Unsupervised primaquine for the treatment of Plasmodium vivax malaria relapses in southern Papua: A hospital-based cohort study

Abstract

BackgroundPrimaquine is the only licensed drug for eradicating Plasmodium vivax hypnozoites and, therefore, preventing relapses of vivax malaria. It is a vital component of global malaria elimination efforts. Primaquine is efficacious when supervised in clinical trials, but its effectiveness in real-world settings is unknown. We aimed to determine whether unsupervised primaquine was effective for preventing re-presentation to hospital with vivax malaria in southern Papua, Indonesia.Methods and findingsRoutinely-collected hospital surveillance data were used to undertake a pragmatic comparison of the risk of re-presentation to hospital with vivax malaria in patients prescribed dihydroartemisinin-piperaquine (DHP) combined with primaquine versus those patients prescribed DHP alone. The omission of primaquine was predominantly due to 3 stock outages. Individual clinical, pharmacy, and laboratory data were merged using individual hospital identification numbers and the date of presentation to hospital. Between April 2004 and December 2013, there were 86,797 documented episodes of vivax malaria, of which 62,492 (72.0%) were included in the analysis. The risk of re-presentation with vivax malaria within 1 year was 33.8% (95% confidence Interval [CI] 33.1%–34.5%) after initial monoinfection with P. vivax and 29.2% (95% CI 28.1%–30.4%) after mixed-species infection. The risk of re-presentation with P. vivax malaria was higher in children 1 to <5 years of age (49.6% [95% CI 48.4%–50.9%]) compared to patients 15 years of age or older (24.2% [95% CI 23.4–24.9%]); Adjusted Hazard Ratio (AHR) = 2.23 (95% CI 2.15–2.31), p < 0.001. Overall, the risk of re-presentation was 37.2% (95% CI 35.6%–38.8%) in patients who were prescribed no primaquine compared to 31.6% (95% CI 30.9%–32.3%) in those prescribed either a low (≥1.5 mg/kg and <5 mg/kg) or high (≥5 mg/kg) dose of primaquine (AHR = 0.90 [95% CI 0.86–0.95, p < 0.001]). Limiting the comparison to high dose versus no primaquine in the period during and 12 months before and after a large stock outage resulted in minimal change in the estimated clinical effectiveness of primaquine (AHR 0.91, 95% CI 0.85–0.97, p = 0.003). Our pragmatic study avoided the clinical influences associated with prospective study involvement but was subject to attrition bias caused by passive follow-up.ConclusionsUnsupervised primaquine for vivax malaria, prescribed according to the current World Health Organization guidelines, was associated with a minimal reduction in the risk of clinical recurrence within 1 year in Papua, Indonesia. New strategies for the effective radical cure of vivax malaria are needed in resource-poor settings.

The risk of morbidity and mortality following recurrent malaria in Papua, Indonesia: a retrospective cohort study

“…The blood stage infections of all Plasmodium species were treated with the same schizontocidal regimens (quinine before March 2006 and dihydroartemisininpiperaquine after March 2006). Patients with P. vivax were also offered radical cure with 14 days of primaquine to eradicate the dormant liver stages, but previous studies in this population have shown that when unsupervised this regimen is associated with very poor effectiveness [3]. Furthermore, many of the malaria re-presentations following initial infection with P. falciparum will also have been attributable to P. vivax, since in co-endemic areas, there is a high risk of heterologous P. vivax relapse following falciparum malaria [23][24][25][26][27].…”

“…Whereas the risk of death due to P. falciparum over the same time period halved, the proportion of deaths due to P. vivax remained steady. The differential impact of malaria control activities on the two species is likely due to the inadequate radical cure of P. vivax and prevention of multiple relapses [3]. Young children are at particularly high risk of recurrent vivax infection and associated morbidity and mortality [9].…”

“…The acute illness of malaria is attributable to the asexual blood stages of the parasite, which are treated by administration of blood schizonticides, such as chloroquine-or artemisinin-based therapies. Each recurrence of malaria, irrespective of whether it is a recrudescence, re-infection or a relapse, is associated with haemolysis due to rupture of both infected and uninfected red blood cells, compounded by dyserythropoesis, both of which lead to an increased risk of severe anaemia and associated morbidity and mortality [3,4]. Primaquine, the only widely available antimalarial active against the dorman liver stages, can be used to prevent P. vivax relapses; however, poor adherence to the standard 14-day regimen limits its effectiveness [3] and its associated risk of haemolysis in G6PD-deficient patients makes health providers reluctant to prescribe it [5,6].…”

Malaria-related hospitalization during childhood in Papua, Indonesia: A retrospective cohort study

“…Some of the increased risk of https://doi.org/10.1371/journal.pone.0228018.g005 recurrence will be attributable to P. vivax relapses, preventable, in those who are eligible, by using radically curative courses of primaquine [19][20][21]. Unsupervised primaquine has previously been shown to be relatively ineffective for preventing re-presentation to hospital with vivax malaria in this region, likely due to poor medication adherence [12]. Supervision of therapy and/or primaquine regimens that encourage better adherence compared with the existing 14-day course would be highly desirable.…”

“…This was a retrospective cohort study of children who were either born at Mitra Masyarakat Hospital (RSMM) in Timika, Papua between April 2004 and December 2013 or whose first presentation to hospital during this accrual period occurred within the first 7 days of life. Follow-up information for these children was obtained passively from routinely-collected hospital data via unique hospital identification number linkage, as described previously [12,13].…”