Artemisinin resistance: the Achilles heel of antimalarial treatments?

By Arunima Pande

Eliminating malaria in at least 35 countries by 2030 is one of the aims of the World Health Organisation. As we celebrate World Malaria Day on 25th April this year, it is apt to take a closer look at artemisinin resistance, a threat to malaria elimination efforts worldwide. 

Artemisinin and ACTs

The highly effective, all-powerful ACTs have an Achilles heel in the form of tiny mutations.

Artemisinin,  isolated from the plant Artemisia annua,  is a powerful drug used in the first-line of treatment of malaria. Derivatives of artemisinin include artesunate, artemether, and dihydroartemisinin [DHA]. 

What makes artemisinin compounds such effective antimalarial drugs?

Artemisinin combination therapies (ACTs) are combinations of rapidly acting artemisinin and a slow-acting partner drug (like piperaquine, mefloquine etc). The beauty of ACTs is that artemisinin and the partner drug complement each other in their mechanisms to combat malaria. They also lower the chances of the ACT failing in case resistance develops to one of the drugs. 

Cause of artemisinin resistance

The highly effective, all-powerful ACTs have an Achilles heel in the form of tiny mutations.

Single Nucleotide Polymorphisms in the K13 propeller domain of Plasmodium falciparum lead to artemisinin resistance, additionally acting as a molecular marker that can be used to monitor and map artemisinin resistance. 

ACT failures in western Cambodia

Studies of dihydroartemisinin-piperaquine (DHA-PPQ) efficacy in western Cambodia showed a failure to cure P. falciparum malaria in >10% of patients, with 11% to 54% failure rates being reported from 2008 to 2014 in four provinces. 

ACTs, considered the most potent antimalarial drugs of today, are failing fast. 

It is important to note that ACT failure does not imply artemisinin resistance. In fact, the affected areas showed a failure of ACTs because of resistance to piperaquine(PPQ). 

Now, whether artemisinin resistance precipitated PPQ resistance, or if it helped select for parasites that were already PPQ resistant, or if PPQ resistance emerged independently, remains to be discovered. 

Transmission

The rapid spread of artemisinin resistance is more alarming than its existence itself.

Till date partial resistance has been confirmed in 5 Southeast Asian countries, but it is crucial to stop this spread to Africa, where there are the most transmission, morbidity and mortality rates of malaria in the world. 

What causes this swift spread of artemisinin resistance?

It’s simple: the resistant parasites are able to infect almost all native vector species. This was proved by an experiment where 3 artemisinin resistant Plasmodium clones from western Cambodia, successfully infected native mosquitoes of SEA; along with Anopheles coluzzi, native of Sub-saharan Africa. 

This study is pivotal as it not only confirms the reason for the spread of resistance in SEA, but also demonstrates that Anopheles coluzzi may not provide any hindrance to  the spread of artemisinin resistance to Africa.

Future Possibilities 

Now that we know that artemisinin resistance is spreading rapidly, and may potentially even spread to Africa, what are our alternatives?

One possibility is using artesunate-mefloquine combinations, as in parasites with PPQ resistance, mefloquine is more potent. The chances of the parasite developing a resistance to mefloquine are also low. However, the efficacy of this combination remains to be tested. 

Another potential solution being tested is using triple ACTs (TACTs) that combine an artemisinin with two partner drugs. 

Finally, ways can be found to interrupt transmission of artemisinin-resistant parasites: through the development of new gametocytocidal drugs, transmission blocking vaccines, and mosquito repellents.

Bibliography:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992992/

https://www.who.int/malaria/media/artemisinin_resistance_qa/en/

https://www.who.int/news-room/fact-sheets/detail/malaria

Leave a Comment

Your email address will not be published.