Tafenoquine and its potential in the treatment and relapse prevention of Plasmodium vivax malaria: the evidence to date

Figures & data

Figure 1 Life cycle of P. vivax and hypnozoite.

Notes: Reproduced with permission from Elsevier. This image was published in Trends Mol Med, 21(12), Popovici J, Ménard D, Challenges in antimalarial drug treatment for vivax malaria control. 776–788. Copyright Elsevier 2015.⁸
Abbreviation: P. vivax, Plasmodium vivax.

Figure 2 Chemical structure of PQ.⁹⁹

Abbreviation: PQ, primaquine.

Figure 3 Metabolism of TQ (A) to 5,6 ortho-quinone TQ (B) in the presence of 2D6 isoenzyme.⁷⁷

Abbreviation: TQ, tafenoquine.

Table 1 Efficacy of TQ in radical cure

Serial no	Study design	Study site	Study participants	Intervention arms	Relapse rate (95% CI), n	Outcome measure	References
1	Double-blind, randomized, placebo-controlled Phase IIb study (DETECTIVE trial)a	Peru, India, Thailand, and Brazil	329 vivax malaria cases	CQ + TQ 50 mg single dose CQ + TQ 100 mg single dose CQ + TQ 300 mg single dose CQ + TQ 600 mg single dose CQ + PQ 15 mg/d for 14 d CQ alone	29.1% (17.1–41.1), 55 28.1% (16.4–39.8), 57 3.5% (0–8.3), 57 1.8% (0–5.3), 56 10% (1.7–18.3), 50 31.5% (19.1–43.9), 54	Recurrence rate in 6 months for homologous P. vivax	^Citation84
2	Double-blind, randomized, placebo-controlled Phase IIb study (DETECTIVE trial)	Peru, India, Thailand, and Brazil	329 vivax malaria cases	CQ + TQ 50 mg single dose CQ + TQ 100 mg single dose CQ + TQ 300 mg single dose CQ + TQ 600 mg single dose CQ + PQ 15 mg/d for 14 d CQ alone	42.3% (29.2–55.3), 55 45.9% (32.9–58.9), 57 10.1% (2.3–18), 57 8.1% (0.95–15.2), 56 22.7% (11.1–34.3), 50 62.5% (49.6–75.4), 54	Recurrence rate in 6 months period	^Citation85
3	Controlled trialb	Bougainville	411 vivax malaria cases	TQ 3-d course PQ 14-d course	3.48% (0.95–6.0), 201 3.3% (0.9–5.7), 210	Relapse rate	^Citation88
4	Single-arm study	Australia	27 patients relapse after PQ therapy	CQ + TQ 200 mg/d for 3 d and then 200 mg weekly for 8 wks	3.7% (−3.4–10.8), 27	Relapse rate with 6 months of therapy	^Citation97
5	Randomized, open-label, controlled trial	Thailand	44 vivax malaria cases	CQ + TQ 300 mg/d for 7 d CQ + TQ 500 mg/d for 3 d and repeat 1 wk after CQ + TQ 500 mg single dose CQ alone	0%, 15 9.1% (0–26.1), 11 11.1% (0–31.6), 9 44.4% (11.9–76.9), 9	Positive blood smears in 2–6 months study period	^Citation86
6	Randomized, open-label, controlled trial	Thailand	80 vivax malaria cases	CQ + TQ 300 mg/d for 7 d CQ + TQ 600 mg/d for 3 d CQ + TQ 600 mg single dose CQ + PQ 15 mg/d for 14 d CQ alone	0%, 18 0%, 19 5.6% (0–16.2), 18 25% (0.5–49.5), 12 61.5% (35–88.0), 13	Positive blood smears in 6 months study period	^Citation87

Notes:

a At the 300 mg TQ, a ninefold reduction in homologous recurrence compared with CQ alone. Heterologous recurrences reduced by threefold.

b Dosage regimen of TQ was not accessed.

Abbreviations: TQ, tafenoquine; 95% CI, 95% confidence interval; CQ, chloroquine; PQ, primaquine; d, day; P. vivax, Plasmodium vivax; wk, week.

Table 2 Chemoprophylactic efficacy of TQ

Serial no	Study design	Study site	Study participant	Outcome measure	Intervention arms	Efficacy/relapse rate (95% CI), n	References
1	Randomized, placebo-controlled, double-blinda human challenge model	Experimental study: USA	Six normal volunteers	Rate of positive blood smears in 65 d (P. falciparum)	TQ 600 mg single dose Placebo	25% (0–67.4), 4 100%, 2	^Citation89
2	Randomized, double-blind, placebo-controlled chemoprophylaxis trial	Ghana	509 health volunteers	Protective efficacy relative to placebo in 16 wks (4 wks after the last dose; P. falciparum)	TQ 200 mg/d for 3 d + weekly TQ 100 mg/d for 3 d + weekly TQ 50 mg/d for 3 d + weekly TQ 25 mg/d for 3 d + weekly MQ 250 mg weekly Placebo	85.6% (76.2–91.6), 91 87.2% (78.3–92.7), 94 84.4% (74.8–90.7), 91 31.8% (20.2–43.4), 93 85.7% (71.9–93.3), 46	^Citation90
3	Double-blind, placebo-controlled, randomized study	Kenya	225 health volunteers	Protective efficacy relative to placebo in 13 wks (1 wk after the last dose; P. falciparum)	TQ 400 mg/d for 3 d + weekly TQ 400 mg/d for 3 d TQ 200 mg for 3 d + weekly Placebo	89% (77–95), 57 68% (53–79), 54 86% (73–93), 53	^Citation91
4	Randomized, double-blind, placebo-controlled study	Thailand	205 participants	Rate of positive blood smears during 6 months (P. vivax and P. falciparum)	TQ 400 mg/d for 3 d +400 mg monthly Placebo	1% (0–3.0), 96b 32.6% (23–42.2), 92c	^Citation98
5	Randomized, placebo-controlled study	Gabon	410 Gabonians	Rate of positive blood smears by day 77 (P. falciparum)	TQ 250 mg/d for 3 d TQ 125 mg/d for 3 d TQ 62.5 mg/d for 3 d TQ 31.3 mg/d for 3 d Placebo	0%, 84 1.3% (0–3.8), 79 3.5% (0–7.4), 86 20.3% (11.4–29.2), 79 17.1% (8.9–25.2), 82	^Citation92
6	Randomized, double-blind, controlled Phase III study	East Timor	654 Australian soldiers	Rate of positive vivax blood smears in 6 months	TQ 200 mg/d for 3 d + weekly MQ 250 mg/d for 3 d + weekly	0.9% (0.07–1.7), 492 0.7% (0–1.98), 162	^Citation93

Notes:

a TQ concentration in the oligosymptomatic case was one half of that in the protected individuals.

b One vivax case.

c 30 cases, 21 vivax and eight falciparum cases and one mixed infection.

Abbreviations: TQ, tafenoquine; 95% CI, 95% confidence interval; P. falciparum, Plasmodium falciparum; wk, week; d, day; MQ, mefloquine; P. vivax, Plasmodium vivax.

Table 3 Efficacy of TQ in terminal prophylaxis

Serial no	Study design	Study participants	Outcome measure	Intervention arm	Relapse rate (95% CI), n	References
1	Randomized, open-label controlled trial	348 Australian defense force personnel returning from Bougainville	Relapse rate after 12 months	TQ 200 mg bid for 3 d TQ 400 mg/d for 3 d PQ 7.5 mg tid + doxycycline 100 mg/d for 14 d	1.2% (0.03–6.3), 86 2.3% (0.3–8.1), 87 3.4% (1.3–7.3), 175	^Citation94
2	Randomized, open-label controlled trial	925 Australian defense force personnel returning from Timor-Leste	Relapse rate after 12 months	TQ 200 mg qd for 3 d TQ 200 mg bid for 3 d TQ 400 mg qd for 3 d PQ 7.5 mg tid + doxycycline 100/d for 14 d	4.9% (3–7.5), 406 5.3% (1.5–13.1), 75 11% (6.5–17), 155 10% (6.8–14.1), 289	^Citation94
3	Randomized, controlled trial	592 Australian defense personnel volunteers returning from Bougainville	Positive blood smear within 12 months	TQ 200 mg bid or 400 mg/d for 3 d PQ 22.5 mg for 14 d	1.9% (0.5–3.3), 378 2.8% (0.6–5), 214	^Citation95

Abbreviations: TQ, tafenoquine; 95% CI, 95% confidence interval; d, day; PQ, primaquine; bid, twice daily; tid, three times daily; qd, once daily.

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