Are three drugs for malaria better than two?
Authors: Philip J Rosenthal
Journal: The Lancet (2020)

Malaria, in particular that which is caused by Plasmodium falciparum, remains a huge problem, and its control is threatened by resistance to available drugs.1WHOWorld malaria report 2019. World Health Organization, Geneva2019Google Scholar The most important antimalarial drugs available are artemisinin-based combination therapies (ACTs), which include a rapid-acting artemisinin component plus a slower-acting partner drug. The artemisinin rapidly kills parasites, but, with a standard 3-day regimen, might not eliminate all Plasmodium. The partner drug eliminates remaining parasites and restricts selection of artemisinin resistance. Despite their pharmacologically mismatched components, ACTs offer remarkable efficacy for the treatment of uncomplicated malaria caused by drug-sensitive parasites. However, ACT resistance, which manifests as delayed clearance of parasites after initiation of therapy, and is mediated by mutations in a Kelch (K13) protein of P falciparum, is now widespread in parts of southeast Asia.2Ashley EA Dhorda M Fairhurst RM et al.Spread of artemisinin resistance in Plasmodium falciparum malaria.N Engl J Med. 2014; 371: 411-423Crossref PubMed Scopus (1246) Google Scholar, 3Ariey F Witkowski B Amaratunga C et al.A molecular marker of artemisinin-resistant Plasmodium falciparum malaria.Nature. 2014; 505: 50-55Crossref PubMed Scopus (1115) Google Scholar Furthermore, resistance to the ACT partner drugs mefloquine4Phyo AP Ashley EA Anderson TJC et al.Declining efficacy of artemisinin combination therapy against P falciparum malaria on the Thai-Myanmar border (2003–2013): the role of parasite genetic factors.Clin Infect Dis. 2016; 63: 784-791Crossref PubMed Scopus (110) Google Scholar and piperaquine5Amaratunga C Lim P Suon S et al.Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study.Lancet Infect Dis. 2016; 16: 357-365Summary Full Text Full Text PDF PubMed Scopus (277) Google Scholar has moved artemisinin resistance from a mainly theoretical concern, since ACTs are still generally effective with resistance only to the artemisinin component, to a pressing problem. Treatment with the previous national regimen dihydroartemisinin-piperaquine, for example, is failing for most patients infected with P falciparum in parts of Cambodia.6van der Pluijm RW Imwong M Chau NH et al.Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study.Lancet Infect Dis. 2019; 19: 952-961Summary Full Text Full Text PDF PubMed Scopus (110) Google Scholar With artemisinins limited by their delayed clearance phenotype and partner drugs failing, our ability to treat malaria in southeast Asia is seriously jeopardised. Other ACTs are available, but each has limitations. One might anticipate that continued use of combinations including failing artemisinins will lead to the loss of one partner drug after another. New combination therapies that do not include artemisinins would be welcome, but the current pace of development suggests that no new chemical entities to treat malaria will be available for some years.7Hooft van Huijsduijnen R Wells TN The antimalarial pipeline.Curr Opin Pharmacol. 2018; 42: 1-6Crossref PubMed Scopus (36) Google Scholar What should be done now? An interesting new strategy is triple ACT (TACT). The concept is simple: just add a third drug to an ACT. One might argue that this is a recipe to lose more drugs to resistance. Indeed, an axiom in the treatment of infectious diseases is to never add a single new drug to a failing regimen. But, perhaps axioms are meant to be broken, and the simple TACT concept might simply be a great strategy. TACT benefits from two key points. First, artemisinin resistance is not full-blown resistance; parasites with K13 mutations are eliminated by artemisinins, albeit more slowly than are wild-type parasites. Second, key ACT partner drugs have counteracting drug resistance mechanisms. The same transporter polymorphisms that mediate decreased sensitivity to amodiaquine and, to a lesser extent, piperaquine mediate increased sensitivity to lumefantrine and mefloquine.8Conrad MD Rosenthal PJ Antimalarial drug resistance in Africa: the calm before the storm?.Lancet Infect Dis. 2019; 19: e338-e351Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar On the basis of this simple but compelling logic, a new multisite randomised controlled trial in The Lancet by Rob van der Pluijm and colleagues9van der Pluijm RW Tripura R Hoglund RM et al.Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial.Lancet. 2020; (published online March 11)https://doi.org/10.1016/S0140-6736(20)30552-3Summary Full Text Full Text PDF PubMed Scopus (54) Google Scholar has compared efficacies of three standard ACTs (dihydroartemisinin–piperaquine, artesunate–mefloquine, and artemether–lumefantrine) and two TACTs containing partner drugs with opposing resistance mechanisms (dihydroartemisinin–piperaquine plus mefloquine and artemether–lumefantrine plus amodiaquine) for the treatment of P falciparum malaria. The study design was complex, with different regimens studied in 1100 patients (median age 23 years [IQR 13–34], 854 [78%] male) with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species in different regions of Cambodia, Thailand, Laos, Vietnam, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. The key results were straightforward. At sites where artemisinin resistance is not established, all regimens showed excellent efficacy, with tolerability and toxicity of the TACTs similar to those of the ACTs. Most importantly, in regions of southeast Asia with relevant ACT resistance (Cambodia, Thailand, and Vietnam), 42-day PCR-corrected efficacies were 98% (95% CI 94–100) for dihydroartemisinin–piperaquine plus mefloquine versus a dismal 48% (39–56) for dihydroartemisinin–piperaquine. The study was limited by a lack of blinding and by a relative lack of paediatric participants, who are the highest risk group for malaria worldwide, but who make up a small proportion of malaria cases in areas with ACT resistance. These new results suggest that TACTs might replace ACTs. The addition of mefloquine to dihydroartemisinin–piperaquine rescued the regimen from unacceptably poor efficacy, and mefloquine might additionally restrict selection of resistance to piperaquine. If safety and tolerability remain acceptable in follow-up studies, use of optimally dosed and formulated TACTs to treat P falciparum malaria might soon be appropriate in regions with artemisinin resistance. However, most cases of P falciparum malaria occur in regions without established artemisinin resistance. Should TACTs be implemented in these regions? On the one hand, TACTs might delay the development of resistance to multiple antimalarials, a vital benefit.10White NJ Triple artemisinin-containing combination anti-malarial treatments should be implemented now to delay the emergence of resistance.Malar J. 2019; 18: 338Crossref PubMed Scopus (12) Google Scholar On the other hand, despite promising initial results, adding another drug to established regimens will likely add to challenges regarding tolerability, toxicity, and drug interactions, especially considering known concerns for the partner drugs mefloquine and amodiaquine.11Krishna S Triple artemisinin-containing combination anti-malarial treatments should be implemented now to delay the emergence of resistance: the case against.Malar J. 2019; 18: 339Crossref PubMed Scopus (9) Google Scholar On the ground, there might be little enthusiasm for changing highly efficacious regimens because implementing any policy change is difficult. Thus, this study offers promise for TACTs in regions with artemisinin resistance, but whether we should implement TACTs in other areas is uncertain. In any event, TACTs should be seen as a stopgap; novel combination therapies to treat malaria are greatly needed. I declare no competing interests. Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trialDihydroartemisinin–piperaquine plus mefloquine and artemether–lumefantrine plus amodiaquine TACTs are efficacious, well tolerated, and safe treatments of uncomplicated P falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance. Full-Text PDF Open Access