Failure of dihydroartemisinin plus piperaquine treatment of falciparum malaria by under-dosing in an overweight patient

Jean Baptiste Roseau, Bruno Pradines, Nicolas Paleiron, Serge Vedy, Marylin Madamet, Fabrice Simon, Emilie Javelle

Artemisinin-based combination therapy (ACT) introduced in the mid-1990s has been recommended since 2005 by the World Health Organization as first-line treatment against Plasmodium falciparum in all endemic countries. In 2010, the combination dihydroartemisinin-piperaquine (DP) was recommended for the treatment of uncomplicated P. falciparum malaria. DP is one of the first-line treatments used by the French army since 2013. A case of P. falciparum clinical failure with DP at day 20 was described in a 104 kg French soldier deployed in Djibouti. He was admitted to hospital for supervision of oral treatment with DP [40 mg dihydroartemisinin (DHA) plus 320 mg piperaquine tetraphosphate (PPQ)]. This corresponded to a cumulative dose of 4.6 mg/kg DHA and 37 mg/kg PPQ in the present patient, which is far below the WHO recommended ranges. No mutation was found in the propeller domain of the Kelch 13 (k13) gene, which is associated with artemisinin resistance in Southeast Asia. Pfmdr1 N86, 184F, S1034 and N1042 polymorphisms and haplotype 72-76 CVIET for the pfcrt gene were found in the present case. There was no evidence of resistance to DP. This case confirms the risk of therapeutic failure with dihydroartemisinin-piperaquine by under-dosing in patients weighing more than 100 kg. This therapeutic failure with DP by under-dosing highlighted the importance of appropriate dosing guidelines and the need of research data (efficacy, pharmacokinetics and pharmacodynamics) in over-weight patient group.