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CDC Announces Change in Recommendations for use of Antivirals; Clinicians Should Not Prescribe Two Common Antivirals

January 14, 2006

Dr. Gerberding I do thank you for being here. We have some very important news for clinicians and patients this year about treatment for seasonal influenza. Our CDC research scientists have tested 120 flu isolates this year—these are H3N2 isolates, the dominant strain of influenza causing disease in the United States—and 91 percent of these flu strains are resistant to amantadine and rimantadine, two of the important drugs that we have available to treat influenza. This is in contrast to the situation in the recent past, where very few isolates were resistant to these drugs. What this means is that clinicians should not use amantadine and rimantadine to prevent flu or to treat patients suspected of having influenza, because the drugs will not be effective.

The good news is that we have other drugs that are effective. These isolates, everything we’ve tested this year at the CDC is susceptible to Tamiflu and Relenza, two drugs from a different family, that remain very effective for certain patients. We have those drugs available and we’re getting the word out again to physicians that if they’re going to treat or prevent flu with drugs they should be using Tamiflu or Relenza, not amantadine or rimantadine.

We don’t know what accounts for the unexpected increase in resistance. One theory is that the virus strain circulating this year may have undergone a spontaneous mutation. This is not surprising. We know flu is unpredictable. We know flu viruses constantly evolve. So this could have happened. Another theory is that this is related to the use of these drugs in the over-the-counter setting in other parts of the world, where people can go into a store and buy drugs off the shelves and don’t necessarily require a physician prescription. This is certainly one of the factors that’s been associated with rapid appearance of drug resistance in a number of other categories of infectious diseases and could be playing a role here as well.

We don’t think this is going to affect a large number of patients, because not many patients typically are treated with amantadine or rimantadine, but there are some situations where these drugs are used, prophylaxis in nursing homes, for example, treatment in a clinical setting, so we are working very hard this weekend to make sure that clinicians around the country get this information. We sent out a health advisory to the public health community and also to the clinician organizations and groups around the country, and they will, in turn, send it to their members, and over the next 24 to 48 hours we hope that most people will be able to have this information. We’ll be using our Internet and a number of other tools to facilitate dissemination.

I do want to emphasize that we’re talking about seasonal flu here. This has nothing to do with avian flu. This has nothing to do with flu pandemics. We’re just talking about good old garden-variety seasonal influenza, which is challenging enough. What I can tell you about seasonal flu this year is that we’ve had a bit of an increase in the number of cases since the holidays and we’re showing widespread activity in at least seven states, primarily in the western and southwestern part of the United States. It’s too soon to say whether we’ve peaked or when we will peak, but we know that there are still people with influenza and prevention remains a very high priority for people around our country. Vaccine is available. Sanofi Pasteur has vaccine for sale and vendors have vaccine available for distribution. The CDC also has 3.5 million doses of vaccine in our stockpile and we are making them available. So if people need to be vaccinated, clinicians can contact health officials and we will do what we can to help make sure that the supply is made available to them as quickly as we can.

Where do we go from here? In terms of drug resistance and treatment of influenza, the CDC will continue its comprehensive monitoring program. So as isolates come in from around the country we will continue to test them. If we discover any new items of interest in terms of resistance or new strains of flu emerging, of course we will be reporting that out. But we do anticipate that for the foreseeable future Tamiflu and Relenza will remain effective drugs for treatment and prevention of influenza in the United States. If we learn anything new, we’ll let you know. As a reminder, the most important components of preventing flu are not drugs, the most important components are keeping your hands clean, covering your mouth and nose when you sneeze and cough, staying home from school and work if you’re sick, and most importantly getting a flu vaccine. Thank you for what you’re doing to help us with that.

I’ll be happy to take some questions. I want to check and make sure that the people on the telephone can hear me, and we will be taking questions from the phone and in the room. I’ll start with a question in the room. Go ahead.

Question: You touched on this a moment ago, but how many of these drugs have been administered so far in comparison with the other flu drugs that have been administered ? The second part of that is, did the people who got those vaccines ... other vaccines ... they’ve already gotten those ...?

Dr. Gerberding: What we’re talking about today are drugs used to treat influenza. The question was: should the people who have received these drugs receive alternate therapy? When people are treated with influenza drugs they’re treated for a short period of time, so most of the people who received amantadine or rimantadine for treatment probably are already finished with their course. Those who are currently on the drug should be switched to the alternative regimens, and that’s part of the reason why we took action this weekend. Just as soon as the information came out of the laboratory, Dr. Cox and her team had a very short period of time to go through and verify the accuracy of the results, and we’re here today because we didn’t want to wait for that small number of people.

The total number of people treated throughout flu season with amantadine and rimantadine this year we are not able to report on. I don’t think we’ll have that until we can look, in retrospect, and work with the manufacturers to try to make that determination.

A question on the telephone.

Operator: Our first question comes from Robert Bazell from NBC News.

Mr. Bazell: Hi. Just in relationship Dr. Gerberding, to what you just said, you don’t know anything about past use—there are two parts to this. One is, do you know from past seasons how widespread the use of these two drugs was for either treatment or prophylaxis? That’s part one. Actually, there are three parts. The second thing is, given the societal desire to, and individual desire to stockpile Tamiflu and the shortages of Tamiflu right now, is it really realistic to say that that isn’t even an appropriate alternative for people who are getting seasonal influenza? The third thing is I just wanted you to repeat, because of the sound problems before, why this is so important that you have to announce it on a Saturday of a holiday weekend. Thank you.

Dr. Gerberding: Your first question about, in retrospect, how much amantadine and rimantadine has been used to treat influenza in the past? ...(Inaudible) cross-over period, because the new drugs have been on the market for a very limited period of time, so as those drugs have become available less and less of amantadine and rimantadine have been used. There are a number of reasons for that. First of all, Tamiflu and Relenza have activity against both influenza A and influenza B, so they have the advantage of having a broader spectrum of activity. They may also have fewer side effects, particularly in elderly people, that give them some advantages in certain clinical situations. So there has been less and less use of rimantadine and amantadine. The main advantage of the older drugs is that they are less expensive, and that’s the reason why they are still used in some clinical settings and for prevention in some nursing homes. So I’m not able to give you specific information and I’m not sure that the past would predict, accurately, use this year.

The Tamiflu supply, we have been checking with the manufacturers and we recognize that overall there’s a bottleneck of production that’s limiting our ability to quickly build up a large stockpile for pandemic planning, but in terms of treating patients with Tamiflu, we have not experienced any shortages this year, there’s plenty of Tamiflu out there. As I mentioned, the CDC also has a stockpile of Tamiflu that, in the worst case scenario, we could make available if there are isolated shortages during flu season. The amount of Tamiflu we currently have in our stockpile far exceeds the number of courses of antivirals that have ever been used to treat seasonal influenza, so we’re not anticipating that to affect health status of people who really need that kind of treatment.

Bob, I regret, I lost your third question, I think you were asking me about why are we doing this on a weekend. The main reason we’re doing this today is because the information just became available to us beginning on Friday, and the scientists spent the last 24 hours verifying the accuracy of the results. We’re using a new test that’s only been available for a year or so, it’s a rapid and high throughput test, and we’ve had nothing but 100 percent reliability with it, but we wanted to be absolutely certain of our accuracy before we went out. So we did not put this announcement out when we had the preliminary picture on Friday, because it was important to take the time necessary to be certain. Now that we do have certainty about the findings, we just didn’t feel it was responsible to wait three more days to get through a three-day weekend before we let clinicians know. The most efficient way to let clinicians know is through our usual mechanisms, but also by having the information go out more widely, and the media is one mechanism to really help us do that, so we appreciate everyone’s patience with us on the weekend. Yes?

Questions: Doctor, how surprised were you by these findings ...?

Dr. Gerberding: …On the one hand, when you use any drug eventually resistance emerges. That’s been the rule of thumb in infectious disease for a long time. The question is: how fast does it show up? We’ve been aware that there has been an increase globally in the resistance to amantadine and rimantadine, the CDC did some work last year, that Dr. Cox may want to tell us about, looking at the global picture with resistance. So there is certainly a trend in the direction of increasing resistance, but I don’t think we were expecting it to be quite as dramatic so soon this year.

Nancy, do you want to say a word or two? Dr. Nancy Cox is the head of our Influenza branch in the National Center for Infectious Diseases, and it is her team of scientists that have been doing this work. Nancy.

Dr. Cox: Thank you very much, Dr. Gerberding. As Dr. Gerberding mentioned, we have been using a test that allows us to do very high throughput screening for resistance, and last year we published a paper in The Lancet where we had screened over 7,000 viruses for resistance to the (inaudible)..., amantadine and rimantadine. We noted that there was really a marked increase in resistance over that decade, and so what we saw is that particularly in certain Asian countries resistance had risen to, in one case, about 70 percent. We also saw, as Dr. Gerberding mentioned, that in the United States resistance grows from about 2 percent three years ago to the 91 percent reported today. So we have seen the trend globally, we had reported on it last year, and now we have seen an increase in drug resistance in the United States. We will be monitoring the situation globally as well as nationally, and we have notified our international partners as well.

Dr. Gerberding: And another question from the telephone.

Operator: The next question is from Betsy McKay from the Wall Street Journal.

Ms. McKay: Thank you very much, Dr. Gerberding. I had a couple of questions. One is that, do these findings, you said these findings mean that there has obviously been a mutation in the virus, would that equate to its becoming more virulent? Then the second question I had is related to avian flu. I’m wondering what implications, if any, the findings have for the possible use of those two drugs to combat certain strains of the H5N1 virus, which I believe is something that the WHO was investigating.

Dr. Gerberding: Thank you. We don’t know exactly why resistance has risen so much to these drugs this year, and that’s something that we’ll have to do more investigation to determine. The hypothesis that a mutation accounted for this is just a hypothesis right now. Certainly the mechanism of resistance is a change in an amino acid associated with the activity of the drug, but we will have to do a great deal more science before we have clearly understood why, and why now, and why so much.

Your question about virulence is one that we don’t have enough information to address, but we’ve certainly seen strains of influenza that have shown this resistance pattern before. We have no evidence that it increases or decreases the virulence of the organism; again, that is something that is more complicated than a single point mutation, in most cases. We also say that we know that H3N2 viruses, generally speaking, are more virulent than other forms of seasonal influenza, so it’s not the drug resistance that we’re concerned about per se, it’s the characteristics of the specific virus.

You asked about implications for avian influenza or pandemic influenza, and let me just put that into context by saying that we are monitoring the H5N1 avian influenza isolates in real-time as they emerge and arrive at CDC. They’re not all alike. Some of the isolates are susceptible to these drugs and some of the isolates are resistant to these drugs. We knew this from the very beginning of the outbreak in Vietnam, and we are not finding this to be unexpected, particularly since we know that there’s increased resistance to these drugs in seasonal isolates from the same part of the world.

We will continue to stockpile Tamiflu and Relenza. We do have a stockpile of some of the other drugs already in case we have a situation where different strains emerge and they would be useful. But I think the lesson here is that flu constantly evolves and we are always one mutation away from drug resistance, so there’s not going to be a reliable (inaudible)... for any flu, whether it’s seasonal or pandemic, and we have to continuously invest in developing a robust vaccine manufacturing capacity so that we can deal with the emerging strains through vaccinations and we will be less dependent on drug treatment.

I will mention that the investments that Congress just made in the President’s Emergency Supplemental for Influenza do allow us not only to purchase more drugs for our stockpile, but there is a portion of those resources, several hundred million dollars, that will be used to develop new anti-viral drugs so that we have a broader family of drugs down the road that we hope will help us out as resistance emerges. But this is an expected complication of drug exposure. As an infectious disease expert sometimes we say, “When you use it, you lose it,” and that really just means that these viruses and bacteria are very crafty critters and they know how to make changes in their genes to get around all of the drugs that we have in our pharmacy.

Let me take another question from the room. Now I’ll take a question from the telephones.

Operator: The next question comes from Maryn McKenna from the Atlanta Journal Constitution. Your line is now open.

Ms. McKenna: Thank you. A little more detail, if you don’t mind, about the isolates that were tested at the CDC, how did they come to the CDC? And if they came through the sentinel physician program, did they come from any specific geographic area within the United States, or are you seeing this resistance all across the United States?

Dr. Gerberding: I think the correct characterization of the geography of these isolates would be simply to say it’s coast-to-coast. This is a representative sample of influenza isolates that have been evaluated in state health laboratories around the country as part of our comprehensive influenza monitoring system. If you check CDC’s Web site, at www.cdc.gov, and go to our flu pages you will see information about the most recent status of influenza. Those data come from the partnership of our state laboratories, the sentinel physicians, the state health officers, as well as all the local people who are actually seeing the patients and the CDC. So we feel that this represents a sample of H3N2 influenza viruses that is broad enough and comes from a wide enough geographic area of the United States to have broad population implications and so we’re issuing this recommendation to the entire United States, not just on a geographic by geographic basis.

We will continue to do more testing and ultimately we may detect some subtle variations in one location to another, it’s too soon to say that, but I think for practical purposes and for the purposes of making decisions about taking care of patients, we have to assume that the viruses are resistant until proven otherwise. Remember that with Tamiflu and any of these drugs, with amantadine, rimantadine, Tamiflu, Relenza, treatment works when you start it within the first 48 hours of the onset of symptoms and may not be as effective if you wait. So it’s important that we don’t wait until we have resistance tests back, we have to go ahead and offer the patient the best choice up front, and that’s why we’re recommending right now the best choice is Tamiflu and Relenza for treatment.

Yes? A question here.

Question: You mentioned that these are older drugs, how long have the two been around? (Inaudible.)

Dr. Gerberding I can’t give you a quick answer on how old they are, but they’re off patent and they’ve been around long enough to be past the point where they’re non-generic, so we have a lot of experience with both of the drugs. Rimantadine is a bit younger than amantadine. I don’t know if you have any specific information ... We can get back to you with the history. It’s also on the CDC Web site embedded in the MMWR document that describes recommendations for treatment of influenza, and it discusses a little bit of the history of both of these families of drugs in the document.
Question: (Inaudible)... the reason ...?

Dr. Gerberding There are a number of reasons. These drugs work. We’ve used them for a long time. We know what their side effects are, we’re familiar with them. They are much less expensive, so they have those advantages. Sometimes using a drug that’s (inaudible)... and that you’re familiar with is more sensible than using a new drug if there’s not a reason to make a change. So there are a number of reasons. I will emphasize, however, that the two drugs that we’re not recommending, the amantadine and rimantadine, are not effective against influenza B, which has caused some outbreaks. For example, there was a large outbreak in a nursing home in New York caused by influenza B, so there are other reasons why they may not always be the drug of first choice, and ... this year now a very strong reason not to use them.

May I take a question from the telephone, please?

Operator: Thank you. Helen Branswell from the Canadian Press. Your line is now open.

Ms. Branswell: Thank you very much. If I could follow up on—well, I actually have two questions—if I could follow up on something Dr. Cox was just saying, she was referring to the paper by Rick Bright that was in The Lancet earlier this year showing that this type of increase in resistance with these drugs was occurring globally. You mentioned, Dr. Cox, that you had been reaching out to some of your counterparts in labs across the world and I was wondering if you’re hearing from other parts of the globe that this problem is also getting worse elsewhere.

My second question relates to a comment that Dr. Gerberding made a few minutes ago, about “if you use it, you lose it.” I’m wondering if there is concern that if you’re instructing clinicians not to use this drug, the ... this season, that the increased use of ... inhibitors will endanger their usage or their effectiveness if there’s a pandemic any time soon. You mentioned that there’s going to be investment in developing new ... inhibitors, but that’s not a quick process and I’m just wondering if it’s wise to be urging doctors to be increasing usage of this drug at this point.

Dr. Gerberding: I’m going to ask Dr. Cox to handle the question about the global picture and then I’ll take your question about what the implications are for emergence of resistance.
Dr. Cox: We are, actually, at the CDC, monitoring viruses globally, as I mentioned before, the viruses that we receive, plus we’re in touch with our partners in other countries. We have relatively little information because the influenza season has taken off rather slowly in Europe, for example, but we have heard from our counterparts in the U.K. that as they’ve been monitoring for resistance, they had seen resistance among the H3N2 viruses that they have tested. Our Canadian colleagues are testing viruses over the weekend, and so they will have some additional information. So there will be a lot more information available over the coming weeks and months about the global picture.

Dr. Gerberding: With respect for the implications for pandemic preparedness, again, we know less about Tamiflu and Relenza because those drugs are relatively new, so we don’t have a long experience to predict what are the factors that promote resistance. What we see so far is that they actually are less likely to cause the emergence of resistance and I’m not aware that we’ve documented any cases where a resistant virus has been transmitted from one person to another, but of course that could change. So we don’t want to have overconfidence that we won’t see a resistance problem. In isolated patients with H5N1 we’ve seen isolates that are resistant to the drugs and if we see more of that it’s not going to be a surprise to anyone. So what we need to do in a situation like this is what we always say about use of antimicrobial or antiviral agents, do not use these drugs unless the clinician recommends that they’re appropriate. Do not stockpile drugs and take them when you think you may or may not have a viral illness. It’s very important that we restrict the use of any antimicrobial in a situation where there’s a definite infection and the drug will truly make a clinical benefit to the patient. So unnecessary use of any antibiotic should be avoided, and of course that’s also true with Tamiflu and Relenza. We want to have them available so that people can benefit from them, it can help people survive flu with fewer complications, and they’re certainly important drugs to have in our medicine chest. We don’t want to lose them, so let’s use them properly.

I’ll take another question from the telephone. This will be my last question.

Operator: Thank you. August Cole, from Market Watch, your line is open.

Mr. Cole: Good afternoon. I was wondering if you knew who makes amantadine and rimantadine?

Dr. Gerberding I don’t know the manufacturers—maybe Ray or Nancy can give us that real quickly. Why don’t we just get back to you with the answer to that question after the press briefing?

Mr. Cole: Thank you.

Dr. Gerberding I really appreciate your attention and your patience. We commit to getting our experts here in the press conference room back in to solve some of these audiovisual problems we have, and we will continue to provide you information as we go forward. Thank you.

END

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