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 a few 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."
Mar 26 CID abstract
Mar 26 NIAID press release