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.

Authors:
Nanhua Chen
Nanhua Chen
Australian Army Malaria Institute
Australia
Simone Dowd
Simone Dowd
Army Malaria Institute
Michelle L Gatton
Michelle L Gatton
Queensland Institute of Medical Research
Australia
Alyson Auliff
Alyson Auliff
Australian Army Malaria Institute
Australia
Michael D Edstein
Michael D Edstein
Australian Army Malaria Institute
Australia
Qin Cheng
Qin Cheng
Huazhong University of Science and Technology
China

Malar J 2019 Apr 18;18(1):140. Epub 2019 Apr 18.

Australian Defence Force Malaria and Infectious Disease Institute, Brisbane, QLD, Australia.

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.

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Source
https://malariajournal.biomedcentral.com/articles/10.1186/s1
Publisher Site
http://dx.doi.org/10.1186/s12936-019-2774-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471761PMC
April 2019
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