Search

In a randomized controlled trial Tim Davis and colleagues investigate Artemisinin-naphthoquine versus artemether-lumefantrine for the treatment of P. falciparum and P. vivax malaria. Please see later in the article for the Editors' Summary, Background Artemisinin combination therapies (ACTs) with broad efficacy are needed where multiple Plasmodium species are transmitted, especially in children, who bear the brunt of infection in endemic areas. In Papua New Guinea (PNG), artemether-lumefantrine is the first-line treatment for uncomplicated malaria, but it has limited efficacy against P. vivax. Artemisinin-naphthoquine should have greater activity in vivax malaria because the elimination of naphthoquine is slower than that of lumefantrine. In this study, the efficacy, tolerability, and safety of these ACTs were assessed in PNG children aged 0.5–5 y. Methods and Findings An open-label, randomized, parallel-group trial of artemether-lumefantrine (six doses over 3 d) and artemisinin-naphthoquine (three daily doses) was conducted between 28 March 2011 and 22 April 2013. Parasitologic outcomes were assessed without knowledge of treatment allocation. Primary endpoints were the 42-d P. falciparum PCR-corrected adequate clinical and parasitologic response (ACPR) and the P. vivax PCR-uncorrected 42-d ACPR. Non-inferiority and superiority designs were used for falciparum and vivax malaria, respectively. Because the artemisinin-naphthoquine regimen involved three doses rather than the manufacturer-specified single dose, the first 188 children underwent detailed safety monitoring. Of 2,542 febrile children screened, 267 were randomized, and 186 with falciparum and 47 with vivax malaria completed the 42-d follow-up. Both ACTs were safe and well tolerated. P. falciparum ACPRs were 97.8% and 100.0% in artemether-lumefantrine and artemisinin-naphthoquine-treated patients, respectively (difference 2.2% [95% CI −3.0% to 8.4%] versus −5.0% non-inferiority margin, p = 0.24), and P. vivax ACPRs were 30.0% and 100.0%, respectively (difference 70.0% [95% CI 40.9%–87.2%], p, Editors' Summary Background Malaria is a mosquito-borne parasitic disease that kills more than 600,000 people (mainly young children in sub-Saharan Africa) every year. Plasmodium falciparum causes most of these deaths, but P. vivax is the most common and most widely distributed cause of malaria outside sub-Saharan Africa. Infection with malaria parasites causes recurring flu-like symptoms and must be treated promptly with antimalarial drugs to prevent the development of anemia and potentially fatal damage to the brain and other organs. In the past, malaria was treated with “monotherapies” such as chloroquine, but the parasites quickly developed resistance to many of these inexpensive drugs. The World Health Organization now recommends artemisinin combination therapy (ACT) for first-line treatment of malaria in all regions where there is drug-resistant malaria. In ACT, artemisinin derivatives (fast-acting antimalarial drugs that are rapidly cleared from the body) are used in combination with a slower acting, more slowly eliminated partner drug to prevent reemergence of the original infection and to reduce the chances of the malaria parasites becoming resistant to either drug. Why Was This Study Done? Because falciparum and vivax malaria respond differently to antimalarial drugs, wherever there is transmission of both types of malaria but limited facilities for species-specific malaria diagnosis—as in Papua New Guinea—compromises have to be made about which ACT should be used for the treatment of malaria. Thus, Papua New Guinea's national guidelines recommend artemether-lumefantrine, which is effective against the more deadly P. falciparum, for first-line treatment of uncomplicated (mild) malaria even though this ACT is ineffective against the more common P. vivax. In this open-label randomized trial (a study in which participants are randomly assigned to receive different drugs but know which drug they are being given), the researchers ask whether an alternative ACT might be preferable for the treatment of uncomplicated malaria in young children in Papua New Guinea by comparing outcomes after treatment with artemether-lumefantrine versus artemisinin-naphthoquine (an ACT that should be more effective against vivax malaria than artemether-lumefantrine because naphthoquine stays in the body longer than lumefantrine). Specifically, the researchers test the non-inferiority of artemisinin-naphthoquine compared to artemether-lumefantrine for the treatment of falciparum malaria (whether artemisinin-naphthoquine is not worse than artemether-lumefantrine) and the superiority of artemisinin-naphthoquine compared to artemether-lumefantrine for the treatment of vivax malaria (whether artemisinin-naphthoquine is better than artemether-lumefantrine). What Did the Researchers Do and Find? The researchers assigned nearly 250 children (aged 0.5 to 5 years) with falciparum malaria, vivax malaria, or both types of malaria to receive six doses of artemether-lumefantrine over three days or three daily doses of artemisinin-naphthoquine. They then followed the children to see how many children in each treatment group and with each type of malaria were free of malaria 42 days after treatment (an “adequate clinical and parasitological response”). Among the patients originally infected with P. falciparum, 97.8% of those treated with artemether-lumefantrine and 100% of those treated with artemisinin-naphthoquine were clear of their original P. falciparum infection (though some had acquired a new P. falciparum infection) 42 days after treatment. By contrast, among the patients infected with P. vivax, 30% of those treated with artemether-lumefantrine and 100% of those treated with artemisinin-naphthoquine were clear of P. vivax infection 42 days after treatment. Both ACTs were safe and well tolerated. What Do These Findings Mean? These findings indicate that artemisinin-naphthoquine was non-inferior to artemether-lumefantrine for the treatment of uncomplicated falciparum malaria among young children in Papua New Guinea and had greater efficacy than artemether-lumefantrine against vivax malaria. The accuracy of these findings may be limited by several aspects of the study design. For example, not all the artemether-lumefantrine doses were directly observed, so some children may not have received the full treatment course. Moreover, because all the study participants lived in coastal communities in Papua New Guinea where malaria is highly endemic, treatment responses among children living in areas with lower levels of malaria transmission might be different. Nevertheless, these findings suggest that artemisinin-naphthoquine should be considered alongside other ACTs for the treatment of uncomplicated malaria in regions where there is transmission of multiple Plasmodium species and that artemisinin-naphthoquine may be better than artemether-lumefantrine for the treatment of uncomplicated malaria in young children in regions where P. vivax predominates. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001773. Information is available from the World Health Organization on malaria (in several languages); the World Malaria Report 2013 provides details on the current global malaria situation, including information on malaria in Papua New Guinea; the World Health Organization's Guidelines for the Treatment of Malaria is available The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish), including personal stories about malaria Information is available from the Roll Back Malaria Partnership on the global control of malaria, including information about malaria in Papua New Guinea, malaria in children, and ACTs The Malaria Vaccine Initiative has a fact sheet on Plasmodium vivax malaria MedlinePlus provides links to additional information on malaria (in English and Spanish) More information about this trial is available