An NIH study published in The Lancet Infectious Disease earlier this month indicates that the anti-malarial medication dihydroartemisinin-piperaquine has failed to treat Plasmodium falciparum malaria infection in some provinces in Cambodia. Researchers found parasitic resistance to both artemisinin and piperaquine, a first-line artemisinin-based combination therapy (ACT) used to treat P. falciparum infections [1].
During 2012 to 2013, researchers enrolled 241 patients aged 2–65 years with uncomplicated P. falciparum malaria in three Cambodian provinces: Pursat, Preah Vihear, and Ratanakiri. Enrolled patients were treated with standard three-day courses of dihydroartemisinin-piperaquine. Researchers measured the peripheral blood parasite densities to determine recrudescence, a new episode of clinical malaria caused by surviving parasites in red blood cells after the original treatment. According to the study result, recrudescence of P. falciparum was lower in Ratanakiri (2%), where artemisinin-resistance was uncommon, compared to the Pursat (46%) and Preah Vihear (16%) areas. Recrudescent parasites showed high resistance against piperaquine. These parasites didn’t carry the genetic marker of mefloquine resistance [1].
This finding provided evidence to support the policy of switching first-line treatment of P. falciparum from artemisinin-piperaquine to artesunate-mefloquine in west Cambodia, where the resistance to artemisinin emerged [2]. This is especially important since antimalarial drug resistance may hinder progress made by malaria control in Cambodia and worldwide. In 2015, Cambodia’s malaria cases increased to 41,000 over the first nine months, compared to 25,000 over the same period in 2014 [2].
Why is drug resistance a big concern?
Malaria is a parasitic disease transmitted by Anopheles mosquitoes. The protozoan parasite belongs to genus Plasmodium. These parasites damage red blood cells. Early symptoms may be mild as fever, headache, chills and vomiting. Without prompt treatment, some cases may develop lethal severe symptoms, such as multi-organ failure, severe anemia, respiratory distress related to metabolic acidosis, and cerebral malaria [3].
Malaria carries a huge global burden and many programs exist aim to eliminate this disease. In 2000, reversing the incidence of malaria by 2015 was included as a target in the Millennium Development Goals (MDG). According to the MDG report in 2015, there are still 97 countries and territories considered as malaria endemic areas [4]. Global malaria incidence decreased by 37% and the fatality rate dropped by 60% from 2000 to 2015 [4]. Globally, 80% of malaria cases and 78% of deaths occurs across 15 countries, primarily in sub-Saharan Africa [4]. Regardless of the significant progress made, there remained an estimated 214 million malaria cases and 438,000 malaria-related deaths in 2015 [4]. Children aged under 5 years of age are at the greatest risk of infection and severe outcomes [4].
Among the five species of Plasmodium, P. falciparum and P. vivax are responsible for the majority of malaria disease burden. P. falciparum is the most prevalent strain of malaria on the African continent and is responsible for the majority of the malaria-related deaths. ACTs are currently the most effective treatment for uncomplicated P. falciparum malaria infection [4,5]. Therefore, artemisinin-resistance has been considered an important threat to the global progress made towards eliminating malaria.
What has been done?
In order to protect ACTs as an efficacious treatment against malaria, containment activities began in 2008 on the Cambodia–Thailand border and expanded gradually to the Greater Mekong Sub-region, where the resistance is prevalent [5]. The WHO developed a Global Plan for Artemisinin Resistance Containment (GPARC) in 2011 to respond to the emerging artemisinin-resistance threat [6].
GPARC introduced five recommendations to fight against artemisinin-resistant malaria [6]. The group’s first recommendation was to stop the spread of resistant parasites. Malaria control should be adopted in all areas to stop the transmission of resistant parasites. The second was to increase monitoring and surveillance to evaluate the threat of resistance. Drug resistance patterns may differ between geographic regions and parasite species. Ineffective treatments accelerate the development of drug resistance, so it is important to gather surveillance data of drug resistance, to implement efficacious treatment protocols against the disease. Early detection of drug resistance also helps authorities to respond promptly. The third recommendation was to improve access to diagnostics and rational treatment with ACTs. Compliance of treatment decreases the risk of developing resistance to artemisinin and partner drugs. Patients may stop taking medicine when they feel less ill. Unpleasant side effects of medication or lack of medical resources also lead to treatment non-compliance. Improving access to medical resources and educating people on the correct usage of medications can help to achieve better health outcomes. The fourth recommendation was investing in artemisinin-resistance-related research. Scientists have discovered the molecular marker of artemisinin-resistance and have been trying to find a solution since [7]. There is also research happening to develop new antimalarial drugs. However, drug development usually takes much longer compared to the speed of the evolution of drug-resistance [2]. The fifth recommendation was to motivate action and mobilize resources to ensure the implementation of these strategies.
Since the plan was enacted, more sites of resistance have been detected [5]. The containment of artemisinin-resistant parasites still requires global cooperation and effort to ensure that the objectives are achieved.
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Sources
[1] http://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(15)00487-9.pdf
[3] http://www.who.int/mediacentre/factsheets/fs094/en/
[4] http://apps.who.int/iris/bitstream/10665/184521/1/9789241509442_eng.pdf?ua=1
[5] http://apps.who.int/iris/bitstream/10665/79940/1/9789241505321_eng.pdf?ua=1
[6] http://www.who.int/malaria/publications/atoz/artemisinin_resistance_containment_2011.pdf
[7] http://www.who.int/malaria/publications/atoz/status_rep_artemisinin_resistance_jan2014.pdf?ua=1