Therapeutic efficacy of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in four malaria endemic states of India
Authors: Krishna Sri , Mishra Sweta , Tiwari Prakash , Vishwakarma Anup K. , Khandai Sushrikanta , Shrivastava Suyesh , Verma Anil K. , Tiwari Shashikant , Barman Hari , Jhariya Surendra , Tiwari Pradeep , Tidgam Anup S. , Varun Brij M. , Singh Sunil , Yerane Naresh , Tembhurne Chintaman R. , Mandavi Prem L. , Tekam Shyam S. , Malik Manas , Behera Kali P. , Jayswar Himanshu , Sonwani Khemraj , Diggikar Mukund S. , Pradhan Madan M. , Khasotiya Sher S. , Kumar Avdhesh , Dhingra Neeraj , Bustos Maria Dorina G. , Christophel Eva-Maria , Ringwald Pascal , Kumari Roop , Shukla Man M. , Singh Neeru , Das Aparup , Bharti Praveen K. 
Published: May 2021

Abstract
Background
Malaria is a major public health problem in India and accounts for about 88% of malaria burden in South-East Asia. India alone accounted for 2% of total malaria cases globally. Anti-malarial drug resistance is one of the major problems for malaria control and elimination programme. Artemether-lumefantrine (AL) is the first-line treatment of uncomplicated Plasmodium falciparum in north eastern states of India since 2013 after confirming the resistance against sulfadoxine-pyrimethamine. In the present study, therapeutic efficacy of artemether-lumefantrine and k13 polymorphism was assessed in uncomplicated P. falciparum malaria.

Methods
This study was conducted at four community health centres located in Koraput district of Odisha, Bastar district of Chhattisgarh, Balaghat district of Madhya Pradesh and Gondia district of Maharashtra state. Patients with uncomplicated P. falciparum malaria were administered with fixed dose combination (6 doses) of artemether-lumefantrine for 3 days and clinical and parasitological response was recorded up to 28 days as per World Health Organization protocol. Nucleotide sequencing of msp1 and msp2 gene was performed to differentiate between recrudescence and reinfection. Amplification and sequencing of k13 propeller gene region covering codon 450–680 was also carried out to identify the polymorphism.

Results
A total 376 malaria patients who fulfilled the enrolment criteria as well as consented for the study were enrolled. Total 356 patients were followed up successfully up to 28 days. Overall, the adequate clinical and parasitological response was 98.9% and 99.4% with and without PCR correction respectively. No case of early treatment failure was observed. However, four cases (1.1%) of late parasitological failure were found from the Bastar district of Chhattisgarh. Genotyping of msp1 and msp2 confirmed 2 cases each of recrudescence and reinfection, respectively. Mutation analysis of k13 propeller gene showed one non-synonymous mutation Q613H in one isolate from Bastar.

Conclusions
The study results showed that artemether-lumefantrine is highly effective in the treatment of uncomplicated P. falciparum malaria among all age groups. No functional mutation in k13 was found in the study area. The data from this study will be helpful in implementation of artemether-lumefantrine in case of treatment failure by artesunate plus sulfadoxine-pyrimethamine.