Randomized trial of primaquine hypnozoitocidal efficacy when administered with artemisinin-combined blood schizontocides for radical cure of Plasmodium vivax in Indonesia

Abstract

Background: Safety and efficacy of primaquine against repeated attacks of Plasmodium vivax depends upon co-administered blood schizontocidal therapy in radical cure. We assessed primaquine (PQ) as hypnozoitocide when administered with dihydroartemisinin-piperaquine (Eurartesim®, DHA-PP) or artesunate-pyronaridine (Pyramax®, AS-PYR) to affirm its good tolerability and efficacy. A third arm, artesunate followed by primaquine, was not intended as therapy for practice, but addressed a hypothesis concerning primaquine efficacy without co-administration of blood schizontocide.

Methods: During March to July 2013, an open-label, randomized trial enrolled Indonesian soldiers with vivax malaria at Sragen, Central Java, after six months duty in malarious Papua, Indonesia. No malaria transmission occurred at the study site and P. vivax recurrences in the 12 months following therapy were classified as relapses. A historic relapse control derived from a cohort of soldiers who served in the same area of Papua was applied to estimate risk of relapse among randomized treatment groups. Those were: 1) AS followed 2d later by PQ (0.5 mg/kg daily for 14d); 2) co-formulated AS-PYR concurrent with the same regimen of PQ; or 3) co-formulated DHA-PP concurrent with the same regimen of PQ.

Results: Among 532 soldiers, 219 had vivax malaria during the four months following repatriation to Java; 180 of these were otherwise healthy and G6PD-normal and enrolled in the trial. Subjects in all treatment groups tolerated the therapies well without untoward events and cleared parasitemia within three days. First relapse appeared at day 39 post-enrollment, and the last at day 270. Therapeutic efficacy of PQ against relapse by incidence density analysis was 92 % (95 %CI = 83-97 %), 94 %(95 %CI = 86-97 %), and 95 %(95 %CI = 88-98 %) when combined with AS, AS-PYR, or DHA-PP, respectively.

Conclusions: This trial offers evidence of good tolerability and efficacy of PQ against P. vivax relapse when administered concurrently with DHA-PP or AS-PYR. These offer alternative partner drugs for radical cure with primaquine. The AS arm demonstrated efficacy with a total dose of 7 mg/kg PQ without concurrently administered blood schizontocide, another option when primaquine therapy is removed in time from the treatment of the acute malaria or applied presumptively without an attack.

Trial registration: Current Controlled Trials ISRCTN82366390, assigned 20 March 2013.

Fig. 1

Plasmodium vivax in Indonesia and location of exposure of study battalion. Map of Indonesia illustrating predicted prevalence of P. vivax in 2010 published elsewhere [24]. Black box at far right indicates the area where both a prior study battalion [7] and the current one were exposed to risk of infection, and the black box at center left indicates location of the current study site in Central Java

Fig. 2

Study flow diagram

Fig. 3

Abnormal blood values at enrollment. Graphs illustrating blood laboratory values that significantly changed during the course of treatments among groups. Each graph shows median (horizontal line), interquartile range (box), 1.5 times that range (horizontal line), and outlying observations (points). The lightly shaded area shows the range of normal values

Fig. 4

Changes in liver and blood chemistry and QTc values prior to and up to 63 days following treatment commencement of therapy. Graphs illustrating liver and blood laboratory values and QTc measurements that significantly altered after the commencement of therapy among groups. Each graph shows median (horizontal line), interquartile range (box), 1.5 times that range (horizontal line), and outlying observations (points). The lightly shaded area shows the range of normal values, except for ΔQTc which reflects the mean ΔQTc ± standard deviation. MetHb measurements for AS + PQ represent days post-dosing with PQ (commencing on day 9 post-patency). MetHb methemoglobin, AS artesunate, PQ primaquine

Fig. 5

Relapse attack among groups during year after therapy. Relapse timing and extent among treatment groups (AS + PQ, solid black; AS-PYR + PQ, black dashed; DHA-PP + PQ, black dotted) in the current trial. The upper solid red line (AS) represents the relapse control group used as the denominator in estimating efficacy, taken from a prior trial in soldiers deployed to the same region [7]. The other upper red line that is dashed (ACT only) represents relapse events among 39 soldiers with vivax malaria at Sragen who declined participation and were treated with DHA-PP but without primaquine. AS artesunate, PQ primaquine, PYR pyronaridine, DHA-PP dihydroartemisinin-piperaquin