Recrudescence, reinfection or relapse? A more rigorous framework to assess chloroquine efficacy for vivax malaria.

Background: Plasmodium vivax resistance to chloroquine has been reported worldwide, although the WHO clinical drug efficacy studies protocol does not allow to classify patient outcomes.

Methods: We enrolled 40 vivax malaria patients in northeastern Cambodia, where >17% treatment failures were previously reported. Patients were treated with chloroquine (30mg/kg) and followed for two months, with frequent clinical examination and capillary blood sample collection for microscopy, molecular parasite detection and genotyping, and drug concentration measurements. Reinfections were prevented by relocating patients to a transmission-free area.

Results: P. vivax parasites were eliminated in all patients by day3. Genomic analyses revealed that all clones in polyclonal infections were cleared at the same rate, indicating their equal susceptibility to CQ. Chloroquine blood concentration were below the therapeutic level in all recurrent infections (24/40 patients), which were efficiently cleared by a second course of chloroquine treatment. Whole genome sequencing indicated that two-third (6/8) of the recurrent parasites resulted from heterologous relapses whose 50% are from by sibling/recombinant clones.

Conclusions: No evidence of chloroquine resistance were observed. Our data suggest that P. vivax antimalarial drug resistance is likely overestimated and that the current guidelines for clinical drug studies in vivax malaria need to be revised.