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.
Hi James and thanks for posting here on the forum, appreciate someone who is obviously a m malaria expert weighing in here with this useful feedback. I will say I was aware of much of the factual information in your feedback, but chose to leave it out for storytelling purposes—for better or worse.
Overall I was going for a short, simplified narrative article which briefly walked through 5 “acts” in the story of artesunate, while highlighting the incredible discovery story, pointing out that we may have unnecesarily delayed the mass roll out of artemisin treatment and the emerging resistnace issues. I’m writing for a general audience so I didn’t focus on scientific details or get into the weeds, while doing my best to not to be misleading . Of course I compromised at times to bring the story out more vividly. I would argue that I make few factual errors, rather I missed out some aspects of the story that could be considered important. I’m interested if you disagree with any of my major points in the article, besides the important scientific information that I omitted? You write that I “confuse the main issues” and I’m interested in what you think those main issues are?
Thanks to your great feedback I’ve made a few changes based on your feedback to be more precise—I suspect you won’t be completely satisfied as I still leave out much detail but I hope it helps.
I didn’t want to get into the nitty gritty of treatment during the war (simplicity again), but you’re right that for much the war chloroquine was dominant. I’ve changed the wording to to “Chloroquine and quinine took too long to cure malaria and side effects could be rough”. I wonder what you make of the US army’s reports of both apparent chloroquine and Quinine resistance during the war? My main point here was that the Vietnam war stimulated the development of artemesin derivatives.
I’ve added in those 1996 studies to the timeline thanks!. This only further adds in my mind to demonstrate how slow we were to figure out how much better artemisin derivatives could be than the status quo. I found these 2 studies super interesting as the signal in both of them was leaning towards artemether being better than quinine (although of course not statistically significant). Unfortunately here in Northern Uganda we still use artemether injections for some of our patients here that can’t afford artesunate (aware that it is not as good), as artemether is less than half the price of artesunate. Fortunately in only the last 2 years, artesunate prices have reduced by about 30% which is great so we are using less artemether than ever.
I chose to leave out the combination treatment part of the story (see below for reasons), but for accuracy’s sake in the final paragraph have added the combination therapy point and changed to “In combination with other medication, artesunate cures over 99%...”
A little pushback
You’re right that I didn’t get into differentiating between the different artemesin derivatives. Although this is a little imprecise, I don’t think explaining the nature of these different derivatives is a critically important piece of information for the story. Again I’m simplifying for storytelling reasons.
I considered describing the combination therapy part of the story, which I agree is important, but decided to leave it out because the injectable artesunate seems to have had a far more important mortality impact than co-artem, and it would have meant telling a slghtly confusing parallel story ;). Feel free to push back here and I agree there is a good argument for adding them to the story—if I wrote a longer article I would have.
- This Rethink Priorities research here estimates that injectable artesunate saved about 1.7 million lives by 2022 while co-artem saved abuot 300,000. This would mean Artesunate is responsible for 85% of the lives saved by artemisin derivatives and co-artem only 15%. This makes sense to me as artesunate provides a large mortality benefit in severe malaria, while other medications if taken properly cure malaria almost as effectively as co-artem. I agree there are many other benefits from co-artem in uncomplicated malaria (side effects, shorter course, faster clearance) and there is a mortality benefit vs alternatives, but far less extreme than for artesunate.
Much of the co-artem development story happens in Southeast Asia, which while important accounts for under 5% of malaria deaths.
3) don’t really understand your disagreement with my statement here “adding a 3rd drug to the treatment cocktail – a blunt and expensive instrument but one that could buy us another 10 years.” You write “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.”
What’s “wrong” about my statement here exactly? The Lancet article I quoted discusses the idea of adding a third drug to artemether-lumefantrane as you say, and yes its to avoid the emergence of resistance. It will be expensive to add a third drug and I consider a 3 drug combination a bit of a sledgehammer/blunt tool. Perhaps we largely agree here?
Thanks again for the feedback and I hope to hear more from you here on the forum :).
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.
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.
Hi James and thanks for posting here on the forum, appreciate someone who is obviously a m malaria expert weighing in here with this useful feedback. I will say I was aware of much of the factual information in your feedback, but chose to leave it out for storytelling purposes—for better or worse.
Overall I was going for a short, simplified narrative article which briefly walked through 5 “acts” in the story of artesunate, while highlighting the incredible discovery story, pointing out that we may have unnecesarily delayed the mass roll out of artemisin treatment and the emerging resistnace issues. I’m writing for a general audience so I didn’t focus on scientific details or get into the weeds, while doing my best to not to be misleading . Of course I compromised at times to bring the story out more vividly. I would argue that I make few factual errors, rather I missed out some aspects of the story that could be considered important. I’m interested if you disagree with any of my major points in the article, besides the important scientific information that I omitted? You write that I “confuse the main issues” and I’m interested in what you think those main issues are?
Thanks to your great feedback I’ve made a few changes based on your feedback to be more precise—I suspect you won’t be completely satisfied as I still leave out much detail but I hope it helps.
I didn’t want to get into the nitty gritty of treatment during the war (simplicity again), but you’re right that for much the war chloroquine was dominant. I’ve changed the wording to to “Chloroquine and quinine took too long to cure malaria and side effects could be rough”. I wonder what you make of the US army’s reports of both apparent chloroquine and Quinine resistance during the war? My main point here was that the Vietnam war stimulated the development of artemesin derivatives.
I’ve added in those 1996 studies to the timeline thanks!. This only further adds in my mind to demonstrate how slow we were to figure out how much better artemisin derivatives could be than the status quo. I found these 2 studies super interesting as the signal in both of them was leaning towards artemether being better than quinine (although of course not statistically significant). Unfortunately here in Northern Uganda we still use artemether injections for some of our patients here that can’t afford artesunate (aware that it is not as good), as artemether is less than half the price of artesunate. Fortunately in only the last 2 years, artesunate prices have reduced by about 30% which is great so we are using less artemether than ever.
I chose to leave out the combination treatment part of the story (see below for reasons), but for accuracy’s sake in the final paragraph have added the combination therapy point and changed to “In combination with other medication, artesunate cures over 99%...”
A little pushback
You’re right that I didn’t get into differentiating between the different artemesin derivatives. Although this is a little imprecise, I don’t think explaining the nature of these different derivatives is a critically important piece of information for the story. Again I’m simplifying for storytelling reasons.
I considered describing the combination therapy part of the story, which I agree is important, but decided to leave it out because the injectable artesunate seems to have had a far more important mortality impact than co-artem, and it would have meant telling a slghtly confusing parallel story ;). Feel free to push back here and I agree there is a good argument for adding them to the story—if I wrote a longer article I would have.
- This Rethink Priorities research here estimates that injectable artesunate saved about 1.7 million lives by 2022 while co-artem saved abuot 300,000. This would mean Artesunate is responsible for 85% of the lives saved by artemisin derivatives and co-artem only 15%. This makes sense to me as artesunate provides a large mortality benefit in severe malaria, while other medications if taken properly cure malaria almost as effectively as co-artem. I agree there are many other benefits from co-artem in uncomplicated malaria (side effects, shorter course, faster clearance) and there is a mortality benefit vs alternatives, but far less extreme than for artesunate.
Much of the co-artem development story happens in Southeast Asia, which while important accounts for under 5% of malaria deaths.
3) don’t really understand your disagreement with my statement here “adding a 3rd drug to the treatment cocktail – a blunt and expensive instrument but one that could buy us another 10 years.” You write “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.”
What’s “wrong” about my statement here exactly? The Lancet article I quoted discusses the idea of adding a third drug to artemether-lumefantrane as you say, and yes its to avoid the emergence of resistance. It will be expensive to add a third drug and I consider a 3 drug combination a bit of a sledgehammer/blunt tool. Perhaps we largely agree here?
Thanks again for the feedback and I hope to hear more from you here on the forum :).
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.