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Background. Reducing the risk of recurrent P. vivax malaria is critical for malaria control and elimination. Primaquine (PQ) is the only widely available drug against P. vivax dormant liver stages, but is recommended as a 14-day regimen, which can undermine adherence to a complete course of treatment. Methods. This is a mixed-methods study to assess socio-cultural factors influencing adherence to a 14-day PQ regimen in a 3-arm, treatment effectiveness trial in Papua, Indonesia. The qualitative strand, consisting of interviews and participant observation was triangulated with a quantitative strand in which trial participants were surveyed using a questionnaire. Results. Trial participants differentiated between two types of malaria: tersiana and tropika, equivalent to P. vivax and P. falciparum infection, respectively. The perceived severity of both types was similar with 44.0% (267/607) perceiving tersiana vs. 45.1% (274/607) perceiving tropika as more severe. There was no perceived differentiation whether malaria episodes were due to a new infection or relapse; and 71.3% (433/607) of survey respondents acknowledged the possibility of recurrence. Participants were familiar with malaria symptoms and delaying health facility visit by 1-2 days was perceived to increase the likelihood of a positive test. Prior to health facility visits, symptoms were treated with leftover drugs kept at home (40.4%; 245/607) or bought over the counter (17.0%; 103/607). Malaria was considered to be cured with ‘blue drugs’ (referring to dihydroartemisinin-piperaquine). Conversely, ‘brown drugs,’ referring to PQ, were not considered malaria medication and instead were perceived as supplements. Adherence to malaria treatment was 71.2% (131/184), in the supervised arm, 56.9% (91/160) in the unsupervised arm and 62.4% (164/263) in the control arm; p = 0.019. Adherence was 47.5% (47/99) among highland Papuans, 51.7% (76/147) among lowland Papuans, and 72.9% (263/361) among non-Papuans; p < 0.001. Conclusion. Adherence to malaria treatment was a socio-culturally embedded process during which patients (re-)evaluated the characteristics of the medicines in relation to the course of the illness, their past experiences with illness, and the perceived benefits of the treatment. Socio-cultural logics and practical challenges that underlie adherence are crucial to consider in the development and rollout of effective malaria treatment policies.

Strongyloides stercoralis is a parasitic worm that is of considerable clinical relevance. Indeed, it may persist asymptomatically for many years, but can lead to potentially fatal dissemination when the host's immune status is impaired. As commonly employed stool microscopy techniques (e.g. Kato-Katz thick smear) fail to detect S. stercoralis, the epidemiology is poorly understood. In 2013, we conducted a cross-sectional household survey in the district of Mimika in Papua, Indonesia. A total of 331 individuals, aged 1 month to 44 years, had a single stool sample subjected to real-time polymerase chain reaction (PCR) for S. stercoralis diagnosis. The prevalence of S. stercoralis infection was 32.0% (106/331 individuals); higher than any of the three main soil-transmitted helminths (Ascaris lumbricoides, 23.9%; Trichuris trichiura, 18.4%; and hookworm, 17.2%). Amongst the S. stercoralis-infected individuals, 73.6% were concurrently infected with another helminth, with hookworm being the most frequent co-infection (27.4%). Fourteen percent of the S. stercoralis infections had low cycle threshold values on real-time PCR, which may indicate a higher infection intensity. Multivariate logistic regression analysis revealed that age ≥5 years (adjusted odds ratio (OR) 5.8, 95% confidence interval (CI): 3.1-10.8) was significantly associated with S. stercoralis infection. There is a need for in-depth clinical and diagnostic studies to elucidate the public health impact of S. stercoralis infection in Indonesia.

Background The COVID-19 pandemic has resulted in millions of infections, hundreds of thousands of deaths and major societal disruption due to lockdowns and other restrictions introduced to limit disease spread. Relatively little attention has been paid to understanding how the pandemic has affected treatment, prevention and control of malaria, which is a major cause of death and disease and predominantly affects people in less well-resourced settings. Main body Recent successes in malaria control and elimination have reduced the global malaria burden, but these gains are fragile and progress has stalled in the past 5 years. Withdrawing successful interventions often results in rapid malaria resurgence, primarily threatening vulnerable young children and pregnant women. Malaria programmes are being affected in many ways by COVID-19. For prevention of malaria, insecticide-treated nets need regular renewal, but distribution campaigns have been delayed or cancelled. For detection and treatment of malaria, individuals may stop attending health facilities, out of fear of exposure to COVID-19, or because they cannot afford transport, and health care workers require additional resources to protect themselves from COVID-19. Supplies of diagnostics and drugs are being interrupted, which is compounded by production of substandard and falsified medicines and diagnostics. These disruptions are predicted to double the number of young African children dying of malaria in the coming year and may impact efforts to control the spread of drug resistance. Using examples from successful malaria control and elimination campaigns, we propose strategies to re-establish malaria control activities and maintain elimination efforts in the context of the COVID-19 pandemic, which is likely to be a long-term challenge. All sectors of society, including governments, donors, private sector and civil society organisations, have crucial roles to play to prevent malaria resurgence. Sparse resources must be allocated efficiently to ensure integrated health care systems that can sustain control activities against COVID-19 as well as malaria and other priority infectious diseases. Conclusion As we deal with the COVID-19 pandemic, it is crucial that other major killers such as malaria are not ignored. History tells us that if we do, the consequences will be dire, particularly in vulnerable populations.

Background The sensitivity of rapid diagnostic tests (RDTs) for malaria is inadequate for detecting low-density, often asymptomatic infections, such as those that can occur when screening pregnant women for malaria. The performance of the Alere™ Ultra-sensitive Malaria Ag Plasmodium falciparum RDT (uRDT) was assessed retrospectively in pregnant women in Indonesia. Methods The diagnostic performance of the uRDT and the CareStart™ Malaria HRP2/pLDH VOM (Plasmodium vivax, Plasmodium ovale and Plasmodium malariae) Combo RDT (csRDT) were assessed using 270 stored red blood cell pellets and plasma samples from asymptomatic pregnant women. These included 112 P. falciparum negative and 158 P. falciparum positive samples detected by a composite test (qPCR, LAMP, nPCR) as reference standard. Diagnostic indicators: sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), diagnostic odds ratio (DOR) and the level of agreement (kappa) were calculated for comparison. Results Compared with the reference test, the uRDT had a sensitivity of 19.6% (95% CI 13.9–26.8) and specificity of 98.2% (93.1–99.7%). The csRDT was 22.8% (16.7–30.3) sensitive and 95.5% (89.4–98.3) specific for P. falciparum infections. Performance of the uRDT was non-significantly different to the csRDT (p = 0.169). RDT outcome was stratified by qPCR cycling threshold (Ct), and performance of the RDTs was found to be comparable across parasite loads. Conclusion The uRDT performed similarly to the currently used csRDTs in detecting P. falciparum infections in asymptomatic pregnant women. In these settings, molecular diagnostics are currently the most sensitive for malaria.

Background Intravenous artesunate and its follow on full course dihydroartemisinin–piperaquine are the standard treatment for severe malaria in Indonesia. The current policy suggests that intravenous and oral quinine could be used when standard therapy is not available. Its pragmatic use of both treatment combinations in a field hospital is evaluated. Methods A retrospective study among hospitalized malaria patients receiving intravenous anti-malarial treatments at Mitra Masyarakat Hospital, Timika from April 2004 to December 2013 was conducted. The length of hospital stay (LoS) and the risk of malaria recurrence within 28 days after hospital admission were compared between patients receiving intravenous artesunate and oral dihydroartemisinin–piperaquine (Iv Art + DHP) and those receiving intravenous and oral quinine (Iv + Oral Qu). Results Of 10,514 patients requiring intravenous therapy, 2759 received Iv + Oral Qu and 7755 received Iv Art + DHP. Plasmodium falciparum infection accounted for 65.8% (6915), while Plasmodium vivax, Mixed infections, Plasmodium malariae and Plasmodium ovale were accounted for 17.0% (1789), 16.4% (1729), 0.8% (79) and 0.01% (2) of the infections, respectively. The majority of severe malaria hospital admissions were highland Papuans (78.0%, 8201/10,501). In total 49% (5158) of patients were older than 15 years and 3463 (32.9%) were children under 5 years old. The median LoS was shorter in patients receiving intravenous artesunate compared to those treated with intravenous quinine (median = 2 [IQR 1–3] versus 3 days [IQR 2–4], p Conclusions Intravenous artesunate reduced the LoS of malaria patients and in combination with DHP reduced the risk of malaria recurrence within 28 days after hospital admission compared to those with Iv + Oral Qu treatment. Thus, ensuring continuous supply of intravenous artesunate and artemisinin-based combination therapy (ACT) should be a priority.

Background In Papua (Indonesia), infants with P. falciparum and/or P. vivax malaria are at risk of severe anaemia and death. We hypothesized that in an area of high malaria transmission, intermittent screening and treatment of infants with malaria (ISTi) will reduce morbidity compared to passive case detection (PCDi). Methods We conducted a cluster randomised, open label, superiority trial. A total of 21 clusters of village health posts (VHP) were randomised 1:1 to either IST for infants coinciding with 4 routine immunisation visits or PCDi. Healthy term infants born to consenting mothers enrolled into a maternal malaria cluster randomised trial were included in the study and followed for 12 months. Point of care malaria rapid diagnostic tests were used to detect peripheral parasitaemia at 2, 3, 4 and 9 months old in all infants in ISTi clusters and when symptomatic in PCDi clusters. Infants with detected peripheral parasitaemia were treated with dihydroartemisinin-piperaquine. The co-primary outcomes were the incidence rate of clinical malaria in the first year of life and the prevalence of parasitaemia at age 12 months. The incidence rate ratio and prevalence ratio between ISTi and PCDi were estimated using mixed-effects Poisson and log-binomial regression modelling (accounting for clustering at VHP level). Results Between May 2014 and February 2017, 757 infants were enrolled into the study, 313 into 10 ISTi clusters, and 444 into 11 PCDi clusters. Overall, 132 episodes of parasitaemia were detected, of whom 17 (12.9%) were in symptomatic infants. Over 12 months, the incidence rate (IR) of clinical malaria was 24 [95% CI, 10–50] per 1000 children-years at risk in the ISTi arm and 19 [95% CI, 8,38] per 1000 children-years in the PCDi arm (adjusted incidence rate ratio [aIRR] 1.77 [95% CI, 0.62–5.01]; p = 0.280). The prevalence of parasitaemia at 12 months was 13% (33/254) in the IST clusters and 15% (57/379) in the PCD clusters (adjusted prevalence ratio (aPR) = 0.92 (95% CI, 0.70–1.21), p = 0.55). There was no difference in the risk of anaemia between treatment arms. Conclusions In high malaria transmission area outside of Africa, our study suggests that compared to PCDi, ISTi offers no significant benefit in reducing the risk of clinical malaria in infants born to women receiving effective protection from malaria during pregnancy. Trial registration ClinicalTrials.gov NCT 02001428, registered on 20 Nov 2013.

Background Inadequate prevention and treatment of malaria can lead to reinfections and recurrent episodes, and for vivax malaria, further recurrences from the dormant liver stage. This study quantified the impact of recurrent malaria episodes on morbidity and mortality. Methods Routinely collected data were available from 68,381 malaria patients presenting to the primary referral hospital in Papua, Indonesia. A multi-state modelling framework, with Cox regression for transition rates, was employed to determine the risks of re-presentation to hospital, receiving in-patient treatment, and early (≤14 days post treatment)/late death following multiple malaria episodes. Results The risk of re-presentation to hospital increased from 34.7% (95%CI: 34.4%–35.1%) at first episode to 58.6% (57.5%–59.6%) following the third episode. Infection with vivax malaria increased the rate of re-presentation to hospital by 1.48-fold (Hazard Ratio 1.48; 95%CI 1.44–1.51) and late hospital in-patient admission by 1.17-fold (1.11–1.22), compared to falciparum. Falciparum malaria caused a higher overall rate of early death (1.54 (1.25–1.92)), however, after multiple episodes, there was a trend towards a greater rate of early death for vivax infection (1.91 (0.73–4.97)). Conclusions Recurrent episodes of malaria can cause substantial morbidity and mortality, highlighting the importance of prevention and effective treatments for both falciparum and vivax malaria. Key messages To achieve elimination of malaria in South-East Asia, where prevalence of vivax malaria is high, we must prioritise the radical cure of vivax to eliminate the liver-stage of this species that causes relapses of infection.

IFN-γ–driven responses to malaria have been shown to modulate the development and function of T follicular helper (TFH) cells and memory B cells (MBCs), with conflicting evidence of their involvement in the induction of antibody responses required to achieve clinical immunity and their association with disease outcomes. Using high-dimensional single-cell mass cytometry, we identified distinct populations of TH1-polarized CD4+ T cells and MBCs expressing the TH1-defining transcription factor T-bet, associated with either increased or reduced risk of Plasmodium vivax (P. vivax) malaria, demonstrating that inflammatory responses to malaria are not universally detrimental for infection. Furthermore, we found that, whereas class-switched but not IgM+ MBCs were associated with a reduced risk of symptomatic malaria, populations of TH1 cells with a stem central memory phenotype, TH17 cells, and T regulatory cells were associated with protection from asymptomatic infection, suggesting that activation of cell-mediated immunity might also be required to control persistent P. vivax infection with low parasite burden.

Drug resistant Plasmodium parasites are a major threat to malaria control and elimination. After reports of high levels of multidrug resistant P. falciparum and P. vivax in Indonesia, in 2005, the national first-line treatment policy for uncomplicated malaria was changed in March 2006, to dihydroartemisinin-piperaquine against all species. This study assessed the temporal trends in ex vivo drug susceptibility to chloroquine (CQ) and piperaquine (PIP) for both P. falciparum and P. vivax clinical isolates collected between 2004 and 2018, by using schizont maturation assays, and genotyped a subset of isolates for known and putative molecular markers of CQ and PIP resistance by using Sanger and next generation whole genome sequencing. The median CQ IC50 values varied significantly between years in both Plasmodium species, but there was no significant trend over time. In contrast, there was a significant trend for increasing PIP IC50s in both Plasmodium species from 2010 onwards. Whereas the South American CQ resistant 7G8 pfcrt SVMNT isoform has been fixed since 2005 in the study area, the pfmdr1 86Y allele frequencies decreased and became fixed at the wild-type allele in 2015. In P. vivax isolates, putative markers of CQ resistance (no pvcrt-o AAG (K10) insertion and pvmdr1 Y967F and F1076L) were fixed at the mutant alleles since 2005. None of the putative PIP resistance markers were detected in P. falciparum. The ex vivo drug susceptibility and molecular analysis of CQ and PIP efficacy for P. falciparum and P. vivax after 12 years of intense drug pressure with DHP suggests that whilst the degree of CQ resistance appears to have been sustained, there has been a slight decline in PIP susceptibility, although this does not appear to have reached clinically significant levels. The observed decreasing trend in ex vivo PIP susceptibility highlights the importance of ongoing surveillance., Graphical abstract Image 1

Malaria and the Spleen In this report, patients living in a malaria-endemic area underwent trauma-related splenectomy. In these asymptomatic patients who were naturally infected with Plasmodium fal...

People in close contact with tuberculosis should have screening and appropriate management, as an opportunity for active case detection and prevention. However, implementation of tuberculosis contact screening and management is limited in high-burden settings. Behaviour change is needed across three levels of the healthcare system—policymakers, healthcare providers, and patients. To bridge the wide policy-practice gap, this study draws on the Consolidated Framework for Implementation Research, the Behaviour Change Wheel, and the RE-AIM model (Reach, Effectiveness, Adoption, Implementation, Maintenance) to respectively understand barriers, implement change, and evaluate process and outcome. This methods paper describes a mixed-methods intervention study in Eastern Indonesia. Quantitative data will be collected during baseline, intervention, and sustainability periods and analyzed using time series analysis. The primary outcome is the number of individuals completing tuberculosis preventive therapy by the end of the two-year intervention phase. Of an estimated 10,000 contacts during this period, we anticipate that a minimum of 416 will be found to have active TB or will complete preventive therapy. Qualitative data (semi-structured interviews, focus group discussions, and observations) will be collected from consenting healthcare providers, patients, and contacts. Activities to promote policy implementation include healthcare provider training, quarterly continuous quality improvement workshops, a social media discussion forum, and promotional materials. The Consolidated Framework for Implementation Research will be used to identify reasons for limited policy implementation at baseline. The Behaviour Change Wheel will be used to ensure that a suitable range of activities are implemented to facilitate change. The RE-AIM model will be used as the evaluation framework. Use of theoretical frameworks in combination can ensure a comprehensive understanding of, and robust response to, health policy underimplementation. The selected frameworks are highly applicable to this pragmatic intervention study, in a setting where End TB Strategy targets will not be met without substantial behavior change within health systems. Continuous quality improvement cycles will provide a way to engage staff and stakeholders in understanding local data to motivate behavior change. If successful, up to 500 people could be prevented from developing complications of tuberculosis through early case-finding or receiving preventive therapy over a two-year period. Australian New Zealand Clinical Trials Register 375803 .

Background There is a high risk of Plasmodium vivax recurrence in patients treated for Plasmodium falciparum malaria in co-endemic areas. Primaquine radical cure has the potential to reduce P vivax recurrences in patients presenting with P falciparum as well as P vivax malaria but is undermined by poor adherence to the currently recommended 14-day regimen. We aimed to assess the efficacy and safety of supervised versus unsupervised primaquine radical cure in patients presenting with uncomplicated malaria. Methods We did a cluster-randomised, controlled, open-label superiority trial in Papua, Indonesia. 21 clusters of village health posts, matched by annual parasite index, were randomly assigned (1:1) to treat patients (age >12 months and body weight >5 kg) presenting with confirmed uncomplicated P falciparum or P vivax malaria with oral dihydroartemisinin–piperaquine plus either a supervised or unsupervised 14-day course of oral primaquine (0·5 mg/kg per day). Patients in the supervised group were supervised taking their primaquine dose on alternate days. Patients were followed-up for 6 months and those who presented again with malaria were retreated with the same drug regimen. Masking was not possible due to the nature of the study. The primary outcome was the incidence risk of P vivax malaria over 6 months, assessed in the modified intention-to-treat population (all patients who were assigned to a treatment group, excluding patients who were lost to follow-up after their first visit). This trial is now complete, and is registered with ClinicalTrials.gov, NCT02787070. Findings Between Sept 14, 2016, and July 31, 2018, 436 patients were screened for eligibility and 419 were enrolled; 223 (53%) patients in 11 clusters were assigned to supervised primaquine treatment and 196 (47%) in ten clusters to unsupervised primaquine treatment. 161 (72%) of 223 patients in the supervised group and 151 (77%) of 196 in the unsupervised group completed 6 months of follow-up. At 6 months, the incidence risk of P vivax recurrence in the supervised group was 29·7% (95% CI 16·4–49·9) versus 55·8% (32·3–81·8) in the unsupervised group (hazard ratio 0·23 [95% CI 0·07–0·76]; p=0·016). The incidence rate for P vivax recurrence was 539 (95% CI 390–747) infections per 1000 person-years in the supervised group versus 859 (673–1096) in the unsupervised group (incidence rate ratio 0·63 [95% CI 0·42–0·94]; p=0·025). The corresponding rates in the 224 patients who presented with P falciparum malaria were 346 (95% CI 213–563) and 660 (446–977; incidence rate ratio 0·52 [95% CI 0·28–0·98]; p=0·043). Seven serious adverse events were reported (three in the supervised group, four in the unsupervised group), none of which were deemed treatment-related, and there were no deaths. Interpretation In this area of moderate malaria transmission, supervision of primaquine radical cure treatment reduced the risk of P vivax recurrence. This finding was apparent for patients presenting with either P falciparum or P vivax malaria. Further studies are warranted to investigate the safety and efficacy of radical cure for patients presenting with uncomplicated falciparum malaria in other co-endemic areas. Funding The Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Foreign Affairs and Trade of the Australian Government. Translation For the Indonesian translation of the abstract see Supplementary Materials section.

Dihydroartemisinin-piperaquine (DP) is a long-acting artemisinin combination treatment that provides effective chemoprevention and has been proposed as an alternative antimalarial drug for intermittent preventive therapy in pregnancy (IPTp). Several pharmacokinetic studies have shown that dose adjustment may not be needed for the treatment of malaria in pregnancy with DP., Dihydroartemisinin-piperaquine (DP) is a long-acting artemisinin combination treatment that provides effective chemoprevention and has been proposed as an alternative antimalarial drug for intermittent preventive therapy in pregnancy (IPTp). Several pharmacokinetic studies have shown that dose adjustment may not be needed for the treatment of malaria in pregnancy with DP. However, there are limited data on the optimal dosing for IPTp. This study aimed to evaluate the population pharmacokinetics of piperaquine given as IPTp in pregnant women. Pregnant women were enrolled in clinical trials conducted in Kenya and Indonesia and treated with standard 3-day courses of DP, administered in 4- to 8-week intervals from the second trimester until delivery. Pharmacokinetic blood samples were collected for piperaquine drug measurements before each treatment round, at the time of breakthrough symptomatic malaria, and at delivery. Piperaquine population pharmacokinetic properties were investigated using nonlinear mixed-effects modeling with a prior approach. In total, data from 366 Kenyan and 101 Indonesian women were analyzed. The pharmacokinetic properties of piperaquine were adequately described using a flexible transit absorption (n = 5) followed by a three-compartment disposition model. Gestational age did not affect the pharmacokinetic parameters of piperaquine. After three rounds of monthly IPTp, 9.45% (95% confidence interval [CI], 1.8 to 26.5%) of pregnant women had trough piperaquine concentrations below the suggested target concentration (10.3 ng/ml). Translational simulations suggest that providing the full treatment course of DP at monthly intervals provides sufficient protection to prevent malaria infection. Monthly administration of DP has the potential to offer optimal prevention of malaria during pregnancy. (This study has been registered at ClinicalTrials.gov under identifier NCT01669941 and in the ISRCTN under number ISRCTN34010937.)

Background: In co-endemic areas there is a high risk of P. vivax recurrence in patients treated for P. falciparum malaria. Primauine radical cure has the potential to reduce P. vivax recurrences in patients presenting with P. falciparum as well as P. vivax malaria, but is undermined by poor adherence to the currently recommended 14 day regimen. We assessed the effectiveness of supervised primaquine radical cure in patients presenting with uncomplicated malaria. Methods: We conducted a cluster-randomised, controlled, open-label superiority trial in Papua, Indonesia. Twenty one clusters (village health post matched by location, size and malaria transmission) were assigned randomly (1:1) by a statistician independent to the trial to treat patients presenting with uncomplicated P. falciparum or P. vivax malaria with dihydroartemisinin-piperaquine plus either a supervised or unsupervised 14-day course of primaquine (0.5mg/kg per day). Patients were followed for 6 months and those representing with malaria were retreated with the same drug regimen. The primary outcome was the incidence risk and rate of P. vivax recurrent episodes over 6 months assessed in the intention to treat population. Findings: Between September 2016 and July 2018, 419 patients were enrolled. Overall the incidence risk of P. vivax recurrence in the 10 unsupervised clusters was 55.8% (95%CI, 32.3-81.8) compared to 29.7% (95%CI, 16.4-49.9) in the 11 supervised clusters (HR 0.23, 95%CI, 0.07-0.76, p=0.016). The incidence rate in unsupervised clusters was 859 (95%CI, 673-1,096) P. vivax infections per 1000 person years compared to 539 (95%CI, 390-747) in the supervised clusters (IRR 0.63, 95%CI, 0.42-0.94, p=0.025). The corresponding rates in the 224 patients presenting with P. falciparum malaria were 660 (95%CI, 446-977) and 346 (95%CI, 213-563); IRR 0.52 (95%CI, 0.28-0.98), p=0.043. There were no serious adverse events attributable to primaquine. Interpretation: In this area of moderate malaria transmission, supervision of primaquine radical cure reduced the risk of P. vivax recurrence and this was apparent for patients presenting with either P. falciparum or P. vivax malaria. Clinical Trial Registration Details: The trial was registered with the US National Library of Medicine, registered at ClinicalTrials.gov (NCT 02787070). Funding Information: The Bill and Melinda Gates Foundation, The Wellcome Trust and The Department of Foreign Affairs and Trade of the Australian Government. Declaration of Interests: No conflict of interests reported. Ethics Approval Statement: Ethical approval was obtained from the Human Research Ethics Committee of the Northern Territory Department of Health, Australia (HREC 15.2517) and the Health Research Ethics Committees of the University of Gadjah Mada, Indonesia (KE/FK/522/EC/2016).

The widespread use of primaquine (PQ) radical cure for P. vivax, is constrained by concerns over its safety. We used routinely collected patient data to compare the overall morbidity and mortality in patients treated with and without PQ without prior testing of Glucose-6-Phosphate-Dehydrogenase (G6PD) deficiency in Papua, Indonesia, where there is a low prevalence of G6PD deficiency. Records were collated from patients older than 1 year, with P. vivax infection, who were treated with an artemisinin combination therapy (ACT). The risks of re-presentation, hospitalization, major fall in haemoglobin and death within 30 days were quantified and compared between patients treated with and without PQ using a Cox regression model. In total 26,216 patients with P. vivax malaria presented to the hospital with malaria during the study period. Overall 27.56% (95% Confidence Interval (95%CI): 26.96–28.16) of 21,344 patients treated with PQ re-presented with any illness within 30 days and 1.69% (1.51–1.88) required admission to hospital. The corresponding risks were higher in the 4,872 patients not treated with PQ; Adjusted Hazard Ratio (AHR) = 0.84 (0.79–0.91; p, Author summary The radical cure of vivax malaria requires killing the blood stages and the dormant liver stages (hypnozoites) of Plasmodium vivax. Primaquine (PQ) is currently the only widely available drug to kill hypnozoites, but its use is hampered by concerns over haemolysis in patients with Glucose-6-Dehydrogenase (G6PD) deficiency. At a recent round table discussion of the Asia Pacific Malaria Elimination Network (APMEN) policy makers prioritised further studies to determine the risk-benefit of PQ in different endemic settings. We used a large dataset of more than 26,000 patient treated in a routine care setting in Papua, Indonesia over a 9-year period to explore the risk of adverse outcomes following PQ. Even though patients were treated with PQ without G6PD testing, those patients receiving PQ had a 20% lower risk of all cause re-presentation and 50% lower risk of hospitalization than those not treated with PQ. The risk of mortality was 20% lower, although this didn’t reach statistical significance. Great emphasis is placed on the risks of PQ induced haemolysis, inhibiting its widespread use. It is critical that these risks are interpreted in the context of the substantial benefits of reducing the recurrence of episodes of malaria and associated morbidity and mortality. Our analysis provides reassuring evidence that, in an area with a high burden of malaria and low G6PD prevalence the beneficial effects of PQ outweigh its risks.

Background The radical cure of Plasmodium vivax and P. ovale requires treatment with primaquine or tafenoquine to clear dormant liver stages. Either drug can induce haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, necessitating screening. The reference diagnostic method for G6PD activity is ultraviolet (UV) spectrophotometry; however, a universal G6PD activity threshold above which these drugs can be safely administered is not yet defined. Our study aimed to quantify assay-based variation in G6PD spectrophotometry and to explore the diagnostic implications of applying a universal threshold. Methods and findings Individual-level data were pooled from studies that used G6PD spectrophotometry. Studies were identified via PubMed search (25 April 2018) and unpublished contributions from contacted authors (PROSPERO: CRD42019121414). Studies were excluded if they assessed only individuals with known haematological conditions, were family studies, or had insufficient details. Studies of malaria patients were included but analysed separately. Included studies were assessed for risk of bias using an adapted form of the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Repeatability and intra- and interlaboratory variability in G6PD activity measurements were compared between studies and pooled across the dataset. A universal threshold for G6PD deficiency was derived, and its diagnostic performance was compared to site-specific thresholds. Study participants (n = 15,811) were aged between 0 and 86 years, and 44.4% (7,083) were women. Median (range) activity of G6PD normal (G6PDn) control samples was 10.0 U/g Hb (6.3–14.0) for the Trinity assay and 8.3 U/g Hb (6.8–15.6) for the Randox assay. G6PD activity distributions varied significantly between studies. For the 13 studies that used the Trinity assay, the adjusted male median (AMM; a standardised metric of 100% G6PD activity) varied from 5.7 to 12.6 U/g Hb (p < 0.001). Assay precision varied between laboratories, as assessed by variance in control measurements (from 0.1 to 1.5 U/g Hb; p < 0.001) and study-wise mean coefficient of variation (CV) of replicate measures (from 1.6% to 14.9%; p < 0.001). A universal threshold of 100% G6PD activity was defined as 9.4 U/g Hb, yielding diagnostic thresholds of 6.6 U/g Hb (70% activity) and 2.8 U/g Hb (30% activity). These thresholds diagnosed individuals with less than 30% G6PD activity with study-wise sensitivity from 89% (95% CI: 81%–94%) to 100% (95% CI: 96%–100%) and specificity from 96% (95% CI: 89%–99%) to 100% (100%–100%). However, when considering intermediate deficiency (, Daniel Pfeffer and coauthors report on the assessment of glucose-6-phosphate dehydrogenase activity, which is required for safe use of some malaria treatments., Author summary Why was this study done? Complete cure of vivax malaria, the most geographically widespread malaria species, requires the use of 8-aminoquinoline drugs to clear dormant liver stages of the parasite (‘radical cure’); however, these drugs can cause severe haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Ultraviolet (UV) spectrophotometry is used as the reference test to measure G6PD activity, for validating new point-of-care diagnostics, and to determine population-specific definitions of G6PD deficiency. Currently, there is no universal threshold to define G6PD deficiency, and each laboratory must invest time and resources to derive site- and laboratory-specific definitions of G6PD deficiency. What did the researchers do and find? We pooled measurements of G6PD activity from studies conducted across different countries and laboratories worldwide. We assessed the comparability of spectrophotometry results between these laboratories to see whether a universal definition and diagnostic cutoff for G6PD deficiency could be determined. There was substantial variation in the performance and absolute measurements of spectrophotometry conducted in different laboratories, hindering the definition of a universal cutoff for G6PD deficiency. What do these findings mean? These findings highlight the importance of quality-control measures to minimise the influence of laboratory procedures on observed measurements. The data suggest that while a robust universal, assay-specific G6PD activity cutoff value can be established for diagnosis of severe G6PD deficiency (

Background There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. Methods and findings A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0–29.0 years; range = 0–80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9–33.4) after AL, 14.1% (95% CI 10.8–18.3) after AA, 7.4% (95% CI 6.7–8.1) after AM, and 4.5% (95% CI 3.9–5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6–43.3), 42.4% (95% CI 34.7–51.2), 22.8% (95% CI 21.2–24.4), and 12.8% (95% CI 11.4–14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0–19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6–8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4–3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0–1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4–2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. Conclusions In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas., Mohammad S. Hossain and colleagues explore P. vivax infection following P. falciparum treatment in this analysis of 42 published studies., Author summary Why was this study done? Plasmodium vivax is the most geographically widespread human malaria species; outside of sub-Saharan Africa, it almost invariably coexists with P. falciparum. A recent systematic review of 153 studies across 21 countries revealed that within 63 days of being treated for P. falciparum monoinfection, more than 15% of patients treated with an artemisinin-based combination therapy (ACT) had an episode of P. vivax malaria, far greater than expected for patients in similar locations who do not have acute malaria. We hypothesised that patients presenting with P. falciparum in coendemic locations are at high risk of carrying P. vivax dormant liver stages (hypnozoites) and would therefore potentially benefit from presumptive radical cure. What did the researchers do and find? We undertook an individual patient data meta-analysis to define the risk of vivax parasitaemia (blood stream infection) after treatment of P. falciparum malaria in different coendemic environments and to explore the factors underlying these risks. In total, 42 studies enrolling 15,341 patients were included in the analysis. By day 63, the risk of P. vivax ranged from 12.8% following dihydroartemisinin-piperaquine (DP) to 42.4% following artesunate-amodiaquine (AA). The highest rate of P. vivax malaria was in patients residing in areas with high risk of relapses and those who were slow to clear their initial parasitaemia. What do these findings mean? There is a high risk of vivax malaria after treatment of falciparum infection after all ACTs, although the risk varies substantially between locations. The correlation between the risk of P. vivax and the initial clearance of P. falciparum raises the possibility that the host response to acute malaria may be triggering the reactivation of P. vivax dormant liver stages. Universal radical cure with treatment to kill the liver stages may be warranted for reducing P. vivax, but the benefits will vary considerably between geographical locations, and further prospective clinical efficacy studies will be needed to determine the risks and benefits of such a strategy.

Summary Malaria disproportionately affects children younger than 5 years. Falciparum malaria is responsible for more than 200 000 child deaths per year in Africa and vivax malaria is well documented as a cause of severe anaemia and excess mortality in children in Asia and Oceania. For the treatment of malaria in children, paediatric dosing recommendations for several agents, including parenteral artesunate and dihydroartemisinin–piperaquine, have belatedly been shown to be suboptimal. Worsening antimalarial resistance in Plasmodium falciparum in the Greater Mekong Subregion threatens to undermine global efforts to control malaria. Triple antimalarial combination therapies are being evaluated to try to impede this threat. The RTS,S/AS01 vaccine gives partial protection against falciparum malaria and is being evaluated in large, pilot studies in Ghana, Malawi, and Kenya as a complementary tool to other preventive measures. Seasonal malaria chemoprevention in west Africa has resulted in declines in malaria incidence and deaths and there is interest in scaling up efforts by expanding the age range of eligible recipients. Preventing relapse in Plasmodium vivax infection with primaquine is challenging because treating children who have G6PD deficiency with primaquine can cause acute haemolytic anaemia. The safety of escalating dose regimens for primaquine is being studied to mitigate this risk.

Background A very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human individuals infected with Plasmodium vivax. The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P. vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival. Methods and findings We examined spleen tissue in 22 mostly untreated individuals naturally exposed to P. vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from individuals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or sample size considerations in both patient cohorts for this demanding approach. In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic Plasmodium infection (7 P. vivax, 13 P. falciparum, and 1 mixed infection). Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P. vivax-infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times (IQR: 2,600 to 4,130) higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P. vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P. vivax- than in P. falciparum-infected spleens. Histological analyses revealed 96% of P. vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted. Conclusions Immature CD71+ reticulocytes and splenic P. vivax-infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P. vivax infection. Findings provide insight into P. vivax-specific adaptions that have evolved to maximise survival and replication in the spleen., Dr. Anstey and co-authors found that P. vivax-infected immature reticulocytes and erythrocytes accumulate in the same splenic compartments, suggesting existence of a cryptic endosplenic lifecycle in chronic P. vivax infection that maximizes survival and replication in the spleen., Author summary Why was this study done? There is a surprisingly large biomass of intact Plasmodium vivax parasites in the spleen of people living in malaria endemic areas, greater than with Plasmodium falciparum. Why P. vivax accumulates so intensely in the spleen is not known. P. vivax requires very young red cells (immature reticulocytes) for invasion and replication. What did the researchers do and find? The accumulation of P. vivax and immature reticulocytes were evaluated in spleens from people undergoing splenectomy in malaria-endemic Papua. P. vivax parasites and immature reticulocytes accumulated in the same splenic compartments. All stages of P. vivax accumulated in the spleen at magnitudes unexplainable by replication occurring in the circulation alone, with the proportion of each stage in the spleen consistent with the duration in their lifecycle. What do these findings mean? Taking advantage of the large physiological splenic reservoir of immature reticulocytes, the majority of the P. vivax lifecycle can take place in the spleen in chronic malaria. Chronic vivax malaria should be considered predominantly an infection of the reticulocyte-rich spleen, with secondary involvement of the intravascular compartment. The spleen is not solely a compartment for parasite destruction and clearance. Specific adaptations have likely evolved to maximise P. vivax survival in the spleen.

Genetic epidemiology can provide important insights into parasite transmission that can inform public health interventions. The current study compared long-term changes in the genetic diversity and structure of co-endemic Plasmodium falciparum and P. vivax populations. The study was conducted in Papua Indonesia, where high-grade chloroquine resistance in P. falciparum and P. vivax led to a universal policy of Artemisinin-based Combination Therapy (ACT) in 2006. Microsatellite typing and population genetic analyses were undertaken on available isolates collected between 2004 and 2017 from patients with uncomplicated malaria (n = 666 P. falciparum and n = 615 P. vivax). The proportion of polyclonal P. falciparum infections fell from 28% (38/135) before policy change (2004–2006) to 18% (22/125) at the end of the study (2015–2017); p, Author summary Genetic epidemiology is gaining widespread interest as a tool that can enhance conventional malaria surveillance. However, few studies have assessed the utility of molecular analyses in quantifying long-term changes in malaria transmission. The current study compared changes in the genetic diversity and structure of co-endemic P. vivax and P. falciparum populations sampled over 14 years (2004–2017) in Papua Indonesia, during which the incidence of both P. falciparum and P. vivax malaria halved. The study found larger genetic changes in P. falciparum than P. vivax, reflecting a greater impact of local interventions, including the implementation of a new drug policy (universal Artemisinin-Based Combined Therapy) in 2006, on P. falciparum. Both species exhibited decreasing complexity of infections over time, consistent with declining transmission. However, the P. falciparum population showed greater evidence of a recent bottleneck than the P. vivax population. Four subpopulations were observed amongst the P. falciparum isolates, one of which predominated in 2016–2017, potentially reflecting recent adaptation. The results concur with epidemiological studies performed in the same area, that found declining transmission in both species, with less impact on P. vivax infections. Radical cure to treat the dormant liver stages may enable larger reductions in P. vivax transmission. The results support the great potential of molecular surveillance in complementing traditional malariometric approaches.

Background Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax. Methods and findings Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7–49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1–12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40–24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48–0.84), p = 0.0013 and 0.83 (0.73–0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99–1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01–0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10–0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01–0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups. Conclusions In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis., In this systematic review and individual patient data meta-analysis, Robert Commons and colleagues compare the clinical efficacy of different artemisinin-based combination therapies for treating Plasmodium vivax malaria., Author summary Why was this study done? The susceptibility of Plasmodium vivax to chloroquine is decreasing in many malaria-endemic locations. Artemisinin-based combination therapies (ACTs) are recommended in areas of emerging chloroquine resistance; however, the optimal ACT is not clear. Knowledge of the comparative advantages and disadvantages of different ACTs will help guide national policy makers. What did the researchers do and find? Following a systematic review, individual data from 2,017 patients were pooled from 19 studies undertaken between January 1, 2000, and January 31, 2018. Cox regression analysis showed that the risk of recurrence at day 42 was 12-fold greater following treatment with artemether-lumefantrine (AL) alone compared with dihydroartemisinin-piperaquine (DP), although by day 63 the risk of recurrence following DP was also high. For every 5-mg/kg increase in the dose of piperaquine, the risk of recurrence at day 42 fell by 37%. A delay in the time to symptomatic recurrence was associated with an increase in haemoglobin. Coadministration with primaquine reduced the risk of recurrence at day 42 after AL by 80% and at day 63 after DP by 92%. What do these findings mean? There is a high risk of recurrence following AL or DP unless they are combined with primaquine. Compared with AL, patients treated with DP have a reduced risk of early P. vivax recurrence. Delaying the time to recurrence was associated with greater haematological recovery, and this has potential to prevent morbidity related to multiple rapid recurrences by preventing a cumulative risk of anaemia.

Summary Background Malaria infection during pregnancy is associated with serious adverse maternal and birth outcomes. A randomised controlled trial in Papua, Indonesia, comparing the efficacy of intermittent preventive treatment with dihydroartemisinin-piperaquine with the current strategy of single screening and treatment showed that intermittent preventive treatment is a promising alternative treatment for the reduction of malaria in pregnancy. We aimed to estimate the incremental cost-effectiveness of intermittent preventive treatment with dihydroartemisinin-piperaquine compared with single screening and treatment with dihydroartemisinin-piperaquine. Methods We did a provider perspective analysis. A decision tree model was analysed from a health provider perspective over a lifetime horizon. Model parameters were used in deterministic and probabilistic sensitivity analyses. Simulations were run in hypothetical cohorts of 1000 women who received intermittent preventive treatment or single screening and treatment. Disability-adjusted life-years (DALYs) for fetal loss or neonatal death, low birthweight, moderate or severe maternal anaemia, and clinical malaria were calculated from trial data and cost estimates in 2016 US dollars from observational studies, health facility costings and public procurement databases. The main outcome measure was the incremental cost per DALY averted. Findings Relative to single screening and treatment, intermittent preventive treatment resulted in an incremental cost of US$5657 (95% CI 1827 to 9448) and 107·4 incremental DALYs averted (–719·7 to 904·1) per 1000 women; the average incremental cost-effectiveness ratio was $53 per DALY averted. Interpretation Intermittent preventive treatment with dihydroartemisinin-piperaquine offers a cost-effective alternative to single screening and treatment for the prevention of the adverse effects of malaria infection in pregnancy in the context of the moderate malaria transmission setting of Papua. The higher cost of intermittent preventive treatment was driven by monthly administration, as compared with single-administration single screening and treatment. However, acceptability and feasibility considerations will also be needed to inform decision making. Funding Medical Research Council, Department for International Development, and Wellcome Trust.

Background An acute episode of malaria can be followed by multiple recurrent episodes either due to re-infection, recrudescence of a partially treated parasite or, in the case of Plasmodium vivax or P. ovale, relapse from the dormant liver stage of the parasite. The aim of this study was to quantify the impact of recurrent malaria episodes on morbidity and mortality in Papua, Indonesia. Methods We undertook a retrospective analysis of routinely collected data from malaria patients attending the primary referral hospital in Papua, Indonesia, between April 2004 and December 2013. Multi-state modelling was used to estimate the effect of recurring malaria episodes on re-presentation and admission to hospital and death. The risks of early (≤ 14 days) and late (15 to 365 days) hospital admission and death were estimated separately in our study to distinguish between the direct and indirect effects of malaria recurrence on adverse outcomes. Results A total of 68,361 patients were included in the analysis, of whom 37,168 (54.4%) presented initially with P. falciparum, 22,209 (32.5%) with P. vivax, and 8984 (13.1%) with other species. During 12 months of follow-up after each of the first four malaria episodes, 10,868 (15.9%) patients were admitted to hospital and 897 (1.3%) died. The risk of re-presenting to the hospital with malaria increased from 34.7% (95% CI 34.4%, 35.1%) at first episode to 58.6% (57.5%, 59.6%) following the third episode of malaria. After adjusting for co-factors, infection with P. vivax was a significant risk factor for re-presentation (hazard ratio (HR) = 1.48 (95% CI 1.44, 1.51)) and late admission to hospital (HR = 1.17 (1.11, 1.22)). Patients infected with P. falciparum had a greater overall rate of mortality within 14 days (HR = 1.54 (1.25, 1.92)), but after multiple episodes of malaria, there was a trend towards a higher rate of early death in patients infected with P. vivax compared to P. falciparum (HR = 1.91 (0.73, 4.97)). Conclusions Compared to patients initially infected with P. falciparum, those infected with P. vivax had significantly more re-presentations to hospital with malaria, and this contributed to a high risk of inpatient admission and death. These findings highlight the importance of radical cure of P. vivax to eliminate the dormant liver stages that trigger relapses.

Background Malaria 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 findings A 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. Conclusions In 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., Ric Price and colleagues report on changes in Plasmodium falciparum and vivax malaria following a universal malaria treatment programme in Papua, Indonesia., Author summary Why was this study done? Multidrug-resistant malaria results in recurrent parasitaemia, a cumulative risk of anaemia, and progression to severe and fatal disease. Whilst artemisinin combination therapies (ACTs) and intravenous (IV) artesunate can reduce morbidity and mortality associated with P. falciparum malaria, they have no activity on the hypnozoite stages of P. vivax, which can relapse weeks to months following an initial infection and sustain ongoing transmission of the parasite. In Papua, Indonesia, antimalarial resistance has emerged in both P. falciparum and P. vivax. We used a prospective malariometric surveillance network to investigate the differential impact of a universal policy of ACTs for uncomplicated malaria and IV artesunate for severe malaria on the morbidity and mortality attributable to P. falciparum and P. vivax. What did the researchers do and find? After controlling for population growth and changes in treatment-seeking behaviour, the incidence of malaria after policy change fell by about 60% for P. falciparum and 40% for P. vivax. There was a 50% fall in the proportion of patients with malaria requiring admission to hospital and a 30% fall in malaria-related mortality. Bed occupancy due to admission with malaria fell by 25%. Whilst there was a small decrease in the absolute incidence of P. vivax infections over the 9-year study period, the proportion of malaria cases and malaria-attributable deaths to P. vivax increased with time. What do these findings mean? The results highlight the importance of highly effective blood schizontocidal antimalarial drugs in reducing the overall burden of drug-resistant malaria. The rising proportion of malaria due to P. vivax emphasizes the need for safe and effective drug regimens that clear both the blood and liver stages of P. vivax in malaria elimination efforts in coendemic regions.

Platelets are understood to assist host innate immune responses against infection, although direct evidence of this function in any human disease, including malaria, is unknown. Here we characterized platelet–erythrocyte interactions by microscopy and flow cytometry in patients with malaria naturally infected with Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, or Plasmodium knowlesi. Blood samples from 376 participants were collected from malaria-endemic areas of Papua, Indonesia, and Sabah, Malaysia. Platelets were observed binding directly with and killing intraerythrocytic parasites of each of the Plasmodium species studied, particularly mature stages, and was greatest in P vivax patients. Platelets preferentially bound to the infected more than to the uninfected erythrocytes in the bloodstream. Analysis of intraerythrocytic parasites indicated the frequent occurrence of platelet-associated parasite killing, characterized by the intraerythrocytic accumulation of platelet factor-4 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling of parasite nuclei (PF4+TUNEL+ parasites). These PF4+TUNEL+ parasites were not associated with measures of systemic platelet activation. Importantly, patient platelet counts, infected erythrocyte-platelet complexes, and platelet-associated parasite killing correlated inversely with patient parasite loads. These relationships, taken together with the frequency of platelet-associated parasite killing observed among the different patients and Plasmodium species, suggest that platelets may control the growth of between 5% and 60% of circulating parasites. Platelet–erythrocyte complexes made up a major proportion of the total platelet pool in patients with malaria and may therefore contribute considerably to malarial thrombocytopenia. Parasite killing was demonstrated to be platelet factor-4-mediated in P knowlesi culture. Collectively, our results indicate that platelets directly contribute to innate control of Plasmodium infection in human malaria.

Background In southern Papua, Indonesia, malaria is highly prevalent in young children and is a significant cause of morbidity and early mortality. The association between malaria and delayed mortality is unknown. Methods Routinely-collected hospital surveillance data from southern Papua, Indonesia, were used to assess the risk of recurrent malaria and mortality within 12 months of an initial presentation with malaria in all children younger than 5 years old attending the local hospital. Analysis was primarily by Kaplan Meier and Cox regression methods. Results In total 15,716 children presenting with malaria between April 2004 and December 2013 were included in the analysis; 6184 (39.3%) with Plasmodium falciparum, 7499 (47.7%) with P. vivax, 203 (1.3%) with P. malariae, 3 with P. ovale and 1827 (11.6%) with mixed infections. Within 1 year, 48.4% (7620/15,716) of children represented a total of 16,957 times with malaria (range 1 to 11 episodes), with the incidence of malaria being greater in patients initially presenting with P. vivax infection (1334 [95%CI 1307–1361] per 1000 patient years) compared to those with P. falciparum infection (920 [896–944]). In total 266 (1.7%) children died within 1 year of their initial presentation, 129 (48.5%) within 30 days and 137 (51.5%) between 31 and 365 days. There was no significant difference in the mortality risk in patients infected with P. vivax versus P. falciparum either before 30 days (Hazard Ratio (HR) 1.02 [0.69,1.49]) or between 31 and 365 days (HR = 1.30 [0.90,1.88]). Children who died had a greater incidence of malaria, 2280 [95%CI 1946–2671] per 1000 patient years preceding their death, compared to 1141 [95%CI 1124–1158] per 1000 patient years in those surviving. Conclusions Children under-5 years old with P. vivax malaria, are at significant risk of multiple representations with malaria and of dying within 1 year of their initial presentation. Preventing recurrent malaria must be a public health priority in this vulnerable population.

Chloroquine (CQ) has been the mainstay of malaria treatment for more than 60 years. However, the emergence and spread of CQ resistance now restrict its use to only a few areas where malaria is endemic. The aim of the present study was to investigate whether a novel combination of a CQ-like moiety and an imipramine-like pharmacophore can reverse CQ resistance ex vivo . Between March to October 2011 and January to September 2013, two “reversed chloroquine” (RCQ) compounds (PL69 and PL106) were tested against multidrug-resistant field isolates of Plasmodium falciparum ( n = 41) and Plasmodium vivax ( n = 45) in Papua, Indonesia, using a modified ex vivo schizont maturation assay. The RCQ compounds showed high efficacy against both CQ-resistant P. falciparum and P. vivax field isolates. For P. falciparum , the median 50% inhibitory concentrations (IC 50 s) were 23.2 nM for PL69 and 26.6 nM for PL106, compared to 79.4 nM for unmodified CQ ( P < 0.001 and P = 0.036, respectively). The corresponding values for P. vivax were 19.0, 60.0, and 60.9 nM ( P < 0.001 and P = 0.018, respectively). There was a significant correlation between IC 50 s of CQ and PL69 (Spearman's rank correlation coefficient [ r s ] = 0.727, P < 0.001) and PL106 ( r s = 0.830, P < 0.001) in P. vivax but not in P. falciparum . Both RCQs were equally active against the ring and trophozoite stages of P. falciparum , but in P. vivax , PL69 and PL106 showed less potent activity against trophozoite stages (median IC 50 s, 130.2 and 172.5 nM) compared to ring stages (median IC 50 s, 17.6 and 91.3 nM). RCQ compounds have enhanced ex vivo activity against CQ-resistant clinical isolates of P. falciparum and P. vivax , suggesting the potential use of reversal agents in antimalarial drug development. Interspecies differences in RCQ compound activity may indicate differences in CQ pharmacokinetics between the two Plasmodium species.

Clinical illness with Plasmodium falciparum or Plasmodium vivax compromises the function of dendritic cells (DC) and expands regulatory T (Treg) cells. Individuals with asymptomatic parasitemia have clinical immunity, restricting parasite expansion and preventing clinical disease. The role of DC and Treg cells during asymptomatic Plasmodium infection is unclear. During a cross-sectional household survey in Papua, Indonesia, we examined the number and activation of blood plasmacytoid DC (pDC), CD141 + , and CD1c + myeloid DC (mDC) subsets and Treg cells using flow cytometry in 168 afebrile children (of whom 15 had P. falciparum and 36 had P. vivax infections) and 162 afebrile adults (of whom 20 had P. falciparum and 20 had P. vivax infections), alongside samples from 16 patients hospitalized with uncomplicated malaria. Unlike DC from malaria patients, DC from children and adults with asymptomatic, microscopy-positive P. vivax or P. falciparum infection increased or retained HLA-DR expression. Treg cells in asymptomatic adults and children exhibited reduced activation, suggesting increased immune responsiveness. The pDC and mDC subsets varied according to clinical immunity (asymptomatic or symptomatic Plasmodium infection) and, in asymptomatic infection, according to host age and parasite species. In conclusion, active control of asymptomatic infection was associated with and likely contingent upon functional DC and reduced Treg cell activation.

Background Anaemia in children under five years old is associated with poor health, growth and developmental outcomes. In Papua, Indonesia, where the burden of anaemia in infants is high, we conducted a community survey to assess the association between Plasmodium infection, helminth carriage and the risk of anaemia. Methods A cross sectional household survey was carried out between April and July 2013 in 16 villages in the District of Mimika using a multistage sampling procedure. A total of 629 children aged 1–59 months from 800 households were included in the study. Demographic, symptom and anthropometry data were recorded using a standardized questionnaire. Blood and stool samples were collected for examination. Results Of the 533 children with blood film examination, 8.8% (47) had P. vivax parasitaemia and 3.9% (21) had P. falciparum; the majority of children with malaria were asymptomatic (94.4%, 68/72). Soil transmitted helminth (STH) infection was present in 43% (105/269) of children assessed; those with STH were at significantly greater risk of P. vivax parasitaemia compared to those without STH (OR = 3.7 [95%CI 1.5–9.2], p = 0.004). Anaemia (Hb

Pregnant women are particularly vulnerable to malaria; they have an increased risk of infection and a greater risk of severe disease, compared with their nonpregnant counterparts [1, 2]. In sub-Saharan Africa, even asymptomatic infections increase the risk of low birth weight, preterm delivery, and perinatal death [3, 4]. In Asia and South America, where the level of Plasmodium falciparum transmission is less than that in Africa, women have little acquired immunity, and malaria infections are more frequently symptomatic, with an associated increased risk of maternal and/or fetal death [5, 6]. In these regions, Plasmodium vivax frequently coexists with P. falciparum, often accounting for more than one-half of malaria infections [7]. Although P. vivax infection has received less attention than P. falciparum infection, it is clearly an important contributor to both maternal anemia and low birth weight [8-10]. The burden of malaria during pregnancy has been complicated by the emergence of antimalarial drug resistance. Whereas chloroquine resistance in P. falciparum emerged in Southeast Asia >40 years ago, drug resistance in P. vivax has been slower to evolve. The first chloroquine-resistant isolates of P. vivax were reported from Papua, Indonesia, and Papua New Guinea in 1991 and have subsequently spread throughout the Indonesian archipelago [11-15]. In southern Papua, multidrug-resistant strains of both P. falciparum and P. vivax are now highly prevalent, with 65% of patients experiencing treatment failure within 28 days after chloroquine monotherapy for P. vivax and 48% experiencing treatment failure after treatment with chloroquine plus sulfadoxine-pyrimethamine for P. falciparum infection [16]. Unsupervised oral quinine is associated with 80% treatment failure, likely because of poor adherence to 7 days of therapy. Despite these limitations, chloroquine and quinine remained the standard treatments for P. vivax and P. falciparum malaria in pregnant women until 2006. The aim of the current study was to quantify the prevalence of P. vivax and P. falciparum infections in pregnant women in an area with high levels of drug resistance to both parasites and to describe the associated health-related consequences.

BACKGROUND: Plasmodium vivax causes almost half of all malaria cases in Asia and is recognised as a significant cause of morbidity. In recent years it has been associated with severe and fatal disease. The extent to which P. vivax contributes to death is not known. METHODS: To define the epidemiology of mortality attributable to vivax malaria in southern Papua, Indonesia, a retrospective clinical records-based audit was conducted of all deaths in patients with vivax malaria at a tertiary referral hospital. RESULTS: Between January 2004 and September 2009, hospital surveillance identified 3,495 inpatients with P. vivax monoinfection and 65 (1.9%) patients who subsequently died. Charts for 54 of these 65 patients could be reviewed, 40 (74%) of whom had pure P. vivax infections on cross-checking. Using pre-defined conservative criteria, vivax malaria was the primary cause of death in 6 cases, a major contributor in 17 cases and a minor contributor in a further 13 cases. Extreme anaemia was the most common primary cause of death. Malnutrition, sepsis with respiratory and gastrointestinal manifestations, and chronic diseases were the commonest attributed causes of death for patients in the latter two categories. There were an estimated 293,763 cases of pure P. vivax infection in the community during the study period giving an overall minimum case fatality of 0.12 per 1,000 infections. The corresponding case fatality in hospitalised patients was 10.3 per 1,000 infections. CONCLUSIONS: Although uncommonly directly fatal, vivax malaria is an important indirect cause of death in southern Papua in patients with malnutrition, sepsis syndrome and chronic diseases, including HIV infection.