Novel Insights into Plasmodium Vivax Therapeutic Failure: CYP2D6 Activity and Time of Exposure to Malaria Modulate the Risk of Recurrence

relapse is one of the major causes of sustained global malaria transmission. Primaquine (PQ) is the only commercial drug available to prevent relapses, and its efficacy is dependent on metabolic activation by cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 function, caused by allelic polymorphisms, leads to the therapeutic failure of PQ as a radical cure for malaria. Here, we hypothesized that the host immune response to malaria parasites modulates susceptibility to recurrences in association with CYP2D6 activity. We performed a 10-year retrospective study by genotyping polymorphisms in 261 malaria-exposed individuals from the Brazilian Amazon. The immune responses against a panel of blood-stage antigens were evaluated by serological assays. We confirmed our previous findings, which indicated an association between impaired CYP2D6 activity and a higher risk of multiple episodes of recurrence (risk ratio, 1.75; 95% confidence interval [CI], 1.2 to 2.6;  = 0.0035). An important finding was a reduction of 3% in the risk of recurrence (risk ratio, 0.97; 95% CI, 0.96 to 0.98;  < 0.0001) per year of malaria exposure, which was observed for individuals with both reduced and normal CYP2D6 activity. Accordingly, subjects with long-term malaria exposure and persistent antibody responses to various antigens showed fewer episodes of malaria recurrence. Our findings have direct implications for malaria control, since it was shown that nonimmune individuals who do not respond adequately to treatment due to reduced CYP2D6 activity may present a significant challenge for sustainable progress toward malaria elimination.