NEW findings from the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health have confirmed that dihydroartemisinin-piperaquine (DP), the first-line treatment for Plasmodium falciparum malaria infection in Cambodia, has failed in certain provinces because of parasite resistance to the two drugs. The study was published in a recent issue of Lancet Infectious Diseases.
DP combines potent, fast-acting artemisinin with a long-acting partner drug, piperaquine. Resistance to artemisinin in parts of South-East Asia is well documented, but until now only a few studies had presented clear evidence of piperaquine resistance. Additional study findings suggest that artesunate, a form of artemisinin, plus mefloquine (A+M), a different long-acting partner drug, should be the first-line treatment in areas where DP treatment has failed, the study authors noted.
The NIAID study compared the efficacy of DP treatment in 204 malaria-afflicted participants aged two to 65 years from three provinces in Cambodia with varying levels of artemisinin resistance. After 63 days, it was found that parasites had re-emerged despite initial clearance in 45.7 per cent of participants in Pursat, 15.9 per cent of participants in Preah Vihear, and 1.67 per cent of participants in Ratanakiri. Earlier studies have suggested that artemisinin resistance is caused by a mutant version of a gene called K13-propeller in P. falciparum parasites. Laboratory tests showed that the parasites from DP failures contained this 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 World Health Organisation guidelines reinstating A+M as the first-line artemisinin combination therapy in Cambodia where DP treatment has failed. The findings also provided evidence to initiate surveillance programmes to track the spread of piperaquine resistance and clinical trials to test alternative combination therapies.
The study has relevance to India where until recently both DP and A+M had been found to be highly efficacious. In a 2012 study, the 63-day cure rates were 100 per cent for A+M and 98.8 per cent for DP. The DP combination was also found to exert a significant post-treatment prophylactic effect, and a significant reduction in the incidence of new infections was observed for DP compared with A+M. But last year, the artemisinin-resistant mutant parasite was detected in some areas close to the border of Myanmar. Because of the possibility of cross-border movement of the mutant varieties from South-East Asia, this study offers lessons for surveillance studies in the north-eastern States of India on piperaquine as well.