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

Abstract

Background

Primaquine 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 findings

Routinely-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.

Conclusions

Unsupervised 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.

Abstract

In a pragmatic hospital-based cohort study, Ric Price and colleagues compared risk of re-presentation with vivax malaria in patients prescribed dihydroartemisinin-piperaquine combined with primaquine versus patients who could not be given primaquine due to stock outages.

Author summary

Why was this study done?

• Plasmodium vivax forms dormant liver stages (hypnozoites) that can cause relapsing illness weeks to months after the initial infection.

• Preventing these relapses has major public health benefits by reducing clinical morbidity and lowering the risk of parasite transmission.

• A 14-day course of primaquine (the only licensed drug that is active against hypnozoites) has been previously shown to have greater than 90% efficacy for preventing relapses, but its effectiveness in nonstudy settings has never been tested and may be substantially lower due to nonadherence to necessarily long treatment regimens.

What did the researchers find?

• Three stock outages of primaquine at a hospital in Papua, Indonesia enabled us to assess whether prescription of primaquine in combination with dihydroartemisinin-piperaquine (DHP) for vivax malaria was associated with a lower rate of subsequent re-presentation to hospital with vivax malaria compared to those patients prescribed DHP alone.

• Between 2006 and 2013, there were 62,492 patient presentations with clinical vivax malaria that were included in analyses, 87% of which were treated with primaquine.

• Overall, one third of patients re-presented to hospital with vivax malaria within 1 year; those prescribed primaquine being only 10% less likely to re-present than those who did not receive primaquine.

What do the findings mean?

• The results of this study suggest that primaquine is substantially less effective for preventing relapses of vivax malaria in real-world practice than is predicted by clinical efficacy trials and that this is a likely consequence of incomplete adherence to treatment.

• Efforts to improve adherence to primaquine and to develop alternative drugs with shorter dosing regimens and greater patient tolerability are needed to achieve the significant public health benefits of the radical cure of P. vivax.