2014 – 2015 Influenza Activity and Antiviral Recommendations

Coordinator:
Welcome and thank you for standing by. At this time all participants are in a listen-only mode. After the presentation, we will conduct a question and answer session. If you would like to ask a question you may press star 1. Today’s conference is being recorded. If you have any objections you may disconnect at this time. Your host of today’s call is Loretta Jackson Brown, thank you, you may begin.

Loretta Jackson Brown:
Thank you (Trish). Good afternoon, I’m Loretta Jackson Brown and I’m representing the Clinician Outreach and Communication Activity, COCA, with the Division of Strategic National Stockpile at the Centers for Disease Control and Prevention.

I am delighted to welcome you to today’s COCA Call, 2014 - 2015 Influenza Activity and Antiviral Recommendations. At the conclusion of today’s session, the participant will be able to describe the current status of influenza activity in the United States, discuss the timing of antiviral treatment and implications for patient evaluations, treatment and testing and state the latest antiviral recommendations for treating patients, especially older patients with influenza.

In compliance with continuing education requirements all planners, presenters and their spouses or partners must disclose any financial or other association with the manufacturers or commercial products, suppliers of commercial services or commercial supporters as well as any use of an unlabeled product or product under investigational use.

CDC, our planners and presenters and their spouses or partners wish to disclose they have no financial interest or other relationships with the manufacturers of commercial products, suppliers of commercial services or commercial supporters.

Planners have reviewed content to ensure there is no bias. This presentation will not include any discussion of the unlabeled use of a product or a product under investigational use with the exception of discussion of the off-label use of neuraminidase inhibitor medications for hospitalized patients, timing of treatment, and for ages not FDA approved, and the investigational use of intravenous zanamivir in hospitalized patients.

Continuing education is available for today’s COCA Webinar. Information on how to obtain continuing education will be provided at the end of today’s session. We’re having a lag in slides so please stand by.

Today’s presenter is Dr. Angela Campbell. Dr. Campbell is a medical officer in the Influenza Division in the National Center for Immunization and Respiratory Diseases at CDC.

Dr. Campbell is board certified in pediatric and pediatric infectious diseases. A former CDC Epidemic Intelligence Service officer, Dr. Campbell spent several years in academic medicine at the University of Washington in Seattle Children’s Hospital before rejoining CDC in 2013.

Dr. Campbell’s current primary research focuses on studies of influenza antiviral treatment and antiviral effectiveness, and she is responsible for developing and revising the CDC clinical guidance related to treatment and prevention of seasonal and novel influenza viruses.

She is an adjunct assistant professor of pediatrics at Emory University School of Medicine and has an active professional staff appointment at Children’s Healthcare of Atlanta. At this time, please help me welcome Dr. Campbell.

Dr. Angela Campbell:
Thank you so much and good afternoon, and good morning if you are on the West Coast. It’s truly a privilege to have this time to talk with you all today.

As Loretta stated, during this talk I will provide an update of influenza activity in the 2014-15 influenza season and especially review and discuss some of the evidence base that supports our antiviral recommendations for appropriate use of neuraminidase inhibitor (or NAI) antiviral medications for treatment of flu.

I will first review data regarding the current season from CDC’s national surveillance systems. So all the data I’m about to show you can be found on CDC’s Flu Activity and Surveillance website.

Information on influenza activity is collected, compiled and analyzed year-round and produces this weekly surveillance report called FluView. This report is updated every Friday. So the information I’m going to show you is updated through week 53, which ended on January 3, 2015. So beginning with virologic surveillance, approximately 140 U.S. WHO Collaborating Labs and National Respiratory and Enteric Viral Surveillance System labs, report the number of specimens tested and the number positive each week to CDC.

This is the most updated information for week 53: 25% of specimens were positive for flu, 96% of those were influenza A, with the influenza A(H3N2) viruses accounting for more than 99% of all subtyped influenza A viruses reported.

Furthermore, as you likely heard this season, of the 288 viruses tested, 68% of these were genetically or antigenically different from the H3N2 vaccine virus. Most of them were similar to the Switzerland H3N2 virus selected for the 2015 Southern Hemisphere vaccine.

Weekly information on patient visits to approximately 1,800 outpatient healthcare providers for influenza-like illness (or ILI) is collected through ILINet. This slide shows the percentage of ILI visits for 2014-15 and selected previous seasons. For the week ending January 3, the proportion of people seeing their healthcare provider for ILI decreased slightly from 6% to 5.6% but remains above the national baseline for the seventh consecutive week. ;Activity is beginning to decline in many parts of the country and increasing in others. It’s too soon to tell whether influenza activity has peaked yet this season.

This map shows ILI activity. During week 53, high or moderate ILI activity was in 34 states, Puerto Rico and New York City; 15 states experienced low or minimal activity.

Another map that helps us follow flu nationally is comprised of data from state health departments that report the estimated level of geographic spread of flu activity in their states each week through the State and Territorial Epidemiologist Reports. Widespread means that more than half the regions in a state are reporting flu activity. During week 53, 46 states and Guam reported widespread activity. Regional or local activity was reported in four states, Washington DC, Puerto Rico and the U.S. Virgin Islands.

The Influenza Hospitalization Surveillance Network, or FluSurv-NET, conducts population-based surveillance for lab-confirmed influenza-related hospitalizations in children and adults in 13 states. For week 53, the highest rate of hospitalization was among adults age 65 years or more at 91.6 per 100,000 population, up from 51.8 in week 52. The next highest rates are followed by children ages zero to four, which was 22 per 100,000.

I’m trying to advance the slide here. There we go, so this figure shows the hospitalization rates for people 65 and older by season. As I mentioned for week 53, the hospitalization rate for people 65 and older was about 92 per 100,000. That’s this blue line here and it’s high but typical of H3N2 seasons, which are more severe for older people and young children. The last H3N2 season that we saw in 2012-13 had a cumulative hospitalization rate for people 65 and older at the end of the season of 181 per 100,000. It would not be surprising for us to see something similar happen this season.

This figure shows the hospitalization rate for children under 5 by season. So for the rate for children, that’s fairly close to the rate seen in 2012-13 and last year’s rate.

This slide shows pneumonia and influenza mortality. These data are reported weekly from Vital Statistics offices of 122 U.S. cities. During week 53, 7% of all deaths reported through the 122 cities reporting system were due to pneumonia and influenza. This percentage was above the epidemic threshold of 6.9% for week 53. Five influenza-associated pediatric deaths were reported to CDC during week 53. ;All five deaths were associated with an influenza A virus for which no subtyping was performed. A total of 26 influenza-associated pediatric deaths have been reported during this season from New York City and 13 states. Of those 26 cases reported, 22 had known vaccination status and only one was fully vaccinated.

This shows underlying conditions of flu hospitalization. I wanted to point out that 59% of hospitalized children and 94% of hospitalized adults had at least one reported underlying medical condition. ;Of course you could flip that and say for children, 40% were previously healthy that were hospitalized. For children the most commonly reported underlying medical conditions were asthma, obesity, and immune suppression. For adults, the most commonly reported were metabolic disorders, cardiovascular disease and obesity.

So in brief, influenza A(H3N2) viruses continue to be the most common so far in the United States, and H3N2 predominant years are often associated with higher mortality and hospitalization rates among older adults and young children. Activity so far this season is similar to the 2012-2013 season, the last season when H3N2 viruses predominated. And so far, about 2/3 of H3 viruses analyzed are antigenically or genetically different from the H3N2 component in the 2014-15 vaccine.

We know also from data from this current season and previous influenza seasons that antiviral drugs are severely underutilized for treatment of influenza.

CDC has done some limited qualitative research into clinician knowledge, attitudes and practices related to antiviral drugs and the findings suggest that there are probably a number of factors involved. These include low clinician awareness of CDC’s recommendations, a wide range in perception about how well these drugs work, and that some clinicians may require a positive flu test before they prescribe. But the results of rapid influenza diagnostic tests, if ordered, may not be accurate. And lastly, some physicians may not prescribe antivirals after the two-day window during which benefit is optimal for treatment.

So these are all areas where we’re working to improve clinician awareness this year. This slide shows the proportion of outpatients with acute respiratory illness who were treated with antivirals or antibiotics during the 2012-13 influenza season. These are grouped by all patients, high-risk patients and high-risk patients with two days or less since symptom onset. The yellow represents antiviral prescriptions and green, antibiotics. So this study showed that less than 1/5, 19%, of patients who were at high risk for flu complications and presented for care within two days of symptom onset, which is the period of time when treatment is most beneficial, received a prescription for antivirals.

Now the study also showed that a positive flu test did increase this proportion treated with antivirals but this study clearly demonstrates that clinicians are still more likely to prescribe antibiotics rather than antiviral medication to outpatients with acute respiratory illness in the flu season including to high-risk patients who would benefit most from early empiric antiviral treatment.

Okay, I’m trying to advance the slide. So let’s move on now to our response to the 2014-15 influenza season. In December, CDC issued a health advisory to make clinicians aware that about half of the influenza A(H3N2) viruses at that time were drifted from the vaccine virus.

The recommendations in this message were two-fold. One, that vaccination should still be the most important first step in protecting against flu because even a vaccine with low vaccine effectiveness can prevent some infection, and provide protection against other viruses such as H1N1 or influenza B that may circulate later this season. This season the use of neuraminidase inhibitor antiviral medications is especially important when indicated for treatment and prevention of flu, and that was the second message of the HAN in December.

On January 9, a health update was issued that was intended to provide straight-forward direct messages about the use of antivirals. This update included two main reminders for clinicians. One, that influenza should be high on the list of possible diagnoses for ill patients. And two, all hospitalized and all high-risk patients with suspected or confirmed flu should be treated as soon as possible without waiting for confirmatory testing.

So I’m going to briefly remind you of the main CDC antiviral treatment recommendations on this and the next slide and then I’ll go into the data behind these recommendations.

Our recommendations are really intended to focus on those patients who are most severely ill and on people at high risk of severe complications. Thus, we recommend that all patients in the following category with suspected or confirmed flu should be treated as soon as possible without waiting for confirmatory influenza testing. This includes hospitalized patients, patients with severe, complicated, or progressive illness, and patients at high risk for complications from flu, either outpatient or hospitalized high-risk patients.

For patients not in those categories, antiviral treatment may be prescribed on the basis of clinical judgment for any previously healthy non-high risk outpatient with suspected or confirmed flu.

So let’s move on to look at the data that provides the foundation for these recommendations. In a quick summary, clinical trials and observational data show that early antiviral treatment can shorten the duration of fever and illness symptoms, reduce the risk of complications such as otitis media in children and pneumonia requiring antibiotics in adults, and can reduce the risk of death among hospitalized patients.

I’m going to begin by providing an overview of the most recent Cochrane review published in 2014. The review included an analysis of treatment and prophylaxis, but in order to focus on details, I will discuss the treatment analysis today. An important point to note regarding the Cochrane meta-analysis is that the authors analyzed treatment randomized controlled trials, referred to as RCTs, evaluating outcomes inthe intention-to-treat population, or ITT, which means people with and without flu were included. For this treatment analysis, the authors included 15 oral oseltamivir and 16 inhaled zanamivir trials. Most of these trials were conducted among otherwise healthy persons with influenza-like illness during seasonal epidemics.

The following bullets very briefly summarize the results of the meta-analysis. So neuraminidase inhibitors reduced time to symptom alleviation. Oseltamivir versus placebo reduced symptoms by about 17 hours in adults and 29 hours in children. Zanamivir versus placebo in adults by about 14 hours and had no significant effect in children. Neuraminidase inhibitors were also found to reduce investigator-mediated unverified pneumonia by 45%. But there were no benefits found in studies that recorded pneumonia in more detail including those studies that required chest x-ray verification of pneumonia.

They also found no evidence to support that treatment reduced other flu-related complications: ;sinusitis, bronchitis, otitis media or hospitalizations. And the main adverse events included a 4 to 5% increase in nausea and vomiting over placebo in adults and a 5% increase in vomiting in children.

So how should one interpret these findings? In general, their findings for effects of treatment on uncomplicated flu in otherwise healthy persons were similar to findings in previously published RCTs. It should be noted that the Cochrane review analyzed only intention-to-treat results because neuraminidase inhibitors are active only against influenza. One analysis that should have been evaluated would have been to look at outcomes in the intention-to-treat-infected, or ITTI, patients but they did not do this.

We would have expected that the ITT results would be diluted because it does include non-flu patients. In addition, and as I have said, these placebo controlled randomized trials evaluated effect of treatment in healthy non-high risk outpatients. ;These trials were not designed or powered to assess severe outcomes such as hospitalization, ICU or death or outcomes in high-risk persons. And in fact, persons at high risk of influenza complications are generally not studied in randomized controlled trials.

And finally, there are no published randomized controlled trials evaluating effects of treatment in hospitalized patients. And because treatment is recommended for these high-risk groups, RCTs are not going to be available because having the placebo group would not be considered ethical at this point. ;So in general while the overall results of the Cochrane review were consistent with reported RCT results, the conclusions of the report were extended to patients not included in RCTs hospitalized and high-risk patients.

So this screen shot and Weblink at the bottom provide many of these points in a response post that was published by CDC last year.

So onto CDC guidelines… As I said earlier our focus is on prevention of severe outcomes. So treatment of those with severe disease and persons at highest risk of severe disease. No randomized controlled trials are available. For that reason we include observational studies and meta-analyses of antiviral effectiveness when providing recommendations on antiviral treatment. The Cochrane review did not consider data from observational studies.

I also want to note that the CDC antiviral recommendations are common to ACIP, IDSA, AAP and in fact to those recommendations of the UK and Canada, in that they all advocate for early neuraminidase inhibitor treatment for individuals at high risk for severe disease and in hospitalized patients with influenza.

Okay so let’s move on and look at some of the data. So this slide shows some of the more robust studies evaluating oseltamivir effectiveness in hospitalized patients. These studies all made some attempt to control for biases that can inherently affect observational studies. The main points to glean from this slide: Most of these studies were in adults and this one in particular was in children. The top three studies were in hospitalized patients and these two in critically ill patients in the intensive care unit. And all of these studies evaluated oseltamivir effectiveness with death as the outcome.

So this first one showed an 80% reduction, the Lee study had a 70% reduction, and even when treated up to four days from symptoms onset there was significant reduction in death. ;The Hiba study compared late versus early treatment and saw increased odds of this composite severe outcome store - score, sorry- in the composite severe complications outcome that combines death, ICU and mechanical ventilation. There was increased odds of poor outcomes with late treatment compared to early. This Louie study in ICU patients with 2009 H1N1 showed increased survival with early treatment but showed that even up to four days there was statistically increased survival compared with those who received no treatment. So early treatment 88% survival, but up to four days still saw 73% survival compared to 58% with no treatment. And then this study in children in the ICU showed over a 60% reduction in death in the treatment group.

I’m just going to look at this 2012 Louie study in a little more detail on the next slide going into the data on timing of treatment. So this shows survival comparison of patients with and without antiviral treatment in the first two bars, showing 75% survival in the all treated group, 58% in the never treated group. And then these bars each show survival by timing of treatment for every day after symptom onset with day zero here as the day of onset. So up until day five – this little “b” is actually a footnote that notes that the proportion of patients who survived were significantly higher than the never treated reference group – ranging from 88 to 89% on day zero and one to 71% survival on day five.

Another large recent meta-analysis adds to the data for effectiveness in hospitalized patients. Published last year this study compiled individual patient-level data from 78 observational studies on more than 29,000 patients hospitalized during the 2009-10 H1N1 pandemic. In adults treatment with the neuraminidase inhibitor was associated with a 25% reduction in likelihood of death compared to no antiviral treatment. In pregnant women the risk of death was nearly cut in half. ;In children mortality was reduced but not significantly so. And when treatment was given within 48 hours of symptom onset, the risk of death was halved compared to no antiviral treatment.

They had data on timing of symptom onset in about 63% of the patients overall so that’s what this last bullet was based on. So just to summarize the observational data for oseltamivir effectiveness among hospitalized patients show a consistent reduction in mortality among adults and a more inconsistent effect among children.

And I won’t go into detail on this but I will point out that these data in children are the hardest to get. In the studies the fewest number of subjects are in the youngest age group. Kids tend to have fewer severe outcomes so fewer studies - so few studies have been published and there may be some methodologic differences that explain some of the inconsistency between studies.

And there are other trials and other data, which I’m not showing today because of time that have suggested a possible reduction in length of stay among children in the ICU, and reduction in mechanical ventilation as well as reduction in influenza viral load with treatment in hospitalized patients. ;So for all of these reasons we interpret these data to say that neuraminidase inhibitors may have a significant impact on severe illness and they are the only flu-specific treatment option we have, and so we do recommend that they be given to all hospitalized patients with suspected influenza.

So now moving on to an evaluation of the literature regarding the effectiveness of antivirals to prevent complications among outpatients. Here is where there have been some studies specifically in kids, which have found a reduction in otitis media, 44% overall in this study and 85% in this one when initiated within 12 hours. The number of complications including hospitalizations and development of pneumonia in children is relatively small compared with adults. So pediatric-specific studies on this are scarce.

This slide compiles recent and large publications that have evaluated effectiveness of neuraminidase inhibitors to prevent complications. So these are all meta-analyses or pooled analyses of randomized controlled trials and one of observational studies. The first two, Hernan and Lipsitch, looked at lower respiratory tract complications requiring antibiotics as the outcome. The first paper included patients with flu confirmed by viral culture or serology, and then this 2013 paper was a reanalysis that excluded the serology-positive patients. ;They both show a reduction in - a significant reduction, 37 and 33% in lower respiratory tract complications with treatment. The Hsu paper showed a 25% reduction in hospitalization and, when antivirals were given within 48 hours of symptom onset, this was 50% – almost a 50% reduction.

The Ebell meta-analysis did not find a significant benefit when looking at the intention-to-treat population, so flu and not flu. But in the intention-to-treat-infected group there was a decrease in the rate of pneumonia and in a composite complications outcome of otitis, sinusitis, pneumonia and bronchitis. ;And as I mentioned before the Cochrane review did find a significant reduction, 45% in investigator-mediated unverified pneumonia but not in chest x-ray confirmed.

So this slide shows - summarizes the data that evaluate reduction and complications after outpatient treatment. In general hospitalization is a difficult outcome to evaluate because it is relatively rare. ;And so many of the studies focus on pneumonia for which there are many different definitions in various studies. And again persons at highest risk of developing severe complications are generally not studied in the randomized controlled trials. ;But overall the pooled data from RCTs consistently show a reduction in pneumonia requiring antibiotics among adults, reduction in otitis media for children.

And I just want to mention that there is another large meta-analysis pending. This will be an individual patient data meta-analysis of randomized controlled trials – so not just a review of the RCTs but an analysis of the individual patient database comparing oseltamivir with placebo for treatment of outpatients with influenza in order to rigorously evaluate the effect on complications.

So because there are data that consistently show a reduction in complications such as otitis media and especially lower tract illness, we do recommend neuraminidase inhibitors for those outpatients who are at the highest risk for severe disease.

And the last slide before we go back to the recommendations with a word on adverse events. So the main adverse events for oral oseltamivir and as noted in the Cochrane review are slightly increased risk of nausea and vomiting over placebo. ;These have generally been noted in trials to be mild and transient, and to be improved when taken with food. Inhaled zanamivir did not really have many adverse events increased over placebo, but there have been cases of bronchospasm reported during postmarketing. ;And it’s not recommended for persons with underlying airways disease such as asthma or chronic obstructive pulmonary disease. And intravenous peramivir does have about 1% increased risk of diarrhea compared with placebo, and has shown about a 2% increased risk of neutropenia over placebo.

So just to remind you again the groups that we do recommend should be treated: ;these are the hospitalized patients, patients with severe, complicated or progressive illness and patients at high risk for complications either outpatient or hospitalized. And those that may be treated are those non-high risk outpatients with suspected or confirmed influenza.

When we say high risk this is just a reminder of those persons who are more likely to get flu complications that result in severe outcomes. ;It includes children less than two years. We do know all children younger than five are considered at higher risk for complications, but the highest risk data have been shown for those less than two. ;Adults 65 years or older, pregnant and postpartum women, American Indians and Alaska Natives, persons who are morbidly obese, residents of long-term care facilities, people with immunosuppression, people younger than 19 who are receiving long-term aspirin therapy and persons with underlying medical conditions, which may be chronic pulmonary, cardiovascular, renal, hepatic, hematologic, metabolic or neurologic or neurodevelopment conditions.

So with respect to timing of treatment – when indicated, antiviral treatment should be started as soon as possible after illness onset. Ideally, it should be initiated within 48 hours of symptom onset but these studies have shown that the earlier the better: 12 hours is better than 24, is better than 48.

And treatment should not be delayed to wait for the results of influenza testing. I also just want to note that a negative rapid influenza antigen diagnostic test does not exclude a diagnosis of influenza. ;These have anywhere from about a 50 to 70% sensitivity and false negatives are common. So for high risk outpatients it may be useful to have a treatment plan in place.

For example, during flu season providers should advise high-risk patients to call promptly if they have symptoms of influenza. Phone triage lines may be useful to enable high-risk patients to discuss symptoms over the phone. ;And to facilitate early initiation of treatment, an antiviral prescription could be provided, when feasible, without testing and maybe before an office visit.

Also in the most recent updates we wanted to remind clinicians that antiviral treatment initiated after 48 hours could still be beneficial in some patients. And I mentioned this when I went through the studies of hospitalized patients, that several observational studies have suggested that treatment might still be beneficial when it’s initiated four or five days after symptom onset. ;Another study of observational data in pregnant women has shown antiviral treatment to provide benefit when started three to four days after onset of symptoms.

And a randomized placebo controlled study suggested clinical benefit when oseltamivir was initiated 72 hours after illness onset. ;And this was a study among febrile children with uncomplicated influenza in Bangladesh. So it may be that it may be that we still have a lot to learn about outpatient treatment after 48 hours, but this study at least suggested there may be some benefit for patients with ongoing fever and potentially viral shedding.

So I did mention the antiviral medications available already but this slide just gives you a little more detail on the three neuraminidase inhibitor medications that are recommended for treatment. ;I should just mention that we aren’t recommending the adamantanes at all based on what we know about viral resistance to the adamantanes. So neuraminidase inhibitors are the ones that we would recommend.

These include oral oseltamivir, or Tamiflu, which is recommended for treatment of all ages. There have been questions about this. It is FDA approved for two weeks and older, but CDC and the American Academy of Pediatrics, we recommend treatment for all ages so even the infants. Chemoprophylaxis is approved and recommended for age - for children three months and older. ;Inhaled Zanamivir is recommended and approved for treatment in children seven years and older and chemoprophylaxis for five years and older.

And then intravenous peramivir or Rapivab was just approved on December 19. ;I’m sure you’ve heard about that and it was approved for treatment of acute uncomplicated influenza in persons age 18 or older, so an adult. It’s given as a 600 milligram dose infused over 15 to 30 minutes. ;I did look, there are data online providing cost information and the cost of these medications before insurance does very widely. A single 600 milligram dose of peramivir costs approximately $1,000, compared to approximately $130 for oseltamivir or $70 for inhaled zanamivir when each is given as a five-day treatment course. ;And I think we still have a lot to understand about how intravenous peramivir may be used best to treat uncomplicated flu. We have a lot to learn about that but it is good to have another available effective drug in our armamentarium.

So, for outpatient treatment any of these neuraminidase inhibitors may be used for treatment. ;And for oseltamivir or inhaled zanamivir as you know it’s twice daily treatment for five days, for peramivir it’s that one single dose on one day. ;And for pregnant women, oral oseltamivir is the preferred drug choice because we have the most data using that.

For hospitalized patients, treatment with oral or enterically administered oseltamivir is recommended. ;There are limited data to suggest that oseltamivir administered by oral or nasogastric tube is well absorbed in critically ill flu patients including those in the ICU, on CRRT, or on ECMO. ;Inhaled zanamivir is not recommended because of lack of data for use in patients with severe disease and we really have insufficient data regarding the efficacy of intravenous peramivir for hospitalized patients.

That said, if there is concern regarding oseltamivir absorption for patients who can’t tolerate it or absorb it because of suspected or known gastric stasis, malabsorption or GI bleeding, that would be a situation where the use of IV peramivir or investigational IV zanamivir should be considered.

If peramivir is used in severely ill patients, I want to make the point that a single dose as approved for outpatient uncomplicated flu should not be given. For severely ill patients we would recommend a full treatment course. And the second bullet, the dosing of 600 milligram IV once daily for five days, or for kids older than six, 10 mg/kg once daily up to 600 milligrams for five days. ;This dosing recommendation comes from this reference, which does refer to the randomized controlled trial in hospitalized patients that was performed using IV peramivir.

Also I don’t have a slide on it but it is in our website, consideration - it on our website as a consideration that many severely ill patients may require longer treatment, so please don’t look at the five days and think that that’s an absolute. ;I think that really the optimal duration is uncertain for severe critically ill patients with influenza, in particular longer treatment might be necessary in immunosuppressed patients who have prolonged viral replication, but just to make the point that a single dose would really I think not be - is not recommended.

And then for consideration of hospitalized patients where there’s some concern of resistance to oseltamivir. It is possible that some influenza viruses can become resistant to oseltamivir and peramivir during treatment with one of these agents and remain susceptible to zanamivir. And so if there is concern for oseltamivir resistance, in that instance we would recommend consideration for investigational use of intravenous zanamivir to be considered for treatment of those severely ill patients.

And then the most recent health update also had some additional information and considerations for clinicians. One was regarding antibiotics and bacterial infections, just to remind that antibiotics aren’t effective against flu and several reports, and I showed you one of them at the beginning of the talk, do suggest inappropriate use of antibiotics for patients with influenza. ;However bacterial infections can certainly occur as a complication of influenza either as a secondary complication or co-infection. And so that should be considered and appropriately treated if suspected.

In addition, because pneumococcal infections are a serious complication of influenza infection, there are new pneumococcal vaccine recommendations for adults 65 years of age or older and adults and children at increased risk for invasive pneumococcal disease due to chronic underlying medical conditions. And those should be followed, and the link to more information about those are provided.

Just one comment on institutional outbreaks. There have been many of those this year and again because we’re seeing disease in the older patients with H3N2. ;The use of antiviral chemoprophylaxis to control outbreaks among high risks persons in institutional settings is recommended, and that would be for all residents regardless of vaccination status as well as for all unvaccinated healthcare personnel. ;But the recommendations have a caveat that, you know, should be considered this year – that chemoprophylaxis should be considered for all healthcare personnel if the outbreak is caused by a virus that is not well matched to the vaccine such as the virus that we’re seeing.

And chemoprophylaxis should be given for a minimum of two weeks or continuing for at least seven days after the last known case in the outbreak is identified, so whichever is longer.

And then just a few slides on antiviral supply. We are aware this has been a concern this year. There are currently no national shortages and manufacturers have stated that they have sufficient product on hand to meet the projected high demand. ;We have been working closely with supply chain partners to monitor these local spot shortages that have been reported, specifically for Tamiflu formulations. ;It may be necessary to tell patients that they have to contact more than one pharmacy to fill a prescription for an antiviral medication, and pharmacies that are having difficulties getting orders filled should contact their distributor or the manufacturer directly.

One sort of piece of really new information is that CDC has established an Antiviral Call Center. So for long-term care facilities or institutions experiencing difficulty accessing antiviral supplies in outbreak settings, CDC will coordinate with commercial partners to facilitate the rapid resolution of large orders of antiviral drugs. ;So as of Monday, January 12, the Division of Strategic National Stockpile, or DSNS, at CDC is available from 7:00 am to 7:00 pm Monday through Friday to assist public health officials and healthcare facilities by coordinating with supply chain partners to rapidly redirect supply to the needed location. And DSNS can also be contacted by this email here to assist. If it’s outside of these hours they can be contacted through the emergency operations center following standard protocol to contact the EOC.

So in summary, early empiric antiviral treatment is recommended for suspected or confirmed influenza among the following: hospitalized patients, patients with severe or progressive illness, patients at high risk for complications.

Decisions about antiviral treatment shouldn’t wait for lab confirmation of flu. We’ve heard a number of anecdotes this year of patients being either not started on treatment or significantly delayed because of waiting for result turnaround. ;Even in hospitals that have molecular testing, which is great, it’s best not to wait for the result of that because it can still take sometimes a day or two to get that.

And lastly, clinical benefit is greatest when antiviral treatment is initiated early but treatment initiated later than 48 hours after onset can still be beneficial for some patients and should be considered.

So for more information there are a few links here that may be useful. The first is our updated summary of flu antiviral treatment recs for clinicians. The second is guidance on the use of molecular assays for diagnosis. This is information on outbreak management in long-term care facilities. And then the FDA Web site has multiple links that will get you to the package inserts for all of the neuraminidase inhibitors including peramivir.

And so I appreciate your time today. ;Thank you so much for calling in. Thank you for all of your efforts in taking care of the large numbers of patients that are severely ill this year. ;And I’m happy to take any questions.

Loretta Jackson Brown:
Thank you, Dr. Campbell, for providing our COCA audience with such a wealth of information. We will now move into the question and answer portion of today’s call.

And joining us for the Q&A session is Dr. Anita Patel, a pharmacist in CDC’s Division of Strategic National Stockpile. You may ask a question on the phone or by using the Webinar system. Operator, we are now ready to take questions.

Coordinator:
Thank you, at this time we will begin the question and answer session. To ask a question please press star 1 and record your first and last name. If you wish to withdraw your question please press star 2. One moment please for your first question.

Loretta Jackson Brown:
And while we’re waiting for this first question on the phone, we do have a question through the Webinar system. Dr. Campbell, is PCR nasopharyngeal swab if it’s negative can treatment still be withheld?

Dr. Angela Campbell:
So I assume it’s sort of asking withheld, or can treatment be stopped if it was started empirically. And I think, you know, there are certain considerations that can also contribute to a negative test such as sample quality, specimen quality from the time of collection to the time it’s collected in the lab. So I think in general if you have confidence in the specimen collection and confidence in the molecular assay that’s being used, treatment could be - it could be considered for treatment to be stopped or not given.

I do think that clinical judgment really has to weigh in on that because even PCR can be negative if the sample is not collected properly or, you know, it’s not 100% but it can be negative. And we have heard anecdotes this year of severely ill patients in the ICU that had negative molecular testing by the hospital’s commercial assay but positive in the state lab. And so if there’s question I think it’s always reasonable to pursue further testing at the public health lab, and certainly if you really are concerned about influenza diagnosis in that patient I think the benefits of starting and keeping them on influenza therapy with a neuraminidase inhibitor, I think those benefits outweigh the risk of starting it and risking treating someone who doesn’t have flu.; And so that would be my answer to that. I know that’s a little long but I think it’s not a simple yes and no and so I hope that’s helpful.

Loretta Jackson Brown:
Thank you. Operator, do we have any questions on the phone?

Coordinator:
Yes your first question comes from (Deb Najdowski), go ahead your line is open. (Deb) your line is open.

Loretta Jackson Brown:
Okay so while we’re waiting for another question on the phone I have received several questions asking for the PowerPoint slides. Currently the slides aren’t ready.

If you would you can check our COCA Webpage in the next several days and you can also email us at coca@cdc.gov, that’s C-O-C-A at CDC dot G-O-V and as soon as the slides are available we will send you the link for the slides.

Our Web page is emergency.cdc.gov/coca and you can look for the January 14 call and follow the links there. Operator, do we have another question?

Coordinator:
Yes, your next question comes from the last name is (Gaury) I was not able to catch the first name, go ahead your line is open.

(Gaury):
Yes, this year would you offer antivirals to healthcare workers who have unprotected exposure to patients with influenza?

Dr. Angela Campbell:
We haven’t been recommending that. You know, the institutional setting such as a long-term care facility or a nursing home where it’s a very closed facility is the one situation where we do recommend prophylaxis for both the residents and the healthcare workers in this situation.

We’ve been asked about chemoprophylaxis of entire VA hospitals, emergency departments, et cetera for the healthcare workers and both - really we don’t recommend that.either for pre-exposure, for people who are working that would need to take it through the entire season – that’s not something we recommend – or for post-exposure. ;At this point we don’t think that a broad approach to chemoprophylaxis like that is the best strategy.

(Gaury):
Thank you.

Dr. Angela Campbell:
You’re welcome, thanks.

Loretta Jackson Brown:
Operator do we have any more questions on the phone? Okay so while we’re waiting for questions on the phone, so Dr. Campbell we have several here through...

Dr. (Dana Sparhark):
Hello.

Loretta Jackson Brown:
Okay I’m sorry go ahead you have a question, state your name?

Dr. (Dana Sparhark):
Yes hi my name is Dr. (Dana Sparhawk) and this is to follow-up I think on that last question. So I mean you had this slide for institutional outbreaks, on vaccinated healthcare personnel you should consider vaccination or consider if an outbreak is caused by a virus that’s not well matched.

So in a regular healthcare setting in a hospital where there is flu exposure to the personnel are you recommending - from what you just said in the emergency room you’re not recommending that, so the same thing on the floors where you’ve got multiple people with flu.

Is that because your slide said institution outbreaks you would consider it so I’m just wondering what your recommendation is I’m getting confused.

Dr. Angela Campbell:
It’s true, that’s a good point, I think, and perhaps for the final version of the slides – I should say that we’re not planning to change the slides, they just have to make them compliant to be read by people with disabilities, which is why you need to wait a few days for them. But that slide is really intended for institutions such as long-term care facilities and nursing homes and I think I will add that so that it doesn’t get...

Dr. (Dana Sparhark):
Okay.

Dr. Angela Campbell:
...misconstrued because I - it’s directly from the section in our clinician guidance about those types of very closed facilities with a number of high-risk patients all mixing and intermingling with each other and with the staff where we think the risk in general is just much higher. And so thank you for pointing that out and I’ll make sure to clarify it on that slide.

Dr. (Dana Sparhark):
That makes a lot of sense and thank you very much.

Dr. Angela Campbell:
Thank you.

Loretta Jackson Brown:
Operator, okay it looks like we may have lost our Operator but we have plenty of questions through the Webinar system. So here is a question Dr. Campbell, when can isolation on hospitalized patients be discontinued?

Dr. Angela Campbell:
So there is a separate web link, which I didn’t include on the references but I can send to the COCA folks that does go through recommendations for infection control in healthcare settings for influenza.

And there is no simple answer to that but often it’s symptom based. So I don’t have - we have been asked a lot whether once patients finish their five days of treatment are they no longer infectious. And unfortunately there are a number of studies that show ongoing PCR shedding after treatment is finished and some that also suggest that there is still culture positivity after a five day course. And so it’s true that if you were to look at those secretions they may still be potentially infectious. Now that doesn’t necessarily mean that if a patient is no longer having symptoms that would spread illness that they would need to stay in isolation.

And so I really think that’s an individual hospital infection control policy issue that I can’t answer directly but I would - I will provide the link and give the information for that website but it doesn’t give any hard and fast answers either, it’s really based on symptomatic illness.

Loretta Jackson Brown:
Okay thank you and we have some requests for the contact information for DSNS, the Strategic National Stockpile. So I went ahead and put that slide back up and for those who are on the phone that is dsns-request@cdc.gov.

And I know that we have Dr. (Patel) with us as well. Dr. (Patel) do you want to make any comments on the contact in DSNS?

Dr. (Anita Patel):
Just that email is the best way of contact and it’s an immediate notifier to our team. So if you could go ahead and use that email address and if it is after hours and you did want to call you could call through the emergency operations center here at CDC at 770-488-7100, 770-488-7100.

Loretta Jackson Brown:
Wonderful thank you, Operator, are you back with us?

Coordinator:
Yes I was checking names. The first you have a next question comes from (Oli Salani), go ahead your line is open.

(Oli Salani):
Yes my question is about the swab for rapid testing. I think in your slide it says a negative swab does not mean that the patient is negative for influenza A. So if that’s the case what is the need for this rapid testing?

Dr. Angela Campbell:
Well, I think that different facilities use it differently and so I don’t have a specific answer for that. I think rapid testing needs to be interpreted with caution and that was the point I was trying to make with that. I know some hospitals don’t even allow rapid tests on their patients because they use molecular testing for hospitalized patients. In an ED that may be different.

We do know looking at studies of antiviral prescribing that having a test performed actually increases the likelihood of getting an antiviral prescription and having a positive test increases it dramatically from someone who is not tested. And so it does seem that providers are very influenced by the positive result of a test and, you know, I think that in itself is good because people are being treated – but we just know that these tests are notoriously not that sensitive and so don’t want people to rely on it.

(Oli Salani):
Okay, thank you.

Dr. Angela Campbell:
You’re welcome and I - while I was waiting for the second question I looked up the website about infection control in healthcare settings.

And if you go to the influenza webpage, which is cdc.gov/flu, there is a section for Health Professionals, and there is a section on Infection Control that does have “Prevention Strategies for Seasonal Flu in Healthcare Settings.” And that will discuss isolation and when to institute it and when to discharge, it – although it does make the point that patients should be discharged from droplet precautions when clinically appropriate, not based on the period of viral shedding or some, you know, empiric recommended duration.

But just to follow-up, that website is available, you can get to it through the professional section of our flu webpage.

Loretta Jackson Brown:
And Dr. Campbell, we link to that website as well from the COCA call page for today’s call. So if you’re familiar and you’ve been on that page already, just scroll down and look under additional materials and you will see a link to the page that Dr. Campbell is referencing. Operator, do we have another question from the phone?

Coordinator:
Yes your next question will come from Dr. (David Hutt). Go ahead your line is open.

Dr. (David Hut):
I wonder if you could clarify for us the use of intravenous peramivir. I think that you said daily for five days and is that correct? And that seems to me to be different from the way it was used when it was an investigational drug a couple of years ago.

Dr. Angela Campbell:
So I think that - thanks for the question about peramivir. I think the point I really wanted to have you take home from that slide is that although it’s approved for a single dose, we would have real concerns about using a single dose in a hospitalized severely ill patient because, you know, you could imagine they have much higher viral replication than an outpatient. And a single dose is going to wane over time and there’s I think potential concern for resistance with that. So at this point I would do - we are recommending a treatment course such that would be used for oseltamivir, with the idea that that may need to be extended.

My understanding - well in the clinical trial that the five days is what was used and when it was previously released under EUA, I think it was allowed to be used for five days and then extended again - is that correct? Is that what you’re getting at?

Dr. (David Hutt):
Yes, yes, and was also just unclear about the - what has been printed and I think circulated over the last couple of weeks at least what I saw referred to just a single dose as opposed to the multiple doses.

Dr. Angela Campbell:
Well right, because truly we’re really recommending it for the FDA-approved indication, which is uncomplicated flu.

Dr. (David Hut):
Right.

Dr. Angela Campbell:
But if you have a patient in the hospital that for all those reasons listed there’s concern for absorption of oseltamivir, we think it makes sense to consider IV peramivir in addition to investigational use of zanamivir because peramivir is an approved drug now.

And I guess to be clear, the randomized trial that looked at peramivir compared with oseltamivir in hospitalized patients was complex and it was peramivir plus standard of care versus placebo plus standard of care. And standard of care so often included oseltamivir, as you can imagine. And so the trial was closed for futility because it wasn’t showing superiority over oseltamivir. So that’s very complex because it didn’t necessarily not work but it was never going to reach the desired endpoint and I think we don’t really know.

And so we wouldn’t recommend it up front for a hospitalized patient but I think in the situations I outlined it should be considered – but if it would be used we just want that to be very carefully used and not a single dose that could lead to concerns of resistance.

So you’re right the health advisory and the circulated materials ;- those are very focused on sort of uncomplicated flu and the indication for which it’s approved.

Dr. (David Hutt):
Okay, thank you.

Coordinator:
Your next question comes from Mr. (Powell), go ahead your line is open.

Mr. (Powell):
Hi Angie and hello from Shiprock, New Mexico. My question goes back to the Cochrane 2014 review, which is oft quoted and I think nicely reviewed in your talk today so thanks for that.

Specifically in that review they draw conclusions about kids with asthma. I’m wondering if you have any further comments about that and whether those conclusions are valid or not.

Dr. Angela Campbell:
Hey Dr. (Powell), it’s great to hear from you. I - you’re right and it’s true that Cochrane didn’t find any significant benefit for children with asthma.
And I don’t - to be totally honest without looking at the asthma trials that they looked at - I don’t think I can tell you the methodological concerns that I might have. I will say when they chose the trials for the study, they eliminated many and the reasons weren’t quite clear for some of the decisions made to include which trials were included.

So I don’t know, I think that asthma is a condition that places kids at such high risk that for the reasons we - the reasons I tried to outline and for the benefits that we see overall for the mostly consistent benefit in lower tract infection in adults mostly, that we still think that it comes back to sort of the potential benefit that it might prevent that complication. I think outweighs the risk and a lot of times the nausea and vomiting is raised as a real concern, but it truly is only about 4 or 5% over placebo and can be mitigated considerably with food.

So I guess my short answer is that I still think that it - the potential benefit outweighs the risk and I can’t entirely explain what Cochrane reported but I also I don’t know the literature well enough to know which studies were included versus not without looking at it again.

Loretta Jackson Brown:
Hey and Dr. (Powell) be sure to stand by we are planning a COCA call that will address influenza in pediatrics and I will definitely add the discussion around that report to the subject matter experts who will be presenting. More information on that will be on our website soon so thank you for that comment.

Dr. Campbell, I have a Tamiflu question that is two parts. One of our participants wanted to know your thoughts on the new dosing changes based on renal function.

And then we have another participant who commented that providers are prescribing Tamiflu for patients once daily for those living with people who have confirmed flu, or have been exposed to someone with confirmed flu, and they want to know if this is a new directive.

So we got the renal portion and we have the new directive for prescribing flu for those who are exposed to others with it.

Dr. Angela Campbell:
Okay, and also as a followup to what you said, I think that’s great that there’s going to be a flu and children COCA and so we’ll be sure to focus on that asthma question.

So as far as the renal function I’m not sure what the question is except for that we did recently update our website to reflect the update and the FDA package insert for renal dosing.

And so that is on that Summary for Clinicians now as well, as there are considerations for renal dosing of peramivir also. So that table is now updated and I think previously there were studies here and there that suggested doses that could be used in patients with renal failure, but now compiling all the data it rose to the level that FDA was able to make that recommendation so we support that.

The second question was basically it sounds like it’s asking about a household chemoprophylaxis I think if I’m hearing it correctly. It sounds like if they’re giving once daily dosing to members of the household with a confirmed flu case that that’s chemoprophylaxis.

And we don’t actually recommend household chemoprophylaxis by and large. We do consider that some situations might be unique so if there’s someone with a high risk of flu complications that lives in the household such as someone with a severe immune deficiency or other extremely high risk that it might make sense to offer chemoprophylaxis to that person if they’ve been exposed to an infected person.

But in general household prophylaxis is not something that we are recommending.

Loretta Jackson Brown:
Thank you. Operator, we have time for one more question.

Coordinator:
And we do have one question, it’s from Mr. (Holly), go ahead your line is open.

Mr. (Holly):
Yes this actually goes back to influenza vaccination. For the past couple of months, I’ve heard from a number of healthcare providers - primarily nurses but I’m sure it applies as well to others - who have said that they didn’t get vaccinated initially, but now that the vaccine quote isn’t effective then they don’t see any reason to be vaccinated now.

And I was just wondering I keep advocating, you know, as long as flu is circulating that people should be vaccinated even though, you know, it does have limitations this year but I’m just wondering if you had a comment on that.

Dr. Angela Campbell:
So we would wholeheartedly support that. You know, we have learned that by this time in the season in mid-January about 90% of the people that are going to get vaccinated have been vaccinated.

And so not that we’re not advocating it anymore, but the main messaging for this month has been on the antivirals. However, I still think that you’re absolutely right that in particular as the season goes on we often see a second strain predominate and sometimes that’s influenza B, we never know, maybe H1N1 will have a little peak.

And so I think that the vaccine could still certainly be beneficial for those strains. And I - it’s a perfect segue for me to say that in the next few days we do anticipate releasing our first interim analysis of the seasonal vaccine effectiveness for this season so that should be out soon.

But I agree with you that there is still some benefit to be received by getting a vaccine now.

Mr. (Holly):
Thank you.

Loretta Jackson Brown:
So on behalf of COCA, I would like to thank everyone for joining us today with a special thank you to our presenter Dr. Campbell. We invite you to communicate to our presenter after the Webinar.

If you have additional questions for today’s presenters please email us at coca@cdc.gov, C-O-C-A at C-D-C dot G-O-V. Put January 14 COCA Call in the subject line of your email and we will ensure that your question is forwarded to the presenter for a response. Again that email address is C-O-C-A at C-D-C dot G-O-V. A recording of this call and the transcript will be posted to the COCA website at emergency.cdc.gov/coca within the next few days.

Free continuing education is available for this call. Those who participated in today’s COCA conference call and would like to receive continuing education you should complete the online evaluation by February 13, 2015 using course code WC2286.

If you will listen to this call on demand, you can complete the online evaluation between February 14, 2015 and December 13, 2015 using course code WD2286.

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To receive information on upcoming COCA calls prescribe to COCA by sending us an email at coca@cdc.gov and write prescribe in the subject line. Also CDC has a FaceBook page for health partners, like our page at https://www.facebook.com/CDCHealthPartnersOutreach to receive COCA updates. Thank you again for being a part of today’s COCA Webinar, have a great day.

Coordinator:
Thank you, this concludes today’s conference, participants you may disconnect at this time.

END