Researchers in the United Kingdom report that a frontline drug combination for the treatment of uncomplicated malaria failed in four patients, a finding they say raises concerns about reduced susceptibility to recommended therapy for the disease.
Meanwhile, a separate study suggests that a gene that enables malaria-carrying mosquitoes to resist insecticides has spread throughout southern Africa.
The case studies, reported this week in Antimicrobial Agents and Chemotherapy, describe the treatment of four patients (two male, two female) diagnosed as having malaria caused by the Plasmodium falciparum parasite after returning from trips to Angola, Liberia, and Uganda in late 2015 and early 2016. Most malaria cases in the UK involve people who've traveled to Africa, where the disease is endemic.
The patients were all treated with artemether-lufemantrine, an artemisinin-based combination therapy (ACT) that the World Health Organization (WHO) recommends as the first-line treatment for uncomplicated malaria. All the patients recovered within a few days, and were discharged once their blood showed no remaining signs of the parasite.
But from 2 and 6 weeks after the initial episode, each patient returned with recurrent symptoms of the disease and increased levels of the parasite in their blood. None of the four patients had traveled back to Africa after the first treatment, which indicated that these were not new infections, since P falciparum is not found in the United Kingdom. Doctors subsequently treated the patients with alternative drugs, and all four recovered.
Genetic analysis of malaria isolates from each patient showed that they all harbored mutations that have been associated with reduced susceptibility to artemisinin or lufemantrine. Still, the authors note, the failure of the initial treatment "cannot be unequivocally ascribed to parasite resistance" in the four patients. They say the findings could have been substantiated by monitoring the patients for full compliance with the initial treatment and measuring lufemantrine levels in the blood a week after treatment to look for signs of malabsorption.
While the four cases represent the first failure of frontline malaria treatment in the United Kingdom, the authors of the study say the real concern is what the findings could potentially mean for malaria treatment in Africa, where the parasite is a constant threat and artemeter-lufemantrine is the most widely used ACT.
Lead study author Colin Sutherland, PhD, MPH, of the London School of Hygiene and Tropical Medicine, said UK doctors can play a role in monitoring for signs of growing resistance.
"A concerted effort to monitor AL [artemether-lufemantribe] outcomes in UK malaria patients needs to be made," Sutherland said in a press release from University College London Hospitals. "This will determine whether our frontline drug is under threat."
As of July 2016, resistance to artemisinin and its partner drugs has been confirmed in the five countries that make up the Greater Mekong subregion: Cambodia, Laos, Myanmar, Thailand, and Vietnam.
Insecticide resistance in Africa
While resistance to artemisinin-based combination therapies has not to date spread to Africa, a study today in PLoS Genetics indicates that one of the major elements of malaria control efforts in Africa is helping fuel the spread of insecticide-resistance in the mosquitoes that carry P falciparum.
According to the study, a vast majority of malaria reduction since 2000 can be attributed to mosquito control with pyrethroid insecticide-based interventions, including the use of insecticide-treated bed netting and indoor spraying. Yet in recent years, growing resistance to insecticide-treated nets has been observed in Africa. That resistance is believed to be caused by a metabolic mutation that enables mosquitoes to detoxify the insecticide before it reaches its target.
To get a better understanding of why this resistance is spreading, and how far it has spread in mosquito populations in Africa, researchers used a combination of sequencing techniques and genetic analyses to examine the continent-wide population structure of the Anopheles funestus mosquito, one of the major malaria vectors in Africa. What they found was that the gene that controls metabolic resistance has now swept through mosquito populations in southern Africa and become almost universal, driven primarily by the selection pressure from the growing use of pyrethroid-treated mosquito netting.
"This highlights the risk of relying on a single insecticide class for vector control and emphasizes the need for novel insecticides and vector control tools to tackle the spread of resistant vector populations," the authors write.
The WHO estimates there were 212 million cases of malaria globally in 2015, and 429,000 deaths. Africa accounted for 90% of the cases and 92% of the deaths.
Jan 30 Antimicrob Agents Chemother study
Jan 31 University College London Hospitals press release
Feb 2 PLoS Genet study