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 ».