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Artesunate causes recrudescence, Artemisia however kills gametocytes

February 16, 2016 - 11:03 -- Pierre Lutgen

A paper from Mali published last week is alarming (AA Djimbe et al., Parasite, 2016. 23, 3). Artesunate does not clear mature gametocytes during oral artesunate treatment and does not prevent the appearance of new gametocytes. This confirms to a large extent the randomized, double blind, large scale clinical trials of Munyanga and Idumbo in Maniema-Congo end of last year (see www.malariaworld.org). After 14 days up to day 28 gametocytes had completely disappeared in those treated with Artemisia herbal infusion, but it was still present on day 28 in 10% of those treated with Coartem. It is in line with the findings of Pamela Weathers (Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):821-6) that dried whole-plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin. It is also in line with our blog posted on www.malariaworld.org Jul 5. 2015 « Arginine, a deadly weapon against gametocytes »). Artemisia annua is very rich in arginine.

The same recrudescence with oral artemisinin monotherapy had already been observed in Vietnam in 2001 (PT Giao et al., Am J Trop Med Hyg, 2001 65 690-695). The conclusion of the authors was that artemisinin monotherapy may offer rapid recovery and fast parasite clearance, but recrudescence is frequent. For up to 20 percent of the cases on day 28, although gametocytes had completely disappeared on day 7. Extending the duration of the monotherapy from 5 to 7 days did not reduce recrudescence. A study from Kenya had also found that gametocyte carriage was much lower on day 14 than on day 28 and 42 for artemether lumefantrine, but not for dihydroartemisinin-piperaquine (P Sawa et al., J Infect Dis, 2013, 207, 1637-45). It is well known that artemisinin drugs are gametocytocidal for immature, but not mature gametocytes (GO Ghotosho et al., Mem Inst Oswaldo Cruz 2011, 106 no5). A paper of the Swiss Tropical and Public Health Institute (BJ Huho et al., Malaria Journal, 2012 11:118) comes to the conclusion that in high perennial transmission settings case management with ACT may have little impact on overall infectiousness of the human population. They even found in their study, that the most direct indicator of human-to-mosquito transmission, namely oocyst prevalence was substantially higher after ACT introduction. A study from Burkina Faso found in a recheck 12 months after a clinical trial with ACTs that the number of symptomatic malaria episodes was even slightly higher in the ACT arm than in the control arm and that after several treatments the prevalence of gametocyte carriers was the same in both arms (AB Tiono et al.,Malaria Journal 2013, 12:79). Another study found that ACT did not significantly reduce the proportion of infectious children. Submicroscopic gametocytaemia is common after treatment and contributes considerably to mosquito infection. (JT Bousema J Infect Dis., 2006, 193, 1151-59). Because of the short half-life of artemisinin and because high doses induce dormancy in the asexual parasite, asexual forms, mostly rings, remaining after completion of ACT may develop into mature gametocytes 7-15 days later. Some patients have the first appearance of gametocytemia 4-8/day after completion of a 3 day-ACT. (Wilairatana P, et al.,Southeast Asian J Trop Med Public Health. 2010 Nov;41(6):1306-11).

What worries the authors of the study from Mali is not only that similar results had been found in a study in 2002-2004, but the fact that baseline gametocyte carriage was significantly higher 6 years after deployment of ACTs in this setting. If artemisinin derivatives really enhance recrudescence and gametocyte carriage, this is indeed alarming. It would mean that ACTs will not eradicate malaria but enhance it in the long run. When IFBV-BELHERB had raised this concern with WHO Geneva and ITG Antwerp the blunt answer received from one of the experts was: “Your arguments do not make any sense from a public health point of view ».

Pierre Lutgen

Comments

Submitted by Pierre Lutgen on

Dear Pierre

Your arguments and findings on non gametocidal effects of artesunate makes sense to those who truly want to eradicate malaria but it does not make sense to those who produce drugs for malaria. It is simple logic if you clear gametocytes then you break transmission cycle then you completely stop the disease. For your information all the antimalarial drugs promoted by drug companies have either been those with weak gametocidal effects or no effect all. Why because you need patients to keep the factory running.
Thank you
Patrick
Uganda

De : Alexandre Poussin
Envoyé : mercredi 17 février 2016 19:44

Quelle bombe ! Quelle terrible aveuglement et culpabilité de l'OMS. Malaria Gate is on it's way, almost ready to burst ! Bravo Pierre pour cette synthèse magistrale qui prouve l'extraordinaire complexité des problèmes que les labos ont suscitée avec leurs produits de synthèse, quand la tisane les surpasse tous...
Amitiés
alexandre

Pierre
Ne comptez pas sur les politiques ou les administratifs pour faire accepter cela; ce que nous avons fait au Congo n’est pas facile à être copié par les autres frères qui comptent sur ces humains sans humain. Nous avons été empoisonnés pas par Big Pharma mais par ces gens qui vivent au dépend des morts de leurs frères. Ce travail nous a coûté la vie et aussi nos carrières et études. L’Afrique a besoin des héros pas les lâches qui pensent à leur propre ventre. La génération future nous traitera soit des courageux soit des lâches. Je continuerais à dire scientifiquement tout haut ce que les africains disent tout bas. A la vie ou à la mort, Que vive l’Artemisia en Afrique
Jerome

Klasse Pierre, ….” Auf in den Kampf Toreador „….
LG
Ingo

Et que vous les Africains ayez compris qu’on massacre vos enfants et hypothèque votre avenir
Pierre

Merci pour le message. Évidemment, tout cela prendra du temps pour que les gens comprennent cela en Afrique

Cordialement
Albert

Submitted by Emile Schmitz (not verified) on

WHO still recommends in areas of stable malaria transmission intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP).
This may create situations worse than the persistence and recrudescence of gametocytemia noticed for artesunate.

Several recent studies show dramatic failure rates for SP-IPTp. In Malawi a recrudescence of 33% after PCR correction was noticed. 95% of the women with asymptomatic parasitaemia carried a quintuple mutant and the survival rate of the malaria infected primigravidae remained disastrous despite the treatment (J Gutman et al., Malaria Journal, 2015 14:197).
In Zambia for a similar clinical trial a 26% failure rate was recorded (KR Tan et al, Malaria Journal, 2014, 13:277).
Since many years it is well known that pyrimethamine-sulfadoxine (SP) even increases the gametocyte density. In a trial in South Africa the duration of gametocyte carriage increased from 3 to 22 weeks between 1998 and 2002 (K Barnes et al., J Infect Diseases, 2008, 197, 1605-1613).
The persistence of WHO recommending SP is irresponsible, even criminal. It will lead to an exponential increase of malaria in Africa.

It would be so easy to prevent this by using Artemisia herbal treatments. Many anecdotic reports have described their prophylactic power against malaria. The recent large scale, randomised, double blind clinical trials in RDCongo have confirmed this. Artemisia annua and Artemisia afra kill gametocytes up to 100 %. ACTs do not. See the blog on www.malariaworld “Breaking news from clinical trials with Artemisia plants”.
Emile Schmitz