The emergence and spread of Plasmodium falciparum resistance to commonly used antimalarial drugs is a major challenge in the control and in the process of achieving elimination of malaria (Olliaro, 2005; The malERA Consultative Group on Drugs, 2011). For this reason, the combination therapies rather than monotherapies have been recommended for efficient management of malaria. WHO endorsed artemisinin-based combination therapies (ACTs) have proven to be extremely effective for management of uncomplicated malaria  as a part of global efforts to control and eliminate malaria worldwide (WHO malaria fact sheet, 2013).

National drug policy on malaria in India has recommended the use of artesunate plus sulphadoxine-pyremethamine (AS+SP) which is the first line of treatment for uncomplicated falciparum malaria. Till 2011, the efficacy of AS+SP was found to be above 95% at all the study sites in the country.  However studies conducted during 2012 in North-eastern states showed high treatment failures to AS+SP in P. falciparum malaria with PCR corrected cure rates ranging between 75-80% (Mishra et al., 2012, Mishra et al., 2014). There after artemether-lumefantrine (AL) has been recommended as the first line antimalarial in North-Eastern region (NVBDCP, 2014).  The present study were undertaken to determine the therapeutic efficacy and safety of artemether-lumefantrine (AL) for the treatment of uncomplicated P. falciparum malaria in three states (Tripura, Mizoram and Arunachal Pradesh) in the north-eastern region of India.

The patients were enrolled in the study during the peak malaria transmission season of P. falciparum in NE region, from April 2014 to August 2014. Patients were followed up for 42 days after initiation of treatment at all the 3 sites participating in the surveillance. The in vivo therapeutic evaluation demonstrated that AL is well tolerated and highly efficacious up to 28 days of follow up.  The 28-day PCR corrected efficacy rates were 96.1% in each of the districts of Tripura (Gomati)and Mizoram (Lunglei). 100% efficacxy was observed in Changlang district, Arunachal Pradesh. However, the PCR corrected efficacy after 42 days follow up was 88.4% in Gomati district, Tripura; 94.3% in Lunglei district, Mizoram and 100% in Changlang district, Arunachal Pradesh. While the efficacy of first-line treatment AL at 42 days after treatment has been found to be high in Arunachal Pradesh and Mizoram, it is below the WHO target efficacy of 90% in Tripura. The use of AL as a first-line treatment at this site warrants close monitoring.

In addition to clinical efficacy, molecular markers of drug resistance of AL were analysed in all the samples collected on Day 0 from above three sites. Single-nucleotide polymorphisms (SNPs) in the pfcrt and pfmdr1 genes are known to be involved in the development of in vitro and in vivo resistance to AL (Wongsrichanalai et al., 2002). A high prevalence of pfcrt 76T mutations were observed in Gomati (54.1%), Lunglei (95.2%) and Changlang district (97.6%). Significant selection of pfmdr1 N86, Y184 and D1246 at Tripura and Mizoram while 86Y, Y184 and D1246 in Arunachal Pradesh has been observed after AL treatment in the present study. Furthermore, we found high rates of two pfmdr1 haplotypes previously associated with lumefantrine resistance, NYD (75%) and YYD (50%) in treatment failure samples from Tripura and Mizoram respectively. None of the 12 isolates from patients who were successfully treated (attained ACPR) from Tripura, Mizoram and Arunachal Pradesh or 12 recrudescent samples from Tripura and Mizoram had an amplified pfmdr1 gene.