Jim Kling

September 17, 2013

DENVER — High-dose oseltamivir speeds up viral clearance in patients with severe cases of H1N1 influenza A, report investigators, who tested the therapy under trying conditions — in the midst of flu epidemics.

"It's a real trick to get a randomized controlled trial up and running from scratch in the middle of a pandemic," acknowledged Anand Kumar, MD, an intensive care physician at the Winnipeg Health Science Centre in Manitoba, Canada.

H1N1 influenza A led to many cases of severe viral pneumonitis, which can result in significant morbidity and mortality. Rapid clearance is associated with better clinical outcomes in other viral syndromes, but some researchers were skeptical that the same would be true in influenza.

"Double- or triple-dose antiviral therapy is often used in the management of these infections and in other severe influenza syndromes, such as those associated with H5N1 and H9N7 infections," said Dr. Kumar. "However, there is a lack of data supporting the clinical utility of this application."

Dr. Kumar presented new data here at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy.

I'll be honest, with so few patients enrolled, I thought there was no way we'd get a positive response.

The study involved 56 adults with severe influenza who were receiving care in an intensive care unit at 1 of 25 Canadian centers. They received twice-daily oseltamivir, either a standard dose (75 mg) or a triple dose (225 mg).

The researchers assessed viral clearance at day 5. Secondary end points included length of mechanical ventilation, survival at 30 days, survival in the ICU, and survival during hospital stay.

Polymerase chain reaction results were positive for H1N1 in 18 patients. Of the 9 patients who received triple-dose therapy, 7 (78%) achieved viral clearance by day 5, but of the 9 who received standard therapy, and just 1 (11%) achieved viral clearance by day 5 (P = .015, Fisher's exact test).

The 2 therapies were identical with respect to the secondary end points.

"I'll be honest, with so few patients enrolled, I thought there was no way we'd get a positive response," Dr. Kumar said.

In addition to the potential therapeutic benefit, the faster viral clearance could ease the burden of infection control and isolation procedures. "Higher-dose therapy may have implications for the required duration of infection control and isolation measures," Dr. Kumar added.

Several audience members said they were impressed with what the researchers accomplished, but the focus on viral clearance rather than clinical outcomes drew some criticism.

Viral Clearance vs Clinical Outcome

"In animal studies, we've seen that in severe flu infections, like the 1918 pandemic virus, you can still have severe disease even when the titer of virus is lower," said Matthew Memoli, MD, director of the clinical studies unit at the laboratory of infectious diseases, National Institute of Allergy and Infectious Disease, in Bethesda, Maryland, who attended the session.

The virus initially damages the patient's respiratory epithelium. "That sets them up for pneumonia and possibly a secondary bacterial infection that puts them in the ICU," Dr. Memoli told Medscape Medical News.

"But it's other things that happen downstream, like an inflammatory response, organ failure, and secondary bacterial infections, that most likely keeps them there," he added. "It's possible that a high-dose treatment might have benefit, especially early on, when the person rolls into the hospital. But I'd rather see a focus on clinical outcome than virologic outcome, because what we care about is making the patient better, not just clearing flu from their body," he said.

Dr. Kumar reports receiving research funding from Roche. Dr. Memoli has disclosed no relevant financial relationships.

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): Abstract V-1470. Presented September 12, 2013.


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