Intravenous Zanamivir for Hospitalized Patients With Flu

Ingrid Hein

August 29, 2016

There could soon be another option for the treatment of influenza, especially in oseltamivir-resistant patients and those unable to digest or inhale medication, according to results from a phase 3 trial.

Intravenous zanamivir (Relenza) "was safe in this large multinational trial," said principal investigator Francisco Marty, MD, from Brigham and Women's Hospital in Boston. "And we need drugs for patients too sick to inhale or take pills to treat their influenza."

"I think it's time to make it available, especially in cases where there is resistance to current drugs. That was the main driver of this trial," Dr Marty explained. "You see this problem of oseltamivir resistance often in bone marrow or organ-transplant patients." Immunosuppressed patients are especially susceptible.

"The 2009 flu pandemic was the wake-up call. There's a need for intravenous antivirals for the treatment of influenza," he pointed out. In fact, he said, the US Food and Drug Administration (FDA) should move faster to get new influenza treatment drugs on the shelf, especially for immunosuppressed patients who are prone to developing drug resistance.

During the 2014/15 influenza season, inhaled zanamivir and oral oseltamivir were the only antivirals recommended by the Centers for Disease Control and Prevention (CDC).

 
We need drugs for patients too sick to inhale or take pills to treat their influenza.
 

The intravenous neuraminidase inhibitor peramivir (Rapivab) was approved for the early treatment of uncomplicated influenza in outpatients 18 years and older in 2014. This is good news for those suffering from vomiting or diarrhea, for whom a 5-day course of oral capsules would be inappropriate, and for those who would have trouble taking an inhaled drug because of upper respiratory symptoms.

But patients who develop resistance to oseltamivir frequently show resistance to peramivir.

Dr Marty presented study results at the Options for the Control of Influenza 2016 Conference in Chicago.

The randomized, double-blind, double-dummy phase 3 trial looked at 626 patients with suspected or confirmed influenza from 97 study-site hospitals.

Patients were treated with intravenous zanamivir — 600 mg or 300 mg — or the current standard of oral oseltamivir 75 mg for 5 to 10 days, and were followed for 28 days.

Time to clinical response for resolution of fever, hypoxia, and other signs of clinical severity was the primary end point. Resolution of more than two abnormal parameters (mechanical ventilation status, heart rate, blood pressure, and hospital discharge) was considered a clinical response.

In the influenza-positive population, 45% of the patients were infected with influenza type A H3N2 virus, 38% with H1N1 virus, 1% with untyped A, and 14% with type B virus. In addition, 2% were coinfected. At baseline, 39% of the patients were in the intensive care unit and 16% were mechanically ventilated.

Table. Clinical Response Stratified by Time of Treatment Initiation

Time to Clinical Response Intravenous Zanamivir 300 mg Intravenous Zanamivir 600 mg Oral Oseltamivir 75 mg
Treatment started ≤4 days after symptom onset
  Influenza-positive patients, n 127 131 121
  Median time to clinical response, days 5.63 4.80 4.80
Treatment started >4 days after symptom onset
  Influenza-positive patients, n 36 31 42
  Median time to clinical response, days 6.48 9.81 19.32

 

Rates of diarrhea, constipation, and elevated alanine transaminase were similar in the zanamivir and oseltamivir groups. The mortality rate was higher in the zanamivir 300 mg and zanamivir 600 mg groups than in the oseltamivir group (7% vs 7% vs 5%). The most common causes of death were respiratory failure and septic shock.

Time to clinical response was not significantly faster in any of the groups, but overall clinical response was highest in patients treated with zanamivir.

This trial showed that zanamivir is similar to oseltamivir in terms of safety and efficacy, making it a good option for patients with severe influenza illness, especially those with drug resistance to oral oseltamivir, Dr Marty and his colleagues report.

The challenges associated with this study highlight the tremendous barriers in trial design encountered when trying to study drugs in a severely ill patient population.

"The straightjacket for this trial was, on the one hand, the FDA requirement for a superiority design but the expectation of noninferiority in the absence of circulating oseltamivir-resistant influenza viruses and, on the other hand, the impossibility of conducting a placebo-controlled trial in patients with severe influenza where there is consensus from the CDC, WHO, and clinicians that these patients should receive antiviral treatment," Dr Marty explained.

"That's the paradox," he said. "The results show it's just as safe as the current drug, but wasn't superior."

Intravenous Drug Development

Drug development takes a long time — from in vitro research to animal to human clinical trials, said Tim Uyeki, MD, chief medical officer of the influenza division at the CDC. "And sometimes it doesn't work out," he said.

"But we are very much in need of antivirals with different mechanisms of action to treat influenza," he explained. "If the prevalence of circulating influenza viruses resistant to oseltamivir were to increase to a high level, that would take oseltamivir treatment off the table for most patients."

Although viruses resistant to oseltamivir are often resistant to peramivir, they "are typically susceptible to zanamivir," he pointed out.

Whereas inhaled zanamivir can be used to treat influenza viruses that are resistant to oseltamivir and peramivir, "an intravenous drug allows the treatment of patients who are critically ill with severe influenza and are unable to take an oral drug because their gastrointestinal tracts do not function," he explained.

Immunosuppressed patients with influenza who are treated with oseltamivir are at the highest risk of developing resistance.

"Prolonged influenza viral replication can occur in these patients, with emergence of antiviral resistant mutations," Dr Uyeki said. Such patients are at risk for clinical deterioration to critical illness and death. And "patients infected with influenza viruses that are resistant to oseltamivir or peramivir pose a risk to public health if such viruses are transmissible to close contacts," he said.

Drugs are needed for the treatment of influenza viruses that are resistant to neuraminidase inhibitors. "We also need combination therapy with drugs with different mechanisms of action and further development of immunotherapeutics," he said.

Currently, the CDC recommends that all hospitalized patients with suspected or confirmed influenza receive a neuraminidase inhibitor as soon as possible.

"We also recommend antiviral treatment with a neuraminidase inhibitor drug as soon as possible for outpatients with influenza who are in a group at high risk for complications from influenza," said Dr Uyeki. This group includes infants younger than 2 years, people 65 years and older, patients with certain chronic medical conditions, pregnant women, and residents of long-term care facilities.

Dr Marty reports receiving a consulting honorarium from GlaxoSmithKline, and that his hospital received research grant support for the trial. Dr Uyeki has disclosed no relevant financial relationships.

Options for the Control of Influenza 2016 Conference: Abstract 070. Presented August 27, 2016.

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