Concurrent Presence of pfkelch13 and pfmdr1 Mutations in Recurring Plasmodium falciparum Infection After Standard Artemether-Lumefantrine Therapy

Overview

This case report describes recurrent Plasmodium falciparum infection after standard artemether-lumefantrine (ART-LUM) treatment in a 50-year-old man with metabolic comorbidities. Genetic analysis identified PfK13 T348I and PfMDR1 T199S variants, whose effects on ART-LUM susceptibility remain uncertain. The patient recovered following second-line treatment.

Background

Artemisinin-based combination therapies are first-line treatments for uncomplicated P. falciparum infections. Certain pfk13 variants are validated markers of partial artemisinin resistance, while pfmdr1 variants or increased copy number are suggested markers of reduced response to lumefantrine. Obesity and metabolic-associated fatty liver disease may also affect ART-LUM metabolism and drug exposure, potentially influencing treatment outcomes.

Data Highlights

Key Findings

• During the initial episode, parasitemia decreased from 3% to below 1% after ART-LUM treatment.

• Recurrent symptoms began approximately 2 weeks after discharge, without further travel outside Portugal.

• Sequencing identified PfK13 T348I and PfMDR1 T199S variants, along with pfmdr1 N86 and Y184 alleles. No increased pfmdr1 copy number was detected.

• The patient had obesity, type 2 diabetes, hypertension, and hepatic steatosis.

• Seven days of intravenous quinine sulfate and oral doxycycline resulted in clinical recovery, with complete parasitological clearance confirmed at follow-up.

Interpretation

The case was managed as ART-LUM treatment failure. The effects of PfK13 T348I and PfMDR1 T199S on drug susceptibility remain uncertain. Metabolic comorbidities may alter drug exposure, but their contribution to recurrence was not established.

Limitations

This single case cannot establish causal relationships between parasite variants, comorbidities, and treatment failure. Plasma drug concentrations were not measured, preventing establishment of a clear link between ART-LUM exposure and clinical failure. The variants’ effects on susceptibility require further in vitro investigation.

Clinical Implications

The authors emphasize optimizing ART-LUM bioavailability, weight-based dosing in large or obese adults, and treatment-outcome monitoring. The effects of the identified variants on ART-LUM susceptibility remain uncertain.

Conclusion

Further investigation is needed into the effects of PfK13 T348I and PfMDR1 T199S on ART-LUM susceptibility and the influence of obesity and metabolic-associated fatty liver disease on pharmacokinetics and treatment outcomes.

Related Resources & Content

1. WHO guidelines for malaria — World Health Organization — World Health Organization, August 13, 2025.

2. Novel Pfk13 and Pfubp1 genotypes in African Plasmodium falciparum isolates exhibiting reduced susceptibility to the antimalarials artemisinin and lumefantrine — Pratt S, van Schalkwyk DA, Stewart L, et al. — mBio, 2026;17:e0367625.

3. Mutation in the Plasmodium falciparum BTB/POZ domain of K13 protein confers artemisinin resistance — Paloque L, Coppée R, Stokes BH, et al. — Antimicrobial Agents and Chemotherapy, 2022;66:e0132021.

4. Pharmacokinetic properties of the antimalarial combination therapy artemether–lumefantrine in normal-weight, overweight and obese healthy male adults — Sugiarto SR, Page-Sharp M, Drinkwater JJ, Davis WA, Salman S, Davis TME — International Journal of Antimicrobial Agents, 2022;59:106482.

5. The alteration of drug metabolism enzymes and pharmacokinetic parameters in nonalcoholic fatty liver disease: current animal models and clinical practice — Zhu Y, Chen L, He Y, et al. — Drug Metabolism Reviews, 2023;55:163–180.