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Foreign Affairs, Defence and Trade References Committee
30/08/2018
Use of the quinoline antimalarial drugs mefloquine and tafenoquine in the Australian Defence Force

BROWN, Professor Graham AM, Australian College of Tropical Medicine

QUAIL, Professor Geoffrey, President, Australian College of Tropical Medicine

[13:58]

CHAIR: Welcome. Information on parliamentary privilege and the protection of witnesses and evidence has been provided to you. We have your very cogent submission. We are unfortunately going to have to truncate at 2.30, but I invite you to make a brief opening statement before we go to questions.

Prof. Quail : Thank you. Firstly, my qualifications: I hold a PhD and a Master of Medicine; I am a fellow of the Royal College of Physicians and a fellow of the Australasian College of Tropical Medicine; and I have a Diploma of Tropical Medicine. The Australasian College of Tropical Medicine is the leading learned body in the Southern Hemisphere involved in the study and practice of the science of tropical medicine. Its members are medical practitioners, scientists and allied health practitioners working in that field. Many of our members are involved in the day-to-day management of providing advice to people travelling to malaria-endemic areas and in managing people when they come back ill from those areas. So we're very much at the coalface of the science of tropical medicine.

As we're all aware, malaria is one of the most serious and common infectious disease in the world. The Australian Defence Force operates predominantly in areas where malaria is endemic, so soldiers are frequently vulnerable to infection. As is the case in bacteria, where we all know about antibiotic resistance, the Plasmodium parasite causing malaria has a great ability to develop resistance to drugs. This has been the case since it was first discovered in about 1945. Even with the common drugs used today, like doxycycline, mefloquine and malarone, there are areas in the world where there is drug resistance. This is a great worry. We have to keep at the edge of research to get ahead of the parasites. We do need to have clinical trials to test new drugs that act effectively and prevent recurrence.

The Australian Army Medical Institute has been at the forefront of drug research in the prevention of malaria since World War 2, when its findings were adopted by all allied forces in the Pacific area. If you're cognisant of that theatre, you'll know that in 1942 in New Guinea, 96 per cent of the 9th Division had malaria. Brigadier Fairley said to General MacArthur, 'Unless we do something about this, in six weeks we'll have no force to fight with.' So malaria has been a huge problem throughout history and it has affected Australia. That's why we have developed our Australian Army Malaria Institute, which has been at the forefront of research and is of world standing.

Before clinical trials are undertaken, the proposed protocol is subject to rigorous investigation by the ADF medical ethics committee. I've had personal experience of this. I did a study of asthma in the Defence Force about 20 years ago, and I found the process of getting my research through the ethics committee was quite rigorous. They asked a number of questions and it was very thorough. At all times it was clear to me that their primary concern was the welfare of the members of the forces themselves.

I'll mention a few brief facts—although I'm sure you've got all this down—about the two drugs that are in question. First of all, mefloquine. There's no doubt that there are side effects with mefloquine. Five to 10 per cent do experience side effects. They're likely to occur early; they are more common in people with a pre-existing illness; they generally resolve after cessation; and they're dose related. The theory that mefloquine causes long-term neuropsychiatric problems relates to work done with older drugs which were more toxic, and also from animal studies. It's very difficult to extrapolate from animal studies to humans. It speculative unless supported by evidence from human treatment with mefloquine. Based on well-conducted studies of over 360,000 US military, which compared mefloquine with alternative drugs for malaria prophylaxis, the long-term mefloquine toxicity is quite minor. If it occurs at all, it's really topping up pre-existing neurological or neuropsychological problems. It is extremely rare for it to occur long term in someone who didn't have other problems. Thus in any subject with common psychological complaints—anxiety, depression, post-traumatic stress disorder—it is overwhelmingly likely to have existed due to factors other than mefloquine exposure.

As far as tafenoquine is concerned, tafenoquine is an analogue of primaquine. One of the biggest problems in someone travelling overseas is drug compliance. We find this with antibiotics and a number of drugs. In the Defence Force what they used to prescribe for years was daily doxycycline. It is a very effective drug that was developed by Professor Reichman, the previous director of the malaria research institute, and it's been used throughout the world. But it has to be taken every day. Mefloquine was an alternative to that. Sure, mefloquine, as we've said, has this side effect profile, but it really is reasonably clear of side effects in about 90 per cent of cases. If it's taken, mefloquine is taken at a dose of 25 milligrams per kilogram, which is a standard dose. The incidence of severe neurotoxicity is less than one in 1,500. As I said, in almost every case that clears away unless there's a pre-existing psychiatric problem. The advantage of taking tafenoquine over primaquine, which was used to prevent the recurrence of malaria—all of you would be aware of the number of perhaps your uncles or grandfathers or someone who came back from the Second World War or the First World War and they got recurrent malaria. That was because of the parasite sitting in the liver. Tafenoquine can be given once a week, whereas primaquine was given daily. Both of them can eradicate that parasite in the liver. Tafenoquine has been proved—I can't say proved, but there has been no evidence that it has caused any neuropsychiatric problems. It can cause what we call him haemolysis in the blood—that's a thinning of the blood—but you can test for that before you use it. So tafenoquine is a very good alternative to primaquine, because troops don't like taking their drug when they come back and they feel well. If you take tafenoquine, it has a longer action and it has to be taken much less frequently.

I could sum up by saying that we believe that the health of the soldiers is absolutely paramount. They must be protected from malaria, and if they are unwell of course they must be managed in the best possible way until they are well again. But we also say that we do need to keep up the clinical trials, because if we don't do clinical trials we will have this problem of malaria which is resistant to treatment, and as our troops are in malaria-prone areas this is unacceptable.

CHAIR: Thank you very much, Professor Quail. Professor Brown, do you have anything to add?

Prof. Brown : I should continue a little more. We've reviewed some of the submissions and talked to many of our members to draw together for the committee some of the conclusions that we would draw from what's been read. Thank you for allowing us to present. I'm a professor emeritus of the University of Melbourne. It's important to say that I do not represent the views of the university. These are my own views as a member of our professional society. I could perhaps admit to a professional conflict of interest. In the service of our Defence Force my grandfather returned from the First World War to Australia and was never able to work again. So I'm particularly sympathetic to the needs of our Defence Forces, who look after us so well.

With respect to my training, I'm a physician trained in infectious diseases. I've worked in Papua New Guinea and Tanzania. I've completed PhD studies through work in Papua New Guinea looking at immunology. I was an acting professor of medicine in Port Moresby for some time. More recently I became head of the division of research in the Walter and Eliza Hall Institute of Medical Research. Early in my career, after completing training at Harvard University in public health, I came back to Australia to work on malaria here. Later I took on the position of James Stewart Professor of Medicine at the University of Melbourne. I was also foundation director of the Victorian Infectious Diseases Service, which rose after the decline of Fairfield Hospital, and I was responsible for setting up the travel clinic.

As Geoff said, many of our members are right at the forefront of keeping up with the literature and advising. I've published more than 200 papers and I've been on the Malaria Policy Advisory Committee for the World Health Organization and their Global Malaria Program. In the past I was deputy chair and chair of the executive committee of the Roll Back Malaria Partnership, which is designed to control and eradicate malaria.

I came in at the end of the last discussion, so I didn't hear it all. I think this issue of first choice, second choice, third choice is perhaps a little confusing for you. At the time, for example—we're talking about 20 years ago, or even today —of the antimalarial drugs, there's a drug like Paludrine, which you would only use if someone was working in certain parts of Central America. There are drugs like chloroquine, which still work somewhere. There's a drug like doxycycline, which has side effects of skin. In the tropics, for example, the sun exposure is very bad. It can cause irritation and it can't usually be used for women who might be pregnant. Then there is mefloquine. So in terms of the decisions made in the Defence Force, saying what's the best thing to use, I wouldn't even discuss Paludrine with you if you're going to Papua New Guinea. The first choice for US troops might be if the best knowledge said, 'We can't use this, we can't use that and we shouldn't use that.' I thought that might clarify the differences in the discussion about yes, no or don't know.

I'd like to emphasise now that as clinical practitioners our first concern is the welfare of the people who have served the country. Whatever their ongoing health issues are, we want to ensure they have all the necessary medical, social and psychological support to facilitate their return to health. We deal with a lot of people with chronic conditions of uncertain origin attributed to various causes. Many of the symptoms are similar. We need to help people with those sorts of illnesses. I should say that supporting their return to health is important. I haven't read all the submissions but I happened to read a couple in the last few days. I've read several but not all of those harrowing accounts from people who feel that their symptoms were attributable to drugs. So whatever their health status, personnel should be informed about and have access to first-class and clear procedures and pathways which the DVA has set up.

With respect to prevention of malaria, it's really important to note that our troops need to be protected from disease that can progress extremely rapidly from mild illness to death. Geoff mentioned World War 2, but we still see it today. Unfortunately, some people listen to certain unwise opinions—'I don't need antimalarials; antimalarials are poison et cetera'—and then they die of malaria. We must never forget that we are weighing up the risks and benefits of a particular drug versus the potential risk of no treatment and no cover for our troops or our travellers. It's always challenging to raise those things. When I gave the example of choices, I could give you an extremely safe drug, but it probably wouldn't work. That's the decision that the Defence Force is required to make to protect our troops who are looking after our nation.

The other issue that's been raised briefly is that there's increasing resistance of these parasites to the available drugs. Each time a new drug comes in, we know that resistance will eventually occur. As you may know, we're particularly worried at the moment about our region. In the Mekong region I did a consultancy last year. Right now our Defence Force must be saying, 'What do we do if our troops are deployed there on peacekeeping issues?' As has been said, the Australian Army Malaria Research Unit has an outstanding reputation for investigating new drugs. It's not enough to be prepared today; we've got to also be prepared for tomorrow. That's really, really important.

We support the views of others making submissions that there can be side effects from mefloquine, particularly in the short term, and of course the drug should be avoided for people with certain underlying conditions. I would say that the available evidence does not support the view that mefloquine has a major role in long-term neurological consequences. But, once again I'd say, whatever the cause of the disability, we must give support to those who need it. I would also add that, in many cases, it would not be possible to conclude that particular symptoms arising at the same time or after taking mefloquine were caused by mefloquine, as similar individuals taking other drugs had no lesser symptoms. We talk about a controlled trial: one group has mefloquine; the other one has the same. So, if there is an effect of mefloquine, it's probably very tiny, and particularly in Defence forces who are under stress.

I was explaining this to a layperson. For example, let's say, you were trying a new flu vaccine in New South Wales two months ago. You did a three-month review, and some people had nightmares and couldn't sleep and were anxious and depressed. You'd say, 'That's the flu vaccine.' Perhaps it was, but the fact that they were firefighters fighting bushfires with people dying could surely have contributed to the symptoms. We couldn't say, 'It's not the flu vaccine,' but most of us would think it's highly unlikely. That's the sort of example. It's a coincidence of things and trying to work out the underlying cause. So, I would stress the importance of controlled trial evidence that we look at. Many of the symptoms reported are found in other conditions. I'm also aware of certain unproved hypotheses about what might cause these problems, and I think it's important to start with the evidence-based information and separate this away from ideas, opinions or hypotheses, which are terribly important in science but they need to be proved and not confused with opinion.

We would strongly recommend that funds be made available to follow these individuals and that dedicated research funds be made available to investigate the best ways of preventing the known side effects, so that people don't get drugs that they shouldn't have, and also the best way to manage them. We're also aware, of course, of the convergence of symptoms of so-called post-traumatic stress disorder and symptoms that some would attribute to the ingestion of mefloquine. You will see that in many of the submissions, and we'd agree.

Tafenoquine has a different mode of action and different indications, and you will have been made aware that, now in the US, it has been licensed for use for eradication of the liver forms but also as a preventive medication—a different set of side effects. And seeing it's been approved, I think it's very important to say that the huge contribution that many groups around the world made to show its use, including the Australian Army, will help to protect our troops and help people living in those endemic areas. So studies were performed, and they were very successful. We'd add that we think Australian Army Malaria Research Unit has a very fine reputation for outstanding work and, as Geoff said, for their strict ethical standards.

There's just another point for the committee that an awful lot is already being done. Our prime purpose is to help the people who have these consequences following service, and we should avoid making things a lot worse. I've seen situations where certain things are asked, such as, 'Have you ever had a headache?' and then they say, 'That might be mefloquine.' We really have to think first about the people who are suffering these awful symptoms regardless of the cause, and we have to also take care of not putting others or other programs at risk by acting on the opinion, 'Drugs are useless; drugs don't work.' We could have tragic consequences from misinformation, like you would have heard when people doubt vaccinations and we see epidemics of childhood illness. We'd hate the same thing to happen with malaria.

Finally, in the use of drugs, one has to weigh up the risks and benefits, as I've said before. I think also there is a point—where research is being performed, as is a very important part of what is done in our Defence Force and the Army Malaria Research Unit—about the strictest and highest ethical standards. As Geoff said, when he went through the process himself in a different research project, he thought it was very strong. If there is concern remaining about that—and I don't know because I haven't read all the submissions—an independent review like the National Health and Medical Research Council ethics review would make sure that the right programs and the right guidelines were being adhered to.

CHAIR: Thank you both very much. I'd just note that, in your submission, the figure is 35 million people in the last 34 years have used mefloquine as a preventative drug?

Prof. Quail : It would be more than that, actually, but, yes, at least.

Prof. Brown : And it's widely recommended by experts in the field, at certain times, as the best drug. And, if you read contemporary papers, they would say so. We've got to remember that malaria can kill you quickly.

CHAIR: Exactly. I was going to ask you about that because I was visiting a travel doctor, and I said: 'I've been bitten by mosquitoes all my life. Why should I care?' And he said, 'If you get this malaria, you could get very sick or you could die.' And I think he prescribed something called Malarone. Is that just another version of these drugs or is it a different thing?

Prof. Brown : That's another newer combination that's a lot more expensive and is a combination of drugs—

CHAIR: It was expensive; I can vouch for that.

Prof. Brown : I'm quite sure, if it was felt it was better, that that would be prescribed. Did you take it daily? Was that the recommendation that you were given?

CHAIR: For 14 days, I think, I had to take it.

Prof. Brown : Yes, that's right. Once again there are risks and benefits. If you were to read the brochure about Malarone, there will be rare side effects. In terms of the example that I gave, let's say you were doing a trial of that flu vaccine, you would have to say, 'In the course of the study, people had headaches, anxiety and depression.' You couldn't say in brackets, 'And, by the way, there were fires in the middle of it.' So anything that happens in that time, even if you trip over something in the gutter, has to be recorded because it could be a side effect of the drug—

CHAIR: We are pressed for time and I do accept that your evidence is comprehensive. Your statement is very concise and efficient. But what struck me in some of the evidence we heard this morning from one of the witnesses was that you might get 100 people marching through, getting an injection in either arm, with five medics and five trays of medicine. That doesn't seem to be conducive to informed consent.

Prof. Brown : There are criteria for acceptance.

CHAIR: I accept that there might be nothing untoward in that, but is someone taking a decision that this is all good for these people and they just march through and get an injection in each arm?

Prof. Brown : The requirement for informed consent—you would read an ethics statement, for example, of the National Health and Medical Research Council, and what would tend to happen is that each person needs to understand the potential risk of what they're having.

CHAIR: Some of the other evidence was that, pre deployment, they were apprised of the trial and side effects and the like. But, basically, it all came back to: 'We're a unit. We're a team. Our loyalty is to the unit and the team. We've got a job to do.' And it's pretty hard to opt out. How is that addressed medically?

Prof. Brown : I'll tell you what I used to do. In Papua New Guinea, for example, when I'd be wanting to test—and this was on children—I was frustrated when people opted out, but I'd think, 'Well, I am explaining it properly.' The argument there might be that, by explaining it too well and having people opt out, they're missing out on something potentially valuable, but that does explain to me that some people are opting out, and I don't know if certain people did opt out. But informed consent needs to be informed. My understanding from Geoff's experience about 20 years ago—about the time that many of these studies were happening—is it would have been the same thing.

CHAIR: So, if approximately 3,000 people went and 400 people chose not to participate in a trial, they would have taken one of the other versions that were available?

Prof. Brown : In the trial, you randomise: some get this and some get that. If people said they don't want to go in the trial, they're out of the trial and not considered.

Senator MOORE: They took the other one, doxy—

Prof. Brown : Doxycycline. They might have; that's fine too.

Senator MOORE: According to our records, the people who didn't take either of those—

Prof. Brown : Who didn't enter the trial?

Senator MOORE: Yes.

Prof. Quail : The interesting thing about that, as I was saying to Graham before—and I've looked this up—at one stage, they were offered the option of whether they'd like to take mefloquine once a week or doxycycline every day. And the majority said, 'We'd rather take the once-a-week one than the daily one.' There are pros and cons of both drugs, and doxycycline is an excellent drug. But, with all these drugs, including the one you took, Malarone, there is drug resistance developing, and that's why we're particularly concerned that the Australian malaria institute and other institutes like this are encouraged. Without them, we could be in a lot of trouble in the future and put our service men and women at risk.

Prof. Brown : Let's go back to the trial. Usually, the way a controlled trial is done, people are asked, 'Would you like to participate?' If the answer is no, then you say, 'Okay, we'll give you this to protect you.' These people stay in the trial, and they can compare drug A versus drug B, both known to be effective—which is better, which is more efficient, which has fewer side effects. In fact, they could then compare those who took drug A or drug B versus those who took doxycycline. But you've got to be careful with that because the people who chose doxycycline might be different. They might have opted out for some other reason, for example. In a trial, you're comparing like with like. That's the thing. You're supposed to be alike in all respects, except for you're either having this or this—or sometimes in cancer trials it might be A or A plus C—so that you have two groups. And these are the evidence based trials that we think are so important, and that's when we see the long term. Where they've looked long term, you can't find any difference in these things. So you can't say it's not there, but it means it's probably a very small effect.

Senator MOORE: We've just had a bit of discussion with some witnesses about facts, which in the current world situation is a discussion that's quite difficult! But, nonetheless, I've read a lot of the submissions and a lot of the evidence, and it's very confusing if you are not actually a practitioner in the process.

Prof. Brown : Absolutely.

Senator MOORE: One of the core issues is the impact of side effects of the drugs. Most of the stuff that I've read talks about mefloquine having a number of side effects—usually short term. The people who've come before us are all long term: this happened over 20 years ago that they were involved. They are showing symptoms now which they truly believe are the result of an acquired brain injury, and that's the terminology they use. From your experience in the field, is there any evidence that acquired brain injury, 20 years later, can be directly attributable to mefloquine?

Prof. Brown : It's very hard to say 'no, never', because as we've said here—

Senator MOORE: No-one ever can.

Prof. Brown : No, that's correct. But, for example, as Geoff explained and as many of us did—

Senator MOORE: Yes, and your submission also touches on it.

Prof. Brown : It is well known and no-one would deny in the acute phase there are some people who have problems. The vast majority of these had some pre-existing condition. In fact, the studies in longer term the longer you go, the fewer and fewer the side effects. When I was an honorary medical officer assisting volunteers, for example, this is what we would find. Many people attributed their symptoms to a drug and on specific questions—what about other drugs, recreational drugs, alcohol, exhaustion and stress? And those of us who work in the tropics know that well before mefloquine, there were many people with the stress and strain of a different environment and a different culture. The longer you go, the fewer the symptoms. We don't see any evidence of acquired brain injury, and we can't really understand a mechanism for how that might happen. But, as scientists, we always would keep an open mind. What you would have to somehow do is an enormous trial to allow some sort of statistical analysis—for example, one way might be what we call a case control study, where you would find these people who suggest that they've had this terrible condition related to mefloquine cases, then you get however many—I'm not sure how many people are in this group; you probably know. How many people are considering themselves now to be in such a group?

Senator MOORE: About 1,100 originally, I think.

Prof. Brown : I'm surprised at that.

Senator MOORE: But they're not the people who've identified. We still haven't got figures to say how many people are identifying—

Prof. Brown : Well, let's take a number. Let's say it's 500.

Senator MOORE: Sure.

Prof. Brown : What you could do then is go back to their registration, or their number, or the regimental number, and take the person next to them in the same numbers from the Defence Force, and then say: here are 500 with symptoms and here are 500 people next to them who weren't involved in any trials at all. What's the relationship? What number of those people not in the trial have these symptoms and what number don't? Because we've heard the Vietnam veterans talking of post-traumatic stress over and over, and these people need our help, they need our support, and we want to give it. We don't want to deny them. Our argument is that they need help whatever the cause. And that's what we need to do and put in place. So that's the type of study that you could potentially do. But then, of course, once you started doing this study, those 500 people that haven't come up with this: 'Have you ever had a headache? Have you ever had a bad dream? Have you ever woken up at night? Do you ever think of those bombs or those bodies you saw in Bougainville or East Timor?' What would it do to them, in terms of the ethics of asking them to consider 'am I suffering'?

CHAIR: I think one of the issues is the numbers are not known, at this stage, that claim to have this effect. In fact there may be a lot less than 500. DVA is saying that their claims history is not as—

Prof. Brown : For example, I don't see—amongst my literature and reading or in the submissions—anything that you could specifically attribute to it. And when people do the same with tafenoquine and mefloquine, they are really quite different side effects. Certainly, under observation in clinical trials you don't see these things with tafenoquine. So when they're all rolled together, they're actually quite different drugs.

Senator MOORE: We have had other submissions that claim the same long-lasting, life-destroying impact of tafenoquine.

Prof. Quail : In something like 36 million there's only been one or two possible related cases. Primaquine's been around since the Korean War, and it's a very safe drug. Tafenoquine is just an analogue of it, which is—

Senator MOORE: But can you ever say no?

Prof. Quail : As Graham said, you can never say no, but if you look at it like that, we've got a much better chance of being run over leaving this building and being killed.

Prof. Brown : I could say that I don't like alternative facts, ala Donald Trump.

Senator MOORE: I tried very hard not to say it, Professor, but—

Prof. Brown : I know; don't mention the T word! But let us say it is a fact that some people believe their long-term symptoms are related to ingestion of mefloquine. And it is a fact that the majority of experts in the field do not believe there is an evidence base to make this assertion at this stage. Those are still two facts that are true.

CHAIR: On those words, it is an appropriate time for us to adjourn this hearing. We have to visit the malarial institute.

Senator MOORE: Professors, we may actually have some questions on notice for you as we get more evidence—to come back and test it out. Would that be okay?

Prof. Brown : We would be delighted. We want to assist so people can work through it. I have had patients with similar symptoms from other causes attributed to other illnesses and so on. And I say: 'Look, we don't really know. Our job is to help you, because I can imagine this is burning you up—adding a psychological component to this. Let's work together to help you through this.'

CHAIR: Thank you very much for you evidence.

Committee adjourned at 14 : 31