The story of artemisinin resistance is important and worth telling. Artemisinin resistance is probably one of the major malaria related public health emergencies in Africa right now.
However, this story entirely confuses the main issues and is riddled with factual errors. I would suggest the author retracts it and consults with experts to write an accurate version.
Some of the major problems/factual errors:
There is no distinction made between the different uses of the artemisinin derivatives (artesunate, artemether, arteether, dihydroartemisinin being the main ones). Artesunate is primarily used for the treatment of severe malaria (injectable or rectal). But artemisinin derivatives are also used in combination with slowly eliminated partner drugs (lumefantrine, amodiaquine, mefloquine) to treat uncomplicated malaria (oral treatment). Injectable (and rectal) artesunate are life saving drugs for severe malaria but ACTs (artemisinin-based combination therapies) have had a huge impact on malaria attributable mortality because they replaced chloroquine for the treatment of uncomplicated malaria. See the letter by Ataran et al from 2004. ACTs are not even mentioned in the timeline! They were being used in Southeast Asia by the late-90s following pivotal trials.
The paragraph on the Vietnam war makes it sound like quinine was the main antimalarial drug in use during the Vietnam war. Chloroquine had been discovered in 1934, and was developed after WW2. It was very widely used (even put in table salt in Cambodia). Chloroquine was a remarkably effective drug but first reports of resistance were in 1957 on the Thailand/Cambodia border Piperaquine, mefloquine, sulphadoxine-pyrimethamine were developed in the 1950s/1960s.
“2003 – Small RCT shows artesunate “as effective as quinine” for severe malaria”. Not only does this completely ignore the development of ACTs (recommended by WHO as first line treatment in 2006 after the Attaran letter), but this was not the first trial of artemisinin derivatives in severe malaria. The development of artemisinin derivatives given parenterally for severe malaria was much more complex. Initially artemether was chosen as the candidate drug. Two large trials (over 500 patients in each) published in 1996 (one in Africa, one in Asia) showed that artemether was as good as quinine. However, because of its pharmacology (artemether is variably absorbed) it wasn’t clearly better. A trial done between 1996-2003 in Vietnam showed that artesunate cleared parasites faster due to better absorption, this then led to the SEAQUAMAT study. So the history as presented is wrong and misleading.
“artesunate still cures over 99.9% of malaria cases”: this is meaningless. Artesunate or any artemisinin derivative is not given on its own to treat malaria. The therapeutic objective in severe malaria is to save life (around 5-20% of patients still die following IV artesunate, depending on their severity at presentation). The therapeutic objective in the treatment of uncomplicated malaria is to stop progression to severe illness and clear all parasites from the body. The artesunate component on its own does not clear all parasites when given over 3 days (even without resistance). The brilliant idea of ACTs is that by combining a fast acting but rapidly cleared artemisinin derivative with a slow acting but slowly cleared partner drug, you leave only a few parasites for the partner drug to clear up. This means that even when the partner drug doesn’t work very well, in combination with an artemisinin derivative it can treat the infection. Artemisinin resistance means that there are more parasites that the partner drug needs to clear and so emergence of partner drug resistance occurs. Then the ACT fails to treat the infection. This is what has happened in Southeast Asia. Lumefantrine is the partner drug in around 70% of all treatments used in Africa (artemether/lumefantrine, known by the brand name coartem). If lumefantrine resistance emerged, this would be a major disaster.
“adding a 3rd drug to the treatment cocktail – a blunt and expensive instrument but one that could buy us another 10 years.” No this is wrong. New drugs currently in development are being developed as “triple” therapy. There are good pharmacological reasons for this around prevention of the emergence of resistance.
In summary, this article is highly misleading on the history of the development of the artemisinins into usable treatments for malaria.
I disagree with point 2. ACTs have had a huge impact on malaria mortality and morbidity, primarily because they are so effective, well tolerated, and replaced a completely failing drug (chloroquine). ACTs have lasted in Africa >20 years before starting to succumb to resistance. They have had an enormous impact.
The Rethink Priorities estimate concerns coartem dispersible only, compared to a counterfactual of receiving crushed tablet formulations of Coartem. Two problems: Coartem is the Novartis brand name for artemether lumefantrine (AL), and the dispersible is only a proportion (kids under 3? Not sure about this point) of all AL treatments. And the counterfactual is still an ACT! Novartis only supplies around 10% of all AL. AL is about 70% if all ACTs.
The correct counterfactual question are: how many kids would die from malaria if quinine was still first line treatment for severe malaria; and how many kids would die from malaria if ACTs did not exist (eg if treatment for uncomplicated malaria only used existing non artemisinin drugs). The second counterfactual is really hard to estimate with any confidence because ACTs were such a massive revolution in the treatment of malaria.
To put severe malaria versus uncomplicated malaria in perspective: donor funded procurement of ACTs in 2022 was 257M (Chai estimates). For injectable & rectal artesunate this was 45M (almost 6x difference). The fact that AL (or ACTs in general) were primarily developed and tested in Asia is irrelevant: their use today is in Africa.
Regarding point 3: the future of antimalarial treatment for uncomplicated malaria will be triple combination therapy. For the next 5 to 10 years this will likely be with existing drugs, possibly in combination with new drugs (e.g. ganaplacide). Triple therapy is not a blunt tool, it is what is needed to prevent the emergence of resistance.