Date Published: May 29, 2019
Publisher: Public Library of Science
Author(s): Enny Kenangalem, Jeanne Rini Poespoprodjo, Nicholas M. Douglas, Faustina Helena Burdam, Ketut Gdeumana, Ferry Chalfein
Abstract: BackgroundMalaria control activities can have a disproportionately greater impact on Plasmodium falciparum than on P. vivax in areas where both species are coendemic. We investigated temporal trends in malaria-related morbidity and mortality in Papua, Indonesia, before and after introduction of a universal, artemisinin-based antimalarial treatment strategy for all Plasmodium species.Methods and findingsA prospective, district-wide malariometric surveillance system was established in April 2004 to record all cases of malaria at community clinics and the regional hospital and maintained until December 2013. In March 2006, antimalarial treatment policy was changed to artemisinin combination therapy for uncomplicated malaria and intravenous artesunate for severe malaria due to any Plasmodium species. Over the study period, a total of 418,238 patients presented to the surveillance facilities with malaria. The proportion of patients with malaria requiring admission to hospital fell from 26.9% (7,745/28,789) in the pre–policy change period (April 2004 to March 2006) to 14.0% (4,786/34,117) in the late transition period (April 2008 to December 2009), a difference of −12.9% (95% confidence interval [CI] −13.5% to −12.2%). There was a significant fall in the mortality of patients presenting to the hospital with P. falciparum malaria (0.53% [100/18,965] versus 0.32% [57/17,691]; difference = −0.21% [95% CI −0.34 to −0.07]) but not in patients with P. vivax malaria (0.28% [21/7,545] versus 0.23% [28/12,397]; difference = −0.05% [95% CI −0.20 to 0.09]). Between the same periods, the overall proportion of malaria due to P. vivax rose from 44.1% (30,444/69,098) to 53.3% (29,934/56,125) in the community clinics and from 32.4% (9,325/28,789) to 44.1% (15,035/34,117) at the hospital. After controlling for population growth and changes in treatment-seeking behaviour, the incidence of P. falciparum malaria fell from 511 to 249 per 1,000 person-years (py) (incidence rate ratio [IRR] = 0.49 [95% CI 0.48–0.49]), whereas the incidence of P. vivax malaria fell from 331 to 239 per 1,000 py (IRR = 0.72 [95% CI 0.71–0.73]). The main limitations of our study were possible confounding from changes in healthcare provision, a growing population, and significant shifts in treatment-seeking behaviour following implementation of a new antimalarial policy.ConclusionsIn this area with high levels of antimalarial drug resistance, adoption of a universal policy of efficacious artemisinin-based therapy for malaria infections due to any Plasmodium species was associated with a significant reduction in total malaria-attributable morbidity and mortality. The burden of P. falciparum malaria was reduced to a greater extent than that of P. vivax malaria. In coendemic regions, the timely elimination of malaria will require that safe and effective radical cure of both the blood and liver stages of the parasite is widely available for all patients at risk of malaria.
Partial Text: Prompt and effective treatment of malaria reduces morbidity and limits onward transmission of the Plasmodium parasite [1,2]. Large-scale use of highly efficacious antimalarial treatment regimens has contributed to significant reductions in P. falciparum malaria in many malaria-endemic regions [3,4]. P. vivax is more difficult to cure than P. falciparum because it forms dormant liver stages (hypnozoites) that are intrinsically resistant to standard schizontocidal drugs. Unless patients are treated with an effective drug regimen that clears both the blood and liver stage of the parasite, these hypnozoites can reactivate periodically, causing recurrent blood-stage infections (relapses) and ongoing transmission . Malaria treatment campaigns that do not include radically curative primaquine regimens for patients infected with P. vivax may have only a modest effect on the number of cases of P. vivax malaria and thus are likely to be associated with an increase in the proportion of malaria due to this parasite compared to P. falciparum [6–8]. When primaquine radical cure is included in national guidelines, it is usually prescribed without prior testing for glucose-6-phosphate dehydrogenase (G6PD) deficiency. To mitigate the risks of drug-induced haemolysis, many countries recommend a 15-mg daily dose administered over 14 days despite evidence showing that 30 mg daily is more effective . When supervised, a 14-day regimen of primaquine can reduce the risk of P. vivax relapse by more than 85% [10,11]; however, in most endemic settings, daily supervision of such a prolonged treatment regimen is not practical , and this can result in a significant reduction in primaquine adherence and effectiveness [13–15]. In a large-scale observational study of patients with vivax malaria in Papua, Indonesia, the effectiveness of unsupervised primaquine was estimated to be only 10% .
In March 2006, Indonesia was the first malaria-endemic country to adopt a unified schizontocidal treatment policy for malaria due to any Plasmodium species: DP for uncomplicated malaria and IV artesunate for severe malaria. These changes came on a background of failing treatment regimens due to high-grade multidrug resistance in both P. falciparum and P. vivax species. In Mimika District, southern Papua, the uptake of the new policy was rapid, with the new treatment regimens adopted into practice in most public health facilities within a month. In this high-transmission setting, we found that the implementation of highly effective antimalarial treatment regimens was associated with a marked reduction in both malaria-related morbidity and mortality. The incidence of malaria and the proportion of malaria requiring admission to hospital fell by one-half, bed occupancy of patients with malaria fell by 26%, and malaria-related mortality fell by one-third. Associated with these changes, the proportion of patients with malaria attributable to P. vivax increased from 41% to 54%, and the proportion of malaria-related deaths attributable to P. vivax rose from 15% to 28%.