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Medication, Masks, and Clean Hands Effective Against Flu
 
 
  MedPage Today
August 06, 2009
 
Handwashing, wearing a facemask, and using prophylactic medications are all effective prevention measures against pandemic and seasonal flu viruses, two new studies showed.
 
Action Points
 
* Explain to interested patients that, if implemented quickly, handwashing and wearing facemasks have been shown to be effective at preventing the spread of flu in homes.
 
* Note that both zanamivir (Relenza) and oseltamivir (Tamiflu) were found to prevent symptomatic, but not asymptomatic, flu.
 
In 154 households, handwashing and wearing face masks seemed to slow the spread of flu, but only when the measures were implemented within 36 hours of the first signs of flu symptoms in a member of the household (adjusted odds ratio 0.33, 95% CI 0.13 to 0.87), according to one of two flu-related papers published online Aug. 3 by the Annals of Internal Medicine.
 
"During a pandemic, resources may not be available to isolate all infected individuals, and home isolation of some patients may be required," Benjamin J. Cowling, BSc, PhD, of the University of Hong Kong, and colleagues wrote.
 
"Our results directly inform the personal protective measures that should be taken in such a scenario. Our results also support the use of these nonpharmaceutical interventions in public health control measures against interpandemic influenza in annual epidemics."
 
The researchers investigated the spread of influenza from 407 people who were diagnosed with influenza A or B at Hong Kong clinics.
 
The infected participants and their household contacts were randomly assigned to one of three study groups: control (lifestyle measures), control plus enhanced hand hygiene, and control plus both facemasks and enhanced hand hygiene.
 
The median number of occupants per household was four and the median size of the home was 700 square feet.
 
All households were educated about a healthy diet and lifestyle.
 
The handwashing households were instructed to use liquid soap provided by the researchers after every washroom visit, after sneezing and coughing, and when their hands were dirty. They were also instructed to use an alcohol hand wipe when first returning home and after touching any potentially contaminated surfaces.
 
Households assigned to the facemask group were given the same instructions as those in the handwashing group, but were also asked to wear masks as often as possible during the seven-day follow-up period, except when eating or sleeping and when the infected person was with them outside of the home.
 
Of 794 people who lived with the infected participants, 60 (8%) had confirmed influenza infection within seven days of the study intervention. Infection was confirmed with reverse transcription polymerase chain reaction (RT-PCR) or clinical diagnosis.
 
Enhanced hand hygiene -- with and without facemasks -- seemed to reduce influenza transmission, but the differences compared with the control group were not statistically significant, the researchers said.
 
However, when both handwashing and masks were implemented within 36 hours of symptom onset in the index patient, infection seemed to be reduced (adjusted odds ratio 0.33, 95% CI, 0.13 to 0.87).
 
The authors noted that delays between the time the first household member showed flu symptoms and the implementation of the facemasks and hand hygiene measures and uneven adherence to the measures among the study participants may have hindered the effectiveness of the interventions.
 
Other limitations of the study included recruitment of some households with an additional symptomatic case, which might have then included some contacts with preexisting immunity, reliance on RT-PCR, which might have missed secondary cases after three days, multiple protocol violations, and absence of full follow-up data in a number of households.
 
The other flu-related paper concluded that the neuraminidase inhibitors zanamivir (Relenza) and oseltamivir (Tamiflu) were highly effective at preventing symptomatic influenza in healthy adults when taken for extended periods (28 to 42 days).
 
With concerns growing over the ongoing H1N1 flu pandemic, the drugs could play an important role, said Nayer Khazeni, MD, of Stanford University, and colleagues, particularly since researchers may struggle to produce vaccines effective against evolving viruses.
 
However, during 2007 and 2008 some circulating strains of H1N1 also evolved resistance to oseltamivir, raising questions about the drug's effectiveness. There have also been reports of oseltamivir inducing neuropyschiatric effects, including Japanese adolescents harming themselves after taking the medication.
 
To better characterize the effectiveness of the class and the safety of oseltamivir, the researchers did a systematic review of seven randomized, placebo-controlled, double-blind clinical trials that, combined, enrolled 7,021 participants.
 
The mean age of participants ranged from 28.8 to 81.2 years (median 34.7 years) and none of the studies had participants under age 12.
 
They found that taking a neuraminidase inhibitor for four weeks or longer decreased the frequency of symptomatic influenza by 26% (95% confidence interval 0.18 to 0.37), but did not lower the rate of asymptomatic influenza virus infection.
 
Overall, participants who took the drugs did not experience an increase in adverse effects, but nausea and vomiting were 48% more common among those who took oseltamivir (95% CI 1.86 to 2.33).
 
The study found no statistically significant difference between zanamivir and oseltamivir in preventing flu. None of the studies reviewed directly compared the two drugs.
 
"Extended duration zanamivir and oseltamivir appear to be highly efficacious for preventing symptomatic influenza among immunocompetent Caucasian and Japanese adults," the investigators said.
 
In noting the limitations of their study, they pointed out that all of the trials they reviewed were industry-sponsored. Also, none of the studies were designed to detect rare adverse events, and none included diverse racial groups, children, immunocompromised patients, or individuals who received live-attenuated influenza vaccine.
 
In addition, some of the studies included patients who had received seasonal flu vaccine in addition to neuraminidase inhibitors.
 
The study on hand hygiene and facemasks was funded by the Centers for Disease Control and Prevention, the Government of Hong Kong, and the Area of Excellence Scheme of the Hong Kong University Grants Committee.
 
The authors reported no financial conflicts of interest.
 
The study on neuraminidase inhibitors was supported by the Agency for Healthcare Research and Quality and the VA Palo Alto Health Care System.
 
The authors reported no financial conflicts of interest.
 
Primary source: Annals of Internal Medicine
Source reference:
Khazeni N, et al "Safety and efficacy of extended-duration antiviral chemoprophylaxis for pandemic and seasonal Influenza" Ann Intern Med 2009.
 
Additional source: Annals of Internal Medicine
Source reference:
Cowling B, et al "Facemasks and hand hygiene to prevent influenza transmission in households" Ann Intern Med 2009.
 

Safety and Efficacy of Extended-Duration Antiviral Chemoprophylaxis Against Pandemic and Seasonal Influenza
 
Nayer Khazeni, MD, MS; Dena M. Bravata, MD, MS; Jon-Erik C. Holty, MD, MS; Timothy M. Uyeki, MD, MPH, MPP;Christopher D. Stave, MLS; and Michael K. Gould, MD, MS
 
Annals of Internal Medicine 6 October 2009 | Volume 151 Issue 7
 
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-blinded human trials of extended-duration NAI chemoprophylaxis thatreported 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. NAI chemoprophylaxis 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 diverseracial groups, children, immunocompromised patients, or individuals who received live attenuated influenza virus vaccine.
 
Conclusion: Extended-duration zanamivir and oseltamivir chemoprophylaxis appears 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.
 
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), decreasedimmunogenicity 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 the adamantane class of antiviral agents (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, during 2007-2008, oseltamivir resistance emerged among circulating influenza A (H1N1) virus strains (21, 22) and became highly prevalent worldwide in 2008-2009 (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 treatment of 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).
 
Discussion
 
We performed a systematic review and quantitative analysis of all published randomized, controlled trials of NAI chemoprophylaxislasting longer than 4 weeks to determine the safety and efficacy to prevent seasonal influenza. In addition, in light of increasingoseltamivir resistance, we examined the relative efficacy of zanamivir as compared with oseltamivir. We found that surprisingly few studies had addressed these questions and that no study had been conducted among children younger than 12 years of age. Among adults, extended-duration NAI chemoprophylaxis was efficacious in preventing symptomatic but not asymptomatic influenza virusinfection, 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 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, 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 Food and Drug Administration only for chemoprophylaxis against influenza in children age 5 years and older (44); and is not practical for some elderly individuals, who may have difficulty operating the zanamivir disk inhaler (62, 63). If zanamivir becomes the only antiviral option, these limitations would leave significant 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 in advance. Indeed, sporadic oseltamivir resistance was not noted in the currently 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 randomized, controlled trials have examined the safety and efficacy of extended-durationNAI chemoprophylaxis among children younger than 12 years of age 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 age 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).
 
None of the studies 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 NAIprophylaxis during a pandemic. We encourage the use of randomized, controlled trials to examine the safety and efficacy of NAIs administered 2 weeks after LAIV.
 
Our study was limited by the small 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, 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 do 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 these. Our analysis cannot guide recommendations for extended-duration NAI chemoprophylaxis of individuals vaccinated with LAIV, immunocompromised individuals, or children younger than 12 years of age, 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 age 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 even 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 notexpected 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 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 newantiviral 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 upon 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 upon 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 thatcan be delivered safely and effectively to young children, patients with obstructive lung diseases, and elderly individuals. With these cautions, zanamivir can currently be used in immunocompetent adults without obstructive lung disease to decrease the risk for symptomatic influenza illness when there is a need for extended-duration chemoprophylaxis against seasonal influenza, and it can be stockpiled to distribute to these same individuals for chemoprophylaxis against pandemic influenza.
 
 
 
 
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