Oseltamivir treatment in adults with influenza shortens the time to clinical symptom alleviation by about 1 day and substantially reduces the risk of lower respiratory tract complications and hospitalization, according to findings from a meta-analysis of nine randomized, controlled trials involving 4,328 adult patients.

The findings of the study , which is the first to use individual patient data to evaluate the neuraminidase inhibitor, should put to rest persistent doubts its efficacy and safety, according to Dr. Arnold S. Monto of the University of Michigan School of Public Health, Ann Arbor, who was lead investigator, and his colleagues.

The intention-to-treat population of 1,591 patients with confirmed influenza had a significant 21% shorter time to clinical symptom alleviation, compared with the intention-to-treat infected population of 1,302 patients who received placebo (97.5 hours vs. 122.7 hours, difference of 25.2 hours; time ratio, 0.79), the investigators reported online Jan. 30 in the Lancet.

The effects were somewhat attenuated in the 2,402 treated patients in the overall intention-to-treat population – with a 15% reduction in time to symptom alleviation – compared with the 1,926 placebo patients in that population. But the difference remained significant (median of 17.8 hours; time ratio, 0.85), the investigators said (Lancet 2015 Jan. 30 [ doi:10.106/S0140-6736(14)62449-1 ]).

“In the intention-to-treat noninfected population, the estimated time ratio was close to unity (time ratio, 0.99), so only participants identified as influenza infected benefited from oseltamivir,” the study authors wrote. That suggests efficacy is “confined to the antiviral activity of the drug.”

In addition, treatment significantly reduced the risk of lower respiratory tract complications occurring more than 48 hours after randomization by 44% in the intention-to-treat infected population. Only 4.2% of oseltamivir-treated patients requiring such treatment, compared with 8.7% of those who received placebo (risk ratio, 0.56). The risk of hospitalization for any cause was significantly reduced by 63% (0.6% vs. 1.7% in the groups, respectively; RR, 0.37).

The risk ratios for lower respiratory tract complications and hospitalization were 0.62 and 0.61, respectively, in the overall intention-to-treat population, but the difference in hospitalization between the groups was no longer statistically significant.

The benefits of treatment came at the cost of increased risk of nausea and vomiting (RR, 1.60 and 2.43, respectively), but no effect was seen with respect to neurologic or psychiatric disorders or serious adverse events in either of the groups.

To overcome previous concerns regarding potential publication bias, the investigators included all published and unpublished Roche-sponsored randomized, placebo-controlled, double-blind trials of the standard prescribed oseltamivir dose of 75 mg twice daily in adults, as well other applicable trials of the Roche drug for the treatment of naturally occurring influenzalike illness. The trials were conducted between 1997 and 2001, and included patients who were within 36 hours of feeling unwell, and who had a fever and at least one respiratory symptom and one additional constitutional symptom.

Treatment was administered at 12-hour intervals for 5 days, and patients were followed for 21 days, during which time virus cultures were performed in most cases.

“The safety and effectiveness of oseltamivir has been hotly debated, with some researchers claiming there is little evidence that oseltamivir works,” Dr. Monto said in a press statement. “Our meta-analysis provides compelling evidence that oseltamivir therapy reduces by 1 day the typical length of illness in adults infected with influenza and also prevents complications and reduces the number of people needing hospital treatment. Whether the magnitude of these benefits outweighs the harms of nausea and vomiting needs careful consideration.”

The Multiparty Group for Advice on Science funded the study and assembled a multidisciplinary team to examine available data. The group obtained an unrestricted grant from Roche to cover the costs.

Dr. Monto reported receiving fees from BioCryst and Roche outside of the submitted work. His coauthor, Dr. Richard J. Whitely, reported receiving fees as a board member of Gilead Sciences and travel funding from Roche. The remaining authors reported having no disclosures.


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