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MDR-TB, XDR-TB AND TDR-TB, IS THIS PROGRESSModerator: Donna Setzer

04-11-12/8:40 am CTConfirmation # 21582501

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

Moderator: Donna SetzerApril 11, 20128:40 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.



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.



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.



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.



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.



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.



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.



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.



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



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.



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



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



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.



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.



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



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.



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.



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.



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?"



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.



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.



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.



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.



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.



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.



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.



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.



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.



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



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



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.



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.



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.



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



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?



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.



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.



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.



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.



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.



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.



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.



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.



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.



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.



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



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



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.



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.



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.



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.



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.



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.



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



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



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



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?



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



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?



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?



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.



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.



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.



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?



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



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.



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



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.



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?



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



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.

END

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