Comparison of Efficacy of Intravenous Peramivir and Oral Oseltamivir for the Treatment of Influenza: Systematic Review and Meta-Analysis

Influenza viruses are important global pathogens with an estimated annual attack rate of 5–10% in adults and 20–30% in children, resulting in substantial disease incidence, hospitalization, and mortality.1 The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) recommended three U.S. Food and Drug Administration (FDA)-approved influenza antiviral agents [oral oseltamivir, inhaled zanamivir, and intravenous (IV) peramivir] for the prevention and control of influenza during the 2015–2016 influenza season.2

Oseltamivir (F. Hoffmann-La Roche, Ltd., Basel, Switzerland) is the antiviral agent most frequently used for the treatment and prevention of influenza, and its use has increased since pandemic influenza A (H1N1) 2009. Because oseltamivir is administered via an oral route, it is often difficult to use in some cases, particularly in young children, patients with aspiration tendency, critically ill patients or patients requiring mechanical ventilation. Therefore, novel or additional effective agents are needed.3

Peramivir (BioCryst Pharmaceuticals Inc., Durham, NC, USA) is an antiviral agent that blocks viral growth by selectively inhibiting neuramidase (NA), an enzyme that releases viral particles from infected cells, in human influenza A and B viruses, and is administered once daily through an IV route.3 It was licensed in Japan and South Korea in 2010.3 In the United States, IV peramivir is still under investigation as an NA inhibitor (NAI), but it was made temporarily available in 2009 for hospitalized patients infected with pandemic influenza A (H1N1) under an Emergency Use Authorization.4 Recent randomized controlled trials (RCTs) demonstrated that IV peramivir showed better clinical efficacy and antiviral activity than a placebo in uncomplicated influenza and was safe and well tolerated.5, 6

Since the 2010s, several RCTs or observational studies (OBSs), comparing the clinical efficacy of peramivir with that of oseltamivir in influenza patients, have been published.7, 8, 9, 10, 11, 12, 13 However, there is a lack of evidence regarding whether IV peramivir or oral oseltamivir should be used for initial treatment in patients with influenza. Accordingly, the purpose of the present study was to compare the clinical efficacy of these two antiviral agents through a systematic review and meta-analysis of data from clinical trials.

Our study showed that IV peramivir might reduce the time to alleviation of fever compared with oral oseltamivir among patients with influenza. The clinical efficacy of IV peramivir therapy was first reported in a placebo-controlled, double-blind phase II study in patients with uncomplicated seasonal influenza.5 At both 300 and 600 mg, a single IV peramivir infusion significantly reduced the time to alleviation of symptoms for adult influenza outpatients.5 After that, a randomized, double-blind phase III study conducted in Japan, Taiwan, and South Korea compared IV peramivir (a 300- or 600-mg single infusion) with oral oseltamivir (75 mg twice a day for 5 days) in uncomplicated cases of seasonal influenza, and demonstrated the non-inferiority of peramivir therapy to oseltamivir in terms of the time to alleviation of symptoms.8 However, due to the scar city of clinical comparisons, we sought to determine which antiviral agent was superior through a meta-analysis of previous trials.

In our study, the time to alleviation of fever was considered a primary outcome when evaluating the clinical efficacy of antiviral agents for patients with influenza because it was regarded as the most important parameter in clinical studies. Although OBSs demonstrated the superiority of IV peramivir therapy with regard to fever, we could not draw concrete conclusions because the results of subgroup analysis from RCTs were ambiguous.

In addition, we compared the time to alleviation of fever according to whether patients were hospitalized or not. Although the US FDA approved peramivir as the first IV NAI for patients with uncomplicated influenza,16 a recent placebo-controlled, double-blind RCT did not demonstrate the clinical benefit of IV peramivir in hospitalized patients with influenza.17 No antiviral agents have been approved specifically for the treatment of influenza in hospitalized patients. In our meta-analysis, there were no statistically significant differences between treatment groups in hospitalized patients with influenza. Therefore, we could not confirm whether IV peramivir or oral olsetamivir was more effective in patients with serious influenza requiring hospitalization.

Total mortality, length of hospital stay, and changes in viral titers are key parameters of the clinical and virological effectiveness of antiviral agents. Our results revealed that these parameters did not differ between peramivir and olsetamivir treatment groups. In a RCT that enrolled 288 healthy volunteers (aged 18–45 years) intranasally inoculated with experimental influenza A or B, oral peramivir treatment at a dosage of 400 mg once daily for 5 days significantly reduced viral detection, defined by the area under the curve for nasal wash viral titers of influenza A.18 And both 400 and 800 mg once daily for 5 days reduced viral titer of influenza B.18 Although we evaluated changes in viral titers from base-line to 48 hours, no significant difference in virological effects was found between two groups.

In addition to clinical efficacy, adverse events are critical factors in the selection of an antiviral agent. Although we conducted a meta-analysis of adverse events using two RCT studies and one OBS,7, 8, 13 the results showed no statistically significant differences in rates of any or serious adverse events between patients treated with peramivir and those treated with oseltamivir. Most adverse events were mild or moderate. Pooled estimated results suggested that the incidence of severe adverse events was similar in the peramivir and oseltamivir groups (7.2% and 6.8%, p=0.08). Gastrointestinal symptoms such as diarrhea, nausea, and vomiting were the most common adverse effects in both treatment groups. The similar clinical efficacy and adverse event findings of this systematic review suggest that the choice between oseltamivir and peramivir therapy could be decided based upon the convenience of administration (IV vs. oral), the ease with which medications can be purchased, and the preference of the patient or physician. Several previous OBSs and subgroup analysis in our study showed IV peramivir to have superior efficacy in terms of the time to alleviation of fever. However, the lack of differences in total mortality rate, length of hospital stay and changes in viral titers indicate little or no difference in clinical efficacy between the two agents.

The development of influenza antiviral drug resistance in viruses is a major concern. Therefore, when considering which drug to choose, resistance should be considered. The H274Y mutation is associated with resistance to oseltamivir and peramivir and mutations at I222 and R292 can reduce peramivir sensitivity.19 The incidence of resistance to oseltamivir and/or peramivir in Japan and USA during the 2013–2014 influenza season was 4.2% and 1.2% for influenza A (H1N1) pdm09, respectively. This might mean that, in spite of the low resistance rate, a particular drug could be superior to others in specific situations.

Our study has some limitations. First, since our meta-analysis considered only a small number of trials, our results should be interpreted with caution. Second, the publication bias inherent to all meta-analyses might have influenced these results. However, since the number of included trials was small, we could not estimate potential publication bias with a funnel plot for all outcomes. Third, the dosage and the duration of IV peramivir treatment varied among studies, which could affect the precision of the results. As a result, we think that additional large-scale RCTs are needed to overcome these limitations. Finally, we tried to compare the efficacy of two drugs between children and adults. We found six studies for primary outcome.7, 8, 9, 10, 11, 13 There are three studies for adults,7, 8, 13 and one study for children.9 The remaining two studies examined mixed group including adults and children.10, 11 Accordingly, we could not perform a meta-analysis for children group. Instead, we evaluated the time to alleviation of fever after treatment of antiviral agents on adults group.7, 8, 13 Pooled estimates revealed no significant difference between two treatments (MD, -2.51 hours; 95% CI -11.88 to 6.86; p=0.60; I² =6%).

In conclusion, our systematic review and meta-analysis suggested that IV peramivir might reduce the time to alleviation of fever among patients with influenza compared to oral oseltamivir. However, because the methodological limitations of the included trials and the scarcity of trials prevented us from drawing firm conclusions, the clinical benefit and/or superiority of IV peramivir to oral oseltamivir remains unclear in these patients. Accordingly, further large-scale RCTs are needed to establish appropriate criteria with regard to the selection of optimal NAIs for patients with influenza.