Malaria

Malaria is caused by single-celled Plasmodium parasites that are transmitted to humans by mosquitoes. In 2016, there were an estimated 216 million malaria infections and 445 000 malaria deaths worldwide. Over 90% of all cases and deaths occur in Africa, where it is particularly deadly for children aged <5 years¹.

In the early 2000s advances were made such as the roll-out of insecticide-treated bednets and the introduction of artemisinin-based combination therapy (ACT). Thanks to these interventions the number of deaths declined significantly between 2000 and 2015, but they have recently plateaued. Malaria is Médecins Sans Frontières’ (MSF) single largest morbidity: 2 536 400 cases of malaria were treated by MSF in 2016, representing over one-quarter of MSF outpatient consultations worldwide², which is an obvious justification for Epicentre’s involvement in this field.

Epicentre’s contributions have been focused on the diagnosis, treatment and prevention of malaria in MSF program settings in many different fields.

Epicentre accompanied MSF during the roll-out of seasonal malaria chemoprevention (SMC), a new strategy aimed at children under 5 in the Sahel. They are given prophylaxis drugs once a month during the rainy season when risk of malaria is high³ . Epicentre has carried out program coverage surveys of MSF-implemented SMC in Guinea-Bissau, Mali, Niger, and Chad, and provided advice on the continued roll-out of SMC⁴.

To protect vulnerable population, MSF organized a preventive treatment program for children <15 years in a refugee camp in northern Uganda. We performed a series of studies to describe this intervention⁵.

One of the risks of SMC, is that the malaria parasites may become resistant to the drugs used in the SMC strategy. The World Health Organization has recommended that routine monitoring of this takes place in areas where SMC is implemented. To do this, laboratory methods are used to look at the genes of the malaria parasites, and to see which ones might be resistant to the drugs. Epicentre has performed studies in Chad and Niger on this subject⁶.

Rapid diagnostic tests (RDT) for malaria do not require specialist laboratory capacity, and are widely available in the field. Epicentre performed evaluations of several different types of rapid diagnostic tests (notably HRP2 and pLDH), to see which are best-adapted to different settings. One study in Uganda showed that HRP2 tests continued to give a positive result for up to 6 weeks after a treatment⁷, suggesting that they should be avoided in high transmission areas where early re-infection in common. 

After the roll-out of the SMC strategy in Magaria, Niger, doubts arose about the program’s effectiveness, as the hospitals were still full of children with malaria. In 2016, Epicentre conducted a prospective case-control study to estimate the protective effectiveness of SMC against developing malaria. Because one of the concerns was that children were not correctly adhering to the 3-day course of treatment at home, the blood levels of the SMC drugs were checked. The main results showed that SMC is generally working well despite evidence of very poor adherence to the drug treatment. 

Epicentre has performed and participated in several recent clinical trials related to the treatment of malaria. 

• In Niger, one study evaluated three commonly-used ACTs for the treatment of uncomplicated malaria, and found that all three had good effectiveness⁸. 
• The treatment of malaria in malnourished children can be challenging. In a clinical trial in Mali and Niger, artemether-lumefantrine was found to be equally effective in malnourished and non-malnourished children, but the levels of the drugs in the blood were significantly lower in malnourished children, possibly leaving them more vulnerable to reinfection⁹.  
• Mortality among children with severe malaria is high. Epicentre was one of 11 trial sites for the AQUAMAT trial, which showed that intravenous artesunate therapy reduced mortality in severe malaria by 22% compared to quinine treatment¹⁰. This trial led to a change in WHO recommendations for the treatment of severe malaria. 
• Even with artesunate, mortality in severe malaria remains high, so adjunctive therapies are needed. In a trial, we tested a hypothesis that using inhaled nitric oxide in addition to standard care might reduce mortality, but unfortunately the trial could not confirm this was so¹¹.

References

¹    WHO. World Malaria Report 2017 [Internet]. World Health Organization. Geneva; 2017. doi:10.1071/EC12504
²    Médecins Sans Frontières. International Activity Report 2016 [Internet]. Geneva; 2016. Available: http://www.msf.org/sites/msf.org/files/msf_activity_report_2016_web.pdf
³   WHO Global Malaria Programme. WHO policy recommendation: Seasonal Malaria Chemoprevention for Plasmodium falciparum control in highly seasonal transmission areas of the Sahel sub-region in Africa. Geneva; 2012. 
⁴   Coldiron ME, Von Seidlein L, Grais RF. Seasonal malaria chemoprevention: Successes and missed opportunities. Malar J. 2017;16. doi:10.1186/s12936-017-2132-1
⁵   Coldiron ME, Lasry E, Bouhenia M, Das D, Okui P, Nyehangane D, et al. Intermittent preventive treatment for malaria among children in a refugee camp in Northern Uganda: lessons learned. Malar J. 2017;16. doi:10.1186/s12936-017-1869-x
⁶    Grais RF, Laminou IM, Woi‑messe L, Makarimi R, Bouriema SH, Langendorf C, et al. Molecular markers of resistance to amodiaquine plus sulfadoxine– pyrimethamine in an area with seasonal malaria chemoprevention in south central Niger. Malar J. 2018;17. doi:10.1186/s12936-018-2242-4
⁷  Grandesso F, Nabasumba C, Nyehangane D, Page A-L, Bastard M, De Smet M, et al. Performance and time to become negative after treatment of three malaria rapid diagnostic tests in low and high malaria transmission settings. Malar J. BioMed Central; 2016;15: 496. doi:10.1186/s12936-016-1529-6
⁸   Grandesso F, Guindo O, Woi Messe L, Makarimi R, Traore A, Dama S, et al. Efficacy of artesunate-amodiaquine, dihydroartemisinin-piperaquine and artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Maradi, Niger NCT01755559 NCT. Malar J. 2018;17. doi:10.1186/s12936-018-2200-1
⁹   Denoeud-Ndam L, Dicko A, Baudin E, Guindo O, Grandesso F, Diawara H, et al. Efficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe acute malnutrition: an open comparative intervention study in Mali and Niger. BMC Med. 2016;14. doi:10.1186/s12916-016-0716-1
¹⁰  Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): An open-label, randomised trial. Lancet. 2010;376: 1647–1657. doi:10.1016/S0140-6736(10)61924-1
¹¹   Mwanga-Amumpaire J, Carroll RW, Baudin E, Kemigisha E, Nampijja D, Mworozi K, et al. Inhaled Nitric Oxide as an Adjunctive Treatment for Cerebral Malaria in Children: A Phase II Randomized Open-Label Clinical Trial. Open forum Infect Dis. Oxford University Press; 2015;2: ofv111. doi:10.1093/ofid/ofv111