Was the Nobel price for artemisinin a fatal error

Was the Nobel prize for artemisinin a fatal error?

April 2, 2016 – 06:26 — Irene Teis
In 2015 a Nobel Price was attributed to Youyou Tu, almost 50 years after a report describing artemisinin’s structure, pharmacology, and efficacy had been published in 1979 by the “Qinghaosu Anti-Malarial Coordinating Research Group,” where she was a member of. Mr Huang Shuze, Deputy Minister of Health, stated in his 1981 summary report “Project 523 mobilized multiple departments ; thirty scientific research units and medical schools in 1975”.

WHO for decades hesitated in considering this traditional medicine approach. Only at the end of the nineties, when chloroquine’s resistance became overwhelming did first clinical trials take place. But artemisinin was not water soluble, hardly bioavailable, metabolized very rapidly and gave premature signs of resistance. WHO then prescribed in 1998 extremely high doses up to 1 200 mg of artemisinine for a person of 60 kg on the first day of treatment (WHO/MAL/98.1086) , at the verge of severe neurotoxicty and hepatoxicity.

A RECENT PAPER RINGS AN ALARM BELL. Plasmodium chabaudi malaria parasites through a step-wise increase in artesunate dose evolve extremely rapidly slow clearance rates. These slower clearance rates provide fitness advantages to the parasite through increased overall density, recrudescence after treatment and increased transmission potential. Removal of only the susceptible parasites by artesunate treatment led to substantial increases in the densities of resistant parasites (LC Pollit et al., PloS Pathogens 2014, 10,4, e1004019). The traditional view has been that aggressive chemotherapy , involving high doses applied for sufficiently long time to eliminate parasites, best minimizes the evolution of resistance. For this reason WHO in several statements has condemned the use of Artemisia annua herbal treatment because of low artemisinin concentrations in the infusions. But numerous clinical trials, small and large, demonstrated that Artemisia annua and Artemisia afra infusion or powdered leaves reduce parasitaemia much more efficiently than ACTs and eliminate all gametocytes (see Breaking News for clinical trials with Artemisia plants, on http://www.malariaworld.org).

Previous work using the anti-malarial pyrimethamine has shown that removing susceptible competitors through drug treatment can lead to dramatic increases in the density of resistant parasites.

Resistance can also be affected by the dormancy effect (A. Codd et al., Malaria Journal, 10:56, 2011). One of the side effects of the higher doses of artemisinin is this effect induced in plasmodium. The parasite encapsulates itself against the aggressive peroxide artesunate and reawakens at the end of the treatment. The same effect is called quiescence by a French research team (B. Witkowski et al., Antimicrob Agents Chemother. Doi:10.1128/AAC.01636-09). Under a very high dose of artesunate, a Plasmodium falciparum ring-stage sub-population persists in culture and continues its cycle of development normally after drug removal. This may be one of the causes of resistance.

During the Ebola crisis in West Africa. Medecins sans Frontières administered 1.5 million treatments of artesunate-amodiaquine in Sierra Leone in a mass drug administration campaign. This is the largest-ever mass distribution of antimalarials. It is impossible to find any results on PubMed? Was it a failure with dramatic consequences, deathtoll or resurgence?

Irene Teis

MSF-Coarsucam clinical trial with horrendous death toll

Submitted by Marc Vanacker (not verified) on April 4, 2016 – 17:46
ERRATUM

There is indeed a peer reviewed paper (E Guignoux et al., NEJM, 2016 ;374 :23-32) which refers to the MDA clinical trials made by Médecins sans Frontières with artesunate-amodiaquine during the 2014 Ebola crisis. Not in Sierra Leone but in Liberia. Not with 1 500 000 patients but with 382 (three hundred eighty two).
As per Table 2 there were three branches in the trial : 194 patients for Coartem, 71 for Coarsucam and 63 with no antimalarial drug prescription.
In the Coartem group 125 (64.4%) died, in the Coarsucam group 36 (50.7%) and in the no drug group 41 (65.1%).
It is surprising that the total number of patients quoted in the abstract : 382, does not match the total number of patients in table 1 : 278, neither in table 2: 328, nor table 3: 282 nor in table 4: 295. This needs to be clarified as the statistics become dubious
Whatever, the authors make the dazzling claim that the 71 patients who were prescribed artesunate-amodiaquine had a lower risk of death than did patients who were prescribed artemether-lumefantrine.
A pyrrhic victory for Médecins sans Frontières on a bloody battlefield. Sanofi-Aventis will evidently continue to subsidize them. Amodiaquine is banned in France and artesunate-amodiaquine will now probably become available in French pharmacies

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