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Antivirals in flu: time counts

on Wed, 04/16/2014 - 10:32

Great media impact was given to two recent BMJ papers (1-2) on influenza treatment with neuraminidase inhibitors (oseltamivir and zanamivir). The results of these two quite large systematic scientific literature reviews on clinical studies were not that much new: they confirm that overall those drugs reduce the clinical influenza illness duration of something around one day for adults and children, but that the treatments do  not reduce complications and hospitalizations or death.

Those elements have already been well known since the introduction of the two drugs onto the market in the early 2000s: in fact, most of the national guidelines published in that decade recognize that treatment reduces illness duration of a mean one day and that prevention of complication and deaths has never been demonstrated (3,4,5).
The two studies confirm the knowledge that, anyhow, has already been included also in the producing companies drug prescription notes (6-7).
But the two papers, despite the enormous and highly qualified work, failed to reach their main objective of saying a final word on treatment efficacy since they neglected a central issue: timing of treatment.
Both drugs inhibit the neuraminidase enzyme, which is expressed on the viral surface. The enzyme promotes release of virus from infected cells and facilitates viral movement within the respiratory tract. In the presence of neuraminidase inhibitors, virions stay attached to the membrane of infected cells and are also entrapped in respiratory secretions (8).
Therefore the drugs can only be active during virus replication: in absence of that, no effect should be expected.

Viral replication and shedding are key considerations in the timing of treatment, infection control, and chemoprophylaxis. In general, the incubation period for influenza is estimated to range from 1 to 4 days with an average of 2 days. Influenza virus shedding (the time during which a person might be infectious and transmit the disease) begins the day before illness onset and can persist for 5 to 7 days, although some persons may shed virus for longer periods, particularly young children and severely immunocompromised patients The amount of virus shed is greatest in the first 2-3 days of illness and appears to correlate with fever, with higher amounts of virus shed when temperatures are highest.  For these recommendations, however, the infectious period for influenza is defined as one day before fever begins until 24 hours after fever ends.(9).

This leads to underline a major limit of the two BMJ papers: neither of the two reviews consider the time when treatment was initiated, a overwhelming determinant of treatment efficacy. In fact, we do not expect significant efficacy of antineuraminidase drugs when those drugs are administered after 48 hours from symptoms onset.

Analysis of clinical outcomes in patients grouped by time from symptoms onset and treatment initiation should have been considered. Pooling together patients that started treatment within the first 48 hours from symptoms onset with patients starting treatment several days later (who are, by the way, the vast majority of hospitalized patients) is a major confounding factor in open contradiction with the official treatment recommendations, that insist on a very early treatment (6-7). 

Donato Greco, MD. Rome

  1. Tom Jefferson et al : Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments  BMJ 2014;348:g2545
  2. Carl J Heneghan et al. : Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments BMJ 2014;348:g2547
  3. Fiore, Anthony E., et al. "Antiviral agents for the treatment and chemoprophylaxis of influenza---recommendations of the Advisory Committee on Immunization Practices (ACIP)." MMWR. Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports/Centers for Disease Control 60.1 (2011): 1-24.
  4. Scott A. Harper et al. :  Seasonal Influenza in Adults and Children—Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management: Clinical Practice Guidelines of the Infectious Diseases Society of American Clin Infect Dis. (2009) 48 (8): 1003-1032. doi: 10.1086/598513
  5. PNLG ISS La gestione della sindrome influenzale  DOCUMENTO 16 maggio 2008
  6. Tamiflu® (oseltamivir phosphate) Distributed by: Genentech, Inc. A Member of the Roche Group : HIGHLIGHTS OF PRESCRIBING INFORMATION
  8. Gubareva LV, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors. Lancet. Mar 4 2000;355(9206):827-835.
  9. CDC Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009-2010 Season. December 07, 2009