Japan Reports Peramivir Resistant Virus

 

 

 

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In 1940, even before penicillin could be rolled out for clinical use, a penicillin-resistant organism was detected by researchers in a sample of Gram-negative E. coli.

 

Ever since then, man has been in a ongoing battle to create new antibiotics and antivirals faster than nature can find ways to circumvent them.

 

One of the newest entries onto the antiviral stage has been peramivir (Rapiacta) introduced in Japan in 2010, and used under an EUA (Emergency Use Authorization) here in the United States during the pandemic.

 

Peramivir is an IV neuraminidase inhibitor, developed by BioCryst, and has been viewed as a potential successor to Tamiflu – particularly for severe cases of influenza.

 

Today we are hearing of what appears to be a single spontaneous mutation of the new H1N1 virus in a child receiving the IV peramivir therapy.

 

Spontaneous mutations of this sort, while notable, are not unexpected and are far less serious than a resistant mutation detected in a biologically fit (and circulating) flu strain.

 

The story from Kyodo News, and then I’ll return with more.

 

New flu virus resistant to antiflu drug Rapiacta detected in patient

TOKYO, Feb. 22, Kyodo

A genetic mutation of the H1N1 influenza virus resistant to the Rapiacta anti-influenza drug has been detected in a 5-year-old patient, according to the National Institute of Infectious Diseases.

(Continue . . . )

 

The child has reportedly recovered and has been discharged from the hospital. There are no indications that the mutated virus was transmitted further.

 

In March of 2010 we learned of another case of peramivir resistance (see NIH: Rapid Development Of Antiviral Resistance In Two Cases) during the fall 2009 pandemic wave.

 

Our arsenal of antivirals is limited, and some of the new ones in the pipeline are refinements of older drugs, which may prove vulnerable to some of the same forms of resistance.

 

Overuse of Amantadine, particularly its inclusion into chicken feed during the 1990s to combat bird flu in Asia – has been credited with a dramatic rise in influenza’s resistance to the drug by 2005.

 

Tamiflu (oseltamivir), released in 1999 proved extremely effective against influenza until 2008, when a resistant version of the old seasonal H1N1 appeared and quickly spread around the world.

 

Seasonal H3N2 remained susceptible to the drug.

 

The old H1N1 virus has been replaced by novel H1N1, which fortunately still remains largely sensitive to the drug.  

 

Scientists do worry that over time, the new H1N1 virus could pick up resistance to Tamiflu. And as we’ve seen in these two isolated cases, even newer generations of neuraminidase inhibitors are not immune to resistant spontaneous mutations.

 

The takeaway message from these reports isn’t that peramivir has already been rendered useless (it hasn’t), but that resistance can develop quickly in rare instances in some people while receiving these medications.  

 

Which is another good reason why getting a flu shot every year is an exceedingly good idea.

 

It is almost always better to try to prevent an illness, than to have to treat one.

NIH: Rapid Development Of Antiviral Resistance In Two Cases

 

 

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Victories over continually evolving pathogens are often fleeting at best.   No sooner do researchers release a new generation of antibiotics or antivirals, than these organisms begin to find ways to work around them.

 

Maryn McKenna’s terrific book Superbug: The Fatal Menace of MRSA goes into great detail about the road to antibiotic resistance, but we are seeing a similar path being followed by antivirals as well.

 

Amantadine managed to remain an effective treatment and/or prophylaxis against influenza A for four decades, although it was used only sparingly for the first 30 years or so.   

 

Overuse of Amantadine, particularly its inclusion into chicken feed during the 1990s to combat bird flu in Asia – has been credited with a dramatic rise in influenza’s resistance to the drug by 2005. 

 

Tamiflu (oseltamivir), released in 1999 proved extremely effective against influenza until 2008, when a resistant version of seasonal H1N1 appeared and quickly spread around the world.   Seasonal H3N2 remained susceptible to the drug. 

 

These two seasonal viruses have been (at least temporarily) replaced by novel H1N1, which fortunately remains sensitive to the drug.   Scientists do worry that over time, novel H1N1 could pick up resistance to Tamiflu as well.

 

Which brings us to a report issued yesterday by the NIH about two patients that developed resistance to Tamiflu, and in one case, to the newly approved peramivir.   

 

FOR IMMEDIATE RELEASE
Friday, March 26, 2010

Media Contact: Anne A. Oplinger
(301) 402-1663
niaidnews@niaid.nih.gov

Rapid Development of Drug-Resistant 2009 H1N1 Influenza Reported in Two Cases

Reevaluation of Treatment Strategies for Prolonged Infection Urged

Two people with compromised immune systems who became ill with 2009 H1N1 influenza developed drug-resistant strains of virus after less than two weeks on therapy, report doctors from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. Doctors who treat prolonged influenza infection should be aware that even a short course of antiviral treatment may lead to drug-resistant virus, say the authors, and clinicians should consider this possibility as they develop initial treatment strategies for their patients who have impaired immune function.

 

Both patients in the new report developed resistance to the key influenza drug oseltamivir (Tamiflu), and one also demonstrated clinical resistance to another antiviral agent, now in experimental testing, intravenous peramivir, note senior authors Matthew J. Memoli, M.D., and Jeffery K. Taubenberger, M.D., Ph.D. This is the first reported case of clinically significant peramivir-resistant 2009 H1N1 illness, say the scientists. The report is scheduled to appear in print on May 1 in Clinical Infectious Diseases and is now online.

 

The people in the current case report had immune limitations due to blood stem cell transplants that occurred several years previously. Both recovered from their influenza infections.

 

“While the emergence of drug-resistant influenza virus is not in itself surprising, these cases demonstrate that resistant strains can emerge after only a brief period of drug therapy,” says NIAID Director Anthony S. Fauci, M.D. “We have a limited number of drugs available for treating influenza and these findings provide additional urgency to efforts to develop antivirals that attack influenza virus in novel ways.”

 

The 2009 H1N1 influenza virus is susceptible to just one of the two available classes of anti-influenza drugs, the neuraminidase inhibitors. Besides oseltamivir, other neuraminidase inhibitors are zanamivir (Relenza), which is inhaled, and the intravenously administered investigational drug peramivir. As the H1N1 influenza pandemic unfolded, laboratory tests of virus strains isolated from patients showed that some strains contained a genetic mutation (the H275Y mutation) that makes the virus less susceptible to some neuraminidase inhibitors.

(Continue . . . )

 

 

Lisa Schnirring at CIDRAP News has more details on this story.

 

 

Researchers report peramivir-resistant H1N1 case

Lisa Schnirring Staff Writer

Mar 26, 2010 (CIDRAP News) – Researchers today sounded two warnings for clinicians who manage pandemic H1N1 patients: that even a short course of oseltamivir (Tamiflu) can lead to antiviral resistance and that patients can develop resistance to peramivir, an alternative to oseltamivir in emergency situations.

 

The warnings come from a case report of two patients published today in an early online edition of Clinical Infectious Diseases (CID). The authors are from the National Institute of Allergy and Infectious Diseases (NIAID) and the US Food and Drug Administration (FDA). The study is scheduled to appear in the May 1 issue of CID.

 

The research team, headed by senior authors Matthew J. Memoli, MD, and Jeffery K. Taubenberger, MD, PhD, said the report details the first clinically significant peramivir-resistant pandemic H1N1 case.

(Continue . . .)

 

These are, admittedly, isolated incidents.  

 

And it should be noted that these two cases involved spontaneous resistance forming in immune compromised patients receiving Tamiflu, and are not due to some new Tamiflu/peramivir  resistant strain circulating in the wild.

 

The takeaway message from this report isn’t that these drugs are losing effectiveness, but that resistance can develop quickly in rare instances in some people receiving these medications.  

 

Which is another good reason why getting a flu shot every year is an exceedingly good idea.

 

While not 100% protective, getting the flu shot can significantly reduce your chances of catching the flu.

 

After all, it is better to try to prevent an illness, than to have to treat one.   

FDA Grants EUA For Peramivir

 

# 3881

 

The FDA tonight has issued an EUA (Emergency Use Authorization) for the Injectable antiviral Peramivir for use against the pandemic H1N1 virus under specific circumstances.

This EUA fills an important gap in the treatment of severe influenza, as there are currently no IV/IM antiviral drugs available for use on patients unable to take oral medications.

 

Earlier blogs regarding Peramivir include:

CIDRAP: FDA Weighs Peramivir & Headlines

Maryn McKenna Reporting From ICAAC

Here is the FDA announcement.

 

FDA Authorizes Emergency Use of Intravenous Antiviral Peramivir for 2009 H1N1 Influenza for Certain Patients, Settings

The U.S. Food and Drug Administration announced today that, in response to a request from the U.S. Centers for Disease Control and Prevention, it has issued an emergency use authorization (EUA) for the investigational antiviral drug peramivir intravenous (IV) in certain adult and pediatric patients with confirmed or suspected 2009 H1N1 influenza infection who are admitted to a hospital.

Specifically, IV peramivir is authorized only for hospitalized adult and pediatric patients for whom therapy with an IV drug is clinically appropriate, based on one or more of the following reasons:

1. the patient is not responding to either oral or inhaled antiviral therapy, or
2. when drug delivery by a route other than an intravenous route -- e.g., enteral (absorbed by the intestines) or inhaled -- is not expected to be dependable or feasible;
3. for adults only, when the clinician judges IV therapy is appropriate due to other circumstances.

The FDA has reviewed the available scientific data and has concluded that the criteria for authorizing the emergency use of IV peramivir have been met.

 

There are no FDA-approved intravenously administered antivirals for the treatment of influenza. Peramivir is the only intravenously administered influenza treatment currently authorized for use under EUA for 2009 H1N1 infections.

 

The EUA authority allows the FDA, based on the evaluation of available data, to authorize the use of unapproved or uncleared medical products or unapproved or uncleared uses of approved or cleared medical products following a determination and declaration of emergency, provided certain criteria are met. The authorization will end when the declaration of emergency is terminated or the authorization is revoked by the agency.

For more information, see http://www.cdc.gov/h1n1flu/eua/ or call 1-800-CDC-INFO (1-800-232-4636).

CIDRAP: FDA Weighs Peramivir & Headlines

 

 

 

# 3840

 

Tonight CIDRAP has a report by News Editor Robert Roos on recent calls to license the emergency use of Peramivir, an injectable antiviral created by BioCryst, along with a half dozen other news briefs.

 

 

 

FDA faces decision about use of peramivir for H1N1

 

Robert Roos News Editor

Oct 15, 2009 (CIDRAP News) – In response to questions from citizens at a meeting yesterday, a Food and Drug Administration (FDA) official said the agency would make a decision "fairly soon" about permitting emergency use of the experimental antiviral drug peramivir to help patients severely ill with pandemic H1N1 influenza.

 

The FDA has been reviewing a possible emergency use authorization (EUA) for peramivir, which, like the licensed drugs oseltamivir (Tamiflu) and zanamivir (Relenza), is a neuraminidase inhibitor. Peramivir can be given intravenously (IV) or intramuscularly (IM), whereas oseltamivir is taken orally and zanamivir is inhaled as a powder.

 

During a public teleconference of the National Biodefense Science Board (NBSB) yesterday, Aubrey Miller of the FDA Office of Counterterrorism was asked to comment on the status of the FDA's review of an EUA for peramivir for H1N1 patients. The NBSB is an advisory board to the Department of Health and Human Services (HHS).

 

"There should be information or decisions being made fairly soon. That amongst other medical countermeasures are currently being evaluated by the agency," Miller said. "I don't have a specific time frame at this time, because things are under review."

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Other CIDRAP news stories tonight include:

 

Flu up slightly on US campuses

Hospital uses triage tents for flood of patients

Ill county workers who stay on job could be fired

Massachusetts prioritizes high-risk prisoners for vaccine

Kentucky district targets college students for vaccine

China plans vaccine for hajj pilgrims

 

 

And CIDRAP’s Novel H1N1Influenza Overview page is updated almost continually with the latest information on the virus.   It is a resource that I go to often, and I highly recommend it.

 

 

Novel H1N1 Influenza (Swine Flu)

Last updated October 9, 2009

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Swine Influenza in Pigs
Swine-Origin Influenza in Humans: Historic Perspective
2009 Pandemic: Case Counts and Clinical Features
Pandemic Perspective
Laboratory Testing for the Novel H1N1 Virus in Humans
Community Mitigation Measures
Recommendations for Use of Influenza A H1N1 2009 Monovalent Vaccine
Vaccine Development
Use of Antiviral Agents
Infection Control Considerations
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References