WHO Launches Program to Counter Drug-Resistant Malaria

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On World Malaria Day, the World Health Organization has launched an emergency program in Phnom Penh to tackle a worrying regional trend – a strain of malaria that is proving resistant to the most important anti-malarial drug.

Six years ago, health researchers were worried after a strain of malaria in western Cambodia began to show resistance to the world’s key malaria treatment – Artemisinin-based Combination Therapy, known as ACT.

In response, the Cambodian government and its health partners, including the World Health Organization, put in place a program to prevent the resistant strain (falciparum malaria) from spreading within Cambodia and beyond its borders.

That program appears to have contained the resistant strain. But Thailand, Burma and Vietnam have reported pockets of artemisinin-resistant malaria strains.

The WHO malaria specialist in Phnom Penh, Stephen Bjorge, said it is likely the strains in those countries arose independently of Cambodia’s – which means the containment efforts have worked.

But because artemisinin is the standard treatment, it is important the resistant strains in all of these areas are contained and then eradicated. That is the purpose of a three-year, $400-million program the World Health Organization announced Thursday.

“The risks are significant – not only are they significant for the region in terms of having a reversal of the gains that have been made against malaria, but they are actually significant globally,” said Robert Newman, director of the WHO’s Global Malaria Program. “If history is any guide, if we were not to contain this problem then it is very likely to spread elsewhere. Especially risky is to sub-Saharan Africa, where the greatest burden still exists. And, if we were to lose the efficacy of the ACTs today, this really would be a public health catastrophe in Africa.”

The WHO-led program is being funded by the Global Fund, the Bill & Melinda Gates Foundation and by the Australian government’s development arm called AusAID.

It will cover six countries: the four where resistance has already been found, as well as two more considered to be “at risk” from the resistant strain: Laos and an area of southern China.

Newman said some of the lessons learned from Cambodia’s efforts are being used.

“This is not starting from zero,” he explained. “It is building on the experience initially on the Cambodia-Thailand border where those countries gained a lot of experience in how to reach the populations that are actually most difficult to reach – migrant and mobile populations, how to use village health care workers, how to more aggressively remove substandard medicines from the market.”

The program will distribute insecticide-treated bed nets; monitor fake drugs; ensure people have access to reliable testing and treatment; and track the disease. Migrant communities and people living in border regions will be key targets of the program.

AusAID has provided $5 million of funding for the program.

“Well, our initial funding is fixed, but the reality is Australia is part of this region,” said AusAID’s principal health advisor Ben David. “We are part of the Asia-Pacific and we see this as a critical investment to protect the poor in the region from malaria, but also to protect the interests of countries because if this problem gets out of control and we see malaria drug resistance spread in the region and beyond, then we are in to face a big set of problems.”

David says, last year, malaria killed 42,000 people in the Asia-Pacific region and more than half a million worldwide, most of them children in Africa.

Recent years have seen good progress in tackling malaria, but the WHO warns that could be undone should the resistant strains escape the current pockets in the countries of the Greater Mekong sub-region.

David believes governments will do their part to prevent the spread.

“It has actually got significant economic implications, if this problem of resistance continues. So, we really need to make the economic case to governments to continue to invest in this problem,” he added.

The chloroquine-resistant malaria strain has caused millions of deaths globally since it emerged 60 years ago from the forests of western Cambodia.

The World Health Organization warns the world cannot afford a similar repeat outbreak by allowing the new strain or strains of artemisinin-resistant malaria to escape the region.

Source: VOA News

G6PD Deficiency Prevalence and Estimates of Affected Populations in Malaria Endemic Countries

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Primaquine is a key drug for malaria elimination. In addition to being the only drug active against the dormant relapsing forms of Plasmodium vivax, primaquine is the sole effective treatment of infectious P. falciparum gametocytes, and may interrupt transmission and help contain the spread of artemisinin resistance. However, primaquine can trigger haemolysis in patients with a deficiency in glucose-6-phosphate dehydrogenase (G6PDd). Poor information is available about the distribution of individuals at risk of primaquine-induced haemolysis. We present a continuous evidence-based prevalence map of G6PDd and estimates of affected populations, together with a national index of relative haemolytic risk.

Methods and Findings

Representative community surveys of phenotypic G6PDd prevalence were identified for 1,734 spatially unique sites. These surveys formed the evidence-base for a Bayesian geostatistical model adapted to the gene’s X-linked inheritance, which predicted a G6PDd allele frequency map across malaria endemic countries (MECs) and generated population-weighted estimates of affected populations. Highest median prevalence (peaking at 32.5%) was predicted across sub-Saharan Africa and the Arabian Peninsula. Although G6PDd prevalence was generally lower across central and southeast Asia, rarely exceeding 20%, the majority of G6PDd individuals (67.5% median estimate) were from Asian countries. We estimated a G6PDd allele frequency of 8.0% (interquartile range: 7.4–8.8) across MECs, and 5.3% (4.4–6.7) within malaria-eliminating countries. The reliability of the map is contingent on the underlying data informing the model; population heterogeneity can only be represented by the available surveys, and important weaknesses exist in the map across data-sparse regions. Uncertainty metrics are used to quantify some aspects of these limitations in the map. Finally, we assembled a database of G6PDd variant occurrences to inform a national-level index of relative G6PDd haemolytic risk. Asian countries, where variants were most severe, had the highest relative risks from G6PDd.

Conclusions

G6PDd is widespread and spatially heterogeneous across most MECs where primaquine would be valuable for malaria control and elimination. The maps and population estimates presented here reflect potential risk of primaquine-associated harm. In the absence of non-toxic alternatives to primaquine, these results represent additional evidence to help inform safe use of this valuable, yet dangerous, component of the malaria-elimination toolkit.

Background

Malaria is a parasitic infection that is transmitted to people through the bites of infected mosquitoes. Of the four parasites that cause malaria, Plasmodium falciparum is the most deadly and P. vivax is the commonest and most widely distributed. Malaria parasites have a complex life cycle. Infected mosquitoes inject “sporozoites” into people, a form of the parasite that replicates inside human liver cells. After a few days, the liver cells release “merozoites,” which invade red blood cells where they replicate rapidly before bursting out and infecting other red blood cells. This increase in the parasitic burden causes malaria’s characteristic fever and can cause organ damage and death. Infected red blood cells also release “gametocytes,” which infect mosquitoes when they take a blood meal. In the mosquito, gametocytes multiply and develop into sporozoites, thus completing the parasite’s life cycle. Malaria can be prevented by controlling the mosquitoes that spread the parasite and by avoiding mosquito bites by sleeping under insecticide-treated bed nets. Treatment with effective antimalarial drugs also decreases malaria transmission.

Why Was This Study Done?

The Global Malaria Action Plan aims to reduce malaria deaths to zero by 2015 and to eradicate malaria in the long-term through its progressive elimination in malaria-endemic countries (countries where malaria is always present). Primaquine is a key drug for malaria elimination. It is the only treatment effective against the gametocytes that transmit malaria between people and mosquitoes and against P. vivax “hypnozoites,” which hibernate in the liver and cause malaria relapses. Unfortunately, primaquine induces mild to severe destruction of red blood cells (hemolysis) in people who have a deficiency in the enzyme glucose-6-phosphate dehydrogenase (G6PD). G6PD deficiency (G6PDd) is common in some ethnic groups but the global distribution of individuals at risk of primaquine-induced hemolysis is unknown and there is no practical field test for G6PDd. Consequently, it is hard to design and implement primaquine treatment practices that balance the benefits of malaria transmission reduction and relapse prevention against the risk of hemolysis. Here, the researchers use a geostatistical model to map the prevalence (frequency in a population) of G6PDd in malaria-endemic countries and to estimate how many people are affected in these countries. They also develop a national index of relative hemolytic risk.

What Did the Researchers Do and Find?

The researchers fed data from community surveys of the prevalence of phenotypic G6PDd (reduced enzyme activity) for 1,734 sites (including 1,289 sites in malaria-endemic countries) into a geostatistical model originally developed to map global malaria endemicity. The model predicted that G6PDd is widespread across malaria-endemic regions, with the lowest prevalences in the Americas and the highest in tropical Africa and the Arabian Peninsula, but that most G6PDd individuals live in Asian countries. The predicted prevalence of G6PDd varied considerably over relatively short distances in many areas but, averaged across malaria-endemic countries it was 8%, which corresponds to about 350 million affected individuals; averaged across countries that are currently planning for malaria elimination, the prevalence was 5.3% (nearly 100 million affected individuals). Finally, the researchers used data on the geographical occurrence of G6PD variants classified according to their enzyme activity levels as mild or severe to derive an index of hemolytic risk from G6PDd for each malaria-endemic country. The greatest risk was in the Arabian Peninsula and west Asia where the predicted prevalence of G6PDd and the occurrence of severe G6PD variants were both high.

What Do These Findings Mean?

These findings suggest that G6PDd is widespread and spatially heterogeneous across most of the malaria-endemic countries where primaquine would be valuable for malaria control and elimination. The accuracy of these findings is limited, however, by the assumptions made in the geostatistical model, by the accuracy of the data fed into the model, and by the lack of data for some malaria-endemic countries. Moreover, there is considerable uncertainty associated with the proposed index of hemolysis risk because it is based on phenotypic G6PDd enzyme activity classifications, which is presumed, but not widely demonstrated, to be a surrogate marker for hemolysis. Nevertheless, these findings pave the way for further data collection and for the refinement of G6PDd maps that, in the absence of non-toxic alternatives to primaquine, will guide the design of safe primaquine regimens for the elimination of malaria.

Citation: Howes RE, Piel FB, Patil AP, Nyangiri OA, Gething PW, et al. (2012) G6PD Deficiency Prevalence and Estimates of Affected Populations in Malaria Endemic Countries: A Geostatistical Model-Based Map. PLoS Med 9(11): e1001339. doi:10.1371/journal.pmed.1001339

Academic Editor: Lorenz von Seidlein, Menzies School of Health Research, Australia

Received: February 22, 2012; Accepted: October 4, 2012; Published: November 13, 2012

Funding: This work was supported by a Wellcome Trust Biomedical Resources Grant (#085406), which funded REH, FBP, OAN, and MMH; SIH is funded by a Senior Research Fellowship from the Wellcome Trust (#095066) that also supports PWG and KEB; APP was funded by a Biomedical Resources Grant from the Wellcome Trust (#091835). MD is funded by the Oxford University-Li Ka Shing Foundation Global Health Programme. This work forms part of the output of the Malaria Atlas Project (MAP), principally funded by the Wellcome Trust, UK. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: G6PDd, glucose-6-phosphate dehydrogenase deficiency; GRUMP, Global Rural-Urban Mapping Project; IQR, interquartile range; MEC, malaria endemic country; PPD, posterior predictive distribution; UN, United Nations; WHO, World Health Organization

Full Article: G6PD Deficiency Prevalence and Estimates of Affected Populations in Malaria Endemic Countries: A Geostatistical Model-Based Map (PDF)

Copyyight © 2012 Rosalind E. Howes, Frédéric B. Piel, Anand P. Patil, Oscar A. Nyangiri, Peter W. Gething, Mewahyu Dewi, Mariana M. Hogg, Katherine E. Battle, Carmencita D. Padilla, J. Kevin Baird, Simon I. Hay

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.