THE KELCH PROPELLER HYPOTHESIS
Over the last century all monotherapies (quinine, chloroquine, mefloquine, pyrimethamine, halofantrine,methylene blue, lumefantrine) have lead to rapid resistances of Plasmodium falciparum. Combination therapy betweeen artemisinin and molecules with long lasting action had raised optimism. But already in 2003 first signs of resistance developed in South-East Asia. It has been established meanwhile that they were mostly related to mutations in the kelch13 propeller region of the parasite. Mutations have meanwhile raised to 90%. (Timothy J.C. Anderson, Shalini Nair, Marina McDew-White, Ian H. Cheeseman, Standwell Nkhoma, Fatma Bilgic, Rose McGready, Elizabeth Ashley, Aung Pyae Phyo, Nicholas J. White, François Nosten. Why are there so many independent origins of artemisinin resistance in malaria parasites? bioRxiv preprint first posted online May. 31, 2016; doi: http://dx.doi.org/10.1101/056291).
Artemisinin resistance in Plasmodium falciparum has emerged in South-East Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies.
But the problem is not limited to South-East Asia. Signs of arteminisin resistance have developed in other continents, in at least a dozen African countries.
A study carried out in 2010 at the Carlos III Hospital and the Network of Tropical Diseases Research Centres (Red de Investigación Cooperativa en Enfermedades Tropicales - RICET; Project RD06/0021). Blood samples were collected from 200 patients with P falciparum infection, who had come to Spain from eighteen African countries. This study suggests the appearance of strains related with resistance to ACT. On the other hand, the study shows the existence of mutations in some regions in the African Continent who will put in danger the use of Intermittent Preventive Treatment. (Aranzazu AmorEmail author, Carlos Toro, Amalia Fernández-Martínez, Margarita Baquero, Agustín Benito and Pedro Berzosa. Molecular markers in Plasmodium falciparum linked to resistance to anti-malarial drugs in samples imported from Africa over an eight-year period (2002-2010): impact of the introduction of artemisinin combination therapy. Malaria Journal 201211:100 DOI: 10.1186/1475-2875-11-100).
In Senegal while no mutation was found in the propeller region of K13 in parasites from Dakar in 2012 and 2013, three mutations (5.5%) were identified in this domain in 2013 and 2014. As a result, surveillance of K13 polymorphisms must be implemented. (Agathe Boussaroque, Bécaye Fall, Marylin Madametb,, Cheikhou Camaraf, Nicolas Benoit, Mansour Fall, Aminata Nakoulimah, Pierre Dionnei, Kadidiatou Ba Fall, Bakary Diatta, Yaya Diémé, Boubacar Wadek and Bruno Pradines. Emergence of Mutations in the K13 Propeller Gene of Plasmodium falciparum Isolates from Dakar, Senegal, in 2013-2014. Antimicrob. Agents Chemother. January 2016 vol. 60 no. 1 624-627 doi: 10.1128/AAC.01346-15)( Lo AC, Faye B, Ba el-H, Cisse B, Tine R, Abiola A, Ndiaye M, Ndiaye JL, Ndiaye D, Sokhna C, Gomis JF, Dieng Y, Faye O, Ndir O, Milligan P, Cairns M, Hallett R, Sutherland C, Gaye O. Prevalence of molecular markers of drug resistance in an area of seasonal malaria chemoprevention in children in Senegal. Malar J. 2013 Apr 23;12:137. doi: 10.1186/1475-2875-12-137).
In Kenya a research team looked for mutations in the Plasmodium falciparum K13 propeller gene of an artemisinin-resistant parasite on islands in Lake Victoria, Kenya, where transmission in 2012-2013 was high. 4 new types of nonsynonymous, and 5 of synonymous, mutations we detected among 539 samples analyzed. (Isozumi R, Uemura H, Kimata I, Ichinose Y, Logedi J, Omar AH, Kaneko A. Novel mutations in K13 propeller gene of artemisinin-resistant Plasmodium falciparum. Emerg Infect Dis. 2015 Mar;21(3):490-2. doi: 10.3201/eid2103.140898).
A recent study provides baseline prevalence of K13-propeller mutations in sub-Saharan Africa with samples collected in the past few months. This baseline information will be critical in tracking the emergence and/or spread of P. falciparum resistance to artemisinin in sub-Saharan Africa. There is now an important need for local studies of clinical resistance to artemisinin and for in vitro and ex vivo to clarify the significance of K13-propeller mutations as markers of artemisinin resistance Africa. A total of 1212 P. falciparum samples collected from 12 countries were sequenced. None of the K13-propeller mutations previously reported in Southeast Asia were found, but 22 unique mutations were detected. (Edwin Kamau, Susana Campino, Lucas Amenga-Etego, Eleanor Drury, Deus Ishengoma, Kimberly Johnson, Dieudonne Mumba, Mihir Kekre, William Yavo, Daniel Mead, Marielle Bouyou-Akotet, Tobias Apinjoh, Lemu Golassa, Milijaona Randrianarivelojosia, Ben Andagalu, Oumou Maiga-Ascofare, Alfred Amambua-Ngwa, Paulina Tindana, Anita Ghansah, Bronwyn MacInnis, Dominic Kwiatkowski and Abdoulaye A. Djimde. K13-Propeller Polymorphisms in Plasmodium falciparum Parasites From Sub-Saharan Africa. J Infect Dis. 2016 January 15; 213(2): 327. . doi: 10.1093/infdis/jiu608).
In Rwanda no polymorphisms were observed in 2010 but they were present in 2.5% and 4.5% in 2014 and 2015, respectively. In 2015, two isolates showed candidate K13 resistance mutations (P574L and A675V), which are common in southeast Asia and associated with delayed parasite clearance. Tacoli C1, Gai PP1, Bayingana C2, Sifft K1, Geus D1, Ndoli J2, Sendegeya A2, Gahutu JB2, Mockenhaupt FP3. Artemisinin Resistance-Associated K13 Polymorphisms of Plasmodium falciparum in Southern Rwanda, 2010-2015. Am J Trop Med Hyg. 2016 Aug 29. pii: 16-0483).
In Mali K13-propeller mutations were identified in both recent samples and pre-ACT infections. (Ouattara A1, Kone A1, Adams M1, Fofana B1, Maiga AW1, Hampton S1, Coulibaly D1, Thera MA1, Diallo N1, Dara A1, Sagara I1, Gil JP1, Bjorkman A1, Takala-Harrison S1, Doumbo OK1, Plowe CV1, Djimde AA2. Polymorphisms in the K13-propeller gene in artemisinin-susceptible Plasmodium falciparum parasites from Bougoula-Hameau and Bandiagara, Mali. Am J Trop Med Hyg. 2015 Jun;92(6):1202-6. doi: 10.4269/ajtmh.14-0605).
In Uganda an independent selection was identified of three polymorphisms in the pfmdr1 gene following administration of Artemether-Lumefantrine in a region of Africa where malaria is highly endemic. These polymorphisms were not associated with clinical treatment failure but are evidence for the ability of this drug combination to drive selection of parasites toward resistant phenotypes Christian Dokomajilar, Samuel L. Nsobya, Bryan Greenhouse, Philip J. Rosenthal, and Grant Dorsey. Selection of Plasmodium falciparum pfmdr1 Alleles following Therapy with Artemether-Lumefantrine in an Area of Uganda where Malaria Is Highly Endemic. Antimicrob Agents Chemother. 2006 May; 50(5): 1893–1895. doi: 10.1128/AAC.50.5.1893-1895.2006).
In Tanzania the overall prevalence of NFD haplotype claimed to be associated with emerging artemether-lumefantrine tolerance ranges from 17 to 26% among other haplotypes. With continuation of ALu as first-line drug and in the absence of CQ and AQ, this haplotype is expected to keep rising. There is need for continued pharmacovigilance studies in order to predict early parasite tolerance to the drug (Reginald A Kavishe, Petro Paulo, Robert D Kaaya, Akili Kalinga, Marco van Zwetselaar, Jaffu Chilongola, Cally Roper and Michael Alifrangis Surveillance of artemether-lumefantrine associated Plasmodium falciparum multidrug resistance protein-1 gene polymorphisms in Tanzania. Malaria Journal201413:264 DOI: 10.1186/1475-2875-13-264).
In Tanzania the temporal selection of molecular markers associated with artemether-lumefantrine tolerance/resistance may represent an early warning sign of impaired future drug efficacy. This calls for stringent surveillance of artemether-lumefantrine efficacy and emphasizes the importance of molecular surveillance as a complement to standard in vivo trials.( Maja Malmberg, Billy Ngasala, Pedro E Ferreira, Erik Larsson, Irina Jovel, Angelica Hjalmarsson, Max Petzold, Zul Premji, José P Gil, Anders Björkman and Andreas Mårtensson. Temporal trends of molecular markers associated with artemether-lumefantrine tolerance/resistance in Bagamoyo district, Tanzania Malaria Journal 201312:103 DOI: 10.1186/1.475-2875-12-103).
In Tanzania the difference between individual treatment groups and the next best treatment combination was significant (p<0.001) in every case. Recrudescence rates by day 28, after correction by genotyping, were 48.4%, 34.5%, 11.2%, and 2.8%, respectively. The study shows how few the options are for treating malaria where there is already a high level of resistance to sulfadoxine-pyrimethamine and amodiaquine. (Mutabingwa TK, Anthony D, Heller A, Hallett R, Ahmed J, Drakeley C, Greenwood BM, Whitty CJ. Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial. Lancet. 2005 Apr 23-29;365(9469):1474-80).
In Senegal parasite drug responses changed between 2008 and 2011, as parasites became less sensitive to amodiaquine, artemisinin and chloroquine over time. The prevalence of known resistance-associated mutations also changed over time. Decreased amodiaquine sensitivity was associated with sustained, highly prevalent mutations in pfcrt, and one mutation in pfmdr1 – Y184F – was associated with decreased parasite sensitivity to artemisinin. Daria Van Tyne, Baba Dieye, Clarissa Valim, Rachel F Daniels, Papa Diogoye Sène, Amanda K Lukens, Mouhamadou Ndiaye, Amy K Bei, Yaye Die Ndiaye, Elizabeth J Hamilton, Omar Ndir, Souleymane Mboup, Sarah K Volkman, Dyann F Wirth and Daouda Ndiaye. Changes in drug sensitivity and anti-malarial drug resistance mutations over time among Plasmodium falciparum parasites in Senegal. Malaria Journal201312:441 DOI: 10.1186/1475-2875-12-441).
In Uganda Plasmodium genotypes with decreased sensitivity to artemether-lumefantrine increased from 2008 to 2012 in a study involving 312 children (Conrad M, LeClair N, Arinaitwe E, Wanzira H, Kakuru A, Bigira V,Muhindo M, Kamya MR, Tappero JW, Greenhouse B, Dorsey G, Rosenthal PJ. Comparative impacts over 5 years of artemisinin-based combination therapies on Plasmodium falciparum polymorphisms that modulate drug sensitivity in Ugandan children. Journal of Infectious Diseases 2014. In press. PMID: 24610872).
In Sierra Leone the efficacy of the artesunate-amodiaquuine combination was disappointing. The efficacy of AS + AQ needs to be monitored in Kailahun and in the other regions of Sierra Leone. Grandesso, F; Hagerman, A; Kamara, S; Lam, E; Checchi, F; Balkan, S; Scollo, G; Durand, R; Guthmann, J . Low efficacy of the combination artesunate plus amodiaquine for uncomplicated falciparum malaria among children under 5 years in Kailahun, Sierra Leone. Tropical Medicine & International Health 2006, 11-7, 1017-21).
In Madagascar the results of a study showed the progressive loss of the most susceptible isolates to artemisinin derivatives(Valérie Andriantsoanirina, Arsène Ratsimbasoa, Christiane Bouchier, Martial Jahevitra, Stéphane Rabearimanana, Rogelin Radrianjafy, Voahangy Andrianaranjaka, Tantely Randriantso, Marie Ange Rason, Magali Tichit, Léon Paul Rabarijaona, Odile Mercereau-Puijalon, Rémy Durand and Didier Ménard. Plasmodium falciparum Drug Resistance in Madagascar: Facing the Spread of Unusual pfdhfr and pfmdr-1 Haplotypes and the Decrease of Dihydroartemisinin Susceptibility. Antimicrob. Agents Chemother. November 2009 vol. 53 no. 11 4588-4597 doi: 10.1128/AAC.00610-09).
In Nigeria a study reveals a need to re-evaluate the quality and efficacy of artemisinin-based combination therapy agents in Nigeria and Sub-Saharan Africa. Though six ACT combination therapies are available, but malaria is resistant to one of the longer-acting drugs and patients had bad reactions to another, so only four ACTs are recommended. Christian Happi, a malaria researchers of Redeemer's University in Lagos declares that among thousands of blood samples anlyzed 80–90% have at least one mutation (Ajayi NA, Ukwaja KN. Possible artemisinin-based combination therapy-resistant malaria in Nigeria: a report of three cases. Rev Soc Bras Med Trop. 2013 Jul-Aug;46(4):525-7. doi: 10.1590/0037-8682-0098-2013).
In Kenya authors conclude that parasite clearance time after artemisinin-based combination therapy (ACT) may be increasing. Beshir KB, Sutherland CJ, Sawa P, Drakeley CJ, Okell L, Mweresa CK, Omar SA, Shekalaghe SA, Kaur H, Ndaro A, Chilongola J, Schallig HD, Sauerwein RW, Hallett RL, Bousema T Residual Plasmodium falciparum parasitemia in Kenyan children after artemisinin-combination therapy is associated with increased transmission to mosquitoes and parasite recurrence. J Infect Dis. 2013 Dec 15;208(12):2017-24. doi: 10.1093/infdis/jit431).
On the Kenyan coast the significant, albeit small, decline through time of parasitological response rates to treatment with ACTs may be due to the emergence of parasites with reduced drug sensitivity, Steffen Borrmann Philip Sasi,, Leah Mwai, Declining Responsiveness of Plasmodium falciparum Infections to Artemisinin-Based Elizabeth Juma,Combination Treatments on the Kenyan Coast. PLOS : November 10, 2011 doi.org/10.1371/journal.pone.0026005.
In Kenya the findings of another research team call for close monitoring of parasite genotypic, phenotypic and clinical dynamics in response to current first-line treatment in western Kenya. Having been the first focus of chloroquine resistance in Africa western Kenya will be crucial in informing the next steps on the deployment of first-line treatment of uncomplicated malaria in the possible future era of attenuated response of artemisinin. (Angela O. Achieng,Peninah Muiruri, Luicer A. Ingasia, Benjamin H. Opot,. Temporal trends in prevalence of Plasmodium falciparum molecular markers selected for by artemether–lumefantrine treatment in pre-ACT and post-ACT parasites in western Kenya. Int J Parasitol Drugs Drug Resist. 2015 Dec; 5(3): 92–99. doi: 10.1016/j.ijpddr.2015.05.005).
In Senegal the increased prevalence of Pfmdr1 duplication in P. falciparum isolates from patients in Dakar within a 2-year period is cause for concern and vigilance (Aurélie Pascual, Bécaye Fall, Nathalie Wurtz, Mansour Fall, Cheikhou Camara, Aminata Nakoulima, Eric Baret, Bakary Diatta, Boubacar Wade, Sébastien Briolant, and Bruno Pradines. Plasmodium falciparum with Multidrug Resistance 1 Gene Duplications, Senegal. Emerg Infect Dis. 2013 May; 19(5): 814. doi: 10.3201/eid1905.121603).
In Sudan it was observed that the continuous use of SP as a partner to artesunate may be the cause of declined AS/P efficacy.(Nahla B Gadalla, Tajeldin M Abdallah, Sharanjeet Atwal, Colin J Sutherland and Ishag Adam. Selection of pfdhfr/pfdhps alleles and declining artesunate/sulphadoxine-pyrimethamine efficacy against Plasmodium falciparum eight years after deployment in eastern Sudan. Malaria Journal 201312:255 DOI: 10.1186/1475-2875-12-255).
Increased pfmdr1 copy number and sequence polymorphisms in Plasmodium falciparum isolates was also observed from Sudanese malaria patients treated with artemether-lumefantrine. (Gadalla NB1, Adam I, Elzaki SE, Bashir S, Mukhtar I, Oguike M, Gadalla A, Mansour F, Warhurst D, El-Sayed BB, Sutherland CJ. Increased pfmdr1 copy number and sequence polymorphisms in Plasmodium falciparum isolates from Sudanese malaria patients treated with artemether-lumefantrine. Antimicrob Agents Chemother. 2011 Nov;55(11):5408-11. doi: 10.1128/AAC.05102-11).
In a malaria endemic area in Kenya a K13 propeller sequence analysis of P. falciparum parasites did not detect the predicted artemisinin-resistant genotypes, but some temporal substitutions were observed (Rie Isozumi,corresponding author Haruki Uemura, Isao Kimata, Yoshio Ichinose, John Logedi, Ahmeddin H. Omar, and Akira Kaneko. Novel Mutations in K13 Propeller Gene of Artemisinin-Resistant Plasmodium falciparum Emerg Infect Dis. 2015 Mar; 21(3): 490–492.doi: 10.3201/eid2103.1408981st)( Luicer Anne Ingasia,Lorna Chebon, Artemisinin-based combination therapy efficacy in Kisumu, Western Kenya: selection of parasite subpopulations of Plasmodium falciparum with attenuated response to ACTs.Tropical Medicine & International Health 20:18-18 · September 2015).
In Burkina Faso clinical trial NCT00808951 shows a higher occurrence of recurrent malaria infections during a 28-day follow up period for artemether-lumefantrine.
In Gabon severe artemisinin resistance was noticed (JB Lekana-Douki. High prevalence of markers associated with failure treatments of artemisinin based combination therapy in urban Gabonese regions. 6th MIM Conference 2013 P379).
In Gabon another study confirms these intiguing results. The strongest correlation between diminished DHA sensitivity and MF resistance was observed, followed by correlation between diminished DHA sensitivity and CQ resistance. Cross-resistance between CQ and MF was also observed. (Zatra R, Lekana-Douki JB, Lekoulou F, Bisvigou U, Ngoungou EB, Ndouo FS. In vitro antimalarial susceptibility and molecular markers of drug resistance in Franceville, Gabon. BMC Infect Dis. 2012 Nov 15;12:307. doi: 10.1186/1471-2334-12-307).
In Surinam an increase in the rate of day 3 parasitaemia was observed from 2-31% over a five-year time span. Our study supports the use of day 3 parasitaemia as a tool for screening artemisinin resistance, particularly in the absence of functional molecular markers and standardised in vitro test systems. The WHO advises that an incidence of day 3 parasitaemia that exceeds 10% should prompt governments to take measures to prevent the development of treatment failure (Stephen GS Vreden Jeetendra K Jitan, Rakesh D Bansie, and Malti R Adhin. Evidence of an increased incidence of day 3 parasitaemia in Suriname: an indicator of the emerging resistance of Plasmodium falciparum to artemether Mem Inst Oswaldo Cruz. 2013 Dec; 108(8): 968–973. doi: 10.1590/0074-0276130167).
In Mozambique, after the decrease in clinical malaria incidence observed until 2009, a steady resurgence of cases per year has been reported nationally, reaching alarming levels in 2014. (Beatriz Galatas, Caterina Guinovart, Quique Bassat, John J. Aponte, Lídia Nhamússua, Eusebio Macete, Francisco Saúte, Pedro Alonso and Pedro Aide. A prospective cohort study to assess the micro-epidemiology of Plasmodium falciparum clinical malaria in Ilha Josina Machel (Manhiça, Mozambique). Malaria Journal201615:444 DOI: 10.1186/s12936-016-1496-y).
In Ethiopia high rates of recurrent parasitemia were noted for AL and CQ against Plasmodium vivax (J Hwang, BH Alemayehu, R Reithinger, H Nettey, T Teshi. Vivo Efficacy of Artemether-Lumefantrine and Chloroquine against Plasmodium vivax: A Randomized Open Label Trial in Central Ethiopia. May 22, 2013 .doi.org/10.1371/journal.pone.0063433).
In Ghana the persistent detection of low density Plasmodium sp. infections following antimalarial treatment suggests these may be a hitherto unrecognised obstacle to malaria elimination (Dinko B, Oguike MC, Larbi JA2, Bousema T, Sutherland CJ. Persistent detection of Plasmodium falciparum, P. malariae, P. ovale curtisi and P. ovale wallikeri after ACT treatment of asymptomatic Ghanaian school-children. Int J Parasitol Drugs Drug Resist. 2013 Jan 19;3:45-50. doi: 10.1016/j.ijpddr.2013.01.001).
In Liberia it was found that although treatment is highly efficacious, selection of molecular markers in reinfections could indicate a decreased sensitivity or tolerance of parasites to the current treatments and the baseline prevalence of molecular markers should be closely monitored (Sabina Dahlström Otienoburu, Oumou Maïga-Ascofaré, Birgit Schramm, Vincent Jullien, Joel J. Jones, Yah M. Zolia, Pascal Houzé, Elizabeth A. Ashley, Jean-René Kiechel, Philippe J. Guérin, Jacques Le Bras and Sandrine HouzéSelection of Plasmodium falciparum pfcrt and pfmdr1 polymorphisms after treatment with artesunate–amodiaquine fixed dose combination or artemether–lumefantrine in Liberia. Malaria Journal201615:452 DOI: 10.1186/s12936-016-1503-3).
In Kivu, RDC, the high reinfection rate after Coartem and ASAQ treatment raises concerns and requires further studies.(Marit de Wit, Anna L. Funk, Krystel Moussally, David Aksanti Nkuba, Ruby Siddiqui, Karla Bil, Erwan Piriou, Aldert Bart, Patrick Bahizi Bizoza and Teun Bousema. In vivo efficacy of artesunate–amodiaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria: an open-randomized, non-inferiority clinical trial in South Kivu, Democratic Republic of Congo. Malaria Journal201615:455 DOI: 10.1186/s12936-016-1444-x).
In Sudan the findings of a study call for a need to review the Sudan malaria treatment policy. Epidemiological factors could play a major role in the emergence of drug-resistant malaria in eastern Sudan. (Ahmed A. Adeel, Fahad Awad Ali Elnour, Khalid Abdalmutalab Elmardi, Mona B. Abd-Elmajid, Mai Mahmoud Elhelo, Mousab S. Ali, Mariam A. Adam, Hoda Atta, Ghasem Zamani, Marian Warsame, Amy Barrette, Hanan El Mohammady and Rania A. Nada. High efficacy of artemether-lumefantrine and declining efficacy of artesunate + sulfadoxine-pyrimethamine against Plasmodium falciparum in Sudan (2010–2015): evidence from in vivo and molecular marker studies. Malaria Journal 201615:285 DOI: 10.1186/s12936-016-1339-x).
IS MASS DRUG ADMINISTRATION A SOLUTION
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 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, Bennett S, Schim van der Loeff M, Okunoye K, Targett GA, McAdam KP, Doherty JF, Greenwood BM, Pinder M. 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).
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).
A further 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): e0161311.doi:10.1371/journal.pone.0161311).
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 disadgrees 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."
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. (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).
POLYTHERAPY WITH ARTEMISIA PLANTS AGAINST RESISTANCE
All this may explain why very small quantities of Artemisia annua are sufficient to cure and stop the disease and why Bigpharma-WHO has to work with astronomic doses of artemisinin derivatives to achieve a similar result, but still be plagued with recurrence due to dormancy of parasites and sequestration caused by these massive doses.
The in vivo trials which have been run by our partners in Cameroon, Kenya, Congo, Burundi, Senegal, Central Africa, Uganda with Artemisia annua infusion or whole leaf tablets or capsules operate with artemisinin doses far below 20mg/day and all give excellent results, even at 2mg/day.
A team of medical doctors in RDCongo, Jerome Munyangi and Michel Idumbo, have run randomized clinical trials on a large scale in the Maniema province with the participation of some 1000 malaria infected patients. The trials were run in conformity with the WHO procedures and compared Artemisia annua and Artemisia afra with ACTs (Coartem and ASAQ). For all the parameters tested herbal treatment was significantly better than ACTs: faster clearance for fever and parasitemia, absence of parasites on day 28 for 99.5% of the Artemisia treatments and 79.5% only for the ACT treatments. A total absence of side effects was evident for the treatments with the plants, but for the 498 patients treated with ACTs, 210 suffered from diarrhea, and/or nausea, pruritus, hypoglycemia etc. The efficiency was equivalent for Artemisia annua and Artemisia afra. More important even is the observation for the total absence of gametocytes after 7 days treatment with the herb. A tremendous hope for malaria eradication. The results have been communicated to the local health authorities, and to the Ministries of Health and Research in the RDCongo who were supportive of these trials. The draft of a paper is almost ready and will be submitted to a peer reviewed scientific journal.
It also has been demonstrated that regular consumption of Artemisia annua tea is boosting the immune system and has a strong prophylactic action (PE Ogwang et al., Brit J Pharm Res 1 :4, 124-132) Patrick E Ogwang1,3, Jasper O Ogwal4, Simon Kasasa2, Deogratius Olila3,Francis Ejobi3, David Kabasa3 and Celestino Obua4* Artemisia Annua L. Infusion Consumed Once a WeekReduces Risk of Multiple Episodes of Malaria: A Randomised Trial in a Ugandan Community. Tropical Journal of Pharmaceutical Research June 2012; 11 (3): 445-453 doi.org/10.4314/tjpr.v11i3.14).
The bioavailabity of artemisinin is faster and higher if administered as tea and the therapeutic effect is even much higher if Artemisia annua is administered as whole leaf powder in lieu of pure artemisinin. Dried whole-plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin
(Mostafa A. Elfawal, Melissa J. Towler, Nicholas G. Reich, Pamela J. Weathers, and Stephen M. Rich. Dried whole-plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin. PNAS, vol. 112 no. 821–826, doi: 10.1073/pnas.1413127112).