Abstract
BackgroundPrimaquine, 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.MethodsGenomic 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.Results16 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.ConclusionsCYP2D6 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.
Highlights
Primaquine, an 8-aminoquinoline with anti-hypnozoite activity against Plasmodium vivax, is metabolized by human cytochrome P450 2D6 (CYP2D6) to its active metabolite
CYP2D6 alleles and allele frequency A total of 16 CYP2D6 alleles were observed amongst the 157 Australian Defence Force (ADF) samples examined: 10 alleles were observed in the ADF no P. vivax relapse (ADF-NR) group and 15 in the ADF had P. vivax relapse (ADF-R) group
The results indicate that primaquine tolerance may be the major contributing factor to relapses and the higher dose regimen of primaquine (0.5 mg/kg per day for 14 days) should be used for primaquine anti-relapse therapies (PART)
Summary
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). Plasmodium vivax infection is a major cause of human malaria in areas outside Africa [1, 2], and presents a major challenge to the global malaria elimination programmes due to several underlying biological characteristics of this parasite species. A single P. vivax infection can cause many episodes of relapses days and months after the original infection due to activation of hypnozoites deposited in the liver of the infected host at the time of the original infection. P. vivax is more resilient to malaria control measures and countries have reported increases in proportion of P. vivax infections as they progress from malaria control to elimination [5,6,7]
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