India Needs to Consider Planning a Change to Artemether–Lumefantrine to Treat Plasmodium falciparum Malaria

Abstract

As the malaria elimination target draws closer for India, it must be ensured that the country’s policies, strategies, and tools remain effective. Artemisinin-based combination therapies are the mainstay of Plasmodium falciparum malaria management. India has a differential standard therapy for uncomplicated falciparum malaria in the form of artemether–lumefantrine in its northeastern states and artesunate + sulfadoxine–pyrimethamine in the rest of the country. The clinical failure of artesunate + sulfadoxine–pyrimethamine in the northeast regions were attributed primarily to parasite resistance resulting from mutations in the enzymes dihydropteroate synthase and dihydrofolate reductase. Artemether–lumefantrine was therefore substituted for artesunate + sulfadoxine–pyrimethamine in the region. The change has been a success, as evidenced by the therapeutic efficacy studies conducted at regular intervals in India. However, studies suggest that resistance may be emerging toward sulfadoxine–pyrimethamine in multiple parts of the nation. Hence, there is a possibility that the artesunate + sulfadoxine–pyrimethamine combination may be acting in part as a monotherapy, and this makes the longevity of the artesunate + sulfadoxine–pyrimethamine drug combination therapy uncertain. The increasing presence of drug-resistant mutants in P. falciparum dhps and dhfr genes suggests the need for a policy switch for uncomplicated P. falciparum malaria from artesunate + sulfadoxine–pyrimethamine to artemether–lumefantrine.

Keeping the momentum: suggestions for treatment policy updates in the final push to eliminate malaria in India

“…Double mutations (C50R-N51I, N51I-C59R, N51I-S108N) have been detected in the Northeastern states, Chhattisgarh, Jharkhand, Odisha, West Bengal and Uttar Pradesh [11][12][13][14][15][16][17]. Even quintuple (three mutations in dhfr (N51I-C59R-S108N) and two mutations in dhps (A437G-K540E) and sextuple resistance (three mutations in dhfr (IRN) and three mutations in dhps (A437G-K540E-A581G) mutations have been reported from the Northeastern states and a few areas in West Bengal between 2006 and 2013 [18]. Decreased efficacy of partner medicine (SP) due to resistance, can endanger artemisinin, the most valuable tool available for malaria treatment.…”

Diverse Malaria Presentations across National Institutes of Health South Asia International Center for Excellence in Malaria Research Sites in India

“… 12 , 23 – 25 The findings make it clear that artemisinin, sooner than later, will have to be partnered with compounds for which there is much less circulating, preexisting resistance in India. 26 In the case of antifolate resistance, phenotypic and genotypic surveillance activities will have to be increased to better inform policy-makers. The MESA-ICEMR will continue to monitor resistance to artemisinin and partner drugs at the genotypic and phenotypic levels.…”

Meta-analysis on Plasmodium falciparum sulfadoxine-pyrimethamine resistance-conferring mutations in India identifies hot spots for genetic surveillance

“…The malaria drug policy in India has witnessed two critical changes: switching from chloroquine (CQ) to AS+SP for the entire country in 2010 and then from AS+SP to AL in the NES in 2013. 2,3 . Both these switchovers were backed by sufficient clinical (therapeutic efficacy studies; TES) and molecular (validated genetic markers for drug resistance) evidence for resistance to CQ and SP.…”