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Malaria treatment used in UK failed for the first time

Drug resistance ‘biggest threat’ to beating malaria

Jo Carlowe

Tuesday, 31 January 2017

A first-line drug used in the UK to treat patients with malaria, has failed for the first time.

Artemether-lumefantrine (AL), a type of Artemisinin Combination Therapy (ACT) is commonly used and is usually highly effective, but it failed to cure four patients who contracted malaria while visiting Africa, according to new research* published in Antimicrobial Agents and Chemotherapy.

The UK patients, who all recovered after receiving alternative treatment, were found to be infected with new strains of the malaria parasite Plasmodium falciparum. Although the researchers can’t rule out other factors, they believe the treatment failure was due to these strains showing reduced susceptibility, a potential first sign of drug resistance.

The World Health Organization recommends ACTs as the first-line treatment for uncomplicated Plasmodium falciparum malaria. Crucially, these are among the very first well-described cases of reduced susceptibility to ACT drugs used in Africa, an area of the world where most malaria cases and deaths occur.  

The research team was led by the London School of Hygiene & Tropical Medicine, with partners Public Health England (PHE), the Wellcome Trust Sanger Institute, the Hospital for Tropical Diseases and Cambridge University Hospitals NHS Foundation Trust.

These are the first documented cases of AL failing to treat UK patients, and were all reported within a relatively short period of time - between October 2015 and February 2016. The team is concerned that this pattern may highlight a changing situation for malaria treatment in Africa, as well as in the UK. 

None of the four cases could be explained by the ‘slow clearance’ artemisinin resistance found in the Greater Mekong Region. Instead, each patient was found to have a parasite with a mutation in at least one of the five drug resistance markers specifically investigated by the team.

This report describes four patients who were admitted to two UK hospitals after returning from Angola, Liberia or Uganda. After being diagnosed with malaria caused by the Plasmodium falciparum parasite, they were given artemether-lumefantrine.

Initially, all the patients recovered and were discharged within a week with complete or near complete clearance of detectable parasites in their blood. However, within six weeks of treatment each patient was readmitted with recurrent symptoms and increased levels of Plasmodium falciparum parasites in their blood. None of the patients had travelled to malaria endemic countries between the two hospital admissions.

Blood samples from each patient were sent to the PHE Malaria Reference Laboratory at the London School of Hygiene & Tropical Medicine, where genetic and parasitological investigations were carried out. For one patient, parasite genome sequencing was also conducted by the Sanger Institute.

Dr Colin Sutherland, Reader in Parasitology at the London School of Hygiene & Tropical Medicine who led the study, said: “Artemether-lumefantrine is the recommended treatment for non-life threatening cases of falciparum malaria in the UK. This strategy is considered to be working well, however our findings suggest that it might need reviewing – fortunately there are other effective drugs available. All the patients were identified by self-referral which suggests more cases of treatment failure in the UK may have occurred. Frontline doctors should be alert to the possibility of artemisinin-based drugs failing, and assist with the collection of detailed information about specific travel destinations.

“A concerted effort to monitor AL outcomes in UK malaria patients needs to be made. This will determine whether our frontline malaria treatment drug is under threat. The good news is that our collaborative infectious disease warning and testing systems which are in place, overseen by Public Health England, are highly effective.”

Of particular concern to the researchers is that AL is also the most widely used ACT in Africa.

Dr Sutherland said: “These cases act as a warning for Africa. Drug resistance is one of the biggest threats we face in fighting malaria, and is already starting to occur in parasite strains prevalent in parts of South-East Asia. We need to understand why AL failed to clear these four cases of Plasmodium falciparum infection. Mutations were found in genes previously implicated in drug failure in Africa and these warrant further investigation as candidate genetic markers for AL susceptibility in Africa, a potential first sign of drug resistance.”

* Sutherland CJ, Lansdell P, Sanders M, et al. Pfk13-independent treatment failure in four imported cases of Plasmodium falciparum malaria given artemether-lumefantrine in the UK. Antimicrobial Agents and Chemotherapy, publiched online 30 January 2017. DOI: 10.1128/AAC.02382-16

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