Experts show benefits of IV antivirals for severe H1N1

Oct 29, 2009 (CIDRAP News) – Though only available for emergency use, intravenous (IV) antivirals peramivir and zanamivir have been lifesaving for some pandemic H1N1 patients, including two dramatic cases that doctors presented yesterday during a US Centers for Disease Control and Prevention (CDC) conference call for clinicians.

With rising levels of widespread flu activity sweeping the nation, physicians will face greater numbers of critically ill patients, some of whom will require extreme measures, including investigational regimens. Yesterday's CDC call was designed to get doctors quickly up to speed on the IV antiviral treatment options for the severest pandemic H1N1 infections.

The CDC invited two well-known flu experts to discuss the cases and answer clinicians' questions: Fred Hayden, MD, a virologist at the University of Virginia, and Andrew Pavia, MD, chief of pediatric infectious diseases at the University of Utah.

On Oct 23 federal officials issued an emergency use authorization for IV peramivir, to make it easier for physicians to obtain for their severely ill.

Though IV zanamivir hasn't been studied as long as IV peramivir, physicians can request it through the emergency use provision and have used it during the H1N1 pandemic, especially when managing the few oseltamivir-resistant cases that have surfaced.

Peramivir after failed oseltamivir
In discussing the first case, Stacene Maroushek, MD, a pediatric infectious disease specialist at Hennepin County Medical Center in Minneapolis, described a 17-year-old boy who was first brought to urgent care by his friends after he started experiencing shortness of breath. She said that about a week before his becoming ill he had attended the Minnesota State Fair in late August and had contact with other people who were sick.

Upon hospitalization, he was intubated and placed on high-frequency oscillatory ventilation, and his chest x-ray showed patchy ground-glass opacities. The patient had grossly bloody diarrhea from what physicians discovered was bowel ischemia.

Though he received oseltamivir suspension though his nasogastric tube, his medical team didn't note any improvement in his condition and suspected that the drug wasn't being absorbed properly because of his gastrointestinal condition.

Doctors assessed that the boy was experiencing systemic inflammatory response along with hypotension, pancytopenia, myocarditis, coagulopathy, acute renal failure with oliguria, hepatitis, and pancreatitis.

Maroushek said doctors contacted the Minnesota Department of Health and the CDC to discuss IV antiviral treatment options and received emergency authorization to give the boy 600-milligram (mg) doses of IV peramivir for 5 days. Other treatment measures included norepinephrine, blood transfusions, and antibiotics for pneumonia.

The patient improved 2 days after doctors initiated peramivir treatment. The boy did not develop a secondary bacterial infection. Though he was weak with symptoms of mental slowing at hospital discharge, she said the boy is improving with therapy and rehabilitation. His 25-day hospitalization cost about $300,000, she said.

Oseltamivir-resistant case
In the second case, Aditya Gaur, MD, an infectious disease specialist at St Jude's Children's Research Hospital in Memphis, Tenn., described a severe pandemic H1N1 infection a 10-year-old girl who was immunocompromised because she was undergoing treatment for leukemia.

The patient was initially admitted to the hospital for 5 days with flu symptoms such as cough, runny nose, and fever. During hospitalization she received 150 mg of oseltamivir daily.

In the 12 days after leaving the hospital the patient had mild residual symptoms, but her symptoms got worse and she was hospitalized again, this time with right lower-lobe pneumonia. Gaur said her respiratory status deteriorated and she was intubated and given broad-spectrum antibiotics. She also received oseltamivir through her nasogastric tube.

The girl's tracheal aspirates were positive for influenza A, and about a week later tests showed she had the oseltamivir-resistant H275Y mutation.

Her medical team obtained an emergency investigational new drug clearance to give her IV zanamivir, 600 mg every 12 hours. Over the next 2 weeks the patient tolerated the drug well and her symptoms improved, Gaur said.

Tim Uyeki, MD, a medical epidemiologist in CDC's Influenza Division who moderated the clinician's conference, commented that the child's case pointed to evidence of prolonged viral shedding, which experts have documented in immunocompromised patients.

Indications for IV antivirals
Hayden said the two cases show value of IV antiviral treatment options for severely ill pandemic H1N1 patients. "We've known for some time the need for parenteral, rapid, and reliable delivery of these drugs," he told clinicians.

He said IV zanamivir can be life saving for patients who have oseltamivir-resistant viruses, especially when poor lung function precludes use of the powder or nebulizer version.

Ribavirin is an older drug that has sporadically been used intravenously for severe flu patients and can be obtained on an emergency basis, Hayden said. "There's not enough data on it, but if a patient is not responding to other antivirals, it can be used as a salvage drug," he added.

Physicians who use IV antivirals for critically ill patients should make sure therapy duration is sufficiently long, Hayden said, "It makes sense to push to at least 10 days," he said, adding that immunocompromised patients may need the drugs for even longer.

Hayden urged physicians to move quickly to IV antivirals when they encounter patients who are as severely ill as the two case study patients.

Pavia agreed that early treatment is crucial. "To make the greatest difference, you need to shut off viral replication early, but it's never too late to intervene," he said.

Some clinicians have used antiviral combination treatments that incorporate ribavirin, he said. However, he said the lack of data makes the strategy not an attractive option. "We're very early in using combination treatment," Pavia said.

New drug in clinical trials
Pavia and Hayden both mentioned a new antiviral drug that is in clinical trials, T-705, which is being developed by Toyama Chemical, a Japanese company. The new drug is not available yet for emergency use, but they urged physicians to be alert for any clinical trials of it that might be taking place near them.

Today Fujifilm Holdings Corp, Toyama's parent company, announced the launch of phase 3 clinical trials in Japan of T-705, a viral RNA polymerase inhibitor. The company said in a press release that phase 2 studies showed promising results as a treatment for seasonal flu and that animal studies have shown efficacy against the pandemic H1N1 virus.

The company says because the drug's mechanism of action is different than existing antivirals, it might provide an alternative treatment, especially given concerns about viruses developing resistance to neuraminidase inhibitors like oseltamivir, zanamivir, and peramivir.

See also:

Oct 29 Fujifilm Holdings press release

Oct 26 CIDRAP News story "Emergency authorization for peramivir draws fast response"

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