Opinion: AMR poses a risk to malaria eradication — but how much?

World Antimicrobial Awareness Week from Nov. 18-24 draws attention to the risk that drug resistance poses to global health security. The 2022 theme “Preventing antimicrobial resistance together” focuses on the importance of investment and collaboration to address this threat, which claimed over one million lives in 2019. Recognizing the importance of a coordinated response, the World Health Organization kicked off the week by launching its strategy to respond to antimalarial drug resistance in Africa.

Throughout recent history, the efficacy of malaria medicines has repeatedly been compromised by drug resistance. Progress has been made over the last 20 years in bringing malaria under control through intensified use of a mix of control measures, including insecticide-treated bed nets and artemisinin-based treatments. Today, the utility of these interventions is again under threat.

Earlier this year, The Lancet published the most comprehensive study to date on bacterial antimicrobial resistance. Although discussions about AMR tend to center on antibiotics, it is important to note that antimalarial drug resistance is also included under this umbrella.

The Lancet’s study drew widespread attention to the threat that AMR poses to global health security, determining that it killed an estimated 1.27 million people in 2019. According to the World Health Organization, “AMR occurs when bacteria, viruses, fungi and parasites adapt to drugs over time and no longer respond to medicines. This makes infections harder to treat and leads to the spread of the disease, severe illness, and death.”

AMR remains a persistent threat to malaria eradication efforts

Artemisinin-based combination therapies, or ACTs, are a valuable and relatively recent weapon against malaria. In the early 20th century, chloroquine was successfully used to treat malaria. When resistance to chloroquine arose, health care providers began using sulfadoxine-pyrimethamine to treat malaria. In the 1970s, Chinese chemist Tu Youyou discovered artemisinin, a highly effective antimalarial derived from the sweet wormwood plant. Thanks to this breakthrough, ACTs entered into use in 2005.

ACTs, which are recommended by WHO as a first-line treatment for malaria, have been used to treat malaria patients with great success. Over that time, the availability of ACTs and other control measures has enabled significant progress toward malaria eradication: between 2000 and 2019, global malaria deaths fell from 896,000 to 558,000. But despite ACTs’ effectiveness against malaria, evidence of partial resistance to artemisinin — meaning there is a delay in malaria parasite clearance after treatment with an ACT — has arisen in malaria-endemic regions, posing a risk to continued progress against the disease.

In 2010, researchers uncovered evidence of resistance to dihydroartemisinin-piperaquine, an ACT used to treat Plasmodium falciparum malaria in Cambodia, endangering malaria progress in the Greater Mekong region. Fortunately, recent multistakeholder efforts to accelerate elimination in the region have brought the situation largely under control. In Africa, however — home to over 90% of malaria cases — countries such as Rwanda and Uganda have recently shown evidence of partial resistance to artemisinin.

The increase in AMR in recent years is due to several factors, including the over-prescription of certain medicines, as well as the rising cost to develop new ones. Additionally, patient adherence to the dosing regimen is essential to ensuring a drug’s continued effectiveness. Yet some patients who feel better after a first or second dose of an ACT do not complete their treatment, which can lead to the emergence of drug-resistant parasites. While resistance to artemisinin is currently only partial, the resulting longer time frame to clear parasites gives the parasites an opportunity to develop resistance to the partner drug in the ACT combination, which poses a dual risk.

Today ACTs remain largely effective

One of the aims of the United Nations 2030 Agenda for Sustainable Development and the Sustainable Development Goals is to achieve universal health coverage. Goal 3 calls for countries to “Ensure healthy lives and promote well-being for all at all ages” and more specifically, Target 3.3 is to “By 2030, end the epidemics of AIDS, tuberculosis, malaria and neglected tropical diseases and combat hepatitis, water-borne diseases and other communicable diseases”. However, five years after the adoption of the SDGs, malaria incidence rose from 227 million cases in 2019 to 241 million in 2020. While the increase in cases is partially due to disruptions in health services caused by the COVID-19 pandemic, the potential threat of partial resistance to artemisinin and growing resistance to partner drugs could further impede or reverse our progress to eradicate malaria.

Although it is important to bear this risk in mind when treating malaria patients and developing new antimalarials, ACTs are still largely effective. Therefore, it is crucial to continue employing strategies that allow malaria-endemic countries to benefit from ACTs for as long as possible while new non-artemisinin treatments are developed. Doing so requires both financial and political commitment from decision-makers.

Responding to AMR in the malaria eradication agenda

In the immediate future, resistance can be evaded by partnering artemisinin with two drugs instead of one to create triple ACT combinations. Using multiple first-line drugs, either in parallel or in rotation, will reduce pressure on a partner drug. Lengthening treatment periods will also help maintain the drugs’ effectiveness. Additionally, adding low doses of primaquine, which can kill the stages of the parasite life cycle that are transmitted onwards, could also help limit the spread of resistance.

As per Pillar 4 of WHO’s new strategy, it is crucial to prioritize investment in research and development to develop new combination therapies that do not contain artemisinin. In this regard, the news issued today on the decision by Medicines for Malaria Venture and Novartis to move to a Phase 3 study for a novel non-artemisinin combination to treat uncomplicated malaria is particularly exciting. Eradicating malaria amid the risk posed by AMR will require the successful deployment of a combination of new drugs with a high barrier against resistance, strict adherence to treatment, effective malaria chemoprevention methods, and transmission reduction through vector control methods such as long-lasting insecticide-treated nets and indoor residual spraying. It is also important to take advantage of drugs that may work in new ways against the parasite, and opportunities to identify long-acting compounds that may facilitate greater compliance with full treatment schedules, such as treatments that health care service providers can administer — and therefore observe compliance to — in one encounter.

World Antimicrobial Awareness Week puts a spotlight not only on the threat posed by AMR but also on the importance of cross-sectoral strategies and actions to halt illness and death. Greater collaboration and commitment from governments, international groups, pharmaceutical companies, and research organizations will help save millions of lives.

Visit Medicines for Malaria Venture’s website to learn more about the organization’s work to reduce the burden of malaria in disease-endemic countries by discovering, developing and facilitating the delivery of new, effective and affordable antimalarial drugs.