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. 2020 Sep;30(7):161-165.
doi: 10.1097/FPC.0000000000000407.

Pharmacogenetic assessment of tafenoquine efficacy in patients with Plasmodium vivax malaria

Pamela L St Jean  1 , Gavin C K W Koh  2 , John J Breton  3 , Fe E J Espino  4 , Tran T Hien  5 , Srivicha Krudsood  6 , Marcus V G Lacerda  7 , Alejandro Llanos-Cuentas  8 , Chanthap Lon  9 , Rezika Mohammed  10 , Chayadol S Namaik-Larp  11 , Dhelio B Pereira  12 , David L Saunders  9 , Ivan D Velez  13 , Daniel Yilma  14 , Maria F Villegas  15 , Stephan Duparc  16 , Justin A Green  2
Affiliations

Pharmacogenetic assessment of tafenoquine efficacy in patients with Plasmodium vivax malaria

Pamela L St Jean et al. Pharmacogenet Genomics. 2020 Sep.

Abstract

Plasmodium vivax has the largest geographic range of human malaria species and is challenging to manage and eradicate due to its ability to establish a dormant liver stage, the hypnozoite, which can reactivate leading to relapse. Until recently, the only treatment approved to kill hypnozoites was the 8-aminoquinoline, primaquine, requiring daily treatment for 14 days. Tafenoquine, an 8-aminoquinoline single-dose treatment with activity against P. vivax hypnozoites, has recently been approved by the US Food and Drug Administration and Australian Therapeutic Goods Administration for the radical cure of P. vivax malaria in patients 16 years and older. We conducted an exploratory pharmacogenetic analysis (GSK Study 208099) to assess the role of host genome-wide variation on tafenoquine efficacy in patients with P. vivax malaria using data from three GSK clinical trials, GATHER and DETECTIVE Part 1 and Part 2. Recurrence-free efficacy at 6 and 4 months and time to recurrence up to 6 months postdosing were analyzed in 438 P. vivax malaria patients treated with tafenoquine. Among the approximately 10.6 million host genetic variants analyzed, two signals reached genome-wide significance (P value ≤ 5 × 10). rs62103056, and variants in a chromosome 12 intergenic region, were associated with recurrence-free efficacy at 6 and 4 months, respectively. Neither of the signals has an obvious biological rationale and would need replication in an independent population. This is the first genome-wide association study to evaluate genetic influence on response to tafenoquine in P. vivax malaria.

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Conflict of interest statement

The views expressed here are solely those of the authors and do not reflect the views, policies or positions of the U.S. Government or Department of Defense. Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense. The investigators have adhered to the policies for protection of human participants as prescribed in AR 70–25.

D.P. declares grants and nonfinancial support from GSK and MMV. A.L-C. declares grants and personal fees from GSK. D.Y. declares grants from GSK. J.B. and G.K. are GSK employees and hold shares/options in GSK. J.G. is a ViiV employee and holds shares/options in GSK. S.D. is an MMV employee. P.S. is an employee at Parexel whose work was funded by a contract with GSK. There are no conflicts of interest for the remaining authors.

Figures

Fig. 1
Fig. 1
Proportion, with 95% confidence intervals, of patients who were recurrence-free at 6 months by rs62103056 genotype in PGx TQ and its Asian and South American subgroups. N represents the sample size in the entire PGx TQ group. The number of patients with AA, AG, and GG was 15, 39, and 51 in Asians and 15, 101, and 164 in South Americans.
Fig. 2
Fig. 2
Proportion, with 95% confidence intervals, of patients who were recurrence-free at 4 months by rs11104986 genotype in PGx TQ and its Asian and South American subgroups. N represents the sample size in the entire PGx TQ group. The one patient in PGx TQ with genotype GG was in the African region and had a recurrence within 4 months. The patient numbers with AA and AG genotypes were 103 and 5 in Asians and 279 and 8 in South Americans, respectively.
See this image and copyright information in PMC

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