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

Abstract

Plasmodium vivax 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 P. vivax malaria. Here, we hypothesized that the host immune response to malaria parasites modulates susceptibility to P. vivax recurrences in association with CYP2D6 activity. We performed a 10-year retrospective study by genotyping CYP2D6 polymorphisms in 261 malaria-exposed individuals from the Brazilian Amazon. The immune responses against a panel of P. vivax 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 P. vivax recurrence (risk ratio, 1.75; 95% confidence interval [CI], 1.2 to 2.6; P = 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; P < 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 P. vivax malaria elimination.

Several Plasmodium vivax relapses after correct primaquine treatment in a patient with impaired cytochrome P450 2D6 function

“…Poor metabolizer (PM) phenotypes are defined by AS of 0, intermediate metabolizers (IM) are defined by AS from 0 to 1.25, normal metabolizers (NM) are defined by AS from 1.25 to 2.25, and ultrarapid metabolizers (UM) are defined by AS over 2.25 [ 38 ]. Recent studies, have established the importance of CYP2D6 polymorphisms on primaquine efficacy [ 24 – 27 , 47 ] showing associations between low-activity CYP2D6 phenotypes (poor and intermediate metabolizers) and P. vivax relapses. In the study of Bennett et al [ 24 ] two out of 25 patients relapsed after an initial P. vivax attack with correct chloroquine and primaquine treatment.…”

“…CYP2D6 is responsible for the metabolism of 20–25% of clinically used drugs, and there are more than 46 known major CYP2D6 alleles which can be determined and predict a CYP2D6 phenotype of metabolization (poor, intermediate, normal and ultrarapid) [ 22 ]. It has been suggested that a reduced primaquine metabolism due to impairments in CYP2D6 function may be related to P. vivax relapses [ 24 – 27 ].…”

Monitoring Plasmodium vivax resistance to antimalarials: Persisting challenges and future directions

“…Higher risk of malaria relapse and increased number of relapses were found in sporozoite-challenged volunteers with greatly reduced or absent CYP2D6 activity ( Bennett et al, 2013 ). Since then, a large body of evidence for an association between clinical failure of PQ and impaired CYP2D6 metabolism has accumulated ( Baird et al, 2018a , Baird et al, 2018b ; Brasil et al, 2018 ; Ingram et al, 2014 ; Silvino et al, 2016 , 2020 ).…”

“…Reduced CYP2D6 activity may represent a major confounder in therapeutic efficacy studies across malaria-endemic settings. Two cohort studies in the Amazon Basin of Brazil found 20–25% of individuals with impaired CYP2D6 enzyme (AS ≤ 1) ( Silvino et al, 2020 ), who had increased risk of P. vivax recurrence following CQ-PQ treatment after adjusting for confounding variables ( Silvino et al, 2016 , 2020 ). Nonimmune individuals with impaired enzyme activity were significantly more susceptible to P. vivax recurrence ( Silvino et al, 2020 ).…”

“…Two cohort studies in the Amazon Basin of Brazil found 20–25% of individuals with impaired CYP2D6 enzyme (AS ≤ 1) ( Silvino et al, 2020 ), who had increased risk of P. vivax recurrence following CQ-PQ treatment after adjusting for confounding variables ( Silvino et al, 2016 , 2020 ). Nonimmune individuals with impaired enzyme activity were significantly more susceptible to P. vivax recurrence ( Silvino et al, 2020 ). A third study in the Amazon found 35% of subjects with reduced CYP2D6 activity predicted by genotyping, but no association between impaired enzyme activity and risk of P. vivax recurrence after standard CQ-PQ treatment was found; no adjustment for malaria immunity was made ( Ladeia-Andrade et al, 2019 ).…”