Researchers have confirmed that dihydroartemisinin-piperaquine, the first-line treatment for Plasmodium falciparum malaria infection in Cambodia, has failed in certain provinces due to parasite resistance to both artemisinin and piperaquine.
Dihydroartemisinin-piperaquine is an artemisinin combination therapy (ACT) for malaria that combines potent, fast-acting artemisinin with a long-acting partner drug, piperaquine. Resistance to artemisinin in parts of Southeast Asia is well-documented, but until now only a few studies have presented clear evidence of piperaquine resistance.
The study findings, published this week in Lancet Infectious Diseases, also suggest that artesunate, a form of artemisinin, combined with mefloquine, a different long-acting partner drug, should be the first-line ACT in areas where dihydroartemisinin-piperaquine treatment has failed, the study authors note.
The study, which was led by researchers from the National Institute of Allergy and Infectious Diseases (NIAID), compared the efficacy of dihydroartemisinin-piperaquine treatment in 204 malaria patients aged 2 to 65 years from three provinces in Cambodia, where varying levels of artemisinin resistance have been reported. After monitoring parasite levels in the blood for 63 days, investigators found parasites had reemerged despite initial clearance in 45.7 percent of participants in Pursat, 15.9 percent of participants in Preah Vihear and 1.67 percent of participants in Ratanakiri. The results indicate the ACT is failing in Pursat and Preah Vihear, where artemisinin resistance is common, but is still working well in Ratanakiri, where artemisinin resistance is uncommon.
Laboratory tests and whole genome sequencing showed the parasites from dihydroartemisinin-piperaquine failures contained a genetic marker of artemisinin resistance and had a decreased susceptibility to piperaquine, demonstrating that both artemisinin and piperaquine resistance contributed to treatment failures. However, the parasites also showed an increased susceptibility to mefloquine and completely lacked the molecular marker for mefloquine resistance.
These findings informed new WHO guidelines reinstating artesunate plus mefloquine as the first-line ACT in Cambodia where dihydroartemisinin-piperaquine treatment has failed. The findings also provide evidence to initiate surveillance programmes to track the spread of piperaquine resistance and clinical trials to test alternative combination therapies.
At the Wellcome Trust Sanger Institute, where some malaria parasites used in this study were sequenced, work is underway to further analyse samples from Cambodia. “Clearly the situation with drug resistance is critical. We need to work quickly to identify a molecular marker for piperaquine, and to incorporate it into ongoing genetic surveillance projects,” says Dr Roberto Amato, a co-author on the study and Staff Scientist at the Wellcome Trust Sanger Institute.
Article: Amaratunga C et al. Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infect Dis. 2016 Mar;16(3):357-65. doi: 10.1016/S1473-3099(15)00487-9. Epub 2016 Jan 8.