Malaria

Q&A on artemisinin resistance

April 2014

1. What is artemisinin?

Isolated from the plant Artemisia annua, or sweet wormwood, artemisinin and its derivatives are powerful medicines known for their ability to swiftly reduce the number of Plasmodium parasites in the blood of patients with malaria. Artemisinin-based combination therapies (ACTs) are recommended by WHO as the first-line treatment for uncomplicated P. falciparum malaria. Expanding access to ACTs in malaria-endemic countries has been integral to the remarkable recent success in reducing the global malaria burden. In 2012,  331 million ACT treatment courses were delivered by manufacturers to endemic countries – up from 11 million in 2005.

ACTs combine artemisinin derivatives with a partner drug. There are five different ACTs currently recommended by WHO. The role of the artemisinin compound is to reduce the main parasite load during the first three days of treatment, while the role of the partner drug is to eliminate the remaining parasites. In patients who are infected with artemisinin-resistant strains of malaria, the artemisinin compound does not clear all parasites by the third day of treatment. However, patients are still cured as part of a longer treatment regimen, provided that they are treated with an ACT containing a partner drug that is effective in that geographical area.

2. What is the state of artemisinin resistance around the world?

Parasite resistance to artemisinin has so far been detected in five South-East Asian countries: in Cambodia, the Lao People’s Democratic Republic, Myanmar, Thailand and Viet Nam (all in the Greater Mekong subregion). Artemisinin resistance is also suspected is some parts of South America but confirmatory studies are still ongoing. Resistance is occurring as a consequence of several factors, including poor treatment practices, inadequate patient adherence to prescribed antimalarial regimens, and the widespread availability of oral artemisinin-based monotherapies and substandard forms of the drug.

Given the ever-increasing levels of population movement in Asia and the Pacific, the geographic scope of the problem could widen quickly, posing a health security risk for many countries in the region with ongoing malaria transmission. If resistance were to spread to – or emerge in – India or sub-Saharan Africa, the public health consequences could be dire, as no alternative antimalarial medicine is available at present with the same level of efficacy and tolerability as ACTs. There is therefore a limited window of opportunity to avert a regional public health disaster, which could have severe global consequences.

In late 2013, research identified a molecular marker associated with delayed parasite clearance in patients given treatment containing artemisinin. The molecular marker could allow for a more precise mapping and monitoring of the geographical distribution and spread of resistance. It could also enable a retrospective mapping of possible resistance in a large number of settings. WHO is currently working with researchers, national malaria programmes and other partners – within and outside of the Greater Mekong subregion – to map the presence of artemisinin resistance. More details are expected to be available by the end of 2014. Therapeutic efficacy studies will continue to remain a central tool for monitoring the efficacy of nationally recommended antimalarial treatments in all countries.

3. What does WHO recommend to fight the development of artemisinin resistance?

In May 2007, the World Health Assembly called on malaria-endemic countries to progressively cease the provision of artemisinin-based monotherapies (resolution WHA60.18), and in January 2011, WHO released the Global plan for artemisinin resistance containment (GPARC), calling on all stakeholders to maximize efforts to protect the efficacy of ACTs. The GPARC contains a comprehensive set of technical recommendations on how to contain existing resistance and on how to prevent it from emerging elsewhere. Among others, the GPARC urges endemic countries to increase monitoring and surveillance of possible resistance, including through therapeutic efficacy studies, to expand access to diagnostics, and to rationalize the use of ACTs. It also calls on stakeholders to invest in artemisinin resistance-related research, and to mobilize resources.

4. What is being done to contain artemisinin resistance?

Containment efforts are underway in all areas with suspected or confirmed artemisinin resistance in the affected countries. In higher transmission areas, efforts focus on limiting the risk of spread by lowering the malaria burden through intensified malaria control, by increasing access to diagnosis and appropriate treatment, and by scaling up provision of health-care services to migrant and mobile populations. Containment programmes in lower transmission areas seek to achieve an accelerated elimination of P. falciparum parasites.

Overall, these efforts have been effective but need to be further strengthened and expanded. Scaling up basic prevention and control interventions and implementing all of WHO’s recommendations require considerable financial resources, long-term political commitment, and strong cross-border cooperation. Governments of endemic countries also need to take targeted regulatory measures to remove oral artemisinin-based monotherapies from markets, along with antimalarials that do not meet international quality standards. On 25 April 2013, WHO launched an Emergency response to artemisinin resistance in the Greater Mekong subregion to guide an emergency scale-up of containment efforts in affected countries.

Malaria interventions are being scaled up against the backdrop of increasing political momentum in the region. A high-level malaria summit hosted by the Government of Australia on 31 October – 2 November 2012 in Sydney adopted a Consensus on malaria control and elimination in the Asia-Pacific, which also called for the establishment of an Asia-Pacific Leaders Malaria Alliance (APLMA). This was followed by the adoption of the Declaration of the 7th East Asia Summit on Regional Responses to Malaria Control and Addressing Resistance to Antimalarial Medicines on 20 November 2012 in Cambodia. The APLMA was launched at the East Asia Summit in Brunei Darussalam in October 2013.

5. How serious are the consequences of artemisinin resistance?

In the Greater Mekong subregion, patients with resistant parasites still recover after treatment, provided that they are treated with an ACT containing an effective partner drug. However, there is a real risk of parasites developing resistance to all available medicines. For example, in western Cambodia, ACT options have become so limited in the past few years that until recently a non-ACT drug, atovaquone-proguanil, was recommended as first-line treatment. The national malaria programme has now switched back to ACTs but the programme will apply directly observed treatment for all patients, and monitor resistance through molecular markers.

Similarly to the spread of resistance to chloroquine and other antimalarial medicines in the past, there is a possibility that artemisinin resistance will spread or develop independently around the world. However, this is very difficult to predict or compare to previous patterns of resistance, as malaria control interventions have been significantly scaled up during the past decade, leading to substantial changes in the malaria transmission environment.

6. How does this affect the efficacy of ACTs?

National malaria control programmes need to consider the possibility of emerging resistance to both the artemisinin compound and the partner drug. If resistance to the partner drug exists, it is more likely that resistance to artemisinin will also develop, and vice versa. If the treatment failure rate is higher than 10% after treatment with an ACT, WHO recommends that the country changes its treatment policy by switching to an ACT with a different partner drug.

7. What more needs to be done to fight this threat?

Fighting the threat of artemisinin resistance requires an urgent and coordinated international response, as well as robust and predictable financing. The scale-up of containment efforts has major cost implications for the public health budgets of countries in the Greater Mekong subregion, and affected countries cannot fight this challenge alone. Increased international assistance would deliver significant savings in the long run, improving the sustainability and public health impact of malaria interventions around the world. WHO is working with affected countries and partners to ensure a rapid and comprehensive scale up of malaria interventions and containment efforts in the Greater Mekong subregion.

The WHO coordination efforts, based out of a regional hub in Phnom Penh, Cambodia, are being supported by the Bill & Melinda Gates Foundation and the Government of Australia. In addition, the Global Fund to Fight AIDS, Tuberculosis and Malaria has committed US$ 100 million to tackle this threat between 2014 and 2017. While these are significant steps forward, the funding gap remains substantial. In early 2013, WHO estimated that about US$ 300–350 million in additional funding was required for the 2013–2015 period to fully scale up malaria control and containment activities in the affected countries.

Endemic countries outside this region – and in particular on the African continent, where malaria took an estimated 560 000 lives in 2012 – also need to identify additional resources to fully implement the GPARC’s recommendations. One of the most urgent challenges is to strengthen pharmaceutical market regulation, and remove oral artemisinin-based monotherapies from markets around the world once and for all.

This factsheet was originally issued in April 2013 and was updated in April 2014.


Note

To learn more about which countries still allow the marketing of oral artemisinin-based monotherapies, and which companies still produce and market these products, please visit:

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