Estimation of the Antirelapse Efficacy of Tafenoquine, Using Plasmodium vivax Genotyping

Abstract

Prevention of relapse of Plasmodium vivax infection is a key treatment goal in malaria. Use of P. vivax genotyping in a multicenter, double-blind, randomized, placebo-controlled phase 2b study in Peru, India, Thailand, and Brazil allowed determination of genetically heterologous or homologous P. vivax infection recurrence following receipt of chloroquine plus one of 4 doses of tafenoquine (50, 100, 300, or 600 mg) or chloroquine plus primaquine, compared with receipt of chloroquine alone. The antihypnozoite efficacy of tafenoquine was evident as a reduction in homologous recurrences of P. vivax infection as drug doses were increased. No clear dose-response pattern was evident for heterologous recurrences of P. vivax infection. Rates of homologous recurrence of P. vivax infection appear to be clinically useful for comparing drug efficacy for the prevention of P. vivax infection relapse.

Clinical trials registration: NCT01376167.

Keywords: Plasmodium vivax; antihypnozoite; efficacy; genotyping; tafenoquine.

© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.

Plasmodium vivax infection recurrence (hereafter, “P. vivax recurrence”). A, Frequency of genetically heterologous and homologous P. vivax recurrence following treatment with chloroquine (CQ), with or without one of 4 doses of tafenoquine (TQ), or with CQ and primaquine (PQ). B, Kaplan–Meier analysis of heterologous P. vivax recurrence following treatment with CQ, with or without high-dose (300 or 600 mg) or low-dose (50 or 100 mg) TQ, or with CQ and PQ. C, Kaplan–Meier analysis of homologous P. vivax recurrence following treatment with CQ, with or without high-dose (300 or 600 mg) or low-dose (50 or 100 mg) TQ, or with CQ and PQ. Abbreviations: CQ, chloroquine; PQ, primaquine; TQ, tafenoquine.

Figure 2.

Plasmodium vivax genotype diversity. Pie charts represent allelic frequencies of different-sized fragments for each of 3 potential genetic markers among P. vivax–positive samples at study sites in Peru (n = 199), Brazil (n = 53), India (n = 38), and Thailand (n = 46), indicating that heterogeneity was generally low. Colored sections denote the frequencies of identical alleles in each marker in different sites. White sections denote the frequencies of identical alleles that occurred only at the specified site. The lower chart represents the discernible haplotypes for the Peru site. All sites had only unique haplotypes. Abbreviation: He, virtual heterozygosity index.