ABSTRACT & COMMENTARY

Neuraminidase Inhibitor Therapy of Influenza Virus Infections — Yes or No?

By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University, Hospital Epidemiologist, Sequoia Hospital, Redwood City, CA

Dr. Deresinski does research for the National Institutes of Health and is an advisory board member and consultant for Merck. This article originally appeared in the June 2014 issue of Infectious Disease Alert.

SYNOPSIS: A Cochrane review questions the value of osletamivir and zanamivir in the treatment of influenza virus infections – but the CDC and IDSA disagree.

SOURCE: Jefferson T, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2014;4:CD008965.

Jefferson and colleagues examined data from all available results, including unpublished data, from randomized, placebo-controlled trials of therapy and prophylaxis of influenza virus infection with neuraminidase inhibitors in both children and adults to determine their safety and efficacy. Overall, 107 clinical trials were examined.

TREATMENT — ADULTS

Oseltamivir reduced the time to initial alleviation of symptoms in adults from a mean of 7 days to one of 6.3 days, a mean reduction of 16.8 hours (95% confidence interval [CI], 8.4-25.1 hours; P < 0.0001). Zanamivir reduced this measure from 6.6 to 6.0 days, a 0.60 day reduction (95% CI, 0.39-0.81 days; P < 0.00001). Neither oseltamivir nor zanamivir had a significant effect on hospitalizations or serious complications; this endpoint was not reported in zanamivir studies. Oseltamivir and zanamivir each significantly reduced "unverified" pneumonia, but not more stringently defined pneumonia in the few studies in which this was analyzed. Oseltamivir was associated with an increased risk of nausea and vomiting but decreased risks of diarrhea and cardiac events during treatment.

TREATMENT — CHILDREN

Oseltamivir reduced the time to initial alleviation of symptoms in previously healthy children by a mean of 29 hours (95% CI, 12-47 hours; P = 0.001), but the effect in children with asthma was non-significant. There was also no significant effect of oseltamivir on hospitalizations, serious influenza complications, or unverified pneumonia. Oseltamivir was associated with an increased risk of vomiting.

PROPHYLAXIS — ADULTS AND CHILDREN

Oseltamivir significantly reduced the risk of symptomatic influenza in individuals (risk difference [RD] 3.05%, 95% CI, 1.83-3.88) with a number needed to treat (NNT) of 33. The risk in households was also significantly reduced (RD 13.6%, 95% CI 9.52-15.47) with an NNT of 7. The results with zanamivir were similar.

The authors concluded that, overall, the benefit of neuraminidase therapy in these outpatient studies was small, and that there was no evidence of prevention of serious outcomes. There was, however, apparent benefit of prophylaxis in the prevention of symptomatic infection.

COMMENTARY

The CDC has carefully considered this analysis but, nonetheless, indicates that it does not alter their existing recommendations for influenza treatment that "emphasize initiation of antiviral treatment as soon as possible for patients who are severely ill and for those who are at greatest risk for complications from influenza. This includes hospitalized patients with suspected or confirmed influenza, those with severe or progressive illness, and outpatients who are at high risk of influenza complications (for example, young children, people aged 65 years and older, pregnant women, and persons with certain underlying chronic medical conditions). In addition, because other reviews of randomized clinical trials and observational studies have found consistent clinical benefit of early oseltamivir treatment in reducing the risk of lower respiratory tract complications such as those requiring antibiotics, persons with uncomplicated influenza who are not in a high risk group and who present within 48 hours of illness onset can be treated with antiviral medications based upon clinical judgment."¹

The CDC points out that the studies analyzed by Jefferson and colleagues were not powered to detect the effects of therapy on severe outcomes such as hospitalization and death. Furthermore, patients at highest risk of severe outcome are often not included in randomized trials and, since a virological diagnosis was often not required, many included patients with influenza-like illness may not actually have had influenza virus infection. The trials included in the Cochrane analysis involved outpatients — there are no randomized trials in hospitalized patients — but there are a number of observational studies that have reported benefit from therapy. Thus, Muthuri and colleagues performed a meta-analysis of the effects of neuraminidase inhibitor therapy in hospitalized patients, examining 78 studies and more than 29,000 patients.² They found that administration of a neuraminidase inhibitor was associated with a significantly decreased risk of mortality (adjusted odds ratio [OR], 0.81; 95% CI, 0.70-0.93; P = 0.0024). Initiation of treatment within 2 days of symptom onset was associated with a reduction in mortality risk (adjusted OR, 0.48; 95% CI, 0.41-0.56; P < 0.0001) when compared to later initiation and, when compared to no treatment, a halving of the risk of mortality (adjusted OR, 0.50; 95% CI, 0.37-0.67; P < 0.0001). The benefit was greater in adults than in children.

The Infectious Diseases Society of America has issued a statement that concurs with the CDC recommendation confirming the benefit of neuraminidase inhibitors in both the prevention and treatment of influenza virus infection.³

REFERENCES

1. CDC Recommendations for Early Influenza Antiviral Medications Remain Unchanged. http://www.cdc.gov/media/haveyouheard/stories/Influenza_antiviral2.html
2. Muthuri SG, et al. Lancet Respir Med 2014;2:395-404.
3. Infectious Disease Society of America (IDSA) statement.
   http://www.idsociety.org/Influenza_Statement.aspx.