Artemisinin resistance or artemisinin-based combination therapy resistance?

Abstract

In his recent Comment in The Lancet Infectious Diseases, Joel Breman discussed parasite resistance to artemisinin-based combination therapy (ACT) and the heritability of this resistance.1Breman JG Resistance to artemisinin-based combination therapy.Lancet Infect Dis. 2012; 12: 820-822Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 2Amaratunga C Sreng S Suon S et al.Artemisinin-resistant Plasmodium falciparum malaria in Pursat province, western Cambodia: a parasite-clearance-rate study.Lancet Infect Dis. 2012; 12: 851-858Summary Full Text Full Text PDF PubMed Scopus (253) Google Scholar The differences between artemisinin resistance and resistance to ACT (also termed ACT resistance) merit further clarification. Researchers have used many methods to try to prove the existence of artemisinin resistance. Lengthening of the parasite clearance time suggests artemisinin resistance. Amaratunga and colleagues2Amaratunga C Sreng S Suon S et al.Artemisinin-resistant Plasmodium falciparum malaria in Pursat province, western Cambodia: a parasite-clearance-rate study.Lancet Infect Dis. 2012; 12: 851-858Summary Full Text Full Text PDF PubMed Scopus (253) Google Scholar delayed mefloquine administration to exclude the contribution of mefloquine in parasite clearance during the first 72 h—the period most relevant to artemisinin action. This approach deviates from the standard treatment schedule for the purpose of their study—ie, to investigate the genetic basis of artemisinin resistance. This study design does not have a primary aim to show ACT resistance, which leads to ACT failures. The term “ACT resistance” is used loosely and often interchangeably with “artemisinin resistance”, although it should not be. Artemisinin resistance could contribute to ACT failure, but the combination of artemisinin with an efficacious partner drug can improve cure rates to an adequate level.3World Health Organization Global Malaria ProgrammeUpdate on artemisinin resistance.http://www.who.int/malaria/publications/atoz/arupdate042012.pdfDate: April 2012Google Scholar Evidence of artemisinin resistance has been scarce so far, and only a working definition of such resistance exists. The longer parasite clearance times reported in the Mekong subregion could be due to a non-progressive weakening of artemisinin activity. ACTs are still highly efficacious in most of this subregion, especially in Laos, Burma, and Vietnam.4World Health Organization Global Malaria ProgrammeThe status of drug-resistant malaria along the ThailandûMyanmar border. Revised 9 May 2012.http://www.who.int/malaria/publications/atoz/drug_resistance_myanmar_thailand_border_may_2012.pdfGoogle Scholar One exception is the decreasing efficacy of artesunate–mefloquine at the Cambodian–Thai border. Two locations in western Cambodia are good examples of ACT resistance, where, despite the policy switch from failing artesunate–mefloquine to dihydroartemisinin–piperaquine treatment, the 42 day treatment efficacies are only 73–89%, and more than 40% of patients have positive parasitaemia on day 3.3World Health Organization Global Malaria ProgrammeUpdate on artemisinin resistance.http://www.who.int/malaria/publications/atoz/arupdate042012.pdfDate: April 2012Google Scholar Existing mefloquine resistance and the unregulated availability of dihydroartemisinin–piperaquine in the private sector for the past 10 years could explain its failure. Scientists are trying to elucidate the basis of artemisinin resistance, whereas malaria control programmes focus on ACT resistance, especially the morbidity and mortality associated with inefficacy of the combined drugs. WHO, senior health authorities, and donor agencies have correctly emphasised artemisinin resistance as a public health warning, support for which is essential for maintenance of parasite susceptibility to artemisinins at the highest possible level or for elimination of those parasites. In view of the scarce choices of appropriate partner drugs, if artemisinin resistance becomes established, it will negatively affect global achievements in malaria control. I agree with Breman's concern about Africa, where great care should be taken in deployment of ACTs.5Wongsrichanalai C Thimasarn K Sirichaisinthop J Antimalarial drug combination policy: a caveat.Lancet. 2000; 355: 2245-2247Summary Full Text Full Text PDF PubMed Scopus (26) Google Scholar The availability of ACTs in Africa from drug vendors without parasitological diagnosis is a dangerous problem. For the online parasite clearance estimator see http://www.wwarn.org/toolkit/data-management/parasite-clearance-estimator For the online parasite clearance estimator see http://www.wwarn.org/toolkit/data-management/parasite-clearance-estimator I declare that I have no conflicts of interest. Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate studyHeritable artemisinin resistance is established in a second Cambodian province. To accurately identify parasites that are intrinsically susceptible or resistant to artemisinins, future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation. Full-Text PDF