Experts air kinks in antiviral use during H1N1 pandemic

Jan 28, 2011 (CIDRAP News) – Although antiviral drugs were used to treat many seriously sick people during the H1N1 influenza pandemic, experts at a conference today said they could have been used more widely and that some opportunities to learn from their use were missed.

Experts attending an Infectious Diseases Society of America (IDSA) meeting on influenza said that some antiviral treatment opportunities were missed because of rapid diagnostic tests that yielded false-negative results. The proceedings were streamed over the IDSA's Web site.

Also, officials said efforts to run formal clinical trials of antiviral effectiveness during the pandemic were hindered by delays in getting approval from institutional review boards (IRBs). And one expert said the pandemic, by its nature, generated little scientific progress on the principal question about flu antivirals: their ability to prevent flu complications.

The pandemic experience also revealed considerable gaps and problems in the preparedness of local health departments (LHDs) to manage the distribution and dispensing of antivirals, according to a report released today by the National Association of County and City Health Officials (NACCHO).

Antiviral usage was the focus of several talks and a panel discussion at the IDSA meeting this morning. The presentations pertained mainly to oseltamivir (Tamiflu) and zanamivir (Relenza), the two neuraminidase inhibitors used during the pandemic.

Drugs used 'very sparingly'
"As we think about the way the drugs were used, we've used them very sparingly, probably less than we should have . . . and I'm sure to the detriment of certain groups," said Arnold S. Monto, MD, a professor of epidemiology at the University of Michigan, during the panel discussion.

"I think this was related in part to unfamiliarity in the community with the drugs, but also concern about the evolution of the pandemic and the supply of drugs, and the idea of trying to maintain a stockpile for the most ill," he added.

Monto commented that providers also worried that using antivirals would promote the emergence of resistance to the drugs. Before the pandemic, he noted, seasonal H1N1 viruses had become widely resistant to the neuraminidase inhibitors but remained sensitive to the older flu drugs known as adamantanes. When the 2009 H1N1 virus emerged, its resistance profile was just the opposite, "and that message was a little difficult to get out," he said.

Timothy Uyeki, MD, MPH, of the Influenza Division at the Centers for Disease Control and Prevention (CDC), said the CDC worked hard to urge clinicians to use antivirals in high-risk patients, but the message didn't always get through.

"Clearly there were challenges, and one of the main things was . . . a lot of physicians were relying on rapid diagnostic tests, which unfortunately lacked sensitivity," he said. "Many patients were tested negative on rapid tests, and there were missed opportunities for treatment." He added that the CDC recommends empiric antiviral treatment if a clinician suspects flu.

Uyeki also commented that CDC antiviral guidance during the pandemic emphasized the treatment of high-risk patients, which may have given a wrong impression. "I think the message that unfortunately some primary care physicians heard was 'Don't treat non-high-risk patients with uncomplicated influenza,' though we never said that," he said.

More recent CDC guidance stresses that using antivirals is a matter of clinical judgment and that treatment is worth considering in uncomplicated cases if the patient presents early, he added.

Dr. Andrew Pavia, moderator of the panel, responded that many presenters at the meeting had recounted similar messaging difficulties. "We're not as good as we think we are at actually changing practice in the absence of a crisis, and especially in a crisis," he said. Pavia is a pediatric infectious disease specialist at the University of Utah.

Research frustrations
The difficulty of getting fast IRB approval for clinical studies during the pandemic was mentioned in today's opening presentation, by Dr. Nicole Lurie, assistant secretary for preparedness and response at the Department of Health and Human Services, who reflected on the pandemic's lessons.

Lurie praised the work that many researchers did to mobilize research networks, but she said in many cases it took 6 months to get IRB approvals. "We need to change that," she said.

Her concern was echoed by Elizabeth S. Higgs, MD, of the National Institute of Allergy and Infectious Diseases. While the research community accomplished a lot during the pandemic, the IRBs were "a major obstacle," she commented.

More than one speaker called for setting up a "universal IRB" to expedite research in emergencies. "If we don't have a universal IRB for emerging infections and threats, we're not going to be able to evaluate any of these drugs in a prospective and rigorous way," said Richard J. Whitley, MD, a professor of medicine at the University of Alabama at Birmingham.

Uyeki commented that the pandemic generated evidence supporting the use of antivirals, though not from controlled studies. "We were able to get more data, albeit observational studies, but they all point in the same direction about the benefits of early treatment, up to about 5 days [after illness onset], and we tried to get that information out," he said.

Monto said the pandemic situation ruled out doing randomized trials because of the ethical problems. Because of this limitation, "We really haven't gone further forward on the main reason we use antivirals, and that's to prevent complications. It's not to shorten the duration of illness by a day or a day and a half," he said.

Later in the discussion, Monto commented further on the need for controlled trials, referring to Tom Jefferson and colleagues of the Cochrane Collaboration, whose various meta-analyses have raised questions about the effectiveness of flu vaccines and antivirals.

"Can we perform these studies in an area where we won't have an ethical consideration about using a placebo, and try to come up with some clear answers in a format that even a Tom Jefferson might be forced to agree with?" Monto asked.

Local role in managing antivirals
Hugh Tilson, MD, MPH, DrPH, a county public health official in Maine who also teaches at the University of North Carolina, offered a summary of the new NACCHO report on the problems that LHDs had in dealing with antivirals during the pandemic.

"We were aware of a major gap in our management of antivirals well before the 2009 pandemic," he said.

The 49-page report is based on a "think tank" meeting that was held in St. Paul in June 2010 and facilitated by Tilson. It lists a number of areas where the pandemic exposed clashes between plans and reality. For example:

  • LHDs had plans that included steps for receiving and distributing antivirals, but the plans often lacked the level of detail and infrastructure support to be very useful.
  • LHDs received antivirals from the Strategic National Stockpile without forewarning or much guidance from the state on how to use them, and the local plans did not include clear guidance on use.
  • As CDC antiviral guidance evolved during the pandemic, LHDs found it challenging to modify their plans and communicate the changes. For example, they had trouble explaining to first responders why they no longer had priority over other groups for antiviral treatment.

The report includes a long set of recommendations for state and local health departments and a number of other stakeholders.

Tilson said LHDs should work with state health departments on plans for distributing antivirals. Most LHDs didn't have a way to ensure their availability or to ensure distribution to underserved groups, he commented. He also called on LHDs to help educate medical providers on the appropriate use of antivirals, including treatment versus prevention and the threat of resistance.

The conference also included presentations on emergency use authorizations for intravenous antivirals during the pandemic.

See also:

IDSA Seasonal and Pandemic Influenza 2011 meeting webcast site

NACCHO report on the use and distribution of antivirals

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