Report discourages use of antivirals for seasonal flu

Jan 20, 2005 (CIDRAP News) – Researchers who analyzed numerous clinical trials concluded that the two newest antiviral drugs for influenza, oseltamivir (Tamiflu) and zanamivir (Relenza), should not routinely be used against seasonal flu—a recommendation flatly rejected by the manufacturer of oseltamivir.

The researchers, writing in The Lancet, also raise doubts about using the two drugs, called neuraminidase inhibitors (NIs), in a potential flu pandemic. They say they found no "credible evidence" that the drugs are helpful in human cases of avian flu. If the drugs are used in a flu epidemic or pandemic, they should be accompanied by standard public health measures to prevent spread of infection, the authors say.

The accumulated evidence "suggests that neuraminidase inhibitors should not be used routinely for seasonal influenza and only with associated public health measures in a pandemic situation," says the report by Tom Jefferson and four colleagues with the Cochrane Vaccines Field in Italy and the University of Queensland in Australia.

The scientists also said the two older antiviral flu drugs, amantadine and rimantadine, should not be used for flu, because they don't prevent infection or viral shedding and they have potential serious side effects. The Centers for Disease Control and Prevention (CDC) last week advised doctors not to prescribe the two drugs for the rest of this flu season because circulating flu viruses have a high rate of resistance to them.

Roche, the Swiss-based maker of oseltamivir, said in a statement yesterday, "Roche fundamentally disagrees with the conclusions reached by the authors that oseltamivir should not be used for the treatment or prevention of seasonal influenza. The conclusion is at odds with the opinion of experts and regulatory authorities around the world."

The World Health Organization (WHO) and many countries, including the United States, are stockpiling the NIs, mainly oseltamivir, in the hope that they will be useful if H5N1 avian flu leads to a pandemic. WHO officials say the agency does not plan to change its recommendations about the possible role of antivirals in dealing with a pandemic.

"After carefully reviewing this analysis, WHO will not be changing its stockpiling recommendations," WHO spokesman Dick Thompson told CIDRAP News via e-mail. "There are several concerns we had with this document. Even the authors state that while there is little evidence to support effectiveness for oseltamivir in AI [avian influenza] patients, they also say that it is possible that patients could have been given the drug too late in the course of their illness to be effective."

Roche did not directly challenge the authors' conclusion about the effectiveness of oseltamivir against avian flu strains in humans, but the company reported today that the drug performed well in a recent animal study, as well as previous ones. In the new study, the medication prevented viral replication in ferrets that were treated 4 hours after exposure to the H5N1 virus.

The researchers analyzed 19 randomized controlled trials of oseltamivir and zanamivir along with 34 trials of amantadine and rimantadine. They examined the drugs' record in preventing and treating laboratory-confirmed influenza and influenza-like illness in patients aged 16 to 65.

For treatment of symptomatic flu, oseltamivir had 61% to 73% efficacy, depending on the dosage, and zanamivir had 62% efficacy, the report says.

The NIs were found to have no significant effect when used to prevent flu-like illness. But for preventing flu after exposure to the virus (postexposure prophylaxis), oseltamivir was 58.5% efficacious in households and 68% to 89% efficacious in contacts of index cases, the analysis showed.

The researchers also found evidence that the NIs shortened the duration of symptoms and reduced the viral load in nasal secretions, but the drugs did not eliminate viral shedding. Oseltamivir, 150 mg daily, reduced the incidence of bronchitis and pneumonia in flu cases but not in flu-like illness cases.

"We do not see a role for the use of neuraminidase inhibitors in seasonal inflenza, since the evidence shows that they are ineffective against influenza-like illness," the authors write. But they add that in the context of a known influenza epidemic, flu-like illness is more likely to be actual influenza and the NIs are more likely to be helpful.

In responding to the article, Roche officials said, "The statement by the author that neuraminidase inhibitors should not be used in seasonal influenza control is inappropriate and inconsistent with data. Roche strongly disagrees with this article; surveillance activities and the appropriate use of antivirals are critical to combat influenza."

Roche took issue with using oseltamivir's reported lack of effectiveness against flu-like illness as a reason not to use it for seasonal flu: "Once influenza is circulating and with clearly defined symptoms identified[,] influenza is easy to diagnose. Roche has never advocated the use of Tamiflu for control of influenza-like symptoms."

The researchers also examined reports on the effects of oseltamivir in human H5N1 flu patients in Southeast Asia. There, oseltamivir treatment had no clear effect on mortality, although this could have been a result of starting treatment late in patients who already had a high viral load, the report says. In H5N1 cases, the viral load can be 10 times greater than in seasonal flu, a WHO study showed.

Resistance to oseltamivir was seen in 7 of 43 children and in 2 of 8 Vietnamese children and adults, the report says.

The scientists also found no clear benefits from the use of oseltamivir in people exposed to H7N7 avian flu in the Netherlands in 2003 and H7N3 avian flu in Canada in 2004.

"We could find no credible evidence of the effects of neuraminidase inhibitors on avian influenza" in humans, the authors write.

"As viral load and virulence of pandemic viruses are considerably higher than those of seasonal influenza viruses, the use of neuraminidase inhibitors in a serious epidemic or pandemic should not be considered without concomitant measures, such as barriers, distance, and personal hygiene." The authors add that overestimating the ability of NIs to prevent illness could cause those treated to be less careful, leading to increased spread.

Jefferson T, Demicheli V, Rivetti D, et al. Antivirals for influenza in healthy adults: systematic review. Lancet 2006 Jan 19 (early online publication) [Abstract]

See also:

Jan 19 Roche statement
http://www.roche.com/med-cor-2006-01-19

Jan 20 Roche report on animal trial of oseltamivir
http://www.roche.com/med-div-2006-01-20

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