Malaria: the dramatic failure of mass drug administration

Against the malaria pandemia mass drug administration (MDA) of chloroquine, methylene blue, atabrine, pyrimethamine, mefloquine… was a component of many programs during the eradication era. It is far from a success story. The failure of chloroquine MDA is well known. Twenty years ago all these drugs were replaced by ACTs (artemisinin combined therapy). 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 mass drug administration 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 cluster-randomized trial of mass drug administration with a gametocytocidal drug combination to interrrupt malaria transmission in a lower endemic area in tanzania. Malaria 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 largescale MDA trial was run by Médecins sans Frontières (MSF) 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 A more recent paper gave similar results. During the Ebola virus disease (EVD) epidemic in West Africa in 2014-2016, 2 mass drug administrations (MDAs) of artesunate-amodiaquine (ASAQ) were implemented to decrease the burden of malaria. There was a non-statistically significantly decreased risk of mortality in EVD patients exposed to ASAQ during the 2 MDAs as compared with EVD patients not exposed to ASAQ. Garbern SC, Yam D, Aluisio AR, Effect of Mass Artesunate-Amodiaquine Distribution on Mortality of Patients With Ebola Virus Disease During West African Outbreak. Open Forum Infect Dis. 2019 May 24;6(7): 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 had 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. Meanwhile Artequick is also confronted by resistance. A letter to the editor by DL Saunders et al., in NEJM July 2014 describes the dihydroartemisinin-piperaquine failure in Cambodia. The drug was adopted as first line treatment in this country in 2010. Three years later the efficacy has decreased from 92% to 64%. At 72 hours 56% of patients still had persistent parasitemia. In a high transmission area of western Kenya, Samuels and colleagues evaluated the impact of a community-based mass test and treat strategy on the prevalence of Plasmodium falciparum infection. This cluster, randomized controlled trial involved the delivery of six rounds of mass test and treat in intervention clusters between 2013 and 2015 with household members testing positive by malaria rapid diagnostic test treated with dihydroartemsinin-piperaquine. Despite the impressive effort that went into the design and implementation of this mass test and treat trial, there was no difference between intervention and control clusters for the primary outcome—all-age malaria microscopy prevalence of P. falciparum after years 1 and 2 nor was there any evidence of a reduction of clinical malaria. There are several critically important lessons learned from this study and other studies comparing treatment-based malaria intervention campaigns, as well as modelling efforts, for malaria burden reduction in areas of moderate to high transmission. Hamer DH, Miller JM. Why did mass test and treat have no effect on malaria prevalence in western Kenya? Clin Infect Dis. 2020 Apr 23. pii: ciaa477. doi: 10.1093/cid/ciaa477. Already in 2009 it was reported that patients treated with dihydroartemisinin-piperaquine might have a higher rate of gametocytemia after a few weeks . D'alessandro U. Progress in the development of piperaquine combinations for the treatment of malaria. Curr Opin Infect Dis. 2009 Dec;22(6):588-92. doi: 10.1097/QCO.0b013e328332674a. PMID: 19773652. 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, 2015, 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 longterm 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. 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 stepwise 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 LC Pollitt, S Huijben, A Read, Rapid response to selection and increased transmission potential in artesunate-selected Plasmodium parasites, PloS Pathogens 2014, 10,4, e1004019). Andrew F. Read, Troy Day, and Silvie Huijben. The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy. PNAS June 28, 2011 108 (Supplement 2) 10871-10877 WHO for many years had the dogmatic view 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 (without scientific support) has condemned the use of Artemisia annua herbal treatment because of low artemisinin concentrations in the infusions. More recently in a paper sponsored by Bill Gates, the Global Fund and WHO the following conclusion is reached: Mass drug administration has the potential to reduce transmission for a limited time, but is not an effective replacement for existing vector control. Unless elimination is achieved, mass drug administration has to be repeated regularly for sustained effect. This is in line with the conclusions of a Cochrane study from 2013: few studies showed substantial impact beyond six months. Oliver J Brady, Hannah C Slater, Role of mass drug administration in elimination of P. falciparum malaria: a consensus modelling study Lancet Glob Health. 2017 Jul; 5(7): e680–e687. Poirot E, Skarbinski J, Sinclair D, Mass Drug Administration for Malaria : Cochrane Review. 2013 ;12 :CD008846 A mass administration ACT trial in the Mekong region again failed. P. falciparum infections returned during the follow-up period as the remaining infections spread von Seidlein L, Nosten FH, Dondorp AM, White NJ. The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: A cluster randomised trial, PLoS Med. 2019 Feb 15;16(2):e1002745. doi: 10.1371/journal.pmed.1002745. More recently, in a high transmission area of western Kenya, a cluster, randomized controlled trial involved the delivery of six rounds of mass test and treat in intervention clusters between 2013 and 2015 with household members testing positive by malaria rapid diagnostic test treated with dihydroartemsinin-piperaquine. Despite the impressive effort that went into the design and implementation of this mass test and treat trial, there was no difference between intervention and control clusters for the primary outcome—all-age malaria microscopy prevalence of Plasmodium falciparum after years 1 and 2 nor was there any evidence of a reduction of clinical malaria Hamer DH, Miller JM. Why did mass test and treat have no effect on malaria prevalence in western Kenya? Clin Infect Dis. 2020 Apr 23. pii: ciaa477. doi: 10.1093/cid/ciaa477. Davidson H Hamer, John M Miller, Why Did Mass Test and Treat Have No Effect on Malaria Prevalence in Western Kenya? Clinical Infectious Diseases, Volume 72, Issue 11, 1 June 2021, Pages 1936–1937, https://doi.org/10.1093/cid/ciaa477 A very recent Cochrane review paper came to similar conclusions: for clinical trials with ACTs longer-term data did not demonstrate an effect of MDA after four months. No studies provided evidence of interruption of malaria transmission. All these MDA trials reported adverse side effects. Shah MP, Hwang J, Choi L, Lindblade KA, Kachur SP, Desai M. Mass drug administration for malaria. Cochrane Database Syst Rev. 2021 Sep 29;9(9):CD008846. doi: 10.1002/14651858.CD008846.pub3. Conclusion In a WHO communication the situation is summaried in the following words: MDA may produce a short-term reduction in malaria burden, but so far there is no evidence that MDA will accelerate progress towards elimination. MDA may reduce, but does not interrupt, malaria transmission in the short term (1–3 months). The huge malaria business with ACTs is vanishing. World Health Organization. Meeting report of the WHO Evidence Review Group on mass drug administration for malaria. WHO/CDS/GMP/MPAC/2019.04. 0–12 April 2019, Geneva, Switzerland But numerous clinical trials, small and large, demonstrated that Artemisia annua and Artemisia afra infusions or powdered leaves reduce parasitemia much more efficiently than ACTs, that they inhibit spororoites and eliminate all gametocytes. With Artemisia afra infusions malaria eradication becomes possible. Ashraf K, Tajeri S, Arnold CS, Mazier D. Artemisinin-independent inhibitory activity of Artemisia sp. infusions against different Plasmodium stages including relapse-causing hypnozoites. Life Sci Alliance. 2021 Dec 2;5(3): e202101237. doi: 10.26508/lsa.202101237. Pierre Lutgen. Artemisia afra completely inhibits transmission of gametocytes. www.malariaworld.org. February 27, 2020