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Malaria in crisis?

29 May 2009, 18:08

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by Robert Walgate, reporting for EAGLES, the European Action on Global Life Sciences, and RealHealthNews

Do we face a global malaria epidemic as our key treatment fails and climate warms – or will malaria be eradicated? Research can and needs to be done rapidly to solve fundamental new problems arising, while 500 000 people, mostly children under five, and pregnant mothers, are dying of malaria every year. The solutions are nearly in our grasp. The choice of whether we dare to find them – and act upon them – belongs to decision makers.

Which way does malaria face? Will it reconquer the world it once owned – Russia, Europe, the Southern United States – until good management and DDT expelled it? Tragically the drug on which treatment now relies – the Chinese herbal extract artemisinin – is beginning to fail in South-East Asia; and the global climate is warming, bringing back and entrenching the mosquitoes that carry the Plasmodium malaria parasite.

On the other hand, the Medicines for Malaria Venture, supported by the Bill and Melinda Gates Foundation, with the biggest ‘pipeline’ for potential new malaria drugs in history, tells RealHealthNews it is cautiously optimistic that it can find a substitute for artemisinin, and the Foundation still aims for malaria eradication. Furthermore scientists modelling both climate and the distribution of malaria say the effect of climate change on malaria was overstated.

But for both answers to be definite, decision makers need to spend serious money – and at a time of global financial crisis. We urgently need research to determine if the hopes are true, and then act on the results.

To find new drugs, we need to identify quickly exactly what is going on with malaria on the Thai/Cambodia border, where the current first-line treatments recommended by WHO, artemisinin combination therapies (or ACTs), are taking much longer to clear malaria parasites from some patients’ blood. The situation is “very scary”, say experts, because strangely this is the very region of the world from which resistance to all previous malaria drugs – like chloroquine, SP (sulfadoxine/pyrimethamine), and fansidar – first emerged, while global dependence on ACTs is now huge.

Simultaneously, we need immediately to test available substitute drugs, and get any promising ones into large-scale clinical trials – or if none succeed (the “neutron bomb scenario”, as MMV’s Chief Scientific Officer Tim Wells described it to RealHealthNews), massively increase investment in developing new ones.

On climate, existing models combining malaria and global warming are clearly weak. Early predictions of disaster have been rowed back – but this is largely because they were too simplistic, relying largely on well-predicted temperature change. Now changing rainfall, and the very statistical details of that rainfall, have been identified as the key factors for mosquitoes and malaria – but they are far less well predicted. Thus rainfall predictions of climate models need drastic improvement.

Meanwhile the modellers are divided. There are climate scientists and the malariologists, with the models of each taking simplistic views of the others’ discipline. Malaria is ecologically – and immunologically – complex, further complicated by necessary human health interventions; and climate scientists describe what is physically and mathematically a chaotic system, again affected by human inputs to the atmosphere and political decisions. So those rare souls attempting to combine both climate and malaria tell RealHealthNews that we need a major effort, a “grand model”, where the interfaces between the many complex systems can be thoroughly researched and properly described.

READ ON: The Malaria Atlas Project (MAP) is researching the current distribution of the disease – click map above to expand, or here for more information on the project

The remaining tool is the provision of insecticide-impregnated bednets, “by far the most cost effective public health intervention that there is, for any disease”, one expert told RealHealthNews. Bednets are of best use in Africa, where malaria is worst and where the mosquitoes bite only at night. But despite wide distribution they are only in use over one in five infants; the reasons for this failure need close investigation, and more bednets provided or corrective measures taken.

For the future, malaria vaccines at last look promising, but still need more work.

Malaria control is facing a crisis; but whether we meet and overcome the crisis is entirely in our hands.

Malaria treatment failing on Thai-Cambodian border

“Huge strides have been made in the last ten years to reduce the burden of malaria, one of the world’s major killer diseases. Strong malaria control programs have helped lower infection rates in several countries. The recent shift from failing drugs to the highly effective artemisinin-based combination therapies (ACTs) has been a breakthrough. Appropriate treatment with ACTs succeeds in more than 90% of cases. However, malaria drug resistance now emerging along the Thai-Cambodia border threatens these gains.”

These are not the strong claims of an agitator, but a frightening statement to the media by the World Health Organization (WHO) on 25 February this year (2009).

The Bill and Melinda Gates Foundation has thrilling plans to eradicate malaria from the world, which they believed conceivable with fast treatment of all cases with ACTs, the wide use if insecticide treated bed nets, spraying of some mosquito breeding and resting sites, and other measures, all to be monitored by sophisticated regional computer modelling of malaria. But if a key component of ACTs, the wonder drug artemisinin – which normally clears malaria parasites from patients’ blood in 36 hours – begins to fail, their goal must be in question.

So they have given WHO and the Thai and Cambodian governments US$22.5 million to eliminate this drug-resistant malaria entirely from the region – challenging but not impossible, RealHealthNews is told, because due to malaria control both in Thailand and Cambodia cases now are few in the area and transmission light.

But the resistant parasites – if that’s what they are – could still escape in an infected visitor or a migrant, or perhaps a mosquito packed in a bag or vehicle, as they seem to have done before. For reasons that are still not well understood, this is the exact point on the globe from which other major resistances of malaria to key treatments, like chloroquine, has emerged in the past; for genetic, social, health structural or other reasons, most resistances arose here and later spread across the globe. Hence the fear, bordering on panic, that is now gripping the malaria community.

WHO’s malaria drug resistance expert, Pascal Ringwald, told RealHealthNews the story. “We [WHO] set up routine monitoring with the governments in South East Asia. We discovered for the first time that ACTs were failing in 2005. When I put that in my 2005 drug resistance report, many scientists and pharmaceutical companies said that it was just impossible to create artemisinin resistance – impossible to create in the lab, impossible in people. The whole scientific community was saying ‘this is not real, this is not true, WHO has made a mistake’!

“But we immediately started a war on artemisinin monotherapy, banning it completely. We knew monotherapy [treatment with any drug taken alone] always creates resistance. [Artemisinin monotherapy was rife around Pailin, sold by private suppliers.]

“Then in 2006 another team – headed by Harald Noedl [then working for AFRIMS, the US/Thai Armed Forces Research Institute of Medical Sciences] – did another study in Cambodia, and he found the same as we did! So we called for a scientific meeting in 2007 in Phnom Penh, and invited some of the sceptics. We showed all the data – and for the first time the rest of the scientific community recognized that there was a problem with artemisinin.

“Immediately after we got a grant from the Bill & Melinda Gates Foundation – the ARC3 project [artemisinin resistance confirmation, characterization and containment]. Thanks to this grant, we carried out several trials with many partners – the Wellcome Trust, Mahidol University in Thailand, AFRIMS, University of Vienna, SMUR and Institut Pasteur. One trial was in Pailin. More and more we got the data that showed that what we said was correct – that there is a problem with artemisinin in Pailin.

“Early 2008 we presented our data, and immediately the Gates Foundation started negotiation with us to support containment of the problem.

“But we have not found a genetic marker of resistance [a genetic change in the parasite associated with the resistance], to do a retrospective study [on stored blood samples], so we can’t say when it started.”

However other scientists questioned whether the ACT resistance was really to artemisinin, or to the combination drug, which varies around the world and here was mefloquine, to which resistance was well-known.

But, Ringwald told RealHealthNews, “In further investigation, which we did last year, we s intensively studied artesunate monotherapy [sold illegally by private traders]. Based on this study we can confirm that there is artesunate resistance at the Thai-Cambodian border. [Artesunate being one of the soluble derivatives of artemisinin used in ACTs.] This is the only thing that we can say today. It’s not only based on parasite clearance time but on many many factors, including efficacy and blood levels.

“Although the patient has high blood levels [of the drug], 7-day artesunate is failing”, said Ringwald.

The response to resistance

The first response has been to attempt to eradicate the problem by halting all malaria around Pailin – where it is transmitted by mosquitoes that bite forest workers in the late afternoon and early evening. All conceivable techniques will be used, including mathematical modelling of the process of eradication. This will start in earnest in May 2009, when the malaria season begins with the monsoon.

The second response has been urgently to prepare a portfolio of alternative drugs, in case the battle to save artemisinin from resistance is lost, and the resistant parasites escape.

And the third has been to throw the best fundamental research resources at identifying exactly what the parasite has done to escape attack by artemisinin – does it have mutation in a gene expressed on the parasite’s surface or even on an infected human red blood cell to pump the molecule out of harm’s way, or one that neutralises the molecule’s potent weapon, a pair of oxygen atoms joined in an unstable ‘peroxide’ bond, that more or less ‘explodes’ to destroy the parasite? Or is some other unknown mechanism at work? Once we know, we will be better prepared to develop defences.

Eradication in Pailin

Here, we won’t consider eradication in depth. But it’s going to be a challenge in a remote and once disorderly region of Cambodia to which the Khmer Rouge retreated, and which they land-mined, where there was for a long time small-scale gem mining and cross-country migration, and where much private selling of sometimes fake malaria treatments continues.

But according to Ringwald the region has stabilized in recent years, the gems have been exhausted, the land mines removed, and the Khmer Rouge refugees replace by a settled, farming community. That together with the low-level malaria transmission should make action more feasible – but still difficult.

Global eradication

As for the even more ambitious target of global eradication, evolutionary biologist Ian Hastings told RealHealthNews: “I think most people think we should try everything and hope it works… Bednets are best for Africa, where the main malaria vector species is Anopheles gambiae. But as an evolutionary biologist, what you’d expect is that if a species’ food supply is denied them because you’re sleeping under a net, they’ll start biting earlier, in the daytime.

“So you can make models with certain parameters for eradication but the big problem is to work out – or measure – how things will change as you approach eradication. How will the parasites evolve resistance to drugs? How will the insects evolve resistance to insecticides? And as transmission falls, so will human immunity. So there’s going to be a lot of feedback in the system.”

Simon Hay of Oxford’s Department of Zoology, who led the Malaria Atlas Project (MAP) – see the map above and the final section of this report – told RealHealthNews “I’ve become really interested in the malaria problem of today, as it were. I think that if I do my job properly, and people in the country do theirs properly, by the time we get to 2030 malaria shouldn’t really be a problem any more. It’s a logistical issue; we have all the tools that we need – it’s just a job of actually doing it.

“We’ve known for a decade that bednets halve mortality, when you get them up to scale; and that they are by far the most cost effective public health intervention that there is, for any disease; taking those to scale is a no-brainer, yet only 1 in 5 African children are protected with them.

“And as you go outside Africa the numbers get worse – partly due to different vectors and preferences of vectors. But just bringing bednets up to scale would absolutely transform the prevalence of malaria across the planet.

“There are plenty of other things that people can do too – improve health care, educate people to get prompt effective treatment, indoor spraying etc… Ensure they get real ACTs and not fakes, which is a big problem…

“They’ve certainly found artemisinin is progressing [towards resistance] on the Thai-Cambodia border; people are making some huge strides to eradicate malaria from that small area, to try and get on top of this problem.” But, Hay admitted, “It’s quite a job.”

New drugs

Remarkably, research to find an alternative to artemisinin – already under way – may be more hopeful. RealHealthNews was briefed by Tim Wells, the Chief Scientific Officer of the Medicines for Malaria Venture. MMV claims to have “the strongest antimalarial drug portfolio in history”. So what’s the alternative if artemisinin fails, we asked Wells?

To begin with, MMV has collected “all the synthetic endoperoxides” – a handful of artemisinin-like molecules, depending on the same double-oxygen weapon – from their many partners in industry and elsewhere, and has just begun testing them against the resistant parasites found in Pailin.

Amongst them is one at an advanced stage of development and clinical trials, said Wells, called ‘artemizone’ – developed by Richard Haynes at the University of Hong Kong.

To make the tests, MMV is using infected blood samples from patients who’ve responded poorly to treatment. These contain malaria parasites at different ‘stages’ of their life cycles, as the parasites transform like caterpillars into butterflies, or tadpoles into frogs, but through many different forms.

A challenge is to know which stage of the parasite to study, but new and unpublished data suggests that the ‘ring forms’, taken by the parasite when it infects red blood cells, are the ones showing resistance to artemisinin, another expert told RealHealthNews.

“Then the question to answer is whether the analogues have cross-resistance with artemisinin” Wells told RealHealthNews. In other words, if the parasite is resistant to artemisinin, is it resistant to the other artemisinin-like molecules too?

There is hope that it won’t be, from past experience of success with analogues of previous failed drugs. The failed drugs were eliminated by a mutation in one of many common genes that create channels on the parasite’s surface, and physically pump molecules out; they are finely tuned to a molecule’s shapes, so a slight change in shape can alter their activity.

Thus if the resistance to artemisinin in Pailin is being caused by such a pump, one or other of the artemisinin analogues is likely to get stuck, and remain around to do its destructive work.

“I’d give it a 1 in 5 chance that Richard Haynes’ artemizone will work, for example” said Wells. MMV would also like to test them in patients, and is currently seeking ethical clearance with the Thai and Cambodian authorities. And he has a stock of a nine such drugs to try, although the rest are at earlier stages of development and would take longer to bring to market.

MMV is also trialling the molecules elsewhere, in Laos with the Swiss Tropical Institute, and in Senegal in Africa, said Wells.

But what if the resistance to artemisinin is caused by some other mechanism, not a pump, but something that inactivates its double-oxygen weapon, as shared by all the analogues, asked RealHealthNews?

“That’s the neutron bomb scenario!” said Wells. “Chemically it’s not quite so unlikely. What would take them all out in one shot is a mechanism that would get a lot of free iron close to that endoperoxide and break it down.” It would have to do that in such a way that its force was dissipated, or it would make the drug even more effective; but that’s not inconceivable.

“I’d bet 5 to 1 that this is not the cause of the resistance” he said, but we need to be prepared. “Then you’d be left with two or three interesting approaches. Which is already quite good! First there are antibiotics, which have been unpopular as they are slow killers. Pfizer has just finished Phase III clinical trials on Azythromycin-chloroquine – but that really polarizes the world.

“On its own 2 grams of Azythromycin gives 70% parasite clearance in 28 days; and how can chloroquine be useful in chloroquine resistance areas? But they saw synergy in the lab and believe from Phase II that the pump that would get rid of chloroquine was being blocked. They are seeing results as good as ACTs in adults. And that’s ready to go.

“And there’s malarone – but it’s US$5 per tablet. But we could negotiate a reduction.

“There are various discussions on other antibiotics, and in our research, in our ‘hits to leads’ programme we are saying we need mechanisms that are as different as possible. But they won’t launch before 2016. Early is what we have already, the ACTS; in the middle distance I’ve told you everything – there is nothing else.”

“So you’ll look for your results from Thailand and elsewhere, and potentially it could change your strategy” said RealHealthNews.

“That’s the reason to do it” said Wells.

What’s causing the resistance?

So far, research on the two most obvious possibilities – a pump called PfMDR, and a modification of the hypothetical target of artemisinin, PfATP6 – has drawn a blank, Christopher Plowe, Chief of the Malaria Section at the Howard Hughes Medical Institute, University of Maryland, told RealHealthNews.

Plowe leads the molecular characterization component of the Bill and Melinda Gates Foundation’s ARC3 project, and is just setting to work to identify what’s happened to the resistant parasites. “The blood samples are just coming in” he told RealHealthNews.

Plowe is prepared to consider that he’ll find no mutations. The “resistance” might have already been there in the human population, and is actually a human trait of non-responsiveness to the drug, he suggested. “If so, it may not be the public health emergency that we are concerned that it might be.”

However he’s not going to leave stones unturned. “I’d like to use the most advance genome sequencing techniques” he said, ideally to sequence the whole genome, and compare it with that of non-resistant parasites, to identify the differences. If that proves financially or technically impossible, he’ll use “snip chips” (single nucleotide polymorphism [SNP] chips) that can test 10 000 SNPs (the smallest possible mutations) at a time. Then he’ll focus down on the areas of most change. “It’ll be like a fishing expedition” he said.

Asked how long he thinks it will take, he said “the grant is for three years”. But he aims to identify the mutations, if any there be, soon enough that they will be useful for identifying resistance and planning control measures worldwide. This would be a big advance on the old molecular genetics used to identify the mutations causing resistance to chloroquine, for example, which took so long that by the time they were known they were only of historical interest.

Malaria vaccines

Malaria immunology, on which vaccines rest, is still something of a mystery, needing further investigation. Ian Hastings, Senior Lecturer in Medical Statistics and Epidemiology at the Liverpool School of Tropical Medicine told RealHealthNews: “You can go to areas of high transmission – at our field site in Malawi, for example – and you find a third of the kids will have malaria parasites but not be ill, and some of them will be stuffed with 10 trillion parasites but will literally be running around playing football! And then you go to hospital and find someone with the same number of parasites at death’s door. So we don’t really know what causes that.”

But there has been important recent progress. Scientists need to build on the success of the GlaxoSmithKline RTS,S vaccine, which saved 53% of 1-4-year olds from malaria over an eight-month follow-up, according to results published in December 2008.

But the vaccines can and should do still better. As Hastings told RealHealthNews “Kids have lots of infections with malaria until they are about 5 or 6 years old. If they survive until then they are probably not going to die of it. Want you want to do is to give a vaccine that can duplicate this in a single shot. And I think most people are dubious that you can”.

However RTS,S uses only a single molecule (antigen) of the parasite to create its effect, and the Gates Foundation funded PATH Malaria Vaccine Initiative is sifting published antigens down to a top list of 25 molecules. If more of these could be contained in the vaccine it might be even more effective. Whichever way you look at it, RTS,S looks something like a breakthrough.

Global warming and malaria

Global warming will almost certainly change where and how frequently the mosquitoes that transmit malaria breed – as well as where people live to be affected by them – but producing even those figures, and then estimating malaria levels, is proving to be a very challenging project.

It’s not a simple, for example, as mosquitoes and parasites following the heat, as some naïve models assumed – Russia, for example, was historically badly affected by malaria well before global warming, and has eliminated it, as were the southern United States; and there used to be malaria in England back to Roman times, with outbreaks occurring even after the First World War.

Treatment and DDT clearly played a great part in malaria elimination in the richer world, but as Ian Hastings, an evolutionary biologist at the Liverpool School of Tropical Medicine, told RealHealthNews: “The two prime examples of chaos are climate and ecology; and you are trying to use climate to predict the ecology of mosquitoes! And then you’re trying to figure out how that affects malaria transmission. The question I often ask is are climate people using this to predict commercial things like cotton boll-weevil, where a lot of hard-nosed businessmen might find it very useful? I’ve never heard anyone say, ‘yes’.

“The work I’ve seen is to predict rainfall; and you assume the more rain, the more mosquitoes. But we know that after a certain amount of rain the number starts to go down as it washes out all the breeding sites.

“Humidity is another thing – a lot of mosquitoes die of desiccation. And if you get more rain you get more vegetation for mosquitoes to hide under. But you might get an outbreak of mice and the mosquitoes start feeding on them! I think a lot of people view the climate models as being very simplistic – while making very grandiose claims about malaria prediction. That can irritate some people.

“So malariologists are receptive to climate modelling but probably unconvinced at the moment.”

Simon Hay of Oxford’s Department of Zoology told RealHealthNews that he was previously involved with climate mapping and modelling for malaria – but grew sceptical of its predictive power, at least as the models were then constituted. “You are dealing with such uncertainties into the future that if I were placing my money on looking at any predictions relative to malaria it would be just to use normal demographic growth and urbanization trends.”

So the modelling is difficult, but the answer, RealHealthNews suggests, is not to give up, but – given the lethality of malaria to non-immune populations – to pursue the problem more seriously and with greater resources than we have so far.

The Swiss Tropical Institute, for example, has been heavily funded by the Gates Foundation to study one side of the problem – to model malaria and the impact of different human interventions against it. But they don’t consider climate change.

One brave scientist attempting to bridge malaria modellers with climate modellers, coincidentally in Liverpool like Ian Hastings – but at the University – is Andy Morse. But he admits his model has limitations. “We’ve run it across all of Africa, but because we don’t include human immunity it’s only a model for the epidemic fringe – where we can assume there is no immunity. And we don’t assume any intervention programmes – we’re just running the model with the climate drivers, to see what the maximum number of cases might be.”

“We are studying climate variability at a variety of scales, mostly for driving malaria at sub-seasonal scales – so we’re looking at the ability of the climate models to predict things like the number of rainy days, the frequency of rainy days above a certain amount, the ability to use the models to get the temperatures right. We’ve concentrated on interfacing the climate data to the malaria model – it’s a way of taking the data from the climate model and processing it so it has some value for the malaria model.

“Connecting with the users – like ministries of health, or NGOs focused on intervention – would be another big step. They can tell us if the malaria model is good for their area, and if the climate model is reasonably good. Then they should be able to inform a ministry of years of high and low – one year at a time, with 4-6 months’ lead-time.

“That beats the current system where they have to wait for the rains to start, when they might discover that it was becoming an unusually wet rainy season. Then they could put extra resources into intervention – if of course they had the infrastructure and the funding.

“On the near climate scales – 10-20 years – although those models are very experimental, they may inform whether the malaria problem in their region is going to get easier or worse” said Morse.

But we desperately need support for a ‘Grand Model’, Morse told RealHealthNews.

“The idea of a Grand Model is to draw together the [malaria and climate] research communities, which I think are very disparate at the moment.

“We need climate scientists, including people to develop the models; people to interface the models to the disease modelling communities; and a whole raft of ‘post-processors’ to get the data into a form that is usable by malaria people: for example you may want to down-scale it [from the 300 X 300 km scale of climate models]; or to use ensemble techniques by varying the models [to give measures of uncertainty in the predictions]; and so on.

“Then let’s assume the climate data’s cleaned up and ready to go. Then you need malaria modellers who can understand how go from a series of equations to a model, with strong mathematical and biological skills. You need to allow for a lot of variability. We need to allow for mosquito breeding sites, and for breeding sites to remain intact long enough for parasites to develop and so on.

“I think climate models can give us seasonal signals for the relevant quantities at a seasonal level, and maybe at a monthly level. We think there’s even information at a level below that, and we are trying to verify that. You might be able to say that this season will have a higher frequency of rainy days. And I think that’s critical for a lot of vector-borne diseases. Some people think you might need even to go to hourly information to match models of parasite development in the vector.

“So we need to involve people who understand the transmission of disease in depth, from field work, lab work, sampling – it’s very laborious and rarely funded, by contrast with genetic work.

“There not much funding for combining all these disciplines either. Probably this boils down to the funding schemes, which are often quite narrowly defined. And some of these projects would be long, 10-20 years, and funding is usually only for 2-3 years. A lot of the empirical work on entomology for example is scattered in the literature, some half a century old, and not always for the region you want.

“To do this properly needs donors with a big vision, both in breadth of work and duration.

“You could say just spend the money on control. But where I think the integrated model will win hands down is to spot emerging areas of epidemics, as the climate or its variability change; and in testing interventions, to show where you might best target which strategy. Eradication obviously needs on the ground interventions, malaria treatment, vaccines, and mosquito control – and climate sensitive modelling should be one part of that whole raft.

“And we have to remember”, Morse told RealHealthNews, “that if eradication efforts do begin to be successful, climate and malaria modelling will be important in predicting where it will come back, rather than just relying on surveillance. We’re talking 10-20 years down the line, and with the right support malaria and climate modelling could be advanced enough by then to make a major impact.”

The response to resistance

The first response has been to attempt to eradicate the problem by halting all malaria around Pailin – where it is transmitted by mosquitoes that bite forest workers in the late afternoon and early evening. All conceivable techniques will be used, including mathematical modelling of the process of eradication. This will start in earnest in May 2009, when the malaria season begins with the monsoon.

The second response has been urgently to prepare a portfolio of alternative drugs, in case the battle to save artemisinin from resistance is lost, and the resistant parasites escape.

And the third has been to throw the best fundamental research resources at identifying exactly what the parasite has done to escape attack by artemisinin – does it have mutation in a gene expressed on the parasite’s surface or even on an infected human red blood cell to pump the molecule out of harm’s way, or one that neutralises the molecule’s potent weapon, a pair of oxygen atoms joined in an unstable ‘peroxide’ bond, that more or less ‘explodes’ to destroy the parasite? Or is some other unknown mechanism at work? Once we know, we will be better prepared to develop defences.

Eradication in Pailin

Here, we won’t consider eradication in depth. But it’s going to be a challenge in a remote and once disorderly region of Cambodia to which the Khmer Rouge retreated, and which they land-mined, where there was for a long time small-scale gem mining and cross-country migration, and where much private selling of sometimes fake malaria treatments continues.


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