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

Abstract

Background: Plasmodium vivax malaria is characterized by the presence of dormant liver-stage parasites, called hypnozoites, which can cause malaria relapses after an initial attack. Primaquine, which targets liver hypnozoites, must be used in combination with a schizonticidal agent to get the radical cure. However, relapses can sometimes occur in spite of correct treatment, due to different factors such as a diminished metabolization of primaquine. Case presentation: In January 2019, a 21 years old woman with residence in Madrid, returning from a trip to Venezuela with clinical symptoms compatible with malaria infection, was diagnosed with vivax malaria. Chloroquine for 3 days plus primaquine for 14 days was the elected treatment. Two months later and after a second trip to Venezuela, the patient presented a second P. vivax infection, which was treated as the previous one. A third P. vivax malaria episode was diagnosed 2 months later, after returning from a trip to Morocco, receiving chloroquine for 3 days but increasing to 28 days the primaquine regimen, and with no more relapses after 6 months of follow up. The genotyping of P. vivax in the three malaria episodes revealed that the same strain was present in the different relapses. Upon confirmation of correct adherence to the treatment, non-description of resistance in the infection area and the highly unlikely re-infection on subsequent trips or stays in Spain, a possible metabolic failure was considered. CYP2D6 encodes the human cytochrome P450 isoenzyme 2D6 (CYP2D6), responsible for primaquine activation. The patient was found to have a CYP2D6*4/*1 genotype, which turns out in an intermediate metabolizer phenotype, which has been related to P. vivax relapses. Conclusions: The impairment in CYP2D6 enzyme could be the most likely cause of P. vivax relapses in this patient. This highlights the importance of considering the analysis of CYP2D6 gene polymorphisms in cases of P. vivax relapses after a correct treatment and, especially, it should be considered in any study of dosage and duration of primaquine treatment.

CYP2D6 Genetic Variation and Its Implication for Vivax Malaria Treatment in Madagascar

“…Vivax malaria relapse following PQ treatment has predominantly been observed in patients carrying decreased function alleles such as CYP2D6*10, *36, and *41, and nonfunctional alleles such as CYP2D6*4 and *5 in various combinations giving rise to IM and PM phenotypes (Bennett et al, 2013;Ingram et al, 2014;Dijanic et al, 2018;He et al, 2019;Martin Ramirez et al, 2020;Mat Salleh et al, 2020;Silvino et al, 2020). In most cases where there was drug failure, the following genotypes were observed: CYP2D6*4/*41 (Bennett et al, 2013), *5/*41 (Ingram et al, 2014), *5/*10, *10/*10, and *10/*41 Mat Salleh et al, 2020), *1/*4 (Martin Ramirez et al, 2020), and *2/*36 (He et al, 2019), all predicting IM status. In addition, there were two genotypes, CYP2D6*5/*6 (Bennett et al, 2013) and *4/*5 Dijanic et al, 2018) that were reported to completely abolish enzyme activity and give rise to PM status.…”

“…Interestingly, some studies have shown that relapses also occurred in patients with CYP2D6*1/*10 and *2/*10 (Baird et al, 2018) genotypes, predicting NM status. However, subjects in these studies (Bennett et al, 2013;Ingram et al, 2014;Dijanic et al, 2018;He et al, 2019;Martin Ramirez et al, 2020;Mat Salleh et al, 2020;Silvino et al, 2020) may harbor rare or novel alleles that may not have been detected by screening for the common allelic variants only. Similar results have been reported when the AS system (activity value >1.0, normal function; activity value ≤1.0, decreased function), instead of genotypes and/or predicted phenotypes, was considered to determine the odds or risk of relapse; AS ≤ 1.0 were significantly associated with higher odds or risk of relapse Brasil et al, 2018;Silvino et al, 2020).…”

“…In another study, an IM subject (genotyped as CYP2D6*5/*41) suffered multiple attacks of vivax malaria at approximately two-month intervals despite taking PQ as prescribed (Ingram et al, 2014). Since those findings were reported (Bennett et al, 2013;Ingram et al, 2014), there have been several other reports suggesting that decreased or absence of CYP2D6 activity contributes to PQ therapeutic failure Dijanic et al, 2018;He et al, 2019;Martin Ramirez et al, 2020;Mat Salleh et al, 2020;Silvino et al, 2020). In contrast, in clinical trials using tafenoquine in combination with chloroquine, the IM phenotype was reported to have had no significant effect on the efficacy of tafenoquine in preventing P. vivax relapse; however, more data on PM persons are required (St Jean et al, 2016;Lacerda et al, 2019).…”

Decreasing trend of imported malaria cases but increasing influx of mixed P. falciparum and P. vivax infections in malaria-free Kuwait

“…Though, the most common cause of P . vivax relapse is poor adherence to treatment or inappropriate dose, however, failure in treatment due to impairment in CYP2D6 enzyme is also being investigated [ 36 ].…”

“…A number of studies have reported in mixed malaria, an increase in relapse rates by P. vivax following treatment of P. falciparum [35]. Though, the most common cause of P. vivax relapse is poor adherence to treatment or inappropriate dose, however, failure in treatment due to impairment in CYP2D6 enzyme is also being investigated [36].…”