The failure of mass drug administration in malaria

Is mass drug administration fighting fire with a fire? Mass drug administration (MDA) was a component of many malaria programs during the eradication era, but later was seldomly deployed due to concerns regarding efficacy and feasibility and fear of accelerating drug resistance. The failure of chloroquine MDA is well known. R D Powell, and C W D Tigertt. Drug Resistance of Parasites Causing Human Malaria. Annual Review of Medicine. Vol. 19: 81-102 (Volume publication date February 1968) DOI: 10.1146/annurev.me.19.020168.000501 In The Gambia a double-blind, placebo-controlled trial was conducted in December 1999 to test whether a reduction in the infectious reservoir can reduce malaria transmission. 14,017 individuals living in the study area were treated with either placebo or sulfadoxine-pyrimethamine (SP) combined with a single dose of artesunate (AS). After 2 months the incidence was slightly higher in the MDA group but this was not statistically significant. Overall, no benefit of the MDA could be detected. von Seidlein L, Walraven G, Milligan PJ, Alexander N, Manneh F, Deen JL, Coleman R, Jawara M, Lindsay SW, Drakeley C, De Martin S, Olliaro P,. The effect of mass administration of sulfadoxine-pyrimethamine combined with artesunate on malaria incidence: a double-blind, community-randomized, placebo-controlled trial in The Gambia. Trans R Soc Trop Med Hyg. 2003 Mar-Apr;97(2):217-25. In a large scale trial with thousands of participants in Tanzania, despite this high participation rate, no impact of MDA on malaria transmission was observed. Shekalaghe SA, Drakeley C, van den Bosch C. A clusster-randomized trial of mass drug administration with a gametocytocidal drug combination to interrrupt malaria transmission in a lower endemic area in tanzania. Maalaria J 10, 247 (2011). Another disastrous MDA trial was run in Sierra Leone covering several millions of people. The effect of the MDA waned in a matter of few weeks and malaria intensity returned to the pre‑MDA levels but the authors do not address the issue of resistance this MDA trial may have created. As emergency response to the Ebola epidemic, the Government of Sierra Leone and its partners implemented a large‑scale Mass Drug Administration (MDA) with artesunate–amodiaquine (ASAQ) covering >2.7 mil‑ lion people in the districts hardest hit by Ebola during December 2014–January 2015. Maru Aregawi, Samuel . Smith, Musa Sillah‑Kanu, John Seppeh, Anitta R. Y. Kamara, Ryan O. Williams, John J. Aponte, Andrea Bosman and Pedro Alonso. Impact of the Mass Drug Administration for malaria in response to the Ebola outbreak in Sierra Leone Malaria J (2016) 15:480 DOI 10.1186/s12936-016-1493-1 Another large scale MDA trials was run by Médecins sans Frontières in Liberia after the Ebola outbreak. In total, 1,259,699 courses of ASAQ-CP were distributed. The conclusions are very prudent and hypothetical. « The reduction in self-reported fever cases from 4.2% to 1.5% following the intervention suggests that MDAs may be effective in reducing cases of fever during Ebola outbreaks ». The effect on morbidity, mortality and prophylaxy was not studied. Lastly, the analysis does not include fever incidence figures from non-MDA areas. It is therefore difficult to determine whether the observed differences in reported incidence were exclusively attributable to the intervention Kuehne A, Tiffany A, Lasry E, Janssens M, Besse C, Okonta C, et al. (2016) Impact and Lessons Learned from Mass Drug Administrations of Malaria Chemoprevention during the Ebola Outbreak in Monrovia, Liberia, 2014. PLoS ONE 11(8): Another paper refers to the MDA clinical trials made by Médecins sans Frontières with artesunate-amodiaquine during the 2014 Ebola crisis in Liberia with 382 patients. 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. Etienne Gignoux, M.P.H., Andrew S. Azman, Ph.D., Martin de Smet, M.D., Philippe Azuma, Effect of Artesunate–Amodiaquine on Mortality Related to Ebola Virus Disease. NEJM, 2016 ;374 :23-32 An MDA trial was run in Zambia with DHA-PPQ : no difference between treatment arms was found in areas of high transmission Eisele TP, Bennett A, Silumbe K, Finn TP, Chalwe V,Short-term Impact of Mass Drug Administration With Dihydroartemisinin Plus Piperaquine on Malaria in Southern Province Zambia: A Cluster-Randomized Controlled Trial. J Infect Dis. 2016 Dec 15;214(12):1831-1839. Massive DHA-PPQ failure in Intermittent Preventive Treatment. Medecins sans Frontières run a large scale IPT trial in a refugee camp in Uganda with dihydroartemisinin-piperaquine (DP). The trial involved 13 537 children. Distributions of DP took place in March 2015, May 2015 and July 2015. Final impact was evaluated in September 2015. Average parasitemia raised from 6.6 in May to 18.7% in September. The authors qualify this as a positive impact of DP on malaria incidence! Mc Coldiron, E Lasry, R Grais, Intermittent preventive treatment in a refugee camp in Uganda. Malaria Journal 2017 16:218 One may wonder why MSF persists in this mass drug administration. In a paper covering results from 2014 they had already concluded that “The low effectiveness of dihydroartemisinin–piperaquine (DHA–PPQ) for symptomatic cases indicates that PPQ is no longer able to complement the reduced potency of DHA to treat falciparum malaria and highlights the need for an alternative first-line treatment”. G Falq, R van den Bergh, Assessing the asymptomatic reservoir and dihydro-artemisinin-piperaquine effectiveness against Plasmodium falciparumMalaria Journal 2016, 15(1) 446). In the Comoros, more than 700,000 people were given three doses of Artequick -- a new combination of anti-malaria drugs which has not been approved for use in humans by any international health body. "The vision is to contribute to the elimination of malaria in the world," Pan Longhua, General Manager of Artequick's maker, Artepharm Co. Ltd (China)., tells CBS News. But the new combination of drugs used to formulate Artequick remains untested and unapproved by the global healthcare community, and there are concerns about testing it on so many people all at once. In the eyes of some scientists and public health experts it is a risky plan. They fear that mass treatments with artemisinin, particularly without associated measures to control the mosquitoes that carry the disease, could hasten the onset of resistance to the world's most effective antimalarial drug. Even Tu Youyou disagrees with the MDA approach in an article published in the International Herald Tribune in June 27, entitled“ Chinese Artequick goes to Africa to wipe out malaria“. "Using artemisinin the way Li wants to use it could increase the prospect of resistance," said TU YOUYOU, director of the Artemisinin Research Center at the China Academy of Chinese Medical Sciences in Beijing, and the scientist credited with first extracting the drug from the sweet wormwood bush years ago. "We went through all the trouble to invent this medicine so we should protect it. We should not abuse it." The long term prospect of MDA is sobering and only offer short term reduction. A recent paper informs us that ex vivo piperaquine resistance developed rapidly in Plasmodium falciparum isolates in northern Cambodia. This raises a lot of concern as DHA-PPQ is being introduced as first-line treatment in several countries Suwanna Chaorattanakawee, Chanthap Lon, David Saunders, Ex vivo piperaquine resistance developed rapidly in Plasmodium falciparum isolates in northern Cambodia compared to Thailand, Malaria Journal 15:519, 21 October 2016 Intermittent preventive treatment has also been recommended (WHO/AFR/MAL/04/01), for children and even for pregnant women, even in areas where 50% parasitological failure is reported on day 14. It has been demonstrated that it can reduce the incidence of clinical malaria. But there is serious concern over the widespread deployment of IPT and that this will enhance the spread of drug resistance. Mutations associated with pyrimethamine and sulphadoxine resistance, respectively, were found significantly more frequently at the end of the malaria transmission season in parasites obtained from children treated by IPT. It was also found that in pregnant women the genetic diversity of Plasmodium falciparum is very high and this threatens the effectiveness of using sulphadoxine-pyrimethamine. Emmanuel Osei Tutu, John Larbi, Bernard Lawson, Genetic diversity of Plasmodium falciparum in pregnant women in an IPTp setting in the Offinso District ofGhana Journal of Parasitology and Vector Biology Vol. 3(1), pp. 12-18, January 2011 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. Laura C. Pollitt , Silvie Huijben, Derek G. Sim, Rapid Response to Selection, Competitive Release and Increased Transmission Potential of Artesunate-Selected Plasmodium chabaudi Malaria Parasites.PLOS, 2014 http://dx.doi.org/10.1371/journal.ppat.1004019 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 parasitemia much more efficiently than ACTs and eliminate all gametocytes.