Peramivir resistance thread

[Ronan Kelly]

Researchers report first 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.

The two patients had immune-system compromise from blood stem cell transplants they underwent several years ago, and both have recovered from the flu. Both had flu infections in October during the second pandemic wave. The patients were among seven other cases of pandemic flu in immunocompromised patients who were observed for 2 months at the National Institutes of Health Clinical Center.

The pandemic H1N1 virus is susceptible to only one of two antiviral drug classes, neuraminidase inhibitors, which include oseltamivir, peramivir, and zanamivir (Relenza).

Many countries have stockpiled oseltamivir, the frontline treatment for flu infections. Months into the pandemic, lab tests in some patients who didn't respond to oseltamivir showed some flu strains contained an H275Y genetic mutation that makes the virus less susceptible to some neuraminidase inhibitors.

In October the FDA issued an emergency use authorization (EUA) for intravenous (IV) peramivir for hospitalized patients. Peramivir gives clinicians a treatment option when a patient can't take an oral oseltamivir or inhaled zanamivir. The drug has also been used to treat patients who have the oseltamivir-resistant virus. An IV version of zanamivir exists but is in an earlier stage of clinical testing.

Previous case reports suggested that the mutation in hospitalized H1N1 patients with immune compromise arose after more than 24 days of continuous antiviral treatment, but mutation in the two patients appeared after 14 days in one and 9 in the other. Though the recommended course of oseltamivir treatment is 5 days, physicians prescribe longer treatment if the patient's infection does not improve.

Both patients continued to shed the virus in nasal secretions throughout treatment. When one patient's condition deteriorated after 24 days of oseltamivir treatment, doctors prescribed peramivir for 10 days, which did not reduce viral shedding or reverse the patient's infection. The patient recovered after doctors prescribed a 10-day course of zanamivir.

Anthony S. Fauci, MD, director of NIAID, said in a press release today that, while the emergence of drug resistance isn't surprising, the cases show that the strains can emerge after brief antiviral therapy. "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," he said.

Memoli said in the press release that more studies are needed to refine the group's findings. "But these cases of rapid appearance of drug-resistant 2009 H1N1 influenza in immune-compromised patients are worrisome and should prompt clinicians to reconsider how they use available flu drugs," he added.

Because the H275Y mutation also reduces susceptibility to peramivir, patients who develop resistant strains after a short course of oseltamivir might not respond to peramivir, Memoli said. Zanamivir might be a good choice when patients don't respond after a few days of oseltamivir treatment, but patients who are very ill and on mechanical ventilation can't receive the inhaled drug.

The authors also recommend more studies to investigate the effectiveness of peramivir in patients who don't respond to oseltamivir.

"As clinicians, we should carefully consider our treatment options and use all the drugs available to us wisely," Memoli said in the press release. "This is especially important in a patient with prolonged infection or when an antiviral drug fails to cure the patient after the recommended course of treatment."

See also:

Mar 26 CID abstract : http://www.journals.uchicago.edu/doi/abs/10.1086/651605

Mar 26 NIAID press release :

http://www3.niaid.nih.gov/news/newsreleases/2010/resistantflu.htm

http://www.cidrap.umn.edu/cidrap/content/influenza/swineflu/news/mar2610resistance.html

[sharon sanders]

Re: Researchers report first peramivir-resistant H1N1 case

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

</center> 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.

The two people in the current case study had pre-existing medical conditions that impaired their immune system function before contracting 2009 H1N1 flu. Strains of 2009 H1N1 influenza containing the H275Y mutation had been reported previously in people with diminished immune function, but in previous cases the mutation arose after more than 24 days of continuous therapy. In the newly described cases, the mutation appeared after 14 days in one individual and after nine days in the second.

?Although the recommended length of treatment with oseltamivir is five days, it is common for physicians to continue giving this first-line drug longer if the patient does not improve,? says Dr. Memoli.

Both people in the current report received oseltamivir for extended periods but they continued to shed virus in their nasal secretions throughout treatment. When one patient?s condition worsened despite 24 days of oseltamivir treatment, doctors administered peramivir for 10 days. The drug did not reduce viral shedding and the patient remained ill, demonstrating what the authors described as clinically significant resistance to peramivir. Next, doctors administered the only other available flu drug, zanamivir, for 10 days. The person then fully recovered.

?Additional, larger studies are needed to further refine our findings,? says Dr. Memoli. ?But these cases of rapid appearance of drug-resistant 2009 H1N1 influenza in immune-compromised patients are worrisome and should prompt clinicians to reconsider how they use available flu drugs.?

The mutation that allows 2009 H1N1 to resist oseltamivir also significantly reduces the virus?s susceptibility to peramivir. If a relatively short course of oseltamivir causes a mutant flu strain to emerge in a particular patient, that person may not respond to peramivir. Zanamivir might be a good choice if a patient does not respond within a few days to oseltamivir, Dr. Memoli says. However, because zanamivir must be inhaled, patients who are very ill and whose breathing is mechanically supported cannot be given zanamivir.

?As clinicians, we should carefully consider our treatment options and use all the drugs available to us wisely. This is especially important in a patient with prolonged infection or when an antiviral drug fails to cure the patient after the recommended course of treatment,? says Dr. Memoli.

NIAID scientist Rachel J. Hrabal contributed to this study along with Arash Hassantoufighi and Maryna C. Eichelberger, Ph.D., of the FDA.

Visit www.Flu.gov for one-stop access to U.S. government information on influenza. Also, visit NIAID?s flu Web portal.

<hr> NIAID conducts and supports research?at NIH, throughout the United States, and worldwide?to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
The National Institutes of Health (NIH)?The Nation's Medical Research Agency?includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

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Reference:

MJ Memoli et al. Rapid selection of oseltamivir and peramivir resistant pandemic H1N1 during therapy in two immunocompromised hosts. Clinical Infectious Diseases DOI: 10.1086/651605 (2010).