Cytochrome P450 2D6 profiles and their relationship with outcomes of primaquine anti-relapse therapy in Australian Defence Force personnel deployed to Papua New Guinea and East Timor

Abstract

Background Primaquine, an 8-aminoquinoline with anti-hypnozoite activity against Plasmodium vivax , is metabolized by human cytochrome P450 2D6 (CYP2D6) to its active metabolite. Human CYP2D6 activities may influence the metabolism of primaquine and the risk of experiencing Plasmodium relapses following primaquine anti-relapse therapies (PART). In this study, the CYP2D6 profile and its relationship with outcomes of PART in Australian Defence Force (ADF) personnel is retrospectively investigated. Methods Genomic DNA was isolated from stored and de-identified serum or blood samples from ADF personnel deployed on peacekeeping duties to Papua New Guinea (PNG) (1999) and East Timor (1999–2000) who received PART before returning to Australia and after experiencing relapses. CYP2D6 allelic type was determined by PCR and Sanger sequencing. CYP2D6 allele frequency, predicted phenotypes and activity scores were compared among personnel who did not experience P. vivax (ADF-NR, n = 48) and those who experience at least one (ADF-R, n = 109) relapse, as well as between those who experienced 1 (n = 79), 2 (n = 21) and 3–5 (n = 9) relapses within the ADF-R group. Results 16 CYP2D6 alleles were observed in 157 ADF personnel. Alleles *1, *4, *2 and *41 were major alleles (> 5%). The CYP2D6 allele frequency profile in the ADF-NR group matched that of a European population. There was an increased proportion of non-functional CYP2D6 alleles in the ADF-R group compared to the European population and ADF-NR group. However, frequencies of predicted CYP2D6 phenotype and activity score were not different between the ADF-R and ADF-NR groups, nor among sub-groups experiencing multiple relapses within the ADF-R group. Conclusions CYP2D6 phenotype or activity score based on the allele classification was not a major contributor to P. vivax relapse in this ADF cohort. Other factors such as adherence and/or parasite tolerance to primaquine are likely contributing factors to P. vivax relapses in this cohort.

<p>Pharmacogene Variation in Thai <em>Plasmodium vivax</em> Relapse Patients Treated with a Combination of Primaquine and Chloroquine</p>

“…Another study conducted by Spring et al 30 confirmed that subjects with CYP2D6 IM or PM phenotypes have reduced PQ metabolism compared to those with an NM phenotype. In contrast, Chen et al 31 found that CYP2D6 phenotype or activity scores were not significantly different between their relapse and non-relapse groups. One explanation of why the present study did not find a relationship between CYP2D6 genotype or metabolizer status and PQ response may be due to the coadministration of CQ.…”

Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population

“…The association of CYP2D6 and relapse has proved harder to confirm in areas of endemicity [19–24]. Two clinical trials found an increased risk of relapse with an AS-A of ≤1.0 [20, 21], yet in Australian soldiers contracting P. vivax while deployed, relapse was not associated with activity score [22]. This latter study, as well as 2 studies in Thailand [23, 24], found the NM phenotype in the majority of patients with relapse.…”

Impact of Plasmodium vivax malaria and antimalarial treatment on cytochrome P450 activity in Brazilian patients

“…We investigated the phenotypic activity of CYP2D6 and CYP2C19 in the course of acute vivax malaria, after completion of antiparasite chemotherapy with primaquine/chloroquine and during convalescence. CYP selection was guided by the evidence that CYP2D6 is the major pathway for conversion of primaquine into its active metabolite(s) [21][22][23][24][25][26][27] and by our previous findings of reduced CYP2C19 activity during the acute phase of visceral leishmaniosis. 16…”