended to not be very good at spreading to other people, so resistance never really caught on. But about 2 years ago, a seasonal strain appeared whose fitness is not diminished by the mutation—perhaps because other mutations compensate for it--—which explains why that strain has spread so fast, even in countries that use little oseltamivir.

H274Y is also responsible in the case of the Danish swine flu patient. But the fact that other patients in the Danish cluster did not have the mutation suggests that her resistance is the more innocuous kind that develops over the course of a patient’s treatment—which explains why scientists aren’t spooked yet.

If, like the seasonal H1N1, resistant pandemic virus finds a way to spread efficiently, however, the situation would be very different. Recently, some countries have added zanamivir (Relenza) and other drugs to their arsenal, but for many, oseltamivir is still the only weapon

Professor Pranab Kumar Bhattacharya
"For the developing and under developed countries with their very poor health infrastructure the risk of pandemic and toll of pandemic by H1N1 is expected to become probably highest. Donation of sufficient oseltamivir and vaccine forH1N1 if in September-09, should be available when the companies would make any vaccine, given up its existing contracts with several rich countries".
Authors
Professor Pranab Kumar Bhattacharya MD(cal) FIc Path(Ind) –Professor of Pathology, Incharge of Histopathology, Cytogenetics, Blood Bank &VCCTC at Institute of Post Graduate Medical Ediucation &Research 244a AJV bose Road, Kol-20, W.B, India and Mr. Rupak Bhattacharya Bsc(cal) Msc(JU), Miss Upasana Bhattacharya, Mr Debasis Mukherjee and Dr. Hriday Das MD(cal), DTM&H(cal) IPGME&R, 244a AJC Bose Road
The head of the World Health Organization Dr. Margaret Chan had declared the first influenza pandemic(H1N1) in 41 years[1], after intense consultations and followed by a meeting on 11 June, with top health officials from countries those are most affected and experiencing rapid transmission of the (H1N1) virus, even today at the community level like[ from previous travel-related cases to more established community types of spread. —the United States, Mexico, Canada, the United Kingdom, Spain, Australia, Japan and Chile] , and with emergency committee of international experts monitoring the global outbreak. The planet is now at the start of the 2009 influenza pandemic. “We are at the earliest days of the pandemic;� She told it Level six[1].— Level six means top level on WHO six-point scale, but of course not in any way, that we are facing the end of the world by the H1N1 virus, neither the virus is changing in the behavior or its genome. It indicates sustained community-level outbreaks in two or more countries [evidence of community spread are now in Australia, the United Kingdom and Chile] in one other WHO regions beyond initial community spread in one WHO region. The term pandemic reflects only the geographic spread of a new disease, not its severity. Pandemics typically infect about a third of the world in a year or two, and sometimes strike in successive waves .It is important to make this message clear because [otherwise] when WHO announce level six it causes unnecessary panics. However Further spread is considered inevitable.
As of 17th June, a total of 40,000 laboratory confirmed cases, including 167 deaths, have been reported by 74 countries to the global health agency. In Asia, first case was reported in Singapore. In India, already 63 cases had been so far confirmed{in Kolkata-# cases] by laboratory and those affected were air travelers from foreign countries. They were kept in isolation. No death has been reported till date by H1N1 in India. Bangladesh, Laos and Papua New Guinea all reported their first cases, while infections continued to rise sharply in Thailand. Australia had reported 1307 cases and no deaths, Canada 2446 and 4 deaths, Mexico 6241 cases and 108 deaths[1], the United States 21,449 cases and 87 deaths. Wisconsin, Illinois and Texas have had the most reported illnesses and the Illinois count rose more than 500 cases. Other nations that have reported large numbers of confirmed cases include Chile, with 1694 cases and two deaths; Japan, with 518 cases; [A high secondary transmission rate of the H1N1 virus in Japan. among minors and suggest that "the population of minors could play a key role as a 'reservoir' for sustained chains of secondary transmission of the virus] the United Kingdom, with 822; Spain, with 357; Argentina, with 256; Panama, with 221; and China, with 174 cases[1]. News from Brazil indicates that a new strain of the virus may have emerged there. Institute Adolfo Lutz, in São Paulo, says it has isolated a new strain, “now known as A / Paulo/1454/H1N1 of swine flue . Authorities in New Zealand said widespread transmission of the virus meant it likely had more than 1,000 cases.
The Question before author is how severe is going to be this pandemic? Moderate or Severe? If it is moderately severe, for the developing and under developed countries with poor health infrastructure there, and whose populations often have high levels of underlying diseases like under nutrition, starvation, malnutrition, TB, HIV, [like in India where more then 25 cores people are living in bellow poverty line] risk of pandemic and toll of that pandemic is expected to become probably highest. There is lack of information" on the pathogenesis and clinical feature of those with severe complications/ illness and treatment regime particularly who are showing unusually severe respiratory illness. Even in developed countries, the virus can cause severe and sometimes fatal illness in pregnant women, babies and people with underlying problems like asthma, heart disease, diabetes, obesity and autoimmune diseases. Most of the fatal infections reported so far had been in adults between the ages of 30 and 50 years[1] noticeably different from epidemics of seasonal influenza. People in those risk groups should seek treatment if they have a fever of at least 100.4, and a cough or a sore throat. The severity of the new virus does not even approach that of the 1918 one, which killed 40 million to 50 million people worldwide. But even the milder flu pandemics took serious death tolls. The one in 1957 killed two million people, and the 1968 pandemic killed about one million. Seasonal flu, by comparison, kills 250,000 to 500,000 people a year[2] The good news so far is that the virulence markers for the 1918 and H5N1 influenza viruses do not appear in the H1N1 strain

No vaccine yet? Vaccine if at all is the final target for pharma industries as preventive one, then it must be thinking for a very cheap or donation purpose for the low income countries like India Bangladesh, African Courtiers and must not for a billion dollars profit. It really remains unclear when the companies would make any donated vaccine available, given its existing contracts with several rich countries and. Dr Margaret Chan said that a donation of five million courses of the antiviral Neuraminidase inhibitor oseltamivir (Tamiflu) by the Roche group has been dispersed to 121 countries. She expected to receive a second donation of 5.6 million doses, part of which would be in paediatric formulation, which would be distributed worldwide so that countries would have something on hand to deal with the pandemic[1] Neuraminidase cleaves sialic acid residues on the cellular receptor that bind the newly formed virions to the cell and to one another, enabling infection to spread to new host cells and ongoing infection to be established. The neuraminidase inhibitors mimic neuraminidase's natural substrate and bind to the active site, preventing the enzyme from cleaving host-cell receptors, thereby preventing infection of new host cells and halting the spread of infection. The two licensed neuraminidase inhibitors, zanamivir (Relenza) and oseltamivir (Tamiflu), have though toxicity but are effective against all neuraminidase subtypes and, therefore, against all strains of influenza virus. But resistance with antiviral oseltamivir (Tamiflu) already noted and spreading.H1N1 viruses containing the His274Tyr resistance mutation became widespread beginning with the 2007–2008 influenza season in the Northern Hemisphere, with a prevalence of about 10% in the United States and about 25% in Europe (except for an astonishing prevalence of about 70% in Norway). These resistant viruses then predominated during the Southern Hemisphere's 2008 influenza season. In the United States today, H1N1 is the dominant circulating strain and is virtually 100% oseltamivir-resistant H1N1 viruses can cause serious complications, and recent data from Norway's 2007–2008 influenza season suggest that patients infected with the resistant virus may be more likely to develop pneumonia or sinusitis than those infected with wild-type virus, although this finding did not reach statistical significance. Could a resistant strain of H3N2 influenza — the virus more commonly associated with death — persist and be transmitted like the current H1N1 strain? In principle, it could, although it would most likely result from different resistance mutations on a different genetic background, given the structural differences between N1 and N2 neuraminidases. These differences mean, for example, that the His274Tyr mutation disrupts the oseltamivir-binding site on N1 but not on N2 and that the Arg292Lys mutation confers more resistance on N2 than N1.We cannot yet anticipate the precise combination of mutations that might enable fitness and persistence of a neuraminidase-inhibitor–resistant H3N2 strain[3]. However No resistance cases Reported in India Yet.
There must be restrictions on travel, or border controls, at stopping spread, and dr. chan called for countries to abstain from trade bans.
References
1)World Health Organization declares A (H1N1) influenza pandemic by John Zarocostas BMJ 2009;338:b2425
2 By DONALD G. McNEIL Jrand DENISE GRADY To Flu Experts, ‘Pandemic’ Confirms the Obvious New York Times Asia Pacific Published: June 11, 2009
3. Anne Moscona Global Transmission of Oseltamivir-Resistant Influenza New.Eng.J.Med 360:953-956March 5, 2009 Number 10

Wednesday, July 01, 2009, 23:39:26

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