Tamiflu and Relenza: Reserve for Pandemic?

January 25, 2006

Controversy continues over the use of antivirals for treating seasonal influenza. According to a new report, none of the four newer antivirals routinely prescribed for seasonal influenza is entirely suitable.

The study by Tom Jefferson and colleagues of Cochrane Vaccines Field, a collaborative evaluation group based in Italy, was published by The Lancet (early online publication) and reported by MedPage Today on January 19, 2006.

Tamiflu (oseltamavir) and Relenza (zanamivir) have recently been found to be ineffective in treating seasonal influenza. However, just last week the Centers for Disease Control and Prevention (CDC) recommended that Tamiflu and Relenza be prescribed in place of the more established antiviral agents, Symmetrel (amantadine) and Flumadine (rimantadine).

CDC vs. Cochrane Group

The CDC disagrees with Dr Jefferson et al's report's recommendations about the newer drugs, and has recently issued an advisory to doctors to prescribe Tamiflu and Relenza for seasonal flu. However, the CDC advises against prescribing rimantadine or amantadine, because the dominant influenza A strain rapidly becomes resistant to these drugs.

While the Cochrane group agreed with the CDC that "the use of amantadine and rimantadine should be discouraged," they went one step further, recommending that Tamiflu and Relenza also be reserved to fight a global influenza pandemic:

"Because of their low effectiveness, neuraminidase inhibitors [Tamiflu and Relenza] should not be used in seasonal influenza control and should only be used in a serious epidemic or pandemic alongside other public-health measures such as use of masks, gowns, gloves, quarantine, and hand washing."

In September 2005, the CDC reported that about 12% of influenza A strains worldwide are now resistant to amantadine and rimantadine-including avian flu strains in Asia that occur in poultry and people. The CDC and the Cochrane group agree that the older antiviral agents, amantadine and rimantadine, are not only ineffective against influenza, but can also cause unpleasant side effects, such as nausea, insomnia and hallucinations.

The study by Dr Jefferson and colleagues found that Tamiflu and Relenza offer moderate relief from symptomatic influenza but do not relieve either asymptomatic influenza or on influenza-like illnesses. Moreover, these drugs reduce but do not completely stop viral shedding from the nose.

Despite these negative findings, the CDC still backs its recommendations.

"Our guidelines and our recommendations are pretty clear," said a CDC spokesperson, according to MedPage Today. "Tamiflu and Relenza have proven to be highly effective in laboratory studies that we've done, and when they are administered at the appropriate time, namely 24 to 48 hours after the onset of influenza symptoms, they have also proven to be effective."

Meta-Analysis of Data

Dr Jefferson and colleagues conducted a meta-analysis that included data from 52 randomized trials of amantadine and rimantadine, and Tamiflu and Relenza. The analysis examined the preventative effects of these drugs as a percentage of relative risk.

The results showed that amantadine prevented 61% of influenza A cases and 25% of influenza-like illnesses. It caused nausea, insomnia and hallucinations, and withdrawals due to adverse events.

"In treatment, amantadine significantly shortened duration of fever compared with placebo but had no effect on nasal shedding of influenza A viruses," the researchers wrote.

The study included fewer data for rimantadine, but these data showed its effects to be comparable to those of amantadine.

Trials comparing the efficacy of Tamiflu and Relenza with placebo showed that these drugs did not affect influenza-like illness, even at higher doses. Moreover, neither drug was effective against asymptomatic influenza. Relative efficacies for Tamiflu 75 mg daily and 150 mg daily were 61% and 73%, respectively, and efficacy of Relenza 10 mg daily was 62%.

Tamiflu proved about 50% effective in preventing post-infection transmission within households, and both Tamiflu and Relenza hastened symptom relief by about 30%, compared with placebo, if taken within 48 hours after symptom onset.

"We cannot explain how neuraminidase inhibitors can affect respiratory complications of seasonal influenza, such as bronchitis and pneumonia, while not preventing infection, and this effect should be further studied," the researchers wrote.

Treating Avian Flu

The researchers noted that no credible evidence exists to support using Tamiflu to right avian influenza. They also noted that, while Tamiflu and Relenza may be useful treatment options in the case of a global influenza pandemic, the fact that they reduce symptoms without fully preventing transmission may in fact increase the spread of the disease, as contagious people may venture out into public, unaware that they are spreading the disease.

"Over-reliance on a pharmacological solution to the ravages of influenza may impede the development and implementation of broader intervention strategies based on public-health measures," Dr Jefferson and colleagues wrote, and the CDC agreed:

"It's important for people to understand that combating an outbreak of influenza, whether it's seasonal or pandemic influenza, is going to require a comprehensive approach, and the important elements of our approach include vaccination, good hygiene, and antivirals," the CDC spokesman said, according to MedPage Today.

Sources:
Save Newer Flu Drugs for Pandemic, Researchers Advise, MedPage Today, January 18, 2006.
Antivirals for influenza in healthy adults: systematic review. Jefferson T et al, The Lancet, early online publication, January 19, 2006.

Posted: January 2006


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