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Cytochrome P-450 polymorphisms and their influence on Plasmodium vivax recurrences

Ana Carolina Rios Silvino 1 ; Gabriel Luíz Costa 1 ; Flávia Carolina Faustino de Araújo 1 ; David Benjamin Ascher 2 ; Douglas Eduardo Valente Pires 3 ; Cor Jesus Fontes 4 ; Luzia Helena Carvalho 1 ; Cristiana Ferreira Alves de Brito 1 ; Taís Nóbrega de Sousa 1
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Primaquine (PQ) is the only licensed drug for the radical cure of P. vivax infection, which has potent antihypnozoite activity. Recent reports have shown that PQ efficacy requires metabolic activation by cytochrome P450 2D6 (CYP2D6) isoenzyme (Malar J, 2013; 12:212). CYP2D6 is highly polymorphic and its variants result in an increase, reduction, or complete loss of activity. Our research group showed an association between polymorphisms in CYP2D6 and increased risk of P. vivax relapse in travelers returning home after visiting malaria transmission area (Plos One, 2016; 11(7). Thus, a higher frequency of polymorphisms in CYP2D6 was observed in individuals that have experienced multiple relapses when compared with the single-relapse group. In addition, we demonstrated that cytochrome P450 2C8-mutated patients frequently had their first episode of recurrence within 42 days after initiation of therapy, suggesting the possibility of recrudescence due to CQ therapeutic failure. As a more comprehensive analysis of the genetic variation of CYP isoenzymes may generate valuable information regarding P. vivax relapses, the present study aimed to extend this investigation to other endemic malaria area in Brazil, including the analysis of a non-relapsed group. Five CYP2D6 polymorphisms (G1846A, G2988A, G3183A, C100T and C1023T) were genotyped by Real Time PCR in 63 patients from Rio Pardo (AM), divided into groups with and without P. vivax relapses. Our results indicated the presence of mutated allele in positions G1846A (30.2%), G2988A (3.2%), G3183A (1.6%), C100T (28.6%) and C1023T (14.3%). Interestingly, a higher frequency CYP2D6-mutated patients was observed in relapse group compared with the non-relapse group (60.61% relapse group vs 30.03% non-relapse group; P= 0.0226). In general, the results showed a higher prevalence of CYP2D6-mutated patients in the relapse group, reinforcing our previous findings that CYP2D6 polymorphisms are implicated in PQ failure and may explain some P. vivax relapses.