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The most important drug in the world—and the plan for saving it

11 Apr 2011

Patrick Adams

Source: TropIKA.net

Figure 1
The new Global Plan for Artemisinin Resistance Containment (GPARC) published by the WHO Global Malaria Programme & Roll Back Malaria

Artemisinin resistance is the single most important threat to global malaria control with the potential to reverse many of the gains made to date. Whether it does may hinge on WHO’s new Global Plan for Artemisinin Resistance Containment (GPARC) and how countries around the world choose to respond.

In a 2005 editorial in the journal Trends in Parasitology, Harald Noedl, a scientist at the Medical University of Vienna and one of the world’s foremost experts on malaria, asked the question on everyone’s mind:

“Is artemisinin-resistant malaria out there?”

Suspected clinical cases had been reported in several countries in Southeast Asia, he wrote. And by intermittently exposing malaria parasites to different drug concentrations, a number of laboratories had managed to obtain resistant strains. But the data were thin.

Noedl reminded readers that “clinical failures or in vitro thresholds alone are not sufficient to prove artemisinin resistance.” For one, he said, there was the common practice of administering artemisinin monotherapy for three to five days rather than the six to seven required – “which inherently leads to high percentages of treatment failure, irrespective of drug resistance.”

Cost was a factor as well. “Pharmacokinetic studies of artemisinin derivatives are difficult and expensive and, therefore, are rarely carried out in the course of artemisinin trials,” he wrote. The result, he added, was that researchers often ignore the role of host metabolism in clinical treatment success.

And lastly, he said, the tools available aren’t adequate to the task. “In vitro drug-sensitivity tests alone are of little help in finding artemisinin resistance because they would have to use artificially defined thresholds of resistance that might have little clinical relevance for this drug.”

Several years later, those tools were still inadequate. But Noedl and colleagues had answered their own question (1) – and the data confirmed what everyone feared: Not only was artemisinin resistance very real, it was emerging in precisely the same spot that sulphadoxine-pyrimethamine (SP) and chloroquine began their rapid decline in the 1950s – along the embattled Thai-Cambodia border, where fighting over a Hindu temple has recently flared up anew.

ARC 3, ARCE and GPARC

As reported previously on TropIKA.net, Noedl’s findings prompted the World Health Organization to commission the multinational Artemisinin Resistance Confirmation, Characterization and Containment (ARC3) project. Funded by a $3.2 million Gates grant, the initiative was designed to confirm clinically relevant artemisinin resistance and establish a reference repository of parasite isolates from clinically validated cases of treatment failure.

If clinical resistance was confirmed, ARC 3 was to further characterize resistance to define resistant in vitro phenotypes and genotypes for use in global surveillance. It was also to identify genes and polymorphisms associated with artemisinin resistance, and to develop standardized validated in vitro assays and rapid molecular assays to predict clinical failure.

ARC 3 soon gave way to the ARCE (Artemisinin Resistance Containment Effort), a $22.5 million undertaking (also funded by Gates) that brings together a number of different research organizations as well as the national malaria programmes of both Cambodia and Thailand – and all of it under the banner of WHO.

Within its first year, ARCE had accomplished most of what it set out to do –distributing more than half a million long-lasting insecticide-treated mosquito nets; successfully lobbying the Cambodian Department of Drugs and Food for a ban on the sale of artemisinin-based monotherapies; establishing reliable village-based diagnosis and treatment services in all high-risk villages; and creating systems to monitor the cross-border movements of people and the status of all cases still positive after three days of treatment.

Despite these achievements, however, preliminary findings of a recent study in the Pailin province of Cambodia indicate that resistance is already eroding the efficacy of the current artemisinin-based combination therapy – DHA+PPQ – established less than three years ago by WHO. Of the 30 infected patients enrolled in that study, 7 were still infected after day 21 of treatment – more than 20% treatment failure.

Hence the new Global Plan for Artemisinin Resistance Containment (GPARC). Developed by the WHO Global Malaria Programme in consultation with more than 100 experts and members of the Roll Back Malaria Partnership, the GPARC is a call-to-action aimed at mobilizing global and local actors to contain resistance where it exists and to prevent its spread to new areas.

According to the document, the GPARC’s objectives are “to define priorities for the containment and prevention of artemisinin resistance; motivate action and describe responsibilities by constituency; mobilize resources to fund the containment and prevention of artemisinin resistance; increase collaboration and coordination among relevant stakeholders; and define governance mechanisms and indicators for continual assessment of progress made in implementing the GPARC.”

Though few in the mainstream media took notice, the plan was praised by experts for its unambiguous position on the gravity of the situation and for engaging the malaria world’s many stakeholders in a high-level, multi-pronged assault. “WHO's new detailed and commendable plan categorizes actions not only for countries where artemisinin resistance has emerged but also for those that border countries with resistance, have inflows of migrants from those countries, or are P. falciparum endemic,” wrote the editors of the Lancet.

“But has resistance spread already?” they asked. “We do not know.”

According to Arjen Dondorp, deputy director of the Mahidol-Oxford Clinical Research Unit (MOCRU), “there are worrying signs that it has.” In order to confirm those findings, Dondorp and colleagues will soon launch a study in 15 sites throughout Cambodia and neighbouring Myanmar investigating parasite clearance dynamics. “If the phenotype has reached Myanmar already, then the strategy should be completely different than it is now,” he says. “We can’t only focus on the Thai-Cambodia border area and only eliminate malaria there.”

With the help of the Worldwide Antimalarial Resistance Network (WWARN), MOCRU researchers will share the results of the study in real time so that control activities can be guided by the most up-to-date information. “The study will start in May, when the malaria season begins here,” says Dondorp. “And we expect to have results by October.”

That kind of vigilant monitoring and evaluation of artemisinin resistance surveillance shouldn’t be thought of as an optional activity, says Philippe Guérin executive director of WWARN, which is currently building a global database of quality-assured data on the whereabouts of resistance. “It’s critical. There’s no point in preparing a plan if you don’t have good, quality data to act on.”

Nevertheless, large gaps in reporting have hindered WWARN’s progress. Indeed, of the 106 malaria endemic countries worldwide, 44 have not conducted studies in compliance with WHO recommendations within the past two years. (As stated in the GPARC, WHO recommends that countries endemic for malaria routinely monitor the efficacy of antimalarial drugs and that national malaria control programmes evaluate the efficacy of first- and second-line antimalarial drugs at sentinel sites at least once every 24 months).

“There’s room for improvement,” says Guérin. “The first question is how do we engage stakeholders to strengthen their capacity for surveillance and ensure that these gaps are bridged? And second, what kind of capacity can we put together? Do we understand why we are still missing some information? What can we do to address that?”

Guérin estimates that there are probably a number of different reasons for the dearth of surveillance data. “Some are technical, some are funding, some are dissemination of information,” he says. “There isn’t one simple solution. But we need to make a proper evaluation of the problem if we’re going to fix it.”

Of GPARC, he says, it’s an extremely important publication. “Artemisinin resistance hasn’t been widely acknowledged as a public health emergency. And this document clearly spells out that it is a major, major issue.” Guérin also credits the GMP for engaging the malaria community’s many stakeholders, paving the way for consensus on a far-reaching plan. “We completely welcome it,” he says.

Still, he adds, the GPARC is only a plan. “I think now it needs to be followed by specific actions in the region of concern. We can’t wait another one or two or three years to do all the perfect studies in Asia and meanwhile do nothing in Cambodia. Eliminating malaria in Cambodia is probably possible. It’s an achievable target. But that will require lots of commitment from every stakeholder.”

Additional measures

“This is where the document isn’t very outspoken,” says Dondorp. “About whether additional unconventional measures should be taken in western Cambodia – and that’s something that needs to be addressed very soon.” The GPARC does call for the evaluation of several “epidemiological or transmission-reduction tools for addressing artemisinin resistance” – including mass screening and treatment (MSAT), focused screening and treatment (FSAT) and mass drug administration (MDA). But the document stops short of embracing any one.

“It says that MDA should be considered, but it doesn’t give a strong recommendation,” says Dondorp. “Some people argue for active case detection with a molecular method and then treating those patients. Others say that we should do a real MDA and just treat everyone in Western Cambodia.” Dondorp favours “something in between,” he says; “Use molecular methods to determine where the hotspots are and then do MDA in that region.”

But judging from the findings of a recent study by researchers at the Institut Pasteur du Cambodge (IPC), that approach may substantially overshoot the mark. “IPC’s role in the study was to do PCR,” says Didier Ménard, head of the Malaria Molecular Epidemiology Unit at IPC. “We screened 20 villages in Pailin province; we collected blood samples and we did PCR to know if they were infected by P. falciparum.”

Of the approximately 6,000 samples collected, fewer than 60 people were found to be infected – less than 1 per cent of the sample population. And that’s a strong argument for FSAT, he says: “If you use MDA, you have to treat everybody whether they’re a parasite carrier or not. In Pailin province, that means out of every 100 people we treat, 99 will not have malaria.”

Yet, as Ménard is well aware, MDA offers a level of certainty that FSAT can’t. For while PCR is highly sensitive – with a threshold detection of 0.8 parasites per microlitre – it isn’t perfect. “If the patient has less than one parasite in the body, I don’t know he is a parasite carrier,” he says. “I’m sure that we miss this case. The question is how many of these cases do we miss? And I can’t respond to this question. I don’t think that anybody can.”

Ménard does hope to change the way things are done in the field though. “The mean delay between the collection and the treatment is 11 days—far too long,” he says. “My proposal is to build a mobile laboratory to do PCR in the field so we can collect samples and treat people the next day. It would help us avoid losing people and it would improve adherence by allowing people to see how we use the blood samples. I think it would really help.”

While experts are divided over the role of MDA, all can agree on what they don’t know: how quickly artemisinin resistance is currently spreading. “We don’t know,” says Guérin. “It could be slow. It could be quick. If it is slow, we’re going to be lucky. If it’s quick, we’re going to be in deep trouble. Because we also need to face the fact that many of the drugs for malaria currently in the development pipeline are artemisinin derivatives.”

“So even if you develop a new molecule tomorrow, the time for registration is many years. And history has shown that it always takes longer than planned.” Then there’s the challenge of ensuring availability and affordability of the drug. “You can get the most beautiful drug developed tomorrow – but it could be another ten years before production is scaled up enough to supply every child in every village that needs it. We want to send a very positive message about the capacity of new drugs to act against this emergence of resistance to artemisinin. But we should make every effort to prevent the spread of resistance and to maintain as long as we can the efficacy of artemisinin, because, as of today, we don’t have an alternative. And we don’t have a vaccine either.”

An in vitro test and a molecular marker

Joel Breman, a senior scientific advisor at the Fogarty International Center, U.S. National Institutes of Health (NIH), echoes those concerns. “This is a looming catastrophe,” says the world-renowned malaria expert. Breman says funding for research is critical to any containment effort. And while drug development is part of that, he says, other R&D needs require urgent attention as well. “We have no in vitro test nor have we identified a molecular marker to screen for resistance,” says Breman. “And that’s costing us time.”

Indeed, as stated in the plan, the availability of a molecular marker would “dramatically improve the speed and accuracy of detection of artemisinin resistance by allowing more efficient population-level screening.” It would also shed light on the mechanisms underlying resistance as well as the mechanism of antimalarial action of the artemisinins, says Dondorp. “We’re completely in the dark at the moment.”

The MALACTRES consortium, a European Union-funded initiative, is currently investigating resistance to ACTs in Nigeria, Burkina Faso and Tanzania. The effort, led by the Dutch firm KIT Biomedical Research, a division of the Royal Tropical Institute, seeks evidence of newly evolving resistant parasite haplotypes by investigating candidate genes, some of which have polymorphisms that have been associated with ACT selection.

“Evidence from previous studies strongly suggests that such studies can provide an early signal of parasite selection by drug action, before widespread treatment failure becomes apparent,” says MALACTRES director Henk Schallig. “Therefore these studies provide an important complementary path to identifying and validating markers of ACT resistance.”

While the action of artemisinins is poorly understood, it is likely that resistance-associated mutations may appear in several genes, as is true of several partner drugs, including amodiaquine and lumefantrine. “Therefore, it is essential that investigations to identify markers of ACT resistance do more than simply consider genes in isolation, but rather to seek evidence of the survival and spread of combinations of resistant genes in different parasite genetic backgrounds,” says Schallig.

Meanwhile, the NIH’s Laboratory of Malaria and Vector Research (LMVR) is developing genome-wide approaches to study mechanisms of drug resistance, genome diversity, population genetics, and evolution of malaria parasites. “We use microarrays to genotype Plasmodium falciparum parasite isolates collected from the field and search for loci under selection and for genes potentially associated with drug responses,” says Xin-zhuan Su, chief of the malaria functional genomics section and senior investigator.

The LMVR team is also screening P. falciparum parasites against thousands of chemical compounds using high-throughput genotyping arrays that employ a novel molecular inversion probe technology. The latter allows for the identification of genetic elements contributing to differential responses to chemicals or drugs in a wide variety of parasite strains. According to Su, this technology can be used to perform rapid analysis of quantitative trait loci on the progeny of genetic crosses or parasite isolates collected from the field.

“We work on the genetic markers of resistance very much in collaboration with different groups all over the world, including the Sanger Institute and University of Maryland,” says Dondorp. “It’s very important; it would facilitate a lot of other studies. Because once you have a molecular marker, you’re no longer dependent on your laborious in vitro studies. You can just collect parasites and see if the molecular marker is there.”

Still, success remains elusive. A study by Dondorp and colleagues at MOCRU (1) published last year investigated four candidate genes – P. falciparum mdr1 (pfmdr1), P. falciparum ATPase6 (pfATPase6), 6-kb mitochondrial genome, and ubp-1--that earlier studies suggested could have a role in conferring resistance to artemisinin. And while experts generally agree that artemisinin resistance is a heritable genetic trait, the study revealed no relationship between the genes and resistance in Western Cambodia.

Vector control

The bedrock of malaria control worldwide, vector control, represents a key strategy for the containment of artemisinin resistance. And as the GPARC makes clear, it’s critical that research to support the development of new tools continue – including entomological research for methods suitable for migrant populations and to control transmission outside the home, as well as on new insecticides and pesticides, “in anticipation of the development of insecticide resistance.”

But as some see it, vector control isn’t getting it’s due. “[The GPARC] seems to be a good plan,” says Richard Tren, director of Africa Fighting Malaria (AFM), a non-profit health advocacy group committed to making malaria control more transparent, responsive and effective. “I think it’s saying the right things, and it’s right and proper that WHO, as well as the US government and the Gates Foundation, are focusing so intently on this.”

Still, Tren worries that despite its importance to containment efforts, vector control isn’t getting its due.

“As someone said to me recently, ‘Medicine has got us into this, but medicine’s not going to get us out.’ You need solid vector control to stop the spread of resistance. And yet there’s a huge need not only for R&D but also for [operation research] and for malaria control programs. It remains woefully underfunded.”

According to Tren, the Roll Back Malaria Vector Control Working Group is developing a kind of parallel GPARC for vector control. The problem is, he says, there’s no money for it. “These people have a good idea of what needs to be done, there’s just very little funding to do it.”

One of those people is Janet Hemingway, CEO of the Innovative Vector Control Consortium (IVCC), a product development partnership devoted to overcoming the barriers to innovation in the development of new insecticides, information systems and other tools. “I think vector control generally is under represented,” she says.

“We just did a funding survey ourselves – IVCC, Medicines for Malaria Venture (MMV), and the Malaria Vaccine Initiative (MVI) –and it’s tight all around. But if you look at the funding going into vector control, it’s disproportionately low.”

As for the containment effort, says Hemingway, it’s a slightly different story. “In that particular part of the world, vector control is not straightforward.” That’s because the data on the outdoor-biting, outdoor-resting mosquitoes found throughout the Thai-Cambodian border region is extremely thin. “All of the standard vector control methodology we’ve got is for indoor biters,” she says. “They’re giving people bed nets, but just how much impact it’s really going to have – it’s hard to say.”

Also challenging is the migratory nature of the population in question. “And so we’ve been looking at what we might do to give them some sort vector control personal protection,” says Hemingway. Several projects are under way, including a collaborative undertaking by the IVCC and the University of Oxford comparing five different interventions – a mix of insecticide impregnated materials and repellents – and their uptake by populations in Cambodia.

“We’re kind of inventing them as we go,” says Hemingway of the new tools. The DFID-supported project will be the first large-scale trial of spatial repellents for outdoor biting. And while putting insecticides on materials isn’t new, she says, “we’re trying to put them on the kinds of materials that people on the ground already use. The technology for impregnating materials is moving quite quickly, and I think we’re now in a position where we can impregnate most types of material and make it wash resistant.”

For Hemingway as for the rest of the malaria community, the containment of artemisinin resistance is priority number one. But no less devastating to malaria control worldwide would be the loss of pyrethroids. “If you’d have looked ten years ago at the amount of pyrethroid resistance we had in the African vectors, it was very, very low.” Today, she says, resistance to the chemical is moving at “lightning speed” through many African countries.

There exists no alternative to pyrethroids for use in bed nets or intermittent residual spraying (IRS), the cornerstones of malaria control. Nor is pyrethroid resistance properly monitored or mapped, says Hemingway. “If it gets to the point where it’s operational, to the level that it takes out bed nets, I think we’ve got serious issues.”

And like artemisinin, time is of the essence. Part of the IVCC mission is to stimulate industry to develop alternatives to pyrethroids. “The problem is that if you’re going for a completely new molecule, you cannot get it to market in less than seven or eight years. Although we have a healthy pipeline, it’s going to be five or six years before anything comes out of that pipeline.” Given that pyrethroid resistance is moving so quickly, she says, “do we really have five or six years?”

The good news is that where artemisinin resistance is highest, pyrethroid resistance is very low. “Since they’re outdoor-biting, outdoor-resting, they haven’t been hit with a huge amount of the insecticide,” she says. The vector remains susceptible – at least for now.

References

1. Noedl H, Socheat D, Satimai W (2009). Artemisinin-resistance malaria in Asia. N Engl J Med 361:5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19641219

2. Dondorp A (2010). Exploring the Contribution of Candidate Genes to Artemisinin Resistance in Plasmodium falciparum. Antimicrob Agents Chemother 54(7):2886-2892. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20421395

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