Anti-malarial Drug Resistance

Planning the next Malaria multicentre study

The Director-General of the WHO and the World Economic Forum have both placed antimicrobial drug resistance (AMR) at the very top of the global health risk register. We are at the forefront of the fight against drug-resistant malaria. Our malaria elimination efforts are driven mainly by the urgent need to get rid of falciparum malaria in SE Asia before it becomes untreatable because of artemisinin and multidrug resistance.

The cornerstone for the antimalarial treatment of both uncomplicated and severe falciparum malaria are the artemisinins, very potent antimalarials derived from the wormwood Artemisia annua.

However, in 2007-2008 we found that parasite clearance rates were dramatically slower in patients in Pailin province in Western Cambodia, and subsequently the same clinical phenotype was observed on the Thai-Myanmar border, and later in South Vietnam, Southern Laos and deeper into Myanmar. Although initially this was not accompanied by reduced efficacy of the ACT, we now observe high treatment failures with ACTs in western Cambodia and on the Thai-Myanmar border caused by concomitant resistance to the partner drugs. The severe threat of artemisinin resistance is an important research subject for our group.

The Unit works to develop new regimens to treat artemisinin-resistant malaria, in particular in areas of failing ACT efficacy. These include novel ways of using existing drugs, such as prolongation of treatment courses or combining three instead of two drugs in combination therapies. In addition, new compounds including the synthetic endoperoxides and the spiroindolones are being tested.

Monitoring the spread and novel emergence of the resistance problem is crucial to guide malaria containment and elimination interventions. In the past both chloroquine and pyrimethamine resistance started on Thailand’s borders with Cambodia and Myanmar before spreading westward to India and then to Africa where they were responsible for millions of malaria deaths.

MORU coordinated the Tracking Resistance to Artemisinin Collaboration (TRAC), involving 15 study sites in 10 countries across Asia and Africa.

TRAC mapped the current geographical extent of artemisinin resistant malaria in Southeast Asia and characterized further the resistance phenotype. Importantly, TRAC also confirmed the molecular marker in a parasite gene on chromosome 13 coding for the propeller region of a Kelch protein (“Kelch 13”), which has been a game-changer in the surveillance for artemisinin resistance. In collaboration with the Sanger Institute the study further elucidated the underlying molecular determinants of artemisinin resistance.

However, many questions remain to be answered regarding the molecular mechanisms, including the importance of low-frequency K13 mutations in parasite populations not considered artemisinin resistant, and the importance of additional gene mutations supporting resistance or compensating for fitness loss. Based at MORU, but also working for the Sanger Institute in the U.K., Senior Informatics Fellow Olivo Miotto is pivotal in taking this field forward in close collaboration with Mallika Imwong, Head of the Molecular Malaria Lab, and Senior Researcher Charlie Woodrow.

The molecular malaria laboratory under Malika Imwong is developing a simple platform to evaluate the K13 mutations in P. falciparum that can be used in large scale field studies. In addition the biological mechanisms underlying artemisinin resistance remain incompletely understood. Together with a team of international collaborators we are working hard to elucidate these questions.

Dr Kesinee's Malaria laboratory team

As a follow-up of the TRAC trial, Rob van der Pluijm is the coordinator for the TRACII study which started in 2015 and will explore in 14-17 sites in eight countries – Bangladesh, Cambodia, Democratic Republic of Congo (DRC), India, Lao PDR, Myanmar, Thailand and Viet Nam – how far west of the Cambodia-Thailand border antimalarial resistance has spread. In addition TRACII will test triple ACT (TACT) therapy for safety and efficacy in areas with artemisinin resistance. Future deployment of TACT might buy important time when ACTs are increasingly failing and new drugs will take still years to registration.

In addition to the clinical studies, Dr Kesinee Chotivanich and her team are working on improving the in-vitro laboratory methods to test the sensitivity of the parasite to the artemisinin drugs, which will be an important additional monitoring tool.