Abstract
BackgroundCYP2D6 pathway mediates the activation of primaquine into active metabolite(s) in hepatocytes. CYP2D6 is highly polymorphic, encoding CYP2D6 isoforms with normal, reduced, null or increased activity. It is hypothesized that Plasmodium vivax malaria patients with defective CYP2D6 function would be at increased risk for primaquine failure to prevent recurrence. The aim of this study was to investigate the association of CYP2D6 polymorphisms and inferred CYP2D6 phenotypes with malaria recurrence in patients from the Western Brazilian Amazon, following chloroquine/primaquine combined therapy.MethodsThe prospective cohort consisted of P. vivax malaria patients who were followed for 6 months after completion of the chloroquine/primaquine therapy. Recurrence was defined as one or more malaria episodes, 28–180 days after the initial episode. Genotyping for nine CYP2D6 SNPs and copy number variation was performed using TaqMan assays in a Fast 7500 Real-Time System. CYP2D6 star alleles (haplotypes), diplotypes and CYP2D6 phenotypes were inferred, and the activity score system was used to define the functionality of the CYP2D6 diplotypes. CYP2D6 activity scores (AS) were dichotomized at ≤ 1 (gPM, gIM and gNM-S phenotypes) and ≥ 1.5 (gNM-F and gUM phenotypes).ResultsGenotyping was successfully performed in 190 patients (44 with recurrence and 146 without recurrences). Recurrence incidence was higher in individuals presenting reduced activity CYP2D6 phenotypes (adjusted relative risk = 1.89, 95% CI 1.01–3.70; p = 0.049). Attributable risk and population attributable fraction were 11.5 and 9.9%, respectively. The time elapsed from the first P. vivax malaria episode until the recurrence did not differ between patients with AS of ≤ 1 versus ≥ 1.5 (p = 0.917).ConclusionsThe results suggest that CYP2D6 polymorphisms are associated with increased risk of recurrence of vivax malaria, following chloroquine–primaquine combined therapy. This association is interpreted as the result of reduced conversion of primaquine into its active metabolites in patients with reduced CYP2D6 enzymatic activity.
Highlights
cytochrome P450 2D6 (CYP2D6) pathway mediates the activation of primaquine into active metabolite(s) in hepatocytes
All patients presented P. vivax malaria diagnosed by microscopy and confirmed by polymerase chain reaction (PCR) [17] and were treated with the therapeutic scheme recommended by the Brazilian Ministry of Health for P. vivax uncomplicated malaria in children and adults, which consists of association of chloroquine (150 mg/day, 3 days) and primaquine (15 mg/day, 7 day) [18]
Population characteristics Of the 213 individuals recruited to the study, 190 (44 with recurrence and 146 without recurrence) were successfully genotyped for CYP2D6 single nucleotide polymorphism (SNP) and copy number variation, and were included in the final analysis
Summary
CYP2D6 pathway mediates the activation of primaquine into active metabolite(s) in hepatocytes. The aim of this study was to investigate the association of CYP2D6 poly‐ morphisms and inferred CYP2D6 phenotypes with malaria recurrence in patients from the Western Brazilian Amazon, following chloroquine/primaquine combined therapy. An original observation by Bennet et al [10] followed by a case report by Ingram et al [11] triggered considerable interest in a novel aspect of the pharmacogenomics of P. vivax malaria. These reports described relapses of P. vivax following chloroquine/ primaquine combined therapy in three individuals with CYP2D6 genotypes encoding CYP2D6 isoforms with reduced (intermediate metabolizers) or null function (poor metabolizers). Relapses were ascribed to failure of primaquine hypnozoiticidal activity, which requires metabolic conversion of primaquine, a pro-drug, into redoxactive metabolite(s) [5]
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