Saving lives through improved use of ACTs
Authors: George Jagoe, John H Amuasi
Journal: The Lancet Global Health (2015)

The new modelling work by Tran Dang Nguyen and colleagues in The Lancet Global Health,1Nguyen TD Olliaro P Dondorp AM et al.Optimum population-level distribution of artemisinin combination therapies: a modelling study.Lancet Glob Health. 2015; (published online Nov 3.)http://dx.doi.org/10.1016/S2214-109X(15)00162-XGoogle Scholar which focuses on optimum distribution strategies of artemisinin combination therapies (ACTs) for treatment of malaria, comes at a crucial juncture in the public health battle to contain drug resistance. At a time that many countries are heeding calls to develop aggressive national plans to eliminate malaria and are reporting encouraging news of declining morbidity and mortality, worrisome evidence in the Greater Mekong subregion of southeast Asia confirms that resistance to artemisinin and to non-artemisinin partner drugs used in ACTs remains a threat.2WHOStatus report on artemisinin resistance.http://www.who.int/malaria/publications/atoz/status_rep_artemisinin_resistance_jan2014.pdf?ua=1Date: January, 2014Google Scholar Safeguarding the effectiveness of ACTs should remain a paramount concern of the malaria community, and choosing optimum strategies for distribution of the various ACT options available to countries is a key component of this challenge. Availability of several ACTs has fuelled years of debate and modelling efforts to understand how this range of options can best be used to safeguard this class of treatments. Boni and colleagues3Boni MF Smith DL Laxminarayan R Benefits of using multiple first-line therapies against malaria.Proc Natl Acad Sci USA. 2008; 105: 14216-14221Crossref PubMed Scopus (98) Google Scholar first suggested the superior performance of concomitant use of multiple first-line therapies (MFT) over sequential application of single first-line therapies with an evolutionary–epidemiological modelling framework. By use of hybrid modelling approaches, Smith and colleagues4Smith DL Klein EY McKenzie FE Laxminarayan R Prospective strategies to delay the evolution of anti-malarial drug resistance: weighing the uncertainty.Malar J. 2010; 9: 217Crossref PubMed Scopus (37) Google Scholar also showed that, compared with sequential use of single first-line antimalarial drugs, MFT strategies were more effective in reducing drug pressure and delaying emergence and spread of resistance. However, with a population genetics model, Antao and Hastings5Antao T Hastings I Policy options for deploying anti-malarial drugs in endemic countries: a population genetics approach.Malar J. 2012; 11: 422Crossref PubMed Scopus (10) Google Scholar suggested that the advantage of MFT over sequential application was not as clearly advantageous as other models had shown, owing to linkage disequilibrium that could yield multidrug resistance earlier than sequential application. These discrepant outputs led the WHO Drug Resistance and Containment Technical Expert Group in 2013 to declare that evidence for the benefits of MFT was inconclusive but that the concept was crucially important and warranted further modelling.6WHOMinutes of the Drug Resistance and Containment Technical Expert Group (TEG).http://www.who.int/malaria/mpac/mpac_sep13_teg_drug_resistance_containment_report.pdfDate: June 27–28, 2013Google Scholar This new work by Nguyen and colleagues is a significant improvement over past efforts at modelling the effect of MFT. The model relies on individual-based microsimulation of regional malaria transmission, taking into consideration individual-level host detail, age-specific effects, explicit tracking of within-host parasite density, and drug-specific pharmacodynamics. Importantly, outputs from this model provide powerful evidence that, compared with drug cycling strategies or sequential deployment of different ACTs, MFT strategies are significantly better at delaying emergence of resistance to both artemisinin derivatives and their partner drugs. The implications of this modelling study invite reflection about the crucial role that ACTs have had for the past 15 years. Although artemisinins used in monotherapy are mostly effective at clearing malaria parasites, the objective of recommending their combination with other antimalarial drugs was to protect the artemisinin component from resistance, as long as the partner drug itself was efficacious and also partly protected by the artemisinin derivative.7WHOWHO guidelines for the treatment of malaria. World Health Organization, Geneva2006: 18Google Scholar Fortunately, development of fixed-dose combinations of ACTs, advocacy to discourage monotherapy, reduced prices, and improved availability have all contributed to widespread use of these life-saving medicines. Together with vector control efforts, use of ACTs has contributed to a substantial reduction in the global malaria mortality rate by 47% (54% in Africa) between 2000 and 2013.8WHOWorld malaria report 2014.http://www.who.int/malaria/media/world_malaria_report_2014/en/Google Scholar Four highly effective fixed-dose ACTs are recommended by WHO at present for treatment of uncomplicated malaria, and they have a crucial role in malaria elimination efforts. Thus, drug resistance spreading to Africa would have disastrous effects on millions of patients—and a crippling effect on the malaria elimination agenda. Building on the authors' validation of their model against a wide range of field and clinical datasets, further scrutiny of this model by other disease modellers would be welcome, especially by those experienced in modelling drug effectiveness in the event of resistance. If the debate about MFT finally moves beyond the purview of modellers into the hands of policy makers and implementing programmes, future research should focus on operational considerations linked to MFT, including new commodity forecasting needs, supply chain capability, and training of health workers in use of several alternative therapies. Finally, operational research should assess the feasibility of different options for randomisation of ACT use in patient populations. GJ is an employee of MMV (Executive Vice President for Access & Product Management). JHA is a consultant to MMV evaluating countries' consideration of and experiences with the implementation of multiple first-line therapies for malaria. Optimum population-level use of artemisinin combination therapies: a modelling studyAdjusting national antimalarial treatment guidelines to encourage simultaneous use of MFT is likely to extend the useful therapeutic life of available antimalarial drugs, resulting in long-term beneficial outcomes for patients. Full-Text PDF Open Access