Systematic Review: Safety and Efficacy of Extended-Duration Antiviral Chemoprophylaxis Against Pandemic and Seasonal Influenza

  1. Nayer Khazeni, MD, MS;
  2. Dena M. Bravata, MD, MS;
  3. Jon-Erik C. Holty, MD, MS;
  4. Timothy M. Uyeki, MD, MPH, MPP;
  5. Christopher D. Stave, MLS; and
  6. Michael K. Gould, MD, MS
  1. From Stanford University Medical Center, Center for Health Policy and Center for Primary Care and Outcomes Research, Stanford Sleep Disorders Center, and Lane Medical Library, Stanford, California; Centers for Disease Control and Prevention, Atlanta, Georgia; and Veterans Affairs Palo Alto Health Care System, Palo Alto, California.
     
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    Abstract

    Background: Neuraminidase inhibitors (NAIs) are stockpiled internationally for extended use in an influenza pandemic.

    Purpose: To evaluate the safety and efficacy of extended-duration (>4 weeks) NAI chemoprophylaxis against influenza.

    Data Sources: Studies published in any language through 11 June 2009 identified by searching 10 electronic databases and 3 trial registries.

    Study Selection: Randomized, placebo-controlled, double-blind human trials of extended-duration NAI chemoprophylaxis that reported outcomes of laboratory-confirmed influenza or adverse events.

    Data Extraction: 2 reviewers independently assessed study quality and abstracted information from eligible studies.

    Data Synthesis: Of 1876 potentially relevant citations, 7 trials involving 7021 unique participants met inclusion criteria. Data were pooled by using random-effects models. Chemoprophylaxis with NAIs decreased the frequency of symptomatic influenza (relative risk [RR], 0.26 [95% CI, 0.18 to 0.37]; risk difference [RD], −3.9 percentage points [CI, −5.8 to −1.9 percentage points]) but not asymptomatic influenza (RR, 1.03 [CI, 0.81 to 1.30]; RD, −0.4 percentage point [CI, −1.6 to 0.9 percentage point]). Adverse effects were not increased overall among NAI recipients (RR, 1.01 [CI, 0.94 to 1.08]; RD, 0.1 percentage point [CI, −0.2 to 0.4 percentage point]), but nausea and vomiting were more common among those who took oseltamivir (RR, 1.48 [CI, 1.86 to 2.33]; RD, 1.7 percentage points [CI, 0.6 to 2.9 percentage points]). Prevention of influenza did not statistically significantly differ between zanamivir and oseltamivir.

    Limitations: All trials were industry-sponsored. No study was powered to detect rare adverse events, and none included diverse racial groups, children, immunocompromised patients, or individuals who received live attenuated influenza virus vaccine.

    Conclusion: Extended-duration zanamivir and oseltamivir chemoprophylaxis seems to be highly efficacious for preventing symptomatic influenza among immunocompetent white and Japanese adults. Extended-duration oseltamivir is associated with increased nausea and vomiting. Safety and efficacy in several subpopulations that might receive extended-duration influenza chemoprophylaxis are unknown.

    Editors' Notes

    Context

    • Neuraminidase inhibitors are a key element of public health strategies to prevent and treat pandemic influenza.

    Contribution

    • This review of 7 trials assessing the efficacy and safety of extended-duration (>4 weeks) treatment with oseltamivir and zanamivir suggests that the drugs prevent symptomatic but not asymptomatic seasonal influenza. The drugs seem to be safe, but oseltamivir causes nausea and vomiting.

    Caution

    • All 7 trials were industry-sponsored. There was strong evidence of publication bias. No trial included children, minorities, or vaccinated populations.

    Implication

    • Extended-duration treatment with oseltamivir and zanamivir seems to be safe and efficacious for preventing symptomatic influenza in immunocompetent white and Japanese adults.

    –The Editors

    Influenza virus infections cause substantial global morbidity and mortality. An estimated 250 000 to 500 000 influenza-related deaths occur annually (1), and 500 000 to 100 million people died in each of the three 20th-century influenza pandemics (2, 3). The ongoing influenza A (H1N1) pandemic has caused 94 512 verified infections and 429 confirmed deaths in 122 countries as of 6 July 2009 (4, 5). Pharmaceutical strategies for preventing seasonal and pandemic influenza include vaccination and antiviral chemoprophylaxis, but current vaccines face several challenges: ongoing seasonal influenza viral antigenic changes (6), decreased immunogenicity among young infants and elderly and immunocompromised individuals (7–10), and the need for multiple dosing with adjuvanted vaccines to induce adequate antibody responses to pandemic vaccines (6).

    More than 65 countries have stockpiled millions of doses of antiviral drugs for use during the next influenza pandemic (11, 12). Antiviral medications can also be used for seasonal influenza chemoprophylaxis among individuals at high risk for complications from influenza who have contraindications to influenza vaccination, among those with a presumed poor response to vaccine, or as an adjunct to vaccination in seasons with a known vaccine–wild virus mismatch (13–17). Because of the emergence of circulating influenza A (H3N2) virus strains that are resistant to adamantanes (18, 19) and given that resistance to susceptible strains can develop rapidly during treatment, all pandemic stockpiles contain neuraminidase inhibitors (NAIs) (20), with a high ratio of oseltamivir to zanamivir (21, 22). However, oseltamivir resistance emerged among circulating influenza A (H1N1) virus strains (21, 22) during 2007 to 2008 and became highly prevalent worldwide in 2008 to 2009 (resistance to zanamivir among circulating influenza virus strains has not been reported to date) (23, 24). Oseltamivir resistance has also been reported among some strains of highly pathogenic avian influenza A (H5N1) virus, a pandemic threat (20, 25–27). In addition, neuropsychiatric effects and self-injury have been reported in Japanese adolescents who received oseltamivir for influenza (28, 29). These issues have raised concerns about the safety and efficacy of NAIs for treatment or chemoprophylaxis of seasonal or pandemic influenza.

    In the context of the emergence of and ongoing pandemic caused by a novel influenza A (H1N1) virus of swine origin that is resistant to adamantanes but susceptible to NAIs (4, 30–32) and the projected 4- to 6-month delay in the availability of a matched vaccine (5, 33), NAIs could be used for prevention. We performed a systematic review and quantitative analysis of NAIs to determine their safety and efficacy in extended-duration chemoprophylaxis against seasonal influenza A and to examine the relative safety and efficacy of zanamivir compared with oseltamivir. We evaluated whether efficacy varied with participant-related factors (such as race or ethnicity, age, high risk for influenza, influenza vaccination status, and outpatient or inpatient setting) or drug-related factors (such as the specific NAI used and dose).

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    Methods

    Data Sources and Searches

    Using systematic methods (34), we sought to identify all studies published in any language that examined NAI use. In conjunction with a coauthor who is a professional research librarian, we developed strategies (Appendix Table 1) using such search terms as gg167, gs4104, gs4071, oseltamivir, tamiflu, zanamivir, relenza, and neuraminidase to identify studies published from 1926 through 11 June 2009 in electronic databases (MEDLINE, EMBASE, BIOSIS, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Cochrane Database of Systematic Reviews, National Health Service Economic Evaluation, Health Technology Assessment, ACP Journal Club, and Database of Abstracts of Reviews of Effects) and trial registries (U.S. Food and Drug Administration, GlaxoSmithKline, and Roche). We also reviewed the bibliographies of retrieved articles to identify additional studies.

    View this table:
    Appendix Table 1. Search Strategy

    Study Selection

    Using systematic methods (35), 2 investigators independently evaluated studies for inclusion and resolved disagreements by re-review and discussion. We included studies that 1) were randomized, controlled trials (RCTs) in humans; 2) examined NAIs (oseltamivir, zanamivir, or peramivir) administered for a minimum 4-week duration; 3) reported at least 1 outcome of interest (laboratory-confirmed symptomatic influenza illness, laboratory-confirmed asymptomatic influenza virus infection, or adverse events); and 4) for those that evaluated efficacy, did so against naturally occurring influenza A virus infection.

    Quality Assessment and Data Extraction

    Two investigators independently assessed English-language studies for methodological quality and subsequently resolved disagreements by discussion. One investigator arbitrated if discussion did not resolve disagreement. A professional translator assessed the quality of 1 non–English-language study (36). We abstracted data on withdrawal frequencies (37); participants' adherence to at least 80% of medication doses (38); intention-to-treat analyses; and score on a validated 5-point scale (39) designed to assess study quality. We also abstracted data on sources of funding, conflicts of interest, and recruitment and compensation methods, all factors that can introduce bias into studies of efficacy (40–42). One investigator wrote to authors of studies that did not report key quality criteria.

    For English-language studies, 2 investigators independently abstracted information on study design; institutions; inclusion and exclusion criteria; demographic characteristics of participants; percentage of patients vaccinated for seasonal influenza; NAI dose and route of administration; adherence; withdrawals; laboratory-confirmed symptomatic influenza and asymptomatic influenza virus infection; and adverse events, including those commonly associated with NAI use (such as nausea, vomiting, diarrhea, abdominal pain, headache, fatigue, somnolence, insomnia, and dizziness) and rarer events (such as unstable angina, anemia, pseudomembranous colitis, humerus fracture, pneumonia, pyrexia, elevated liver enzyme and creatine kinase levels, lymphopenia, arthralgia, urticaria, and peritonsillar abscess) (43, 44). Laboratory confirmation of influenza virus infection was defined by cases verified with positive viral culture of respiratory specimens or a 4-fold increase in influenza antibody titers in paired sera. Symptomatic individuals were defined as those with at least 1 of the following: temperature 37.2 °C or greater, myalgia, fatigue, headache, cough, sore throat, or nasal congestion.

    One professional translator abstracted the same data for the non–English-language study (36), and 1 investigator abstracted the portions of that study (abstract and results tables) that were presented in English.

    Data Synthesis and Analysis

    To evaluate agreement between raters for the assessments of study eligibility and methodologic quality, we calculated the observed percentage agreement and the κ coefficient for interrater reliability (45).

    For each study, we constructed 2 × 2 contingency tables in which participants were classified as having positive or negative outcomes for asymptomatic influenza virus infection, symptomatic influenza, or adverse events. We calculated the risk difference (RD) and relative risk (RR) for each outcome of interest. We calculated summary outcomes by using random-effects models. For each RR, we assessed statistical heterogeneity by calculating the I2 statistic (I2 > 50% represented significant heterogeneity) (46). We evaluated potential sources of heterogeneity by performing predetermined subgroup analyses (age, influenza risk status, vaccination status, inpatient or outpatient setting, NAI used, and NAI dose). To compare subgroups, we performed a t test on log risk ratios, using the square root of the variances of the subgroups as the SE.

    We performed sensitivity analyses to evaluate the robustness of our results. We removed each study individually to evaluate its effect on the summary estimates. We assessed publication bias through funnel-plot analysis (47) and Begg and Mazumdar adjusted rank correlation testing (48).

    We performed analyses by using Comprehensive Meta-Analysis, version 2 (Biostat, Englewood, New Jersey), and Microsoft Excel, version 2003 (Microsoft, Redmond, Washington).

    Role of the Funding Source

    The funding sources had no role in the design, conduct, and analysis of this study or in the decision to submit the manuscript for publication.

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    Results

    Study Identification and Eligibility

    We identified 1876 potentially relevant studies published since 1926 (Appendix Figure 1). We excluded 1865 studies after reviewing their titles and abstracts. After reviewing the remaining 11 full-text studies, we excluded 3 that were duplicates and 1 that was not yet complete, leaving 7 eligible studies (2 separate studies examining regular and high doses of oseltamivir were included in 1 publication [49]) with 7021 unique participants (15, 36, 49–52). Interrater agreement for study eligibility was 100% (κ = 1).

    Appendix Figure 1.
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    Appendix Figure 1. Literature search and selection.

    FDA = U.S. Food and Drug Administration; NAI = neuraminidase inhibitor; RCT = randomized, controlled trial.

    Participant Characteristics

    The mean patient age ranged from 28.8 to 81.2 years (median, 34.7 years); no included study had participants younger than 12 years, and only 1 study evaluated the use of NAIs in participants younger than 18 years (it included 121 adolescents among 3361 total participants) (Table 1). The mean percentage of female participants ranged from 46.1% to 69.0% (median, 62.5%). Participants in 6 studies were predominantly white (median, 87%); in 1 study, all participants were Japanese. Five studies included healthy persons with no indications for influenza vaccination; 1 enrolled only individuals recommended for vaccination (53); and 1 recruited participants from an institutionalized elderly population at high risk for complications of influenza. Three studies excluded people who had received current-season influenza vaccination, 3 included a mix of participants who were unvaccinated or vaccinated with trivalent inactivated influenza vaccine (TIV), and 1 study vaccinated all participants with TIV at the beginning of the trial.

    View this table:
    Table 1. Study and Participant Characteristics

    Study Design Characteristics

    Four studies examined oseltamivir chemoprophylaxis, and 3 studies examined zanamivir chemoprophylaxis; no study directly compared oseltamivir with zanamivir and placebo (Table 1). Duration of NAI chemoprophylaxis ranged from 28 to 42 days (median, 42 days). Most studies were conducted in outpatient settings; 1 was conducted in a nursing home. Of the 6 studies that assessed laboratory-confirmed influenza outcomes, all reported testing for influenza virus strains in circulation during the study's influenza season. One study tested serum samples, and 5 tested serum, oropharyngeal, and nasopharyngeal samples. The proportion of laboratory-confirmed symptomatic influenza illness among participants receiving placebo ranged from 5.8% to 13.7% (mean, 6.38%) (Appendix Table 2), consistent with reported influenza activity (54, 55).

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    Appendix Table 2. Incidence of Laboratory-Confirmed Symptomatic Influenza in Participants Receiving Placebo

    Study Quality

    All 7 studies met our minimum specified quality criteria for inclusion (Table 2). The overall quality of the included studies was good: Six studies used intention-to-treat analyses, and 1 used a modified intention-to-treat analysis. We planned to include studies with modified Jadad scores greater than 3, fewer than 20% participant withdrawals, and adherence of 80% (that is, 80% of participants adhered to at least 80% of medication doses) (37, 38). The average Jadad quality criteria score was 4 (of 5 possible points). Adherence to more than 80% of medication doses ranged from 87.1% to 98.1%. Withdrawal of participants ranged from 1.0% to 10.0%. All studies were funded by pharmaceutical companies, and authors of 6 of 7 studies reported being paid consultants of the sponsoring pharmaceutical company. Recruitment and compensation methods were not described in most studies; 2 studies reported paying participants but did not specify the amount. The mean interrater agreement for assessment of study quality was 91.0% (κ = 0.81), indicating excellent agreement.

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    Table 2. Quality of Included Trials

    Symptomatic Influenza

    Four studies of oseltamivir (15, 36, 49) (n = 1867) and 2 studies of zanamivir (50, 51) (n = 4468) reported the incidence of symptomatic influenza (Figure 1). Heterogeneity among these studies was low (I2 = 0.0). Extended-duration NAI chemoprophylaxis decreased the risk for symptomatic influenza (RR, 0.26 [CI, 0.18 to 0.37]; RD, −3.9 percentage points [CI, −5.8 to − 1.9 percentage points]), with no statistically significant difference in the efficacy of zanamivir versus oseltamivir (P = 0.64).

    Figure 1.
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    Figure 1. Meta-analysis of laboratory-confirmed symptomatic influenza.

    NAI = neuraminidase inhibitor; RD = risk difference; RR = relative risk.

    * Once daily.

    † Twice daily.

    Top. Random-effects analysis of RD and RR for influenza confirmed by serology or positive culture in participants with at least 1 of the following: temperature 37.2 °C or higher, myalgia, fatigue, headache, cough, sore throat, or nasal congestion. Middle. Random-effects analysis of RD and RR for influenza confirmed by serology or positive culture in participants without symptoms. Bottom. Random-effects analysis of RD and RR for severe adverse events.

    Asymptomatic Influenza Virus Infection

    Four studies of oseltamivir (15, 36, 49) (n = 1867) and 2 studies of zanamivir (50, 51) (n = 4468) reported the frequency of asymptomatic influenza virus infection (Figure 1). There was no significant heterogeneity among these studies (I2 = 39.9) for this outcome. Risk for asymptomatic influenza virus infection did not differ between the chemoprophylaxis and placebo groups (RR, 1.03 [CI, 0.81 to 1.30]; RD, −0.4 percentage point [CI, −1.6 to 0.9 percentage point]).

    Adverse Events

    All 7 studies monitored and reported adverse events. Four studies (36, 50–52) (n = 4914) described “severe” or “serious” adverse events, which were not further defined. The chemoprophylaxis and placebo groups did not differ in the risk for serious adverse events (RR, 0.92 [CI, 0.51 to 1.65]; RD, 0.0 percentage point [CI, −0.4 to 0.4 percentage point]) or risk for all adverse events (RR, 1.01 [CI, 0.94 to 1.08]; RD, 0.1 percentage point [CI, −0.2 to 0.4 percentage point]) (Figure 1 and Appendix Figure 2). Four studies, all of oseltamivir (15, 36, 49) (n = 1867), reported nausea and vomiting. Oseltamivir was associated with an increased risk for nausea and vomiting compared with placebo (RR, 1.48 [CI, 1.86 to 2.33]; RD, 1.7 percentage points [CI, 0.6 to 2.9 percentage points]). Overall, withdrawals secondary to adverse events were similar between groups (Appendix Table 3). Among studies, heterogeneity for serious adverse events (I2 = 0.0) and all adverse events (I2 = 31.3) was low, with no difference between zanamivir and oseltamivir (P = 0.32).

    Appendix Figure 2.
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    Appendix Figure 2. Relative risk for all adverse events.

    Abd = abdominal; NAI = neuraminidase inhibitor; RI = respiratory infection; RR = relative risk; UTI = urinary tract infection.

    * Once daily.

    † Twice daily.

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    Appendix Table 3. Withdrawals Secondary to Adverse Events

    Rare Adverse Events

    The U.S. Food and Drug Administration defines rare adverse events as those occurring in 1 in 1000 persons (56); 3000 persons at risk would be required for a 95% chance of detecting 1 rare adverse event (57). According to this definition, no study was powered to detect rare adverse events.

    Dose-Dependent Effects

    Six studies (15, 36, 49 [regular-dose study], 50–52) (n = 6501) administered currently recommended (43, 44) adult chemoprophylactic doses (oseltamivir, 75 mg/d; zanamivir, 10 mg/d), and 1 study (49 [high-dose study]) (n = 1039) administered a higher dose (oseltamivir, 75 mg twice daily). There was no statistically significant difference in efficacy with the higher dose; however, an increase in adverse effects (nausea and vomiting) was suggested in the higher-dose study (RR, 2.17 [CI, 1.52 to 3.09]; RD, 4.4 percentage points [CI, −1.0 to 9.9 percentage points]). Stratification by dose reduced the moderate heterogeneity in adverse events (from I2 = 31.3 for all studies of adverse effects to I2 = 5.3 for regular-dose studies).

    Effect of Influenza Vaccination

    Three studies, all of oseltamivir (36, 49), enrolled only unvaccinated individuals (n = 1867); 1 study of zanamivir (52) enrolled only individuals vaccinated with TIV (n = 138); and 3 studies (15, 50, 51) included both unvaccinated participants and participants vaccinated with TIV (n = 5016). No study included participants vaccinated with live attenuated influenza vaccine (LAIV). We compared studies whose participants had less than 50% influenza vaccine coverage with studies whose participants had greater than 50% vaccine coverage. The incidence of symptomatic or asymptomatic influenza did not differ between groups. Adverse events did not differ among studies with greater than 50% influenza vaccine coverage among participants. When we pooled results of 3 oseltamivir studies that enrolled no current-season vaccinated individuals, estimates of the RRs for symptomatic influenza and asymptomatic influenza in participants receiving NAIs were similar to those in the main analysis (Appendix).

    Effect of Risk Category

    Two studies (15, 50) examining laboratory-confirmed influenza outcomes—1 of zanamivir (n = 3361) and 1 of oseltamivir (n = 548)—enrolled participants at higher risk for complications from influenza virus infection. The incidence of symptomatic or asymptomatic influenza virus infection did not differ between studies of individuals who were not at increased risk and studies of high-risk individuals. There was no difference in adverse events between high- and low-risk individuals in the 6 studies (15, 36, 49 [regular-dose study], 50–52) (n = 6501) that administered regular doses of NAIs (Appendix).

    Effect of Inpatient or Outpatient Setting

    Five studies (36, 49–51) of laboratory-confirmed influenza outcomes enrolled outpatients (n = 6335), and 1 (15) enrolled nursing home patients (n = 548). The incidence of symptomatic influenza, asymptomatic influenza virus infection, and adverse events did not differ by inpatient or outpatient setting (Appendix).

    Effect of Age

    There was no statistically significant difference in symptomatic influenza or asymptomatic influenza (Appendix) among the 5 studies (36, 49, 51, 52) (n = 3912) that enrolled younger participants (mean age <35 years) and the 2 studies (15, 50) (n = 3109) that enrolled older participants (mean age >60 years). Adverse events did not differ between older and younger participants in the 6 studies that administered regular doses of NAIs (Appendix).

    Sensitivity Analysis

    No study, when removed, meaningfully changed the RRs for symptomatic influenza, asymptomatic influenza, adverse events, or severe adverse events (Appendix).

    Publication Bias

    Our assessments for publication bias were limited by the small sample size; however, a funnel-plot analysis (Appendix Figure 3) was asymmetric, and the Begg method suggested bias (P = 0.009).

    Appendix Figure 3.
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    Appendix Figure 3. Funnel plot for symptomatic influenza.
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    Discussion

    We performed a systematic review and quantitative analysis of all published RCTs of NAI chemoprophylaxis longer than 4 weeks to determine the safety and efficacy to prevent seasonal influenza. In light of increasing oseltamivir resistance, we also examined the relative efficacy of zanamivir versus oseltamivir. We found that surprisingly few studies had addressed these questions and that no study had been done in children younger than 12 years. Among adults, extended-duration NAI chemoprophylaxis was efficacious in preventing symptomatic but not asymptomatic influenza virus infection, with no statistically significant difference in efficacy between oseltamivir and zanamivir.

    We found an increased risk for nausea and vomiting with extended-duration oseltamivir chemoprophylaxis but no increase in other adverse events with use of currently recommended chemoprophylactic doses of oseltamivir or zanamivir. In light of serious postmarketing adverse events potentially related to oseltamivir use, predominantly reported in Japanese populations, we had set out to determine whether any trials were powered to detect rare adverse events or included a broad distribution of races or ethnicities; unfortunately, none were.

    Because of the high prevalence of oseltamivir resistance among currently circulating influenza A (H1N1) virus strains (21–24) and reports of oseltamivir-resistant influenza A (H5N1) virus strains (20, 25–27), international public health agencies are considering altering the composition of current pandemic antiviral stockpiles (58). The governments of the United States, the United Kingdom, and Canada recently announced plans to add millions of doses of zanamivir to their antiviral stockpiles (59–61). Our results support the use of zanamivir for extended-duration chemoprophylaxis in certain individuals in this context because we found that zanamivir had a safety and efficacy profile similar to that of oseltamivir. However, with the exception of developing resistance, all the limitations we have described apply to both oseltamivir and zanamivir. In addition, zanamivir, an orally inhaled powdered drug, is contraindicated in patients with obstructive lung disease, in whom it may increase bronchospasm (44); is approved by the U.S. Food and Drug Administration only for chemoprophylaxis against influenza in children aged 5 years or older (44); and is not practical for some elderly individuals, who may have difficulty operating the disk inhaler (62, 63). If zanamivir becomes the only antiviral option, these limitations would leave substantial portions of the population without extended-duration antiviral chemoprophylaxis, especially during a pandemic.

    Although oseltamivir resistance among circulating influenza A (H1N1) virus strains has increased (21–24), all resistant strains identified to date have had the same mutation (64). Whether the high level of oseltamivir resistance among H1N1 virus strains will persist is unknown; the antiviral susceptibility characteristics of an influenza pandemic virus cannot be predicted. Indeed, sporadic oseltamivir resistance was not noted in the circulating pandemic (H1N1) 2009 virus until several months after the initial outbreaks (4, 30–32, 65). Clearly, antiviral resistance can develop during treatment of susceptible influenza virus infection and can also emerge over time (66–68). Therefore, it would be premature to discard oseltamivir from current antiviral stockpiles for pandemic influenza.

    Our conclusions are restricted to the use of these medications in healthy adult populations; these may not represent groups selected to receive extended-duration antiviral chemoprophylaxis in a pandemic. We were surprised to find that no RCTs have examined the safety and efficacy of extended-duration NAI chemoprophylaxis among children younger than 12 years or immunocompromised individuals. Roche is conducting a trial of extended-duration (12 weeks) oseltamivir chemoprophylaxis in immunocompromised individuals (69); we advocate that the findings of that trial be closely reviewed in the context of our results. We also encourage similar studies in children younger than 12 years because NAIs have been recommended for chemoprophylaxis against seasonal influenza in immunocompromised patients (17) and both children and immunocompromised individuals are in designated U.S. priority groups for receiving antiviral chemoprophylaxis in an influenza pandemic (70).

    No study included participants vaccinated with LAIV. Antiviral therapy is contraindicated only 2 weeks after LAIV administration (71). Several studies show that LAIV is more effective than TIV in children and more protective against strain mismatches (72, 73). The relative efficacy of LAIV compared with TIV is also being studied in other age groups. If its use increases, it will be unclear whether individuals immunized with this vaccine could safely receive extended-duration NAI prophylaxis during a pandemic. We encourage RCTs to examine the safety and efficacy of NAIs administered 2 weeks after LAIV.

    Our study was limited by the low number of included articles, which reduced our statistical power to detect small differences between NAI and placebo recipients for the key outcomes. Although we performed thorough literature searches, U.S. Food and Drug Administration requirements for disclosure of clinical trial data were instituted many years after the discovery of oseltamivir and zanamivir (74). Indeed, although our analyses for publication bias are difficult to interpret in light of the small sample sizes, they suggest missing data. In addition, some limitations of our analyses reflect those of the included studies. All studies were sponsored by pharmaceutical companies, potentially increasing bias (41). No study directly compared oseltamivir with zanamivir and placebo. The participants' race and ethnicity distributions were homogeneous, limiting extrapolation of our results beyond white and Japanese individuals. We could not analyze the risk for rare adverse events with extended-duration NAI chemoprophylaxis because none of the included studies was powered to detect such events. Our analysis cannot guide recommendations for extended-duration NAI chemoprophylaxis of individuals vaccinated with LAIV, immunocompromised individuals, or children younger than 12 years—groups that were not included in the studies.

    Future studies of extended-duration antiviral chemoprophylaxis should include new antiviral drugs (67), a broad distribution of racial and ethnic groups, participants previously vaccinated with LAIV, immunocompromised patients, and children younger than 12 years. Studies should be powered to detect rare adverse events, such as neuropsychiatric syndromes, with descriptions of any serious adverse events. To inform pandemic preparedness, studies should examine longer durations of chemoprophylaxis than those in the included studies; pandemic waves are expected to last 6 to 8 weeks (75), and well-matched vaccines are not expected to be available for several months after the start of a pandemic (76). Studies should include information on inducements for participants to stay in the trial or continue receiving medication (not described in any of our included trials) because it is unknown whether the low withdrawal and nonadherence rates in the included studies would apply in a real-world setting. In light of research showing bias in industry-sponsored studies (41), we encourage non–industry-sponsored research of influenza antiviral agents, as is taking place in the setting of the 2009 H1N1 pandemic (77). The authors of 6 of 7 studies were paid consultants of the sponsoring pharmaceutical company; widespread institution of policies to encourage distinct research and consulting roles may decrease the potential for bias in studies of new antiviral agents.

    Our finding that NAIs do not decrease asymptomatic influenza virus infection is consistent with their known mechanism of action, preventing release of new virus particles from infected cells (78). The contribution of asymptomatic influenza virus infection to transmission among household members, institutional residents, or communities is unknown during seasonal epidemics or pandemics (79). Further research should be conducted to investigate the relative role of asymptomatic infection in influenza virus transmission.

    Until new antiviral agents are available (66), and while oseltamivir and zanamivir remain our main antiviral options against seasonal and pandemic influenza, we encourage research on the safety of extended-duration zanamivir and oseltamivir chemoprophylaxis in children and the development of zanamivir formulations that can be delivered safely and effectively to young children, patients with obstructive lung diseases, and elderly individuals. With these cautions, zanamivir can be used in immunocompetent adults without obstructive lung disease to decrease the risk for symptomatic influenza illness when extended-duration chemoprophylaxis against seasonal influenza is needed, and it can be stockpiled to distribute to these individuals for chemoprophylaxis against pandemic influenza.

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    Appendix: Subgroup Analyses and Sensitivity AnalysisGraphic

     
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    Symptomatic Influenza: Relative Risk (95% CI)

    Fixed: 0.257 (0.180 to 0.367)

    Random: 0.257 (0.180 to 0.367)

    Q = 2.442

    I2 = 0.00

     
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    Subgrouped by NAI (Log Relative Risk)

    Oseltamivir: −1.443 (−1.937 to 0.948)

    Zanamivir: −1.272 (−1.796 to 0.747)

    P = 0.64

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    Subgrouped by Dose (Log Relative Risk)

    Regular: −1.379 (−1.175 to −0.983)

    High: −1.272 (−2.104 to −0.446)

    P < 0.001

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    Subgrouped by Risk (Log Relative Risk)

    Regular: −1.267 (−1.653 to 0.881)

    High: −1.906 (−2.846 to −0.967)

    P = 0.22

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    Subgrouped by Setting (Log Relative Risk)

    Outpatient: −1.323 (−1.686 to −0.960)

    Nursing home: −2.500 (−4.533 to −0.466)

    P = 0.25

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    Subgrouped by Vaccination Status (Log Relative Risk)

    <50% vaccinated: −0.060 (−0.352 to 0.231)

    >50% vaccinated: 0.202 (−0.210 to 0.614)

    P = 0.35

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    Subgrouped by Age (Log Relative Risk)

    <35 years: 0.282 (0.191 to 0.414)

    >60 years: 0.149 (0.058 to 0.380)

    P = 0.22

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    Asymptomatic Influenza: Relative Risk (95% CI)

    Fixed: 1.028 (0.180 to 1.304)

    Random: 1.102 (0.737 to 1.389)

    Q = 8.318

    I2 = 39.89

     
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    Subgrouped by NAI (Log Relative Risk)

    Oseltamivir: −0.248 (−0.575 to 0.079)

    Zanamivir: 0.338 (−0.010 to 0.685)

    P = 0.016

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    Subgrouped by Dose (Log Relative Risk)

    Regular: −0.114 (−0.202 to 0.430)

    High: −0.407 (−0.960 to 0.145)

    P = 0.108

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    Subgrouped by Risk (Log Relative Risk)

    Regular: −0.098 (−0.574 to 0.377)

    High: 0.202 (−0.210 to 0.614)

    P = 0.35

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    Subgrouped by Setting (Log Relative Risk)

    Outpatient: 0.023 (−0.390 to 0.343)

    Nursing home: 0.227 (−0.545 to 0.998)

    P = 0.57

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    Subgrouped by Vaccination Status (Log Relative Risk)

    <50% vaccinated: −1.267 (−1.653 to −0.881)

    >50% vaccinated: −1.906 (−2.846 to −0.967)

    P = 0.22

    Previous Section
     

    Subgrouped by Age (Log Relative Risk)

    <35 years: −0.998 (−0.574 to 0.377)

    >60 years: 0.202 (−0.210 to 0.614)

    P = 0.35

    Previous SectionNext Section

    All Adverse Events: Relative Risk (95% CI)

    Fixed: 1.035 (0.969 to 1.106)

    Random: 1.065 (0.961 to 1.180)

    Q = 58.23

    I2 = 31.31

     
    Next Section

    Subgrouped by NAI (Log Relative Risk)

    Oseltamivir: 0.019 (−0.015 to 0.353)

    Zanamivir: −0.004 (−0.078 to 0.069)

    P = 0.32

    Previous SectionNext Section

    Subgrouped by Dose for Both Zanamivir and Oseltamivir (Log Relative Risk)

    Regular: 0.013 (−0.062 to 0.088)

    High: 0.773 (0.419 to 1.127)

    P < 0.001

    Previous Section
     

    Subgrouped by Dose for Oseltamivir Only (Log Relative Risk)

    Regular: 0.031 (−0.190 to 0.252)

    High: 0.773 (0.419 to 1.127)

    P < 0.001

    Previous SectionNext Section

    Regular Dose: Relative Risk (95% CI)

    In light of increased risk for adverse events with high-dose oseltamivir (used in 1 study), these subgroup analyses examine risk for adverse events only in the 6 regular-dose studies.

     
    Next Section

    Subgrouped by Risk (Log Relative Risk)

    Regular: 0.161 (−0.043 to 0.365)

    High: −0.020 (−0.092 to 0.053)

    P = 0.101

    Previous SectionNext Section

    Subgrouped by Setting (Log Relative Risk)

    Outpatient: 0.020 (−0.051 to 0.090)

    Nursing home: −0.139 (−0.412 to 0.133)

    P = 0.27

    Previous SectionNext Section

    Subgrouped by Vaccination Status (Log Relative Risk)

    <50% vaccinated: 0.260 (−0.022 to 0.543)

    >50% vaccinated: −0.015 (−0.085 to 0.055)

    P = 0.064

    Previous Section
     

    Subgrouped by Age (Log Relative Risk)

    <35 years: 0.161 (−0.043 to 0.365)

    >60 years: −0.020 (−0.092 to 0.053)

    P = 0.101

    Previous SectionNext Section

    Severe Adverse Events: Relative Risk (95% CI)

    Fixed: 0.919 (−0.284 to 0.777)

    Random: 0.919 (−0.284 to 0.777)

    Q = 0.998

    I2 = 0.00

    All studies reporting severe adverse events were in outpatient setting and used only regular dose.

     
    Next Section

    Subgrouped by NAI (Log Relative Risk)

    Oseltamivir: −1.112 (−4.304 to 2.081)

    Zanamivir: −0.049 (−0.645 to 0.547)

    P = 0.52

    Previous SectionNext Section

    Subgrouped by Risk (Log Relative Risk)

    Regular: −0.520 (−1.679 to 0.639)

    High: 0.085 (−0.671 to 0.501)

    P = 0.39

    Previous SectionNext Section

    Subgrouped by Vaccination Status (Log Relative Risk)

    <50% vaccinated: −0.476 (−2.568 to 1.161)

    >50% vaccinated: −0.052 (−0.662 to 0.559)

    P = 0.70

    Previous Section
     

    Subgrouped by Age (Log Relative Risk)

    <35 years: −0.520 (−1.679 to 0.639)

    >60 years: 0.085 (−0.671 to 0.501)

    P = 0.39

    Previous Section
     

    Sensitivity Analysis

     
    Next Section

    Cumulative Random-Effects Meta-analysis With 1 Study Removed

    Relative risk (95% CI) of NAI vs. placebo

    Symptomatic influenza: 0.257 (0.180 to 0.367)

    Asymptomatic influenza: 1.102 (0.737 to 1.389)

    Adverse events: 1.065 (0.961 to 1.180)

    Severe adverse events: 0.919 (0.511 to 1.651)

    Previous Section
     

    Publication Bias

    Begg and Mazumdar Test: Symptomatic Influenza

    Kendall S statistic (P-Q) = −15.00

    Kendall [tgr ] Without Continuity Correction

    [tgr ] = −1.00

    z-value for [tgr ] = 2.82

    P (1-tailed) = 0.002

    P (2-tailed) = 0.005

    Kendall [tgr ] With Continuity Correction

    [tgr ] = −9.33

    z-value for [tgr ] = 2.63

    P (1-tailed) = 0.004

    P (2-tailed) = 0.009

    Previous SectionNext Section

    Article and Author Information

    • Disclaimer: The views expressed are those of the authors and do not represent the policies of the Centers for Disease Control and Prevention. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality.

    • Acknowledgment: The authors thank Ms. Corinne Jeannet for her assistance with Japanese language translation.

    • Grant Support: By the Agency for Healthcare Research and Quality (1 F32 HS018003-01A1, Dr. Khazeni) and resources and the use of facilities at the Veterans Affairs Palo Alto Health Care System (Dr. Gould).

    • Potential Conflicts of Interest: None disclosed.

    • Requests for Single Reprints: Nayer Khazeni, MD, MS, Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, 300 Pasteur Drive, H3143, Stanford, CA 94305.

    • Current Author Addresses: Dr. Khazeni: Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, 300 Pasteur Drive, H3143, Stanford, CA 94305.

    • Dr. Bravata: Center for Primary Care and Outcomes Research, 117 Encina Commons, Stanford, CA 94305-6019.

    • Dr. Holty: Stanford Sleep Medicine Center, 450 Broadway Street, Pavilion C, 2nd Floor, Redwood City, CA 94063.

    • Dr. Uyeki: Epidemiology and Prevention Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Coordinating Center for Infectious Diseases, MS A-20, Centers for Disease Control and Prevention, 1600 Clifton Road Northeast, Atlanta, GA 30333.

    • Mr. Stave: Lane Medical Library and Knowledge Management Center, Stanford University Medical Center, 300 Pasteur Drive, RM L109, Stanford, CA 94305-5123.

    • Dr. Gould: Veterans Affairs Palo Alto Health Care System (111P), 3801 Miranda Avenue, Palo Alto, CA 94304.

    • Author Contributions: Conception and design: N. Khazeni, D.M. Bravata.

    • Analysis and interpretation of the data: N. Khazeni, D.M. Bravata, J.E.C. Holty, T.M. Uyeki, M.K. Gould.

    • Drafting of the article: N. Khazeni, D.M. Bravata.

    • Critical revision of the article for important intellectual content: N. Khazeni, D.M. Bravata.

    • Final approval of the article: N. Khazeni, D.M. Bravata, J.E.C. Holty, T.M. Uyeki, M.K. Gould.

    • Provision of study materials or patients: N. Khazeni, D.M. Bravata.

    • Statistical expertise: N. Khazeni, D.M. Bravata, M.K. Gould.

    • Obtaining of funding: N. Khazeni.

    • Administrative, technical, or logistic support: N. Khazeni, T.M. Uyeki.

    • Collection and assembly of data: N. Khazeni, J.E.C. Holty, C.D. Stave.

    Previous Section
     

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