Strategies for Understanding and Reducing the Plasmodium vivax and Plasmodium ovale Hypnozoite Reservoir in Papua New Guinean Children: A Randomised Placebo-Controlled Trial and Mathematical Model

Abstract

Background

The undetectable hypnozoite reservoir for relapsing Plasmodium vivax and P. ovale malarias presents a major challenge for malaria control and elimination in endemic countries. This study aims to directly determine the contribution of relapses to the burden of P. vivax and P. ovale infection, illness, and transmission in Papua New Guinean children.

Methods and Findings

From 17 August 2009 to 20 May 2010, 524 children aged 5–10 y from East Sepik Province in Papua New Guinea (PNG) participated in a randomised double-blind placebo-controlled trial of blood- plus liver-stage drugs (chloroquine [CQ], 3 d; artemether-lumefantrine [AL], 3 d; and primaquine [PQ], 20 d, 10 mg/kg total dose) (261 children) or blood-stage drugs only (CQ, 3 d; AL, 3 d; and placebo [PL], 20 d) (263 children). Participants, study staff, and investigators were blinded to the treatment allocation. Twenty children were excluded during the treatment phase (PQ arm: 14, PL arm: 6), and 504 were followed actively for 9 mo. During the follow-up time, 18 children (PQ arm: 7, PL arm: 11) were lost to follow-up. Main primary and secondary outcome measures were time to first P. vivax infection (by qPCR), time to first clinical episode, force of infection, gametocyte positivity, and time to first P. ovale infection (by PCR). A basic stochastic transmission model was developed to estimate the potential effect of mass drug administration (MDA) for the prevention of recurrent P. vivax infections. Targeting hypnozoites through PQ treatment reduced the risk of having at least one qPCR-detectable P. vivax or P. ovale infection during 8 mo of follow-up ( P. vivax: PQ arm 0.63/y versus PL arm 2.62/y, HR = 0.18 [95% CI 0.14, 0.25], p < 0.001; P. ovale: 0.06 versus 0.14, HR = 0.31 [95% CI 0.13, 0.77], p = 0.011) and the risk of having at least one clinical P. vivax episode (HR = 0.25 [95% CI 0.11, 0.61], p = 0.002). PQ also reduced the molecular force of P. vivax blood-stage infection in the first 3 mo of follow-up (PQ arm 1.90/y versus PL arm 7.75/y, incidence rate ratio [IRR] = 0.21 [95% CI 0.15, 0.28], p < 0.001). Children who received PQ were less likely to carry P. vivax gametocytes (IRR = 0.27 [95% CI 0.19, 0.38], p < 0.001). PQ had a comparable effect irrespective of the presence of P. vivax blood-stage infection at the time of treatment ( p = 0.14). Modelling revealed that mass screening and treatment with highly sensitive quantitative real-time PCR, or MDA with blood-stage treatment alone, would have only a transient effect on P. vivax transmission levels, while MDA that includes liver-stage treatment is predicted to be a highly effective strategy for P. vivax elimination. The inclusion of a directly observed 20-d treatment regime maximises the efficiency of hypnozoite clearance but limits the generalisability of results to real-world MDA programmes.

Conclusions

These results suggest that relapses cause approximately four of every five P. vivax infections and at least three of every five P. ovale infections in PNG children and are important in sustaining transmission. MDA campaigns combining blood- and liver-stage treatment are predicted to be a highly efficacious intervention for reducing P. vivax and P. ovale transmission.

Trial registration

ClinicalTrials.gov NCT02143934

Abstract

Ivo Mueller and colleagues conduct a randomized controlled trial of blood-only or blood- plus liver-stage malaria drugs to identify the contribution of relapses to the burden of P. vivax and P. ovale in children in Papua New Guinea, and model the potential impact of mass-drug administration to prevent recurrent P. vivax infections.

Editors' Summary

Background

Malaria is a mosquito-borne parasitic disease caused by Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. Although P. falciparum is responsible for most of the 600,000 malaria deaths that occur every year, P. vivax is the most common, most widely distributed cause of malaria. All malaria parasites have a complex life cycle. When infected mosquitoes bite people, they inject “sporozoites,” a parasitic form that replicates in the liver. After 8–9 days, the liver releases “merozoites,” which invade red blood cells, where they replicate rapidly before bursting out and infecting more red blood cells. This increase in the parasitic burden causes malaria’s recurring flu-like symptoms and can cause organ damage and death. Infected red blood cells also release “gametocytes,” which infect mosquitoes when they take a blood meal. In the mosquito, gametocytes multiply and develop into sporozoites, thus completing the parasite’s life cycle. Malaria can be prevented by controlling the mosquitoes that spread malaria and by avoiding mosquito bites. Treatment with anti-malarial drugs, which is essential to prevent potentially fatal complications, also decreases malaria transmission.

Why Was This Study Done?

Malaria control programs have greatly reduced the global malaria burden, but the ability of P. vivax and P. ovale to persist undetected in the liver as “hypnozoites” (another parasitic form) is hindering malaria control and elimination efforts. Hypnozoites can cause malaria relapses months or years after a primary infection and are not cleared by anti-malarial treatment unless the treatment includes primaquine, a drug that has to be given for 7–14 days and that causes hemolysis (red blood cell death) in people who have glucose-6-phosphate dehydrogenase (G6PD) deficiency. Here, the researchers determine the contribution that relapses make to the burden of P. vivax and P. ovale infection, illness, and transmission among Papua New Guinean children by undertaking a randomized placebo-controlled trial of a primaquine treatment regimen. The researchers also use mathematical modeling to investigate the effect of mass drug administration (MDA) on the occurrence of P. vivax relapses. A randomized placebo-controlled trial compares the outcomes of individuals randomly chosen to receive an active treatment or a dummy (placebo) treatment; MDA aims to control malaria by treating entire at-risk populations with anti-malarial drugs.

What Did the Researchers Do and Find?

The researchers enrolled 524 children aged 5–10 years (none of whom were G6PD deficient) living in a region of Papua New Guinea where P. falciparum and P. vivax are hyperendemic (always present at high levels). Half the children received a blood-stage plus liver-stage anti-malarial treatment regimen (primaquine arm); the rest received a blood-stage plus placebo anti-malarial treatment regimen (placebo arm). Compared to children in the placebo arm, children in the primaquine arm had a reduced risk of having at least one P. vivax or P. ovale infection detected using PCR (a highly sensitive molecular technique) during eight months of follow-up and a reduced risk of having at least one clinical P. vivax episode. Children in the primaquine arm were also less likely to carry P. vivax gametocytes. Finally, by feeding the trial data into a mathematical transmission model, the researchers predicted that MDA with blood-stage treatment alone, or mass screening and treatment with blood-stage treatment alone or blood- plus liver-stage treatment, would have only a transient effect on P. vivax transmission levels, whereas MDA that includes blood-plus liver-stage treatment would be an effective strategy for P. vivax elimination.

What Do These Findings Mean?

From the trial results, the researchers estimate that, among children living in a malaria-hyperendemic region of Papua New Guinea, relapses cause about four of every five P. vivax infections and three of every five P. ovale infections. Thus, P. vivax and P. ovale relapses are important in sustaining malaria transmission in this population. Notably, mathematical modeling predicts that MDA campaigns that combine blood- and liver-stage treatment are likely to be a highly effective strategy for P. vivax elimination. These findings may not be generalizable to populations with lower malaria transmission levels. Also, because the trial used a 20-day drug regimen to maximize the clearance of hypnozoites and because people would need to be tested for G6PD deficiency before starting primaquine treatment, the chosen treatment regimen may not be applicable to real-world MDA programs. Nevertheless, these findings highlight the importance of developing new anti-hypnozoite drugs and MDA programs that target areas and risk groups with confirmed local transmission of P. vivax to achieve global malaria control and elimination.

Additional Information

This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001891.

• Information is available from the World Health Organization on malaria (in several languages); the World Malaria Report 2014 provides details of the current global malaria situation, including information on malaria in Papua New Guinea; the 2015 guidelines for the treatment of malaria are available

• The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish), including information on different malaria parasites, mass drug administration, and personal stories about malaria

• Information is available from the Roll Back Malaria Partnership on the global control of malaria

• The Malaria Vaccine Initiative has a fact sheet on P. vivax malaria

• The Scientists Against Malaria collaboration applies modern drug design and modeling techniques to developing new treatments against malaria; its website includes information about many aspects of malaria

• MedlinePlus provides links to additional information on malaria (in English and Spanish)

• Wikipedia has a page on mass drug administration (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

• More information about this trial is available