Mdr-Tb, Xdr-Tb and Tdr-Tb, Is This Progress

MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 1

MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS

Moderator: Donna Setzer April 11, 2012 8:40 am CT

Operator: We will now begin the Southeastern National TB Center's Grand Rounds MDR-TB, XDR-TB and TDR-TB Is this Progress.

To provide information and introduction of the speaker we now turn to Karen Farrell, Executive Nursing Director and Director of Education at A.G. Holley Hospital.

Please go right ahead.

Karen Farrell: Welcome everyone this morning to the Southeastern National TB Center here at the clinical training campus at A.G. Holley Hospital.

My name is Karen Farrell. I am the Executive Nursing Director/Director of Education and also the Education and Training Coordinator for the Southeastern National TB Center here at the clinical campus.

This morning we have with us Dr. Dick Menzies, who will be speaking to us on MDR-TB, XDR-TB and TDR-TB, Is This Progress. Today's event is scheduled for two hours, including the question and answer period at the end of the presentation.

Following the event, you will receive an email link to the online evaluation. You must complete this evaluation to receive your continuing education credits. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 2

Now I'd like to welcome our moderator for today's event, Dr. Michael Lauzardo, Director of the Southeastern National TB Center.

Dr. Michael Lauzardo: Good morning. I am filling in for Dr. Dave Ashkin, who had a family emergency today.

If you'll pardon the literary reference, in many ways, these are the best of times and the worst of times in TB control. They're the best of times in the sense that we have - now have tools that we never had before.

We have new ways to diagnose latent TB infection,, we have ways to diagnose drug-resistant TB without even having a culture by diagnosing it using molecular means.

In some ways it's also the worst of times, because despite the fact that we've had a cure for tuberculosis available for more than 50 years, still more than a million people -- almost as many as two million people a year die from the disease, there are eight to ten million new cases every year and untold millions get infected with the disease every year.

Also, as there's a scale up of more diagnostic capabilities in developing countries around the world where there's high incidents of TB disease, we're now either becoming aware or there's a rising incidence -- one of the two -- of drug-resistant tuberculosis throughout the world.

And that is actually the big, bad scary. That's the issue that's going to challenge TB control despite the new tools/despite the new drugs that have given us so much promise. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 3

So speaking of drug resistance, I - it's my pleasure and my honor to introduce you to our speaker today. Dr. Dick Menzies is professor of Medicine and Epidemiology and Biostatistics at McGill University.

And his introduction is actually easy to do, because his reputation precedes him. But I will add a personal note that to many of us who work in TB -- and I'm going to try my best to embarrass him here -- to many of us who work in TB, he represents a role model.

And he has mentored so many of us who have not had the opportunity to work with him directly there at McGill, but have worked with him through a distance and through his work.

So again without further ado, let me introduce to you Dr. Dick Menzies, one of the most productive and most humble guys that you will have in TB today. Dr. Dick Menzies.

Dr. Dick Menzies:All right. Thanks. Thanks, Mike. Thanks for not embarrassing me too much. That was the most important thing.

Mike's going to drive me four hours and I had said to him that I would, you know, berate him for four hours straight if he did anything embarrassing. So he was nice to me this time.

Anyway, thank you. Thanks, Mike. Thanks, actually, to Dave Ashkin -- I'm sorry he's not here. And to everybody who organized the event, thanks for - it's a pleasure to be here -- A.G. Holley. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 4

I haven't ever visited here before, so it's fun to come here. I know there's some - there's a tinge of sadness here, but hopefully that will turn around in the next month or two.

So I'm going to talk about MDR, XDR, and TDR. This is largely - I'm going to present to you work that I've been involved with that has been over the last couple of years.

And I'd certainly invite questions at pretty well any time, but there are a couple of kind of obvious breaks where I'll stop and see at that point if there's questions.

So first - let's see now. Okay. So I'll move on. Oh yes, I'm - just want to point out I'm from (Luchef - sp) in Montreal. So right, disclaimer of no conflicts of interest, sadly.

I'm open to them, but that's the world of TB, you know? It's a sad state of affairs when TB's still - most speakers in TB have no financial conflict of interest. It's - as Mike says, it's the best of times and the worst of times, so okay.

So Global TB -- I think everybody's quite familiar with these kind of statistics. You know, millions of deaths, millions of cases of new - new cases of TB.

And it's estimated that at any one time -- given the survival and the duration of symptoms and so on -- that 20 million people are living with active TB at any one time, which I think is more than the population, for example, in the state of Florida, if I got my figures right yesterday. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 5

And it's estimated that about 1/3rd of all people alive today are infected with latent TB. Obviously, most of these are not in the U.S. and Canada. They're in Asia, they're in Africa, they're in Eastern Europe.

But still, this is a huge pool or reservoir of infections. And it's estimated that out of this two billion, 200 million will develop active TB.

So let me - I'm always hitting the wrong thing here.

So recent trends -- I think everybody's aware that in the 1990's globally -- I mean, here in the U.S. and we saw the same in Canada there was an increase in the late 80's and early 90's, but globally there was a rapid increase in TB rates, largely HIV-driven, but in some countries like Eastern Europe, not HIV- related at all.

It has plateaued globally, even a slight decline. The number of cases -- given the still population growth -- is still increasing and perhaps leveling off.

Okay. So that's kind of very general. I think everybody's familiar with the general situation in TB. So what about drug resistance?

So first of all, how much is there? So again, estimates from WHO -- this is a couple of years ago. So they estimated -- you'll notice that TDR doesn't even appear on this figure.

So total cases in 2006 -- nine million. Almost 500 thousand cases of MDR-TB globally in 2006. I think that number has not changed very much. What's kind of sobering is that out of that 500 thousand cases of MDR-TB, it's estimated that only 3% have adequate diagnosis like access to full drug sensitivity testing and maybe 5% in total have access to adequate treatment. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 6

And that still is more or less the case -- less than 10% of MDR cases today receive any sort of real MDR treatment. So there's a long way in terms of treating these and that's why the emphasis has to be on prevention.

Extensively drug-resistant TB or XDR is a much smaller number. You'll notice the mortality, though, is almost 50%. HIV-associated TB -- actually those numbers have gone up.

Okay. So first, back to the basis. How does drug resistance develop? So just a little primer.

So first of all, most important thing about TB -- and it's true, of course, of all bacteria -- is that their spontaneous mutation -- and these are actually been measured -- the rate of spontaneous mutation.

And what you see is that for the common drugs, you're looking at one in a million to one in ten million - they're - bacteria - mycobacteria growing in culture will develop a spontaneous mutation to a single drug.

To two drugs -- the same bacteria -- that's actually much less likely. So the probability of spontaneous mutation is - it seems fairly rare, but the next obvious question that I'm sure you're all asking yourselves is how many bugs are there?

So that too has been estimated. Now, this was actually estimated in rabbit studies, not humans, but extrapolated to human. So there's a - kind of a rough correlation between the clinical state and the quantity - total quantity of viable bacilli. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 7

And what you see is that in a granuloma with latent TB, you'll have maybe 1,000 viable bacilli in the body. And so if you go back -- so 1,000 viable bacilli, one in a million chance of INH resistance -- you can give a single drug.

And that's really why for latent TB we can treat with one drug and we don't need two or three. But as soon as you have even vague infiltrates on an X-ray, even those clinical cases -- fairly minimal disease that are smear negative, maybe culture positive, there's a big jump up in number of bacilli -- and now you're seeing at least a big enough pool that you can see some spontaneous mutations.

And as you see cavities and more disease, you're going to see more and more bacilli. So if you put those numbers together you can actually work out the probability of resistance emerging, given a single drug or combinations of drugs.

And what you see here -- and I'm going to hope the pointer works right now -- what you see is that here, INH and RIF. So if you give, for example, Streptomycin alone with an infiltrate, you'll see resistance emerge.

If you give INH alone may be less likely, but a person with a single cavity -- so with that kind of bacterial load -- almost certain that they will develop resistance.

You give RIF alone because it's actually lower mutation rate -- it takes more advanced disease, but still, RIF alone will lead to the emergence of resistance -- pretty high degree of certainty. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 8

But you give the two drugs together -- and now you're down in this corner -- with quite advanced disease, though, you still can see the emergence of resistance, which is why we routinely give three drugs to which we expect the person to be sensitive.

Not two, because of this more extensive disease -- there's a - still a probability of emergent - of resistance emerging, okay?

Okay. So - and in fact, this - all this information comes, really, from the very first time that Streptomycin was discovered and tried. You sort of have to put yourself back in 1948 when there was no drugs available for TB -- people were admitted to sanatoria and people hoped for a cure, which was rare.

Spontaneous cure was rare and so a lot of people just came in and died - slowly. So you can imagine when Streptomycin was first tried, there was tremendous excitement and people were getting Streptomycin and rapidly getting better.

But the sad thing was that they found that within a month -- they did serial cultures on people -- and they found that within a month -- you see it here -- you see at a month, they began to see the emergence of resistance -- one month of Streptomycin.

And they started to see - and you see that by four months, almost 80% -- 3/4 of the people -- have Streptomycin resistance, so they were all getting better and then getting sick again.

And they tried with PAS alone a year or two later and you see the same phenomenon -- maybe a little slower. But when they gave both drugs, no resistance emerged. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 9

And this was, in fact, the first sort of realization of the problem of emergence of resistance.

Okay. So this was really what's going on. When you treat a person -- this is a log scale, so 10 to the 8th -- a person with Cavitary TB will have 10 to the 8th organisms that are sensitive and they may have 100 resistant organisms spontaneously.

You give one drug, the resistant organisms are unaffected and steadily grow, the sensitive organisms, of course, disappear steadily. So what you see is that by -- and this is around six to nine weeks, so around two months of therapy -- people are better and then as time goes by, they become sick again.

So you'll see this rise and fall phenomenon stay very predictably with one drug or if you happen to give two drugs but they're already resistant to one, unbeknownst to you, so someone with primary resistance or previous treatment and didn't tell you.

So the other phenomenon that occurs is someone who stops treatment early. Why is default important? So the first problem is a problem where you don't give enough drugs -- that's a medical error.

The second problem is perhaps a combination of medical and patient error, which is default. And so what happens is, when you start treatment -- and again, you're uphill with lots of sensitive bacilli and a small population of resistant bacilli -- and you give several drugs.

And the number of drugs rapidly gets better. So if you have a person smear positive, culture positive, of course, and they're rapidly getting better. And MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 10 again by six to nine weeks, the population of bacteria has gone down, but the resistant population went down more slowly -- they're killed off not as fast.

So what happens at six to nine weeks when the population of bacteria is gone or much less? How do people feel? Of course they feel better. And a normal human response to feeling better that is, in fact, quite logical unless you've been educated well, is, "Well I'm feeling better. Do I need to continue taking this handful of medications that actually I hate? They make me, you know, stomach upset, buzzing in my ear -- whatever."

So a normal human response is when you feel better, it's to stop the meds. And what happens now -- let's say you stop at this point here. I'm going to click here, okay?

So now the population of resistant and sensitive bugs are quite similar. If you stop, what happens to all the bacteria? They all start to grow back, if you will. Okay? Kind of like a vine that you cut back.

And everything grows back, but now the relative proportion of resistant and susceptible has changed. Now you've got almost 50/50. So the next time that -- so in six to eight weeks when they're back up here -- then the population - now you give again the same treatment, but now you've traded fully or seemingly fully sensitive with half/half.

You treat again with the same drugs, the patient again -- there's a decline in the susceptible bugs, the patient feels a bit better, they may default a second time. But now this second time you've replace the population entirely with resistance. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 11

And so certainly one default will lead to some emergence of resistance and multiple defaults inevitably. And so this was the phenomenon, for example, that led to the emergence of MDR in New York City -- very well described, multiple defaults from therapy, multiple restarts.

People would come into a hospital, get treated, be discharged, disappear. And so MDR emerged very rapidly. I would say this same phenomenon is now going on in South Africa, as an example, where the program is struggling to keep up.

So in summary - so emergence of drug resistance. Single drug therapy inevitably leads to resistance. Even two drug therapy can lead to resistance -- or two effective drugs.

Irregular or default -- irregular therapy will also lead to resistance. And, of course, low dose. I didn't talk about that very much, but inadequate doses, poor drug absorption -- all these things as well can lead to selection of the resistant mutants.

And all of these conditions are common in many countries. So low quality drugs -- you can go to countries where you can buy in the pharmacy, but who knows the quality of the drug.

Inadequate regimen -- a survey was done in India in Mumbai. They surveyed over 100 physicians. They simply asked them, "How would you treat a new case of TB?"

For 100 physicians, they actually got more than 100 possible regimens, all right? So everybody had their own cocktail. And -- and this is for new MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 12 treatment, where there really is only one answer -- one correct answer, anyway.

And not only that, when they went through them, they judged that about 50% were inadequate regimens. So some were overkill -- too many drugs -- but a lot were under -- too few drugs.

And then, of course, people have to buy meds in many countries. If you don't have a proper National program, meds are not free. You have to go to the pharmacy.

Well, you can't always afford them all. So with a bit of negotiation, you might buy the cheaper drugs and forget the more expensive ones. Or, you might buy for a month and then, of course, you have to save up to - six months later you buy another month.

So the worst scenarios possible -- And this - these happen in many countries. And then there's just poor follow up -- interrupted therapy.

So short history. So in 1943, Streptomycin was discovered, the first clinical trial and again, the emergence of resistance I showed you. Between 1945 and 1970, 15 new TB drugs were developed, tested and introduced.

In the whole multi-drug therapy, multiple randomized trials were performed into the 1970's and modern - the regimen we use now was really developed by 1970, okay?

Now, between 1971 and 2007, there's been one new TB drug developed, tested and used that's an effective drug. And those are the fluroquinolones, which, of course, were not developed for TB at all. They were developed for MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 13 respiratory or other infections, but a byproduct, fortunately, is that they're good for TB.

So there's been really no new designed TB drug that is on the market since 1970. There are in the pipeline a few, but very few.

Okay. So I'm going to - I don't know if I can see if there's any question about kind of more theoretical before I get into MDR. No one - no questions? Everybody's got that?

Most people are awake still; I'm gratified to see. Coffee's working. Okay, so let me carry on.

So first of all, what is MDR-TB? I - again, I know you all know this, but just to be sure we're all on the same page.

So MDR is resistance to INH and Rifampin. And why is that important? Because those are the two most effective and they're also the two best tolerated TB drugs.

Despite everybody thinks of INH, Hepatitis, this, that, these still are the best drugs in terms of tolerability. And remember that before RIF was available, therapy was 18 to 24 months.

When RIF came out, then suddenly people talked about short-course chemotherapy, which was six months -- which doesn't seem very short. But when you compare it to 18 to 24 months, it's pretty short. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 14

But when you have MDR-TB, you're back to 18 to 24 months, okay? And you're back to some of the old drugs, because we don't have new drugs, except for the fluroquinolone.

Okay. So MDR treatment is prolonged -- minimum is 18 months. It's certainly unpleasant at best, right? Six months of injectable on average -- sometimes longer.

That's - that alone is very unpleasant. It's toxic. Many of the second line drugs have a lot more side effects, that's why they're second line drugs. And it's ineffective. The cure rates of MDR TB overall in three different systematic reviews averaged 50% to 60%, so that is - that's not a good success rate.

So what about costs? This is an older slide, but still gives you some idea of the costs. These are different -- sorry, I'm going to try this again. This is different patterns of resistance.

So this is standard MDR-TB. In a high-income country like the U.S., it costs $10 thousand just for the drugs. And a more complex case with more kind of worse resistance, almost $20 thousand for the drugs alone, okay?

So it's very expensive. And of course on top of that, you're looking at six months of injectable. At minimum, that's a lot of nursing time and resources and it may be hospitalization as here, for example. So that's, again, very expensive.

Okay. So MDR-TB treatment is very controversial. In fact, it's much, much more controversial than treatment of normal standard drug-sensitive TB for one simple reason. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 15

And I - again, I don't know if any of you have ever participated in these Guideline committees which, you know, used to be a group of experts would be invited -- usually by themselves -- self-declared experts.

And they would gather in a room and everybody would announce their opinions and a fairly forceful chairperson would manage to get some consensus at the end of two days -- largely achieved in the last hour because everybody wanted to go home -- and that would be the new set of guidelines.

Then came randomized trials and suddenly, you know, there are no more questions, because the evidence was very clear. Two months was better than six, or six months is better than nine or whatever.

And so debates evaporate when there's good evidence. Opinions, you know, you can just get people to review the literature and sum it up. But with MDR- TB, there's still scope for these expert committees and guidelines, because there's never been a randomized trial in MDR-TB -- not one.

So no one knows how to treat it properly and everybody has their local experience and so everybody has their opinion, which, in the absence of evidence, opinions tend to be very strong.

It's kind of an inverse proportional thing. The better the evidence, the weaker the opinion, right? But when there's absolutely no evidence about it, it's a bit like politics, right? Who knows who's the best politician, but the opinions are very strong.

Okay. So again, here we are. No randomized trials, many cohorts, local experience shapes expert opinion. And that's - and that's valid because the MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 16 patients you see here, you know, that's your experience and they do well, they do badly, over the years, you've gained experience.

The problem is that the patient population you see here may be very different from the patient population I see in Montreal, which is different, again, from the population in Sub-Saharan Africa, for example. And so that's the problem, really, of amalgamating people's experience.

Okay. So first of all in the - in this new era of systematic reviews, the first approach was to say, "Well, let's gather all of these cohort studies, collect that experience, publish the experience and put them together."

And three different groups -- including us at McGill -- did these systematic reviews. And they were all completed about the same time, all based on these observational studies.

So people kind of get treated however they get treated and it was usually individualized as it is here, right? Each patient gets a regimen tailored to their history, to their comorbidities, to their age, et cetera, but this makes it very difficult to pool results together.

And I'll show you an example from our own systematic review. So for example, there was a notion that sex, you know, females/males -- females might do better with MDR-TB -- outcomes were better.

But when you pool across many studies, all you can end up saying is the percent female in a given series and looking at that. And of course, that's kind of ludicrous because that's not very helpful and you want to know - no one is a -- well, maybe in San Francisco -- but no one is a 50% female. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 17

They're, you know, its female or male. Or maybe in Miami -- I don't know. Anyway.

Woman: Yes.

Dr. Dick Menzies:But you get the point.

It's very difficult to make sense out of this kind of thing, where you're looking at the percent female in the series and did they do better or worse in that. And the same with history.

So what percent of patients had previous treatment? Again, it's sort of ludicrous. You can't really make sense out of it.

And here, even worse, you wanted to know whether fluroquinolones are important and so you had series where very few people got fluroquinolones, you have a series where almost everybody got it, you had in-between -- again, it's very difficult to make any sense of it.

So these three systematic reviews -- only the strongest things could come out -- strongest factors that would effect outcome. So what are the problems?

So treatment is individualized and yet you have 100 patients and you're trying to make sense out of pooling this group of 100 with another group. But patients are very different between centers and even within centers.

And you could, again, only analyze the percent with a certain factor and so on.

So the second approach is this -- the individual patient data meta-analysis, which is - sounds like quite a mouthful. Wait until I get to the analysis part. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 18

But what you're doing in a individual patient data analysis is, you're actually getting the data from here -- A.G. Holley, thank you very much -- and from New York City and from San Francisco and from Montreal and from Toronto and from, you know, Thomsk, Russia and so on.

And you're merging them all into one and then you can analyze it individual by individual. So it's one giant cohort.

So this particular study that I'm going to present and drone on about was initiated because WHO wanted to update their MDR treatment guidelines. And so they put together a list of questions and here were the questions which I was asked to answer.

So which drugs, how many drugs and for how long -- which, when you think about it, is - that's - pretty well sums up treatment, right? What do you treat them with? For how long? How many drugs?

So all the basic questions were asked by this committee. And the idea was, we'd put together a giant data set of all studies that we could lay our hands on. So we started with these three systematic reviews, in part because I'd personally been involved in one of them.

So that was already - that work was done. You know, where you kept five thousand titles and worked your way through them and eventually come down to X number of studies.

So we had three studies. So from those, we could identify a group of all studies that had reported on MDR-TB treatment in the last 20 or 30 years and then basically wrote to all the authors. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 19

And some of these studies were older and we had to actually literally write/mail a letter off -- that worked once -- and all the rest were emails or people, you know, that I still - we know who they - who they were or where they were, but it took a while to just track them all down.

And from each group that agreed, we asked them for this kind of information. So about the patients -- age, sex, the basic stuff, HIV, obviously -- we wanted to know about the disease itself -- extent of disease, X-ray findings, AFB smear, those kind of markers of disease severity -- and we wanted to know about the drug sensitivity testing, of course -- were they resistant to the additional drugs or not, or just INH and RIF.

And then the treatment -- how were they treated? So for each patient we got all of this information, without their names, of course -- all non-nominal, just all this information.

And for those of you from here, you know there was a lot of correspondence back and forth, back and forth, back and forth -- what does this variable mean, this is missing, can you send this information, et cetera.

So I would credit the people here. I know Joanne, Dave, actually, answered many emails. But each center, we did the same -- worked our way through the data.

So again, we have to end up with one common data set. And as I was saying, we contacted authors to verify things to get - to even produce sort of summary tables to match the original paper -- so just reanalyzed everybody's data and said, "Could we at least reproduce what they found just to verify that we had kind of a good understanding?" MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 20

And then -- again, I'm not going to go into it too much. I understand there's an evaluation at the end and there is a quiz question which is - you have to be able to explain this method of analysis on the quiz, so take note.

And Mike, on the way North I'll explain to you -- in over four hours -- more about this random effect, logistic regression, blah, blah, blah.

Anyway -- fairly fancy analysis. Took me a long time to understand it. But essentially it's a sort of meta-analysis technique, but it allows you to use each individual patient's bit of information and it also allows you to adjust for things that might be important differences between patients and between centers -- so age and gender.

Obviously, some centers had older patients, some younger, some were mainly HIV-infected, others were not. So this was a way to sort of adjust for all of these differences.

Okay. So just rushing on.

So this is sort of the numbers. I think the stuff on the right-hand side of the slide you don't have to worry about. But basically, we identified 67 different studies out there that had published on MDR-TB in the last 20 years or so.

We ended up getting 32 data sets, so about half responded. Some people never responded, some people we literally couldn't find, a lot of people wrote back that the data was, you know, never - it was lost or they had moved and didn't know where it was. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 21

But at the end of it all, we ended up with almost ten thousand MDR patients in the data set -- nine thousand eight hundred and - anyway. So a lot of patients. And out of this next few slides, nine thousand plus were analyzed -- so it's a big group of MDR patients.

Gives you a lot of statistical power, of course, to look at things. But also, the nice thing was -- with 32 different centers -- what was kind of amazing was when you write to people to say, "Well, how did you treat, you know, how did you approach the injectable?"

So people would write back to say, "Well, of course we gave it for three months. Of course." And someone else would write back to say, "Well, of course we gave it for six months, obviously. You know, what are you asking for?"

So everybody had a different approach. And the approaches, which were sort of local culture, experience, et cetera, differed more than the patients. They could have very similar patients, but their approach was wildly different.

So it's kind of a - almost an experiment going on. Not randomized, but sort of random, because the patients at least -- they randomly went to, you know, A.G. Holley or they went to wherever and they got, you know, the A.G. Holley way of treating patients -- which is, of course, the best way and the right way, absolutely.

But, you know, they got a very different style of treatment in New York City or certainly in Russia or in Peru. So that's actually the beauty of all this. There was a lot of this natural experimentation going on and variation in approach that had nothing to do, really, with the patient characteristics. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 22

Okay. So here's just a quick summary of the patient characteristics. So this is our - actually the full data set -- 9,800. So 2/3rds were men, which is about right, just, you know, most adult TB -- two - about 2/3 are usually men -- 2/3 have had prior TB treatment.

So that means 1/3 it was primary MDR -- had never been treated before -- just bad luck. Only 12% had HIV co-infection -- a relatively small number. I think part of that is, you know, you have to survive to get to MDR and a lot of HIV- infected patients actually die.

They get treatment once, but if they fail that, they actually die before they get diagnosed with MDR-TB. Very few received Antiretroviral therapy, reflecting that this is an older - many of these are older cohorts.

The vast majority had pulmonary TB -- and again, 2/3 were smear positive and about 1/2 had cavitation on X-ray, so fairly extensive disease.

Overall treatment outcomes -- again, this is a - this is MDR -- 54% cure rate and - cure and treatment completion. So that's not bad. That's exactly sort of in the middle of all the published estimates -- which makes sense, because these are the same studies -- but still, it's not very good.

You see death rate of 16% and default is also high, again reflecting the reason that people got into these troubles is the default. So they're manifesting the same behavior.

So now I'm just going to run through some of these results. I don't want to, you know, go over them in too much excruciating detail, but just to show a few examples of what was found. And a little bit, you know, there's some interesting lessons along the way. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 23

Okay. So this is a complicated slide, but I'll just kind of take you through it slowly and then the other slides -- it makes more sense.

But bottom line - bottom line, PZA and Ethambutol -- very little effect. So what I'd draw your attention to is -- hold on, I got to get my mouse working. So this is PZA here. And - oh, water. Okay. My voice is sounding scratchy already.

So there's an odds of success if you got (PZA) compared to if you didn't of 1.2, meaning 20% more likely cure if you got PZA. So 20% more likely is not a very strong affect. And it - you'll notice it's not bold because the consonance intervals around that encompass one.

So it could have been worse -- could have been 10% worse -- could have been 70% better, okay? So not significant. The only thing - again, this is for fail relapse, just sort of treatment efficacy.

Then there's also fail/relapse/death, which is - obviously death is - well, death is very important. I don't - I'm not - the kind of obvious truth. But in MDR-TB treatment, a lot of people -- because the treatment's so long -- they don't fail treatment, they just die of MDR-TB.

So you sort of combine them together as bad outcomes. And PZA was, again, slightly and significantly more likely to result in success compared to fail/relapse/death.

And for default, no -- no effect at all. But default, of course, there's - it's multi- factorial why people default. It's not as much related to the disease as perhaps the program and other things. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 24

Ethambutol -- you'll see absolutely no effect, which is a little bit what we now know and think. It's not a very strong drug, it's a bacteriostatic, it's to prevent further resistance -- it's not a very important drug.

PZA is perhaps a little more surprising, but it's not that effective. Some of this has to do, of course, with a lot of underlying PZA resistance in the population and this is taking all comers.

Okay. So let me go on.

So injectables -- so Kanamycin, Amikacin and Capreomycin. You use all of these - I guess you use Amikacin preferentially here -- certainly we do.

((Crosstalk))

Dr. Dick Menzies:Capreo? Okay.

Woman: We prefer it when it's available with our MDR patients.

Right now it's Amikacin...

Dr. Dick Menzies:Okay.

Dr. Dick Menzies:Okay. And Capreo because you think it's better?

((Crosstalk))

Woman: That's why we're adding other drugs to your regimen. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 25

Dr. Dick Menzies:Okay.

So okay, that's interesting. So I've lumped Kanamycin and Amikacin together. Most people -- because there's almost virtual 100% cross-resistance -- and so most people who - either got one or the other in most series.

Okay. So again, these are complex slides, but what I did here is - so the total numbers is - are actually here. So the total number, for example, who got Kanamycin only was 4 1/2 thousand people, okay?

This is where I'll press the button here, okay -- 4/12 thousand people. And 12,000 people got Capreomycin only. And this is comparing the odds if you got Kanamycin versus Capreo, okay?

So what you see here is that people did worse and odds of a cure were about half that. They got Capreo compared to if they got Kanamycin suggesting that Kanamycin's better. Okay?

So I presented this at this meeting in Geneva to the expert group, all of this stuff that I'm showing you. I presented more. And so on day one I presented this and there was a lot of people in the crowd. There was a group of maybe 20 experts from all around the world.

So they said, no, no, no, Capreo's better. We're sure Capreo's better. That can't be right. So go back and analyze it according to sensitivity. So tell us tomorrow whether it's better if you're Kanamycin-sensitive.

So because of this is a very ric data set with thousands of people, you see, if 4000 people got Kanamycin, you can slice it down into these subsets. So if I'm lucky I'll go to the next slide. And sorry, yeah. Okay. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 26

So Kanamycin-sensitive only. So now this is Kanamycin-sensitive only and the numbers are smaller so still 4000 plus and 400 got Capreomycin. So Kanamycin-sensitive but they got Capreomycin. But again you see in this subset that Capreo was doing worse than the Kanamycin. Right? Everywhere down the board you just see point 6, point 7, consistently, they're doing a little worse. So Capreo looked worse. So what would be the next objection? This was a three-day meeting. Fortunately it was only three days. Yeah.

Dr. Michael Lauzardo: I was informed that I had to come to the microphone so that the online audience can hear. But I would say what was the population because there would be a big difference between what countries were possibly using Capreo versus Kanamycin and were those populations equal?

Dr. Dick Menzies:Okay. So I did - well, first of all, all of this are adjusted. You'll notice there's two estimates, unadjusted and adjusted. I'm going to press the button here. Unadjusted, adjusted.

So it didn't really matter at least in terms of these things that I was adjusting for. But I did also look at characteristics of patients who got Capreo versus Kana and didn't really see a bit difference. Okay? But still the committee said no, no, no, you looked at it wrong. You should look at the Kanamycin- resistant group.

So back to the hotel and that night I re-analyzed it and so the next day I was back, they wanted to know Kanamycin-resistant strains. So now the numbers are much smaller. You only have a 114 got Kanamycin even though they were Kanamycin-resistant and a much larger group got Capreo. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 27

So you can see that, sensibly enough, if they're Kanamycin-resistant, most people are getting but what you now see is indeed Kanamycin-resistant the people who got Capreo did better than the people that got Kanamycin. Quite a bit better. Okay? But yes you should be if you're not - if you're Kanamycin- sensitive, don't give Capreo, give Kanamycin or Amikacin. Right.

So, again, interesting but it also just demonstrates the kind of utility of this data set because you see that almost any which way - someone says look at this, you could look at it and you'd have a hundred patients that fell into that pot. With enough that you could find again the constant intervals are not bad. Very precise estimate. So it's quite a powerful tool.

You know, this is what we call a stratified analysis. You just comb down only on a very small subgroup and look at the effect of, you know, again a drug like Capreomycin versus Kanamycin. Pretty specialized, you know, question, right?

But when you're actually faced with a patient who's got Kanamycin-resistance or sensitivity, you want to know let's say they're Kanamycin-sensitive which drug should I use. I think this data pretty clearly says use Kanamycin, don't use Capreo.

Okay. So I'll go on. So the fluoroquinolones. So the fluoroquinolones I'm going to talk about Ofloxacin because that was the most commonly used florochrinolon and later generation Quinolone which is Moxyi and Levo. Some centers used Gatifloxacin. Actually some centers in lower-middle income countries still do despite the glycemic problems. And occasionally Sparfloxacin. But it's mostly Moxi and Levo. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 28

Okay. So the first is that all of the drugs, even Ciprofloxacin - which I'm not going to show much - were better than no fluoroquinolone in fluoroquinolone sensitive patients. So here's the odds of success.

So you remember PZA had an odd maximum of 1.3 but here are the fluoroquinolones. Much better. Okay? Much more effective, potent drugs, odds of success, you know, two and a half times that of not getting a fluoroquinolone.

Interestingly not much difference compared to no quinolone but when we compared the two head to head if you will, higher fluoroquinolone, later generation fluoroquinolone against Oflox clearly the later generation were superior.

Again not surprising at fifth. Levo, Moxi. I'm not sure what you use here. Moxi? Moxi. So Moxi's clearly superior. In vitro it is. It's nice that the data kind of bears that I and reasonably consistently across the board all three outcomes, all three comparisons, every which way. Okay? So that's fairly easy. The fluoroquinolones are easy.

So what about the so-called group four drugs. So the group four drugs, PAS, Cycloserine and Ethionamide and Prothionamide. I guess here it's Ethionamide would be. Right? But some countries it's Prothionamide. I'm not sure why but they're essentially equivalent.

So what was interesting was that Ethionamide or Prothionamide across the board seemed to be reasonably potent. Not like the quinolones but better than PZA for sure and even better than the injectables. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 29

So this is a drug very similar to INH so there's a fair amount of resistance, cross-resistance between INH and Ethionamide but at least in overall we didn't even separate out because they're all MDR after all.

So we didn't look at Ethionamide-sensitive versus resistant. We just total all in. It seems to be a pretty effective drug. But Cycloserine, not very much, actually this down here must be a mistake. But PAS, the PAS really had no clear effect whether that's - and, again, these are all big numbers.

Ethionamide, 6000 people got Ethionamide or Prothionamide, Cycloserine, 4 or 5000 PZA, several thousand people. So they're based on, you know, quite large numbers. And Cycloserine, really a modest effect but less than Ethionamide.

So of the group four drugs look like Ethionamide, Prothionamide, the most important, the most effective drug, the one that you should certainly want to use. The others, PAS, not clear that it's really adding anything.

And I can say the prevalence of resistance to PAS was very low when tested. So it's not because there's a lot of resistance to it. Maybe it's a question of tolerability and getting enough dosing. I don't know. Okay?

So the group five drugs, so there were in the data set about several thousand people who got these group five drugs. The group five are drugs that are considered at least again by WHO to be of uncertain efficacy and certain toxicity.

So they are very much the reserve that you go to when you've run out of everything else that I've already showed you. And of these, Chlofazamine is MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 30 one that's of interest because it's used in the so-called Bangladesh regimen which has been quite successful.

Thiacetezone is a drug that used to be used a lot especially in Africa. It was well-tolerated in that population. As a companion drug but it's still widely available and very cheap. Then there's the macrolide and then the amoxy class. And, again, I'm not sure which of these group five you might use.

But these all - there was at least a thousand people that took one of these, one of the other so there were enough to analyze and when I analyze them I couldn't find any benefit of all from any of them. Their odds tended to be right at 1.0 across the board.

None of these at least in the same analysis where you could see an effect of these other presumably more potent drugs, none of these drugs stood out as effective or helpful. Now that doesn't mean they aren't' but in this analysis, no evidence. So they remain all of them, you know, at the same of uncertain benefit, something to be tried when you're desperate. Okay?

So the next question was - and this was actually some of this is at least a little more controversial. So how - this was the question of how many drugs and how long.

So the - I'm going to talk about the initial intensive phase which is usually defined when you give injectables and the continuation phase - again, just to make sure everybody's on the same page - and then total therapy.

Okay. So number of drugs to which the patient was apparently susceptible. What you see here is, so the numbers treated. These are smaller numbers because we didn't have information on - sometimes we didn't have MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 31 information on what people got in the initial phase or the continuation phase. Just a total number of drugs given, that sort of thing.

So what you have here is a reference group. So zero to three to which they were susceptible. So some centers had very limited drugs available obviously and they would end up treating people with, you know, four or five drugs but they were actually resistant to all four or five. So they could end up with zero apparently effective or should be effective. Up to three is our reference group so that's a reference of 1.0.

What you see is that with four drugs or five or more you get a very similar almost a plateau-like effect. So the odds of treatment success were about double whether you gave four or five or more drugs. So the conclusion was four is enough, okay, from this. You always want to give enough but when you give more than enough you just add toxicity for nothing.

So the same for the continuation phase and here it was three. So three in odds of cure of two and a half compared to two for example in the continuation phase. So drug sensitive TB we give two, and we're happy with that, but looks like you should probably give three. That should be effective according to DST. And four or more, it's just again it kind of it didn't seem to matter to give more. So three's enough.

Okay. What about the duration. So here, actually, this was sort of the product again of several evenings of delight of trying to slice this because I started out with fairly broad categories and didn't like that. But suffice it to say that the final analysis, what you see is that with one to two and a half months initial intensive phase a very short, you know, two months of injectables. That's our reference group. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 32

So up to four months, two and a half to four months not much better; but as you get over four months of injectable you see an improvement, a significantly - they're doing significantly better than if they got only the short amount of therapy. This is the injectable.

And it keeps getting better until you reach seven to eight months. So it's a long period of injectable therapy. More I don't know whether here or the standard is six month or it's post-conversion or what's your practice. But seven to eight months is a long period of injectable.

But consistently and actually there was quite a bit of controversy on this point but for months after the meeting and because people viewed this as longer than the current standard and was it real and was it correct.

And so I did multiple secondary analyses, sensitivity analyses, the group that got quinolones, the group that didn't get quinolones, adjusting for other drugs, adjusting for a number of drugs and consistently this time period around seven, eight, nine months came out as always the best chance of success.

So that's current guidelines actually that suggest that. And then there's total duration of therapy and here - so here it's around a year. Sorry, not a year, two years. Okay. But you see that it sort of jumps around a little more, but still you're looking at about two years total therapy. Same idea. We're looking for kind of the maximum odds.

You notice that the odds kind of fall off again as therapy gets longer and longer. Of course because some people you're going on and on because they're failing and that's why you carry on and on and on because this is actual duration of therapy. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 33

Okay. So current recommendations was the 2008 recommendation and so the initial phase was three to six months and when I say IPD evidence - and this is the evidence that I've just showed you - by and large this was what was adopted at the current WHO recommendations.

So initial phase is seven to eight months for effective drugs, continuation phase, again, eighteen to make a total of two years with three effective drugs. The fluoroquinolones especially the later generation were emphasized, Ethionamide, Prothionamide and, again, Kanamycin in preference to Capreo with the caveat of Kanamycin sensitivity.

Okay. So before I go to XDR, I'll stop there and see if there's questions about MDR.

Dr. Michael Lauzardo: I have a couple of questions. One came in online so I'm going to put my new addition to my face here with the glasses. This was earlier they came in and it came in from Dr. Richard Wing where it says three recent reviews of ineffective MDR TB treatment, what countries were those done in? It says that our experience in the financial and TB program, Texas, Mexico, has cure rates of about 85%. Our biggest problem is abandonment due mostly to drug and alcohol use.

I guess the heart of the question is when the three recent reviews of ineffective MDR treatment, where were those studies done?

Dr. Dick Menzies:In total, there's 67 different studies and they're done in, you know, 30 or 40 different countries. They're all over the world. I would say five or six would be from the U.S., a couple from Canada, Europe and so on. But easily half of them would be low and middle income countries. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 34

So the other thing I'd say is if you discount default and death then the treatment success rate, just treatment success versus failure relapse, are 85 to 90%. But if you count death and default then your total, your true success rate, because you do have to count those is probably 50 to 60% and, you know, even in the best of series.

Dr. Michael Lauzardo: There's another question here.

Elena Hollender: Hi, Elena Hollender. You mentioned that there was a high degree - I have to grow.

Dr. Michael Lauzardo: Sorry, Elena.

Elena Hollender: You mentioned that there was a high amount of underlying PZA resistance which struck me. Were the M tb complex associated, in other words were some of these bogus as opposed to...

Dr. Dick Menzies:I think - So, sure. But a lot of patients of course either - first of all two-thirds of the patients have been previously treated so they would have received PZA before. Of course many of these were treated in settings for others. DST are not done until they failed or failed several times.

So they could have come in with MDR, INH and RIF resistance but sensitive to PZA and Ethambutol then they get standard treatment and of course become resistant. They acquire additional resistance to PZA or Ethambutol.

And then they're in settings - I mean, again, some of these settings in Russia, primary MDR-TB will come in five drug or six drug resistance right off the bat coming out of prisons or wherever. So I mean, I think the PZA resistance MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 35

is just a marker of a lot of previous therapy, inappropriate therapy in the community.

(Elena Hollender):Just a thought, because since so many countries don't have the exact standards to get out all the bovis, I was just wondering whether that played a factor in it.

Dr. Dick Menzies:So it's a good thought. Most of the series from lower middle income countries, you know, when they did define it as MDR-TB they would do some speciation. They, you know, what methods they used varied of course so they would usually say, you know, this is M.tb in all patients and that sort of thing. They'd made a statement on that.

Elena Hollender: Okay. Thank you.

Man: I think mostly it's MTB.

Dr. Michael Lauzardo: Another question in line is what is the best fluoroquinolone for meningeal TB?

Dr. Dick Menzies:Okay. That's pretty - I still think would be Moxi. I would use Moxi in preference.

Dr. Michael Lauzardo: It's my understanding they all have similar (demonstrations).

Dr. Dick Menzies:So I'd use the one with the most in vitro activity.

Dr. Michael Lauzardo: And Jerry Jean?

Jerry Jean: Did you look at the regimen in relationship to location of the infection? Was it CNS or was it bone or was it other? MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 36

Dr. Dick Menzies:Sure. So we actually ended up because the number of people with extr- pulmonary TB was very small. We have 120-something patients with only extra-pulmonary TB. The difficulty in that group is that microbiologically it's much more difficult to prove cure or failure because you have to re-biopsy them or whatever often. So we actually ended up excluding that group and we - so this is really pulmonary MDR, this analysis focuses on. We're hoping to do that in another run.

Dr. Michael Lauzardo: And here's a loaded question from online that I think is probably a topic of a whole separate grand rounds. It said can you extrapolate any of this data for treating LTBI context MDR cases.

Dr. Dick Menzies:So my recommendation - I'll go out on a limb here - I would use a fluoroquinolone unless the index case has documented fluoroquinolone- resistance in which case I'm not sure what I would do in that case. I would - what we do in Montreal, based largely on the evidence that fluoroquinolones replace INH very nicely in active TB and they're very potent in vitro and they're obviously very potent in MDR-TB, I use fluoroquinolones alone.

Dr. Michael Lauzardo: For how long?

Dr. Dick Menzies:Six months.

Dr. Michael Lauzardo: And the six months is from...

Dr. Dick Menzies:That's a guess.

Dr. Michael Lauzardo: That's a guess. Gotcha. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 37

Dr. Dick Menzies:That's an expert opinion. Well, a non-expert opinion. A self-declared expert.

Dr. Michael Lauzardo: And you will do fluoroquinolones alone? You'll not use a companion drug, say PZA.

Dr. Dick Menzies:No. I think that PZA - first of all in latent TB you only need one drug. So you're just treating yourself by adding a second drug and you're definitely adding toxicity by adding PZA.

Dr. Michael Lauzardo: Absolutely because in our experience there's been a huge jump in toxicity when you try to give fluoroquinolone alone versus fluroquinolone with PZA or PZA and EMB if there's a way you can get around that. So we use fluoroquinolone. But in general we shoot for 12 months. If there's any intolerance we call them done whenever we get them through at least 6 months. 12 is what we shoot for and again we make that number up as well.

One other question. Heidi, can you go to the mike, Heidi, please?

Dr. Dick Menzies:The online people. I can hear you.

Heidi: Would you just since now we're into this new presentation of LTBI, would you use it for kids, fluoroquinolone?

Dr. Dick Menzies:That's interesting. I know that the experience like in South Africa where they treat a lot of MDR in kids is they use fluoroquinolones in the kids. But it's a little dicier with LTBI because it's sort of - you don't have solid evidence whereas an MDR you're treating a life-threatening disease. But they have very good experience with really no serious complications in the kids. They have reported on this actually their experience. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 38

Dr. Michael Lauzardo: And there's decent data in the U.S. from children treated with CF where fluoroquinolones are safe. I mean, you need to be careful and you need individualized therapy but our approach has been to use them when there's been a significant exposure and documented conversion. But, again, there's not a lot of data to support it but that's been our practice. And, again, with sketchy data that's the best we can do.

All right. And one more question from online before you move on. It says are you suggesting that even if organisms are sensitive to EMB and PZA, these should not be relied upon in the continuation phase along with a third drug such as a quinolone.

What if the patient has shown serial intolerance to PAS, Cycloserine and Ethionamide and these have been dropped out at different phases of treatment?

Dr. Dick Menzies:Okay. Well, that's obviously hard to individualize but what I am saying is the data suggests that PZA and Ethambutol are weak drugs in MDR-TB. Exactly whether their individual circumstances that I would use them sure especially in the scenario you're describing where the other drugs are not - you can't count of them but if - are they the only companion drugs to the fluoroquinolone, I'd be worried about that. I'd try to find a fourth drug.

Dr. Michael Lauzardo: One question since - that I had looking at when you're talking about duration of therapy on one of the last few slides. I found this remarkable that in the continuation phase when you only get zero to two drugs, you know, you had the big jump in success with cure rate when you went into three drugs or more but you still had a cure rate when you had zero to two drugs, you still had a cure rate to which there was demonstrated susceptibility saw the cure rate of 81%. That's pretty high. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 39

So I’m just curious as to what your thoughts are and why that cure rate was so high if you still use it in a continuation phase only zero to two drugs to which there was demonstrated susceptibility. Unless I misread the slide but I thought there was 81% cure rate and the others jumped up to 93 or so.

So when I saw that I wondered if maybe there was some sort of selection bias or something there that would skew that because that's higher than what we see in many instances even when there's more drugs used.

Dr. Dick Menzies:Sure, so, there's a couple of things. First of all some of those people may be getting two drugs instead, you know, two drugs to which they're susceptible. The second thing is that these are often susceptibility tests to group four drugs and even Ethambutol and PZA that are less reliable.

When you give more drugs to which they have in vitro resistance you're betting on the chance that the invitro test is wrong. Like when you have nothing else and you give a bunch of drugs to which they seem to be resistant, we've all seen some patients get better. Is that because the test is wrong or is there some synergistic effect? We're not sure.

So, I mean, even if you have someone with across the board resistance as I'll show in a bit, you still end up giving a bunch of drugs and some patients although fewer get better.

Dr. Michael Lauzardo: And I think it's important to add that more resistance doesn't mean 100% of the organisms are resistant. It's anywhere depending on where the test if done anywhere from 1% to 100% of resistance. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 40

So you're going to get some benefit even if there's quote unquote demonstrated resistance and that's some of the sort of squishier area I think of the science in regard to some of the treatment there.

Dr. Dick Menzies:But I mean things like the group four drugs are notoriously unreliable in terms of, you know, you go to one - even good labs, you'll go from one lab to another, same isolate, one lab will declare it susceptible, the next one resistant.

So there is always, you know, you're better to bet with the drug sensitivity test results if you've got enough drugs. But when a patient is resistant to more and more drugs you still may fall back on the possibility of adding drugs that they have in vitro resistance to, especially if they've never taken them before, and maybe you're not going to count them but you still get them.

Dr. Michael Lauzardo: So just one last one and we move along to the next phase. The topic says Is Kanamycin better than Capreo - is the fact that Kanamycin is better than Capreo been supported by in vitro or animal data? And this is from our colleague Ed Kahn sends this in.

Dr. Dick Menzies:Okay. That I don't know. I'll keep the answer short,

Dr. Michael Lauzardo: Gotcha. All right. Okay. With no further adieu we'll keep going and get more questions here at the end.

Dr. Dick Menzies:Okay. So XDR. I think everybody's heard about this epidemic or this outbreak that occurred in South Africa but I'll just kind of review the situation in South Africa for those that are less familiar. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 41

So first of all the incidence of active TB disease is 1100 per 100,000 annually in South Africa. So that works out to 1.1% of the total population of the country develops active TB every year.

And if you think that most TB is in the 15 to 49 age range, that's probably 3 or 4% of that population of TB every year. So that means everybody gets TB there pretty much at least once, right, when you think about it. Some people more than once.

Of course most of these are HIV-infected cases and the - but the sero- prevalence of HIV in some communities in the general population again - I’m sorry - 15 to 45 year olds can be 30% anti-natal clinics would be higher. So a really raging sort of epidemic - dual epidemic going on.

The other thing that's going on in South Africa is that it's a rich country really. There are great disparities but nevertheless it's a rich country so all TB drugs are available, first line, second line, you name it, it's available.

And there are huge problems with non-completion, default. I saw a randomized trial - a couple of randomized trials that were done there and usually in randomized trials you see optimal conditions, right, more staff, more - everybody's very involved, motivated.

So you tend to see sort of artificially high completion rates. Completion rates for 60% in the study and there are clinics - in fact I got one data set from South Africa - I won't say from who - but the default rate was 50%.

This was an MDR mind you, but 50% defaulted and most of the rest where there was an outcome had died. So there was very- they were either dying or defaulting. So very, very disruptive program, chaotic. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 42

So in this setting - and, again, I don't have a slide on this - but I saw someone give a talk on MDR in South Africa at the King George Hospital in Durban and they had showed slides back to 2000. There were one or two cases of MDR TB and by 2010 they had 500 cases a year.

So they had gone from almost no MDR and almost all of their patients also had been a complete transformation from drug sensitive to MDR. Now they are a referral center but still an enormous increase.

So in this setting where MDR is treated but there's a lot of default where drug- sensitive TB is treated, there's a lot of default, you can imagine - and there's a lot of HIV to help with the transmission and generation of an epidemic - that outbreaks occur regularly.

And so sure enough they had this outbreak. 80 HIV infected patients at a single hospital and they all came down with the same strain of TB and 79 out of 80 died. So extraordinary mortality.

Of course they didn't realize as with the - sort of the like the MDR epidemics in the U.S. and Canada in the late 80s - people didn't realize until the thing was upon them that they were in the midst of an MDR epidemic and people had already died before they realized it was MDR. This was the same. They didn't realize it was XDR until most of them had died.

So in the data set that we have - first of all, XDR just to define it is MDR plus resistance to fluoroquinolone and at least one second line injectable. Okay? So Kanamycin or Capreo. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 43

So the data set that we had established was for MDR-TB with the 9000 patients of MDR low and behold in the same data set they turned out with 410 with XDR.

So in fact, even though - and this actually happened around the world. People described XDR in South Africa, everybody was excited about it and everybody went back to their own data set and realized, oh, gosh, right? Happened I'm sure here. You realized you had XDR patients and you had already them. It had been occurring.

So indeed we had theses 410 cases. So in the data set because we had this group unbeknownst to us before that had XDR we had a chance to look at this group and see what (were) they like.

So it turned out they had 410 with XDR. We had 424 that had MDR. They all had MDR but they also had fluoroquinolone resistance and we had as you see 1100 that had MDR and had a second line injectable resistance but not fluoroquinolone. They were sensitive to fluoroquinolone. So we had a sort of this kind of intermediate steps plus XDR. So you look at that kind of in groups.

So the first question was well, let's just compare the characteristics. All right. And what you see is that first of all amazingly enough some people caught XDR and was primary XDR so that's really bad luck. Some of it may have been nosocomial or prison-related, hospital or prison.

But you see fairly consistent. The only real difference was that the XDR were more likely to have been previously treated for MDR and either failed or defaulted (almost a quarter) compared to only 7% of the MDR. And you see a bit of a transition across there. I've got to press this button. Transition across. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 44

But what about outcomes? Okay. So, again, this is a fairly busy slide but really what you want to look at is this cured line. So XDR on top. MDR with injectable resistance, MDR with fluoroquinolone resistance and MDR only.

Now what you see there's kind of a gradient of outcomes. So in the XDR group 40% were cured and a much higher number failed or died. Again, that's kind of consistent. So still 40% cure rate.

On one hand you can say, well, that's terrible which it is but even 40% given how the bad the resistance is is not so bad. But interestingly 48% cured with quinolone resistance, 56% with the injectable and 64% if they only had MDR.

So clearly one thing that drives response to treatment is how much resistance you've got to these other key drugs. And you can see the importance of fluoroquinolone resistance. That's - when you're at fluoroquinolone resistance you are cure rates are not far from XDR but there's a bit of a difference. So it really suggests each drug is important and both in determining prognosis and therefore in presumably in treatment.

Okay. So the analysis of the number of drugs - the specific drugs I had not - I’m not able to do because 400 patients seems like a lot but it's still not enough. They're too scattered across many centers and so on to do the same kind of analysis.

So but I was able to do things like number of drugs. So here now instead of four drugs you need six drugs or more so basically as many drugs as you can find to give to XDR in the initial intensive phase. And in the continuation phase four more. So just kind of a bit of a step up from MDR that four or three are now at six and four. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 45

Duration again a little harder to do accurately and the odds are kind of crazy here because . . . they are a little better but still in the same range. And, again, the groupings are a bit broader, just smaller numbers. But looks like somewhere around seven, eight months seems to be optimal.

I think have total therapy as well. No, sorry. Totally therapy interestingly around 20 to 24 months. So not that much different really. But it doesn't seem as though that initial intensive phase needs to be long with a lot of drugs, obviously an injectable with difficulty knowing what injectable. Typically again with XDR you may have some sensitivity to Capreo or Kanamycin. You don't necessarily have both.

And I don't think I have too much more than that. So that's it for XDR. A more limited analysis, just not - you just can't pull that much more out of it. But clearly you can see the importance of fluoroquinolone resistance and the second line injectable resistance each contributing to the prognosis. Okay? And then - yeah. So XDR questions?

Elena Hollender: I couldn't let you go without an XDR question. You were talking about in the study the number of drugs that they had on board zero to two, three, four and five and more. Five to eight drugs, it would be difficult to think that an XDR could have saved five drugs to which it were susceptible.

Dr. Dick Menzies:So some of this is also the group five drugs where if someone has got a group five drug there is usually no DST for that. We have to count those as likely effective.

Elena Hollender: Okay. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 46

Dr. Dick Menzies:So someone here could have had a bunch of group five drugs and maybe just a sheer number of drugs to give you more. But as you see there's quite a range of resistance in the next few slides so, you know, you may be resistant to XDR but sensitive the group four drugs for example and then get all of the group four drugs. Or you get a bunch of group five drugs which are really unmeasurable in terms of their, yeah.

Elena Hollender: Even say group five drugs which have minimal effect in MDR may seem to have some component effect on XDR?

Dr. Dick Menzies:It seems as though, yeah, again, I'm just sort of - your interpretation of this data is certainly no different from mine which is it looks like more drugs better, how many drugs is a little unclear and it maybe that you need this many drugs because many of them are borderline effectiveness but taken together they seem to add benefit. And it maybe that these are the group five drugs where you need several to get some sort of benefit out of them. I'm speculating.

Woman: Thank you.

Dr. Dick Menzies:And from our colleagues online. Okay. So I have really one last bit and that's about TDR. So, TDR. So, again, this is one of those things where someone publishes a fairly small report. It was actually a letter really to the editor from India, six patients resistant to all known drugs, at least all drugs to which they could test. And of course the patients had poor outcomes, needless to say, and somehow this got picked up and attracted enormous media attention with the usual you know the sky is falling, the sky is falling kind of story.

It really got really picked up in India because, and so they interviewed the guy who reported this who was working on a private hospital in India, very MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 47 dedicated guy who was treating these patients and he had nothing good to say about the Indian National TV program, and so this then, they ended up they actually suspending his license temporarily in retaliation it seemed.

Anyway eventually this all got settled down and but it was a big media event for, especially in India. The up shot of it was that they poured tons of money, much more money into the TV program than they had before so that was a good thing. So it’s not bad to have you know media attention if you can survive it, money comes later.

Anyway so what is TDR? So, and I was actually at again another of these Geneva meetings and the first question was really well how do you define TDR? So TDR, Total Drug Resistance, but of course total depends on you test for six drugs, seven drugs, eight drugs, nine drugs, right? If you’re resistant to nine drugs and then you got a 10th that’s sensitive oh, you’re not quite TDR.

So it’s, the question really is in XDR we know that XDR does worse than MDR and we have a nice clear definition, Fluoroquinolone second-line injectable, but really with TDR is it different or is it just a bit worse?

And is it different enough that it matters that you should know about it, you should know how to treat it or is it just you know do the same but more, give more drugs?

So the first thing, question to ask was while in this group of our XDR patients, so 400 plus XDR patients, maybe there’s some patients that would be, have TDR, you know do the same look back at the data you already have in hand.

So for this we tried different definitions because again the difficulty in the data set that we have is, comes from all over the world, people test for MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 48 different things, data, different data’s available. So one definition was just resistant to XDR definition plus resistant to Kanamycin and Capreo, resistant to both of those major injectables and resistant to Streptomycin if tested, so resistant to all injectables known.

A second definition was the same TDR, so injectables plus group four and then the third was injectables plus group four plus PZA Ethambutol. So try and look at it somewhat sequentially to see whether did one group of drugs really add or worsen the prognosis then more than the others.

So again we’re back to this study population, almost 9,000, we only had 6,700 where they were tested for a fluoroquinolone in the second line injectable and of those 405 had XDR, which works out to about 6% of the MDR cases.

But by the different definitions of TDR we had 68 that met one definition or 48 or 42, depending a little on how stringent you make the definition. So we had again in this same mega-data set we had some patients that fit that definition.

So the question was well are they different, are they worse off? Clinical characteristics hardly at all.

So first looked at just the resistance patterns, so what we have on the left here is number of drugs to which they’re resistant, to five drugs. So to have XDR you have to be resistant to at least five drugs, okay. Actually, no you have to be resistant to four and everybody resistant to more than four. So as you see this XDR group but not TDR 9% will resist only five drugs all the way up to 11 drugs. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 49

And these different definitions of TDR as you see sometimes they’re still sensitive to some drugs tested but they’re resistant to six, seven, eight, nine, and more drugs, so they’re really bad bugs, right.

And this TDR-3 the most stringent definition again you have about 50% of resistance to ten or more drugs, so highly resistant.

Now again this doesn’t mean they’re sensitive to any of the drugs, they’re resistant but they’re not tested, they’re only tested in one lab to six drugs, so they’re resistant to six but that’s all they’re tested for, it’s one of the limitations of this kind of analysis, there isn’t a standard, right? No one is even quite sure how many drugs to test for, depends on how good your lab is, how much money you have to spend, that sort of thing.

So this group with 29% resistant to six drugs they’ve tested the six drugs, they’re resistant to all six and so on. And down here they’re tested to ten and they’re resistant to all ten. Okay, so a pretty resistant group.

Now how did they do? So the real, the first question was did they do worse than XDR but not TDR? So this slide says the likelihood of cure was 40%, 60%, 50%, so their chances of cure were significantly reduced and when we, when I put together the outcome of failure or death the two and a half to three times more likely to fail or die than XDR, so yes, but what’s interesting is it doesn’t really seem to matter what definition.

So in other words the injectables seem to be key. When you lose all injectables that seems to be the most important turning point in terms of worsening your prognosis. Although just to confuse you when I analyze it slightly differently, just a different method of analysis, so here’s just looking at the cure rate. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 50

So XDR cure rate’s 43%, again I haven’t put the defaulters on here, which was how you get up to 100%, but these the TDR-3, the most, so resistant to Group Four, Ethambutol PZA and the injectables 19% cure rate, which is sort of at the spontaneous cure rate level of the pre-antibiotic era and these others seem a little better. I’m not quite sure, just different methods of analysis, so you have to take it with a grain of salt. They’re all worse than plain XDR.

So yes, so TDR is clearly worse, not surprising, more resistant, worse outcome, but whether it’s just the injectable that matters and beyond that nothing else matters I’m not sure. And that’s all I’ve got for TDR, so no helpful hints on how to treat it because partly there’s not enough patients.

So conclusions, so treatment of drug sensitive TB often, not inevitably, leads to MDR-TB, poor treatment leads faster and in more patients so risk containing regimens were introduced in 1970 and MDR was described 20 years later.

But things are getting faster as you see. Treatment of MDR leads to XDR and widespread treatment of MDR, for example in South Africa, was introduced in 2000. And the first XDR case was described in South Africa in 2006. So that took them only six years to get there. And treatment of XDR leads of course to TDR and TDR is described, although it has been present in 2011.

So really what’s next?

So some of the things that you know we need to think about, first of all new drugs. Unfortunately after five years or more of heavy investment by Gates and others we still have only one new drug that’s even close to the market, which is TMC207, a Tebow Tech drug. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 51

There was a publication in New England about a Phase 2 trial and they’re in a Phase 3 trial now, so hopefully it’ll be ready for prime time soon but it is the only, it is only one drug and of course we know that if we introduce one new drug into this mix it could be bad, right.

There are others in the pipeline but they’re, none of them are even at Phase 2 trials, which means it’s probably five years before we get there. A lot of our better use of existing drugs so high dose RIF is being looked at. Turns out that the reason we use 600 milligrams of RIF, right, a little multiple choice question now, was it because that was the optimal dose in multiple human trials or that was the best dose that seemed to work at the lowest price? Which one was it?

Woman: Option B.

Dr. Dick Menzies:Option B? Correct.

So it turned out it was just barely enough and it was very expensive and so the dose of 600 milligrams a day was literally picked upon as the compromise between efficacy and cost.

Of course now, at least outside I don’t know what it’s like in here, but I mean in GDF six months of RIF costs $10. So that’s out the window but now people are saying well maybe we should double the dose of RIF and we’ll get better results, so that’s being looked at.

Daily Rifapentine is another one, Rifapentine can be given once a week as per the New England publication on latent TB, but daily is very much like high dose RIF, you see higher levels and daily Rifapentine may be a better strategy. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 52

High dose INH of course is known, other combinations of drugs, the group five drugs have never really been subject to randomized trials, we don’t know what might work better.

So we need, what we need are randomized trials and I think we need randomized trials now, that requires leadership, that requires money and that requires collaboration. So collaboration I think we’ve got but we need to see, we need to see even now trials start.

And I’ll just show you the next couple of slides, my last two slides, just to show you where we should be and how we’ve fallen from what I think is what we should’ve been doing for the last 30 years.

So this was from, I’ve done a series of systematic reviews; these are Phase 3 randomized trials in new cases of TB. Phase 3 is treating people right through and measuring failure, relapse, death, and those kinds of things.

What you see is that the peak period of randomized trials is the 1970s. And most of these were funded by the British Medical Research Council; some were funded from CDC and a smattering of others. They were all but two were publicly funded, they weren’t funded by Pharma, not at all.

And you can see there’s a terrible fall off in trials, right. Phase 3 trials have almost evaporated and I think in part it’s because we’ve grown accustomed to Pharma, Pharma funds all the other randomized trials, of course they fund their own agenda but in TB that wasn’t the history, the history was publicly funded, I’m not quite sure why we’ve forgotten that. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 53

And the other kind of even worse slide is this one, randomized trials in resistance or just re-treatment. So this is really again the peak, despite the fact that drug resistance we talk about, it’s emerging, right there was no MDR in the, almost no MDR in the 1970s, no there wasn’t MDR in the 1970s, they just invented RIF.

And yet drug resistance has gone up and up and up over the last 30 years and there’s been virtually no response to how to treat it. So that’s why we’re still muddling along with observational studies, meta analysis that no one can understand, that sort of thing.

So there’s a big need for more work, more effort, and yes you know every single center we have small numbers of patients but multi-center studies are feasible and I don’t think they’re that expensive, they don’t need to be.

So I think this is one of the things at least we need to be doing more of. Thank you.

Dr. Michael Lauzardo: Well Dick thank you so much for a fantastic talk and a lot of times we say that it’s a conclusion talk but I think when you look at the impact that this will have, much of this work, this is going to be one of even your and your group’s bigger contributions, just a better understanding of MDR and where it’s headed, and it’s a very, very key piece.

So I’m going to go ahead and open it up again for questions, questions will be first come first served and we’ll be answering the question in the time that we’ve got, we’ve got about another 25 minutes.

And also I know we don’t traditionally get a lot of calls by phone but also the operator’s going to now provide instructions to ask your questions by phone. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 54

Operator: Thank you. Ladies and gentlemen if you’d like to register a question by phone just press the 1 followed by the 4 on your telephone. You will hear a three- toned prompt to acknowledge your request. Once again if you have any questions or comments on the phones it is the 1 followed by the 4 to register your question.

Dr. Michael Lauzardo: Great. So I’ve gotten a few online here that I’m going to go ahead and, go ahead and give you now while we’re waiting for other calls to come in. This first question is for MDR-TB, that’s actually a two-part question, for MDR-TB that’s susceptible to all second-line agents based on your data what is the optimal four-drug regimen?

Dr. Dick Menzies:Four-drug regimen? So yeah, so that’s a tough one. Resistant to every drug known to man?

Dr. Michael Lauzardo: No it’s for MDR-TB.

Dr. Dick Menzies: Okay.

Dr. Michael Lauzardo: Susceptible to all second line agents based on...

Dr. Dick Menzies:Oh

Dr. Michael Lauzardo: . . .your data, what is the optimal four-drug regimen?

Dr. Dick Menzies:Okay. So second line injectable, so Kanamycin or Amikacin because I think they’re pretty much equivalent, fluoroquinolone clearly, later generation, Avelox, Moxifloxacin, or Levo depending a little on where you are working from, and then I think most people still recommend PZA Ethembutol if you’re MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 55

sensitive to those but I would certainly add a group four drug, so probably Ethionamide would be my bet.

Now there is a fair amount of resistance in vitro to Ethionamide, there’s cross- resistance with INH, which is real so if they’re resistant to Ethionamide then Cycloserine.

Dr. Michael Lauzardo: And then the second part of that question is any data or role for Linezolid in drug resistant TB, and I know that wasn’t part of your analysis per say but any comments on that would be very helpful.

Dr. Dick Menzies:Yeah.

Dr. Michael Lauzardo: Oh that would be very helpful I think.

Dr. Dick Menzies:So that’s a good question because we don’t have, this data set very, very few people got Linezolid in part of because of cost and it’s a relatively new drug, people just haven’t been using it. I think there’s growing experience with Linezolid looks like it’s a pretty effective drug.

So if you can afford it, again I think the cost puts it prohibitive in many countries, then I would certainly try it, but the difficulty is I, you know you’re skating on thin ice to know how many companion drugs to give and that sort of thing.

Dr. Michael Lauzardo: Right. It’s tough, I know and Jerry Jean, you can comment to this, and Elena as well with the increased use of Linezolid here we’ve been using it more based a lot on experience of our colleagues in California, Gisela shector and the group in San Francisco and the others in California have used it a lot more and they’ve had very good success with less toxicity and I know we’ve MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 56

had more use of it here and good outcomes with that as well, so I think that’s been very helpful.

Dr. Dick Menzies:Yeah. The other thing is the Korea published that, Korean group published a study using a lower dose of Linezolid, 300 milligrams a day instead of 600, and actually had very good results and much less toxicity.

Dr. Michael Lauzardo: So as far as results, as far as culture conversion and cure.

Dr. Dick Menzies:Culture conversions and cure rates, yeah.

Dr. Michael Lauzardo: Wow.

Dr. Dick Menzies:And giving it for like 18 months.

Dr. Michael Lauzardo: Wow that’s good.

Dr. Dick Menzies:Yeah.

Dr. Michael Lauzardo: And then someone had asked what classifies a drug as a group four or five, I know that was on one of your slides but I think it will be a good review...

Dr. Dick Menzies:Okay. Sure.

Dr. Michael Lauzardo: ...again to kind of go back over it if you would.

Dr. Dick Menzies:So the group four drugs are drugs that were really previously used and demonstrated actually in previous randomized trials in drug sensitive TB to effective. So PAS is known to be effective in drug sensitive TB from trials in MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 57

the 50s, Ethionamide the same and Cycloserine the same, so they’re all drugs that have reasonable proof of efficacy but from studies from a long time ago, not really an MDR per se.

So they are known to be effective but they’re all more toxic, and/or poorly tolerated hence they’re relegated to second line status.

The group five drugs on the other hand there’s no human data that really shows their efficacy from any sort of randomized trial. And so there the drug, even Linezolid is considered at the moment a group five drug but it includes high dose INH, it includes Clofazamine, it includes, which is an effective drug for leprosy, but it’s just not clear that it works for TB, Moxi Clavulin, the Macrolides.

Again the Macrolides in vitro tend to have you know form resistance in vitro yet people have tried them, you know in human studies, but only in observational studies.

Dr. Michael Lauzardo: And you mentioned high dose INH as a group five, what are, define high dose for the group if you may?

Dr. Dick Menzies:So high dose would be double or even triple in some places the dose of INH, so 600 milligrams a day daily or 900 milligrams a day with a fair amount of Pyridoxine. But again I, in this series that I looked at we have too few patients that receive that to be able to analyze it separately, but we couldn’t discern any real benefit.

Dr. Michael Lauzardo: Benefit from that, and you didn’t collect data necessarily on toxicity necessarily? MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 58

Dr. Dick Menzies:No. It wasn’t, it wasn’t, we had some data on toxicity but because it was so, it was hard enough to get a uniform definition of treatment outcomes and the definition of side effects and who stopped for a side effect and how severe they were, that was very poorly standardized from the data set.

So it's tended to be a limitation if you will of this analysis. And we've gotten a sort of a shower of Linezolid-related questions that have come in. I've answered most of them.

But they're teasing through this one question, there is one thing that we haven't talked about is that any impression of the performance of Linezolid in these regimens. And can speculate on its potential role.

Dr. Michael Lauzardo: You already touched on that a little bit. But if you can go into maybe a little bit more depth as to what this caller wanted to have?

Dr. Dick Menzies:Sure. Well again I think probably the best; the biggest published experience is this series from Korea, which I'd have to send you the reference later. But it's actually one of the data sets in here.

Where they used 300 milligrams a day, daily, but for 12 to 18 months. They had good success rates and low rates of hemato - you know, the big ones are hematologic and neurologic toxicity.

But they used, you know, they still use sort four or five other drugs. So it's just part of this multi drug regimen. Which again makes it hard to separate out, tease out the effect of Linezolid.

Certainly would be ideal for a randomized trial. I know CDC did a very preliminary trial in South Africa using Linezolid for the first four months. But MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 59

I know that trial was quite limited in terms of numbers of patients. It was more like a pilot study that never got off the ground.

Dr. Michael Lauzardo: So, we have a question here. Yes, Elena.

Elena Hollender: I have two questions. Did any of the sites, the contributing studies, it would have been probably North America or Europe, do any pharmacokinetic collecting data on the patients and, besides us . . . ?

. . . And if so, did it correlate at all to outcome?

Dr. Dick Menzies:Okay so I didn't analyze that. In fact we didn't really specifically ask for that kind of information, knowing that it would be fairly limited.

Obviously we had A.G. Holly, we had data from Denver. So I'm sure, you know, some of these centers, and from Peru, some of the partners in Health might have done some.

But I didn't analyze it because, you know, there wasn't enough - there weren't patients, there weren't enough centers.

Elena Hollender: Okay that would be interesting. And the second question, one of our experiences here is depending on the lab that we're getting the results from, the levels that they test the different drugs at can be all over the place.

Very differing levels. Is there any call for a somewhat standardization so we're talking more apples and apples?

Dr. Dick Menzies:You mean to get PK data? MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 60

Elena Hollender: For testing the susceptibility.

Dr. Dick Menzies:Oh, okay, I'm sorry. Okay yes. Actually I was just, truthfully I was just at a meeting where again we used this data to look at trying to standardize (it's actually that) for second line drug testing, drug susceptibility testing.

(Elena Hollinger): Even for first line.

Dr. Dick Menzies:Right. So if Ethambutol and PZA was part of, was on that agenda, and I mean I'm not a lab person so I can't, you know, fill you with all the technical details. But yes, they were trying to come up with standardized procedures. And particularly critical concentrations for all of the drugs, second line drugs.

And they will be, you know, those recommendations will be forth coming. In terms of not only what to test for, which may more may not be, you know, what you follow.

But also the critical concentrations to use that seem to be the most reliable and etcetera. Yes so that's coming.

Elena Hollender: Thank you.

Dr. Michael Lauzardo: You have other questions. I'm good to go ahead, go ahead. We've got time.

Woman: No. I just wanted to know, in your studies that you had and the collection data that you had, and mine is on the public health end as far as incarcerated people, internationally and in the whole group of people. Do you have a percentage of what people were incarcerated? MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 61

Dr. Dick Menzies:So first of all, we didn't collect information on that sort of methods. So there's incarcerations to ensure compliance. Is that what you mean?

Woman: No. Incarcerations as a risk factor.

Dr. Dick Menzies:Or...

((Crosstalk))

Dr. Dick Menzies:Okay so we didn't collect that information. You know, some of the centers in Russia of course would have had a fair proportion of the population would come from there. New York City perhaps. I'm not sure about here.

But we didn't actually collect - we collected information on previous treatment history. But didn't collect information like in the primary where they would have got it from. We don’t have that information.

Woman: Thank you.

Dr. Michael Lauzardo: Got several online questions that have come in. This first one is do you have any data on the cost of treatment?

Dr. Dick Menzies:Okay so we didn't again collect information on that. We've done that separately in different studies where we've looked at patient costs. We've looked at obviously the drug costs.

I mean the drug costs I showed a slide ranging from 10 to $20,000 per patient, depending on the pattern of resistance. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 62

We've looked at patient costs in low and middle-income countries. And given the fact that they're often hospitalized for six months and they often can't work for the entire duration, the patient costs are enormous.

Largely because of lost income because they can't, mostly they can't work for the duration of therapy. And then the, you know, the daily DOT and so on, there's a lot of travel and time costs and so on.

Dr. Michael Lauzardo: Right, and that goes back to the New England Journal article that you had way back looking at to the cost of DOT in other countries and the impact on the US and Canada actually from those costs.

Dr. Dick Menzies:Right, right. But there, you know, the cost investment in new cases. But when you look at MDR patients and how much they pay out of pocket and how much they lose in terms of their income, there the costs are enormous.

And then of course you look at the hospital costs, you know, six months of hospitalization typically. Again the health system costs are huge. So you're looking at thousand and thousands of dollars from a patient point of view. And also thousands and thousands of dollars from a health point of view, not counting the drugs.

And the drugs now a days, through global drug facilities, the cheapest regimens out there are still $3,000 to $4,000, even in a low-income country.

Dr. Michael Lauzardo: For total treatment or for per year?

Dr. Dick Menzies:The total treatment, but for an MDR case.

Dr. Michael Lauzardo: Lowest cost. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 63

Dr. Dick Menzies:Lowest cost, $3,000 to $4,000.

Dr. Michael Lauzardo: Wow.

Dr. Dick Menzies:So it's huge.

Dr. Michael Lauzardo: Another question is that did data allow you to compare the effectiveness of the injectables when given IM versus IV?

Dr. Dick Menzies:No.

Dr. Michael Lauzardo: And if a patient, another question is that if a patient is resistant or intolerant of the second and third line drugs except PAS and Quinolone, would you continue the injectable beyond seven to eight months of tolerated?

Dr. Dick Menzies:I think I would, if really you had no other option. You know, I think that they are important drugs. You know, it's hard to, I mean it's hard to make recommendations about very specific situations where you're losing a lot of drugs for intolerance or resistance.

And then what are you left with? And so on. A little bit this data sort of gives you some principles to go by. And then after that you're still, you know, it's still an individualized approach as to what's the most important.

I think again, you have a sense of the number of drugs you need. So, you know, try to make that number of drugs. When you're trying to reach three drugs in the continuation phase; and you're balancing a Group 5 drug with very uncertain efficacy versus a injectable with more certain efficacy, but also more certain toxicity. That's a very individual patient kind of decision. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 64

Dr. Michael Lauzardo: Yes. And you've got to have very good reasons I think to continue and push your luck I guess with the injectables beyond seven, eight months. I think they're toxicity becomes a real issue with anybody, no matter how healthy they were up front.

Another one from online, and then I'll get a couple from the floor here. And this is a little bit of a longer question. And promise I will share it. I'll go ahead and read it word for word.

The biggest issue in MDR-TB in this caller's mind was the relentless and needless creation of drug resistance when physicians and public health systems are aware of the factors that lead to drug resistance.

The caller states I don't pretend to understand the motivations of those responsible for this disgraceful situation. But it does remind me of a thought articulated by a physician who wrote a paper two years ago about why patients in Bolivia died of TB.

He commented that what might really be needed is DOD, directly observed doctors. So I think that's a very enlightening point in many ways. And I think a lot of times it's very easy for us to kind of point the finger at the patients and non-adherence.

But non-adherence, you know, it's a double-edged sword. It cuts our way on the provider’s side and physicians side, as well as on the patient side. So I think that's one good use of DOD where we can actually use that as a positive encouragement here.

So Jerry Jean, another question? MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 65

Jerry Jean: Yes. I would assume that we're still stuck with critical concentrations for TB drugs as opposed to using MICs or MBCs that we used in other diseases. You'd see from your lab meeting or others that there is any chance of us ever getting to an MIC?

It looks like we may be throwing out some perfectly good drugs if we could adjust dosages to overcome MICs instead of...

Dr. Dick Menzies:You mean individual patient, or individual bug I should say?

Jerry Jean: Both.

Dr. Dick Menzies:Okay that's interesting. They - I, again partly because I was, anyway I didn't hear. They were trying to use the published literature to establish kind of evidence-based guidelines.

And the published literature in TB, as you know, is largely based on critical concentration. So they were looking at the reliability, reproducibility and so on of different critical concentrations.

And then the correlates of those with, you know, human response. And the only data they have for human response was really this data set because there's virtually no other data where you've got drug sensitivity tests.

And so the critical concentrations were again, what we had from the individual labs.

Elena Hollender: From an ID point of view, or maybe the token in and among everyone who's listening. But and – owning into what Jerry Jean said, I mean there's really no MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 66

other bacterial disease really that we would accept not having MICs for the drugs.

I mean, you get any biogram now and you're going to have the MICs of the drug and its interpretation. I mean that's what we were getting at. It doesn't necessarily make sense if for TB we're looking at critical concentrations instead of more the standard of MICs.

Dr. Dick Menzies:Okay. Well I definitely don't have the expertise to comment on the issue really. All I know is that the limitation that we have at the moment is that the published evidence or the available evidence is all based on critical concentration.

So for example, this data set of 10,000 people, we have information on drug sensitivity testing using critical concentrations.

To use MICs may be much more logical and sensible. But you would have to almost start over. You would have to produce, you know, a series of 100 or 500 or whatever patients.

And show that your outcomes correlated well with use of the drug, not use of the drug and the MICs that you have. Do you know what I mean?

So it's a - you've got a - you may be absolutely correct. But you've got quite an up hill road ahead of you to prove it.

Dr. Michael Lauzardo: I have another comment from online that one caller sent in by email and said that they did an analysis in their state about the cost of treating one case of MDR. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 67

And this included drug costs, hospitalizations, case management, the whole, the full Monty. It was $700,000 for that state to treat one case. So that's higher than what's been published.

But certainly not unreasonable when you think of the extensive costs and some of the challenges, particularly with some of the lower incident states that might have to have other resource pulled in that are not already established.

So an interesting point. But I want to shift the discussion if I may. Take a question and sort of get two points that really kind of follow along one theme. Is that at the end of your slide you talked about randomized clinical trials?

And talked about sort of what's there as far like what exists. That along with the issue of lab scale up around the world in higher incidence countries because now you've got the issue of more countries doing susceptibility testing, cultures and susceptibility testing. And then kind of dealing with the consequences of that.

Can you comment on two things, both related. One, what's the way forward to sort of help with lab scale up because we're talking about a huge investment potentially? And how to strategically address that with say key reference labs or how that could be best addressed?

And then also with the idea of randomized clinical trials, in the US we have a limited number of places that are capable of doing high-quality randomized clinical trials. It's a lot of infrastructure, good clinical practice, all these things are really challenging.

When you take that into a very low resource setting, some people have done it marvelously and done a fantastic job. But how do you scale that up? And MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 68

what's the way forward to be able to scale up those two things simultaneously?

Dr. Dick Menzies:Sure. So first of all, as you know, there's a big global lab initiative, GLI, actually chaired by Rick O'Brien. And they are pushing to expand, you know, super national lab networks, establishing new regional labs.

So in, for example in West Africa there's as new lab in Benin that is now the regional reference lab. Establishing national reference labs and getting them up to speed.

And then region - within the country, again regional labs that can perform drugs sensitivity testing. Expansion of things like Gene-expert, which gives you at least rapid testing and diagnosis for MDR-TB, especially in South Africa and Eastern Europe and places like that.

So there's quite a lot of initiatives going on in the lab side. I would say the diagnostic side of TB has advanced a lot in the last decade. And in part that's regulatory. It's obviously a lot more difficult to get a new drug from development to use in humans.

Right, there's a lot more steps involved, which appropriately so than a diagnostic test. People don't have to swallow the diagnostic test. They don't have to show safety and all this other stuff.

So I would actually say that the challenge more is establishing the network of investigators and the network of centers. As you say a good quality randomized trial requires a trained infrastructure. MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 69

On the other hand, you know, I'm personally involved in a latent TB trial in several countries. And although it's, I wouldn't say it's easy. But you can achieve a lot with, you know, a lot of visiting and training and so on, there's no question.

But I think a lot more can be achieved with a lot less money. People talk about 50 million for a randomized trial. I think that's - I think you could do five easily myself.

So I think we're kind of, we think it's too much of a barrier. We think it's too big of an obstacle. We're not challenging ourselves in the TB world. We're not, you know, I mean in HIV they are doing trials in the same countries, trial after trial after trial all the time at communities out there.

And they're not saying oh, you know, we'll have to establish this. You’re going to need a network. They just do it. Roll it out, get it done.

Dr. Michael Lauzardo: It would be great to kind of have those clinical trial sites do TB clinical trial sites since it's the same population and the same places where we want to work. I mean somehow to integrate those two and not just reinvent the wheel.

Dr. Dick Menzies:Yes. No, you don't have to - sure. You won't have to start over. But let's get started.

Dr. Michael Lauzardo: We don’t make the rules. Exactly. So there's one last one online as we're wrapping up here at 12 o'clock. You mentioned poor quality of drugs in some countries. Are the second line drugs provided through a DOTS plus programs an issue of any type? MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 70

Dr. Dick Menzies:So the availability of the drugs is certainly a problem and fluctuates enormously. I think it's even a problem here. It's certainly a problem in Canada where sometimes you can't get cycloserine or sometimes you can't get certainly the capreomycin is another one fluctuating.

There the problem is really supply and demand because the manufacturers exist. But they make the drug, and then even though there's 500,000 MDR cases, there's not an effort to get the drugs out there.

So then there, you know, the drugs expire and they don't sell them. So then they don't make them. So it’s a, you know, there's a real problem of delivery. Of getting MDR treatment into patients – to, delivered to patients in many countries.

Dr. Michael Lauzardo: All right, well I think we're coming to the end of our time together. I think you've probably noticed that I'm not Dave Ashkin. And Dave usually is the one here who's more dynamic than me.

I could almost be self-conscious about it. But I think he's more dynamic than just about anybody I've ever met in my life. As you know, Dave is not here. And also Donna Wegener, who's a very important part of the Grand Rounds series that we do. Neither one of them were able to be with us.

If you guys are listening in, we love you guys and wish you could be here with us today. But I want to thank all of you for your time. We're coming close to the end of our time.

And for those of you online, please complete the online survey that will be emailed to your email address. And again, thank you all very much. And MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESS Moderator: Donna Setzer 04-11-12/8:40 am CT Confirmation # 21582501 Page 71

thank you very much Doctor Menzies for an incredible talk and great discussion afterwards.

Dr. Dick Menzies:Thank you.

Dr. Michael Lauzardo: Oh and my last thing is that there will be no M and M today. It's been canceled largely because Dave couldn't be with us today. But we'll pick that back up at the regularly scheduled time in the future. So thank you all very much.