The emerging threat of artemisinin resistance in malaria: focus on artemether-lumefantrine

Abstract

The development of artemisinin resistance in the Greater Mekong Subregion poses a significant threat to malaria elimination. Artemisinin-based combination therapies including artemether-lumefantrine (AL) are recommended by WHO as first-line treatment for uncomplicated Plasmodium falciparum malaria. This article provides a comprehensive review of the existing and latest data as a basis for interpretation of observed variability in parasite sensitivity to AL over the last 5 years. Clinical efficacy and preclinical data from a range of endemic countries are summarized, including potential molecular markers of resistance. Overall, AL remains effective in the treatment of uncomplicated P. falciparum malaria in most regions. Establishing validated molecular markers for resistance and strict efficacy monitoring will reinforce timely updates of treatment policies.

Keywords:

• artemether-lumefantrine
• artemisinin resistance
• clinical efficacy
• molecular markers
• systematic review

Authors’ contributions

All authors are responsible for the content of this review manuscript. They have critically reviewed, revised and approved the content at each stage of development, and have read and approved the final version for submission. The views reflected in this manuscript are those of the authors and not their employers.

Acknowledgements

The authors thank P Hunt, Southdown Medical Writing Ltd, for support with the literature review (funded by Novartis Pharma AG) and K Stricker, Novartis Pharma AG, for her critical review of the manuscript. Medical writing support was provided by R Mason and J Chapman at Seren Communications, an Ashfield company, part of UDG Healthcare plc, and was funded by Novartis Pharma AG.

Financial & competing interests disclosure

A Djimde has worked as an investigator in studies of artemether-lumefantrine funded by EDCTP and MMV, and has previously received speaker’s fees from Novartis. M Makanga has previously been an investigator for Novartis sponsored clinical trials, K Kuhen is an employee of the Genomics Institute of the Novartis Research Foundation, San Diego, CA, USA and K Hamed is an employee of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance was provided by R Mason and J Chapman from Seren Communications.

Key issues

• The artemisinin-based combination therapy artemether-lumefantrine (AL) is used as first-line treatment in a majority of the sub-Saharan African countries due to its high efficacy (most studies report PCR-corrected cure rates >95%), and excellent safety and tolerability profile.

• Outside certain regions of Cambodia/Thailand, treatment failure with AL is uncommon. There are many other reasons for treatment failure, including: non-compliance with the treatment schedule, poor drug quality/counterfeit antimalarials, drug–drug interactions and patient-related factors that may affect drug exposure.

• During the 5-year period of this systematic review, the efficacy of AL as a treatment for malaria remained high, with corrected 28-day cure rates >95% in the majority of studies in sub-Saharan Africa. Lower rates were reported only in Asia, particularly in Cambodia (82%). Most studies that investigated parasite clearance reported that >98% of patients had cleared by day 3.

• These findings are consistent with recent reports from WHO noting that AL remains effective in the treatment of uncomplicated Plasmodium falciparum malaria in most parts of the world, with the exception of Cambodia and possibly some regions of Thailand.

• While a handful of articles, including anecdotal reports, have alluded to the development of resistance to AL, some had incomplete data (e.g., no directly observed therapy or measurement of drug plasma concentrations) and most recorded high cure rates on day 28, suggesting that AL treatment was effective.

• Whole-genome sequencing of P. falciparum samples from Asia and Africa has revealed genomic regions associated with resistance to artemisinin-based drugs. Recently, single nucleotide polymorphisms that potentially confer artemisinin resistance have been identified in a gene on chromosome 13, named K13-propeller. The K13-propeller polymorphism has been found in malaria parasites from several Cambodian provinces, but extensive analysis of samples from sub-Saharan Africa found no evidence of resistance-associated K13 mutations.

• The presence of wild-type alleles of pfmdr1 N86Y has been associated with reduced sensitivity to lumefantrine in vitro. An increased frequency of these wild-type alleles has also been observed during treatment with AL, suggesting that it may be a candidate molecular marker for lumefantrine resistance.

• Continued surveillance of AL treatment efficacy and establishing/monitoring of validated molecular markers of resistance is paramount to ensure the timely review and update of treatment policies, and preservation of the therapeutic value of AL.