Objective:

To describe recurrent Plasmodium falciparum infection following standard artemether-lumefantrine (ART-LUM) treatment and discuss the potential contributions of parasite genetic variants and host metabolic comorbidities.

Approach:

• Case Presentation: A 50-year-old man developed recurrent malaria approximately 2 weeks after discharge following a standard 3-day ART-LUM course. He had returned from Uganda and reported no subsequent travel outside Portugal.
• Genetic Analysis: Blood samples collected during recurrence underwent polymerase chain reaction (PCR) testing and sequencing of pfk13 and pfmdr1. Real-time PCR assessed pfmdr1 copy number.

Key Findings:

• Sequencing identified PfK13 T348I and PfMDR1 T199S variants, along with pfmdr1 N86 and Y184 alleles.
• No evidence of increased pfmdr1 copy number was detected.
• The patient had obesity, type 2 diabetes, hypertension, and ultrasound findings compatible with moderate to severe hepatic steatosis.
• Recurrent parasitemia was 3.5%. After 7 days of intravenous quinine sulfate and oral doxycycline, complete parasitological clearance was confirmed at the 1-week 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. Obesity and hepatic steatosis may influence drug exposure, but their contribution to recurrence was not established.

Limitations:

• A single case cannot establish causal relationships between genetic variants, comorbidities, and treatment failure.
• Plasma drug concentrations were not measured, preventing assessment of the relationship between ART-LUM exposure and clinical failure.
• The variants’ effects on ART-LUM susceptibility require further in vitro investigation.

Conclusion:

Further research is needed to clarify the effects of these variants and metabolic comorbidities on ART-LUM susceptibility, pharmacokinetics, and treatment outcomes. The authors emphasize optimizing bioavailability, weight-based dosing, and treatment monitoring.