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    Patterns of protective associations differ for antibodies to &ITP&IT. &ITfalciparum&IT-infected erythrocytes and merozoites in immunity against malaria in children
    Chan, J-A ; Stanisic, D ; Duffy, MF ; Robinson, LJ ; Lin, E ; Kazura, JW ; King, CL ; Siba, PM ; Fowkes, FJ ; Mueller, I ; Beeson, JG (WILEY, 2017-12-01)
    Acquired antibodies play an important role in immunity to P. falciparum malaria and are typically directed towards surface antigens expressed by merozoites and infected erythrocytes (IEs). The importance of specific IE surface antigens as immune targets remains unclear. We evaluated antibodies and protective associations in two cohorts of children in Papua New Guinea. We used genetically-modified P. falciparum to evaluate the importance of PfEMP1 and a P. falciparum isolate with a virulent phenotype. Our findings suggested that PfEMP1 was the dominant target of antibodies to the IE surface, including functional antibodies that promoted opsonic phagocytosis by monocytes. Antibodies were associated with increasing age and concurrent parasitemia, and were higher among children exposed to a higher force-of-infection as determined using molecular detection. Antibodies to IE surface antigens were consistently associated with reduced risk of malaria in both younger and older children. However, protective associations for antibodies to merozoite surface antigens were only observed in older children. This suggests that antibodies to IE surface antigens, particularly PfEMP1, play an earlier role in acquired immunity to malaria, whereas greater exposure is required for protective antibodies to merozoite antigens. These findings have implications for vaccine design and serosurveillance of malaria transmission and immunity.
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    Point-of-care testing and treatment of sexually transmitted infections to improve birth outcomes in high-burden, low-income settings: Study protocol for a cluster randomized crossover trial (the WANTAIM Trial, Papua New Guinea).
    Vallely, AJ ; Pomat, WS ; Homer, C ; Guy, R ; Luchters, S ; Mola, GDL ; Kariwiga, G ; Vallely, LM ; Wiseman, V ; Morgan, C ; Wand, H ; Rogerson, SJ ; Tabrizi, SN ; Whiley, DM ; Low, N ; Peeling, R ; Siba, P ; Riddell, M ; Laman, M ; Bolnga, J ; Robinson, LJ ; Morewaya, J ; Badman, SG ; Batura, N ; Kelly-Hanku, A ; Toliman, PJ ; Peter, W ; Babona, D ; Peach, E ; Garland, SM ; Kaldor, JM (F1000 Research Ltd, 2019)
    Background: Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and bacterial vaginosis have been associated with preterm birth and low birth weight, and are highly prevalent among pregnant women in many low- and middle-income settings. There is conflicting evidence on the potential benefits of screening and treating these infections in pregnancy. Newly available diagnostic technologies make it possible, for the first time, to conduct definitive field trials to fill this knowledge gap. The primary aim of this study is to evaluate whether antenatal point-of-care testing and immediate treatment of these curable sexually transmitted and genital infections (STIs) leads to reduction in preterm birth and low birth weight. Methods: The Women and Newborn Trial of Antenatal Interventions and Management (WANTAIM) is a cluster-randomised crossover trial in Papua New Guinea to compare point-of-care STI testing and immediate treatment with standard antenatal care (which includes the WHO-endorsed STI 'syndromic' management strategy based on clinical features alone without laboratory confirmation). The unit of randomisation is a primary health care facility and its catchment communities. The primary outcome is a composite measure of two events: the proportion of women and their newborns in each trial arm, who experience either preterm birth (delivery <37 completed weeks of gestation as determined by ultrasound) and/or low birth weight (<2500 g measured within 72 hours of birth). The trial will also evaluate neonatal outcomes, as well as the cost-effectiveness, acceptability and health system requirements of this strategy, compared with standard care. Conclusions: WANTAIM is the first randomised trial to evaluate the effectiveness, cost-effectiveness, acceptability and health system requirements of point-of-care STI testing and treatment to improve birth outcomes in high-burden settings. If the intervention is proven to have an impact, the trial will hasten access to these technologies and could improve maternal and neonatal health in high-burden settings worldwide. Registration: ISRCTN37134032.
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    Point-of-care testing and treatment of sexually transmitted infections to improve birth outcomes in high-burden, low-income settings: Study protocol for a cluster randomized crossover trial (the WANTAIM Trial, Papua New Guinea)
    Vallely, A ; Pomat, W ; Homer, C ; Guy, R ; Luchters, S ; Mola, G ; Kariwiga, G ; Vallely, L ; Wiseman, V ; Morgan, C ; Wand, H ; Rogerson, S ; Tabrizi, S ; Whiley, D ; Low, N ; Peeling, R ; Siba, P ; Riddell, M ; Laman, M ; Bolnga, J ; Robinson, L ; Morewaya, J ; Badman, S ; Batura, N ; Kelly-Hanku, A ; Toliman, P ; Peter, W ; Babona, D ; Peach, E ; Garland, S ; Kaldor, J (F1000 Research Ltd, 2019-03-22)
    Background: Chlamydia trachomatis , Neisseria gonorrhoeae , Trichomonas vaginalis and bacterial vaginosis have been associated with preterm birth and low birth weight, and are highly prevalent among pregnant women in many low- and middle-income settings. There is conflicting evidence on the potential benefits of screening and treating these infections in pregnancy. Newly available diagnostic technologies make it possible, for the first time, to conduct definitive field trials to fill this knowledge gap. The primary aim of this study is to evaluate whether antenatal point-of-care testing and immediate treatment of these curable sexually transmitted and genital infections (STIs) leads to reduction in preterm birth and low birth weight. Methods : The Women and Newborn Trial of Antenatal Interventions and Management (WANTAIM) is a cluster-randomised crossover trial in Papua New Guinea to compare point-of-care STI testing and immediate treatment with standard antenatal care (which includes the WHO-endorsed STI ‘syndromic’ management strategy based on clinical features alone without laboratory confirmation). The unit of randomisation is a primary health care facility and its catchment communities. The primary outcome is a composite measure of two events: the proportion of women and their newborns in each trial arm, who experience either preterm birth (delivery <37 completed weeks of gestation as determined by ultrasound) and/or low birth weight (<2500 g measured within 72 hours of birth). The trial will also evaluate neonatal outcomes, as well as the cost-effectiveness, acceptability and health system requirements of this strategy, compared with standard care. Conclusions: WANTAIM is the first randomised trial to evaluate the effectiveness, cost-effectiveness, acceptability and health system requirements of point-of-care STI testing and treatment to improve birth outcomes in high-burden settings. If the intervention is proven to have an impact, the trial will hasten access to these technologies and could improve maternal and neonatal health in high-burden settings worldwide. Registration: ISRCTN37134032 .
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    A Randomized Open-Label Evaluation of the Antimalarial Prophylactic Efficacy of Azithromycin-Piperaquine versus Sulfadoxine-Pyrimethamine in Pregnant Papua New Guinean Women
    Moore, BR ; Benjamin, JM ; Tobe, R ; Ome-Kaius, M ; Yadi, G ; Kasian, B ; Kong, C ; Robinson, LJ ; Laman, M ; Mueller, I ; Rogerson, S ; Davis, TME (American Society for Microbiology, 2019-10-01)
    Emerging malaria parasite sulfadoxine-pyrimethamine (SP) resistance has prompted assessment of alternatives for intermittent preventive treatment in pregnancy (IPTp). The objective was to evaluate the tolerability and prophylactic efficacy of azithromycin (AZ) plus piperaquine (PQ) in pregnant women in Papua New Guinea. The study was an open-label, randomized, parallel-group trial. A total of 122 women (median gestation, 26 weeks [range, 14 to 32 weeks]) were randomized 1:1 to three daily doses of 1 g AZ plus 960 mg PQ tetraphosphate or single-dose SP (4,500 mg sulfadoxine plus 225 mg pyrimethamine), based on computer-generated block randomization. Tolerability was assessed to day 7, and efficacy was assessed to day 42 (when participants were returned to usual care) and at delivery. Data for 119 participants (AZ-PQ, n = 61; SP, n = 58) were analyzed. Both regimens were well tolerated, but AZ-PQ was associated with more gastrointestinal side effects (31%) and dizziness (21%). Eight women (6.7%) were parasitemic at recruitment but all were aparasitemic by 72 h. There were no differences in blood smear positivity rates between AZ-PQ and SP up to day 42 (0% versus 5.2%; relative risk [RR], 0.14 [95% confidence interval [CI], 0.01 to 2.58] [P = 0.18]; absolute risk reduction [ARR], 5.2% [95% CI, -1.3 to 11.6%]) and at the time of delivery (0% versus 8.7%; RR, 0.11 [95% CI, 0.01 to 2.01] [P = 0.14]; ARR, 8.7% [95% CI, -0.2 to 17.6%]). Of 92 women who were monitored to parturition, 89 (97%) delivered healthy babies; there were 3 stillbirths (SP, n = 1; AZ-PQ, n = 2 [twins]). There was a higher live birth weight (mean ± standard deviation) in the AZ-PQ group (3.13 ± 0.42 versus 2.88 ± 0.55 kg [P = 0.016]; mean difference, 0.25 kg [95% CI, 0.02 to 0.48 kg]). AZ-PQ is a promising candidate for IPTp.
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    Combining different diagnostic studies of lymphatic filariasis for risk mapping in Papua New Guinea: a predictive model from microfilaraemia and antigenaemia prevalence surveys.
    Berg Soto, A ; Xu, Z ; Wood, P ; Sanuku, N ; Robinson, LJ ; King, CL ; Tisch, D ; Susapu, M ; Graves, PM (Springer Science and Business Media LLC, 2018)
    BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis has encouraged countries to follow a set of guidelines to help them assess the need for mass drug administration and evaluate its progress. Papua New Guinea (PNG) is one of the highest priority countries in the Western Pacific for lymphatic filariasis and the site of extensive research on lymphatic filariasis and surveys of its prevalence. However, different diagnostic tests have been used and thresholds for each test are unclear. METHODS: We reviewed the prevalence of lymphatic filariasis reported in 295 surveys conducted in PNG between 1990 and 2014, of which 65 used more than one test. Results from different diagnostics were standardised using a set of criteria that included a model to predict antigen prevalence from microfilariae prevalence. We mapped the point location of each of these surveys and categorised their standardised prevalence estimates. RESULTS: Several predictive models were produced and investigated, including the effect of any mass drug administration and number of rounds prior to the surveys. One model was chosen based on goodness of fit parameters and used to predict antigen prevalence for surveys that tested only for microfilariae. Standardised prevalence values show that 72% of all surveys reported a prevalence above 0.05. High prevalence was situated on the coastal north, south and island regions, while the central highland area of Papua New Guinea shows low levels of prevalence. CONCLUSIONS: Our study is the first to provide an explicit predictive relationship between the prevalence values based on empirical results from antigen and microfilaria tests, taking into account the occurrence of mass drug administration. This is a crucial step to combine studies to develop risk maps of lymphatic filariasis for programme planning and evaluation, as shown in the case of Papua New Guinea.
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    Efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated malaria in Papua New Guinea
    Tavul, L ; Hetzel, MW ; Teliki, A ; Walsh, D ; Kiniboro, B ; Rare, L ; Pulford, J ; Siba, PM ; Karl, S ; Makita, L ; Robinson, L ; Kattenberg, JH ; Laman, M ; Oswyn, G ; Mueller, I (BMC, 2018-10-05)
    BACKGROUND: In 2009, the Papua New Guinea (PNG) Department of Health adopted artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PPQ) as the first- and second-line treatments for uncomplicated malaria, respectively. This study was conducted to assess the efficacy of both drugs following adoption of the new policy. METHODS: Between June 2012 and September 2014, a therapeutic efficacy study was conducted in East Sepik and Milne Bay Provinces of PNG in accordance with the standard World Health Organization (WHO) protocol for surveillance of anti-malarial drug efficacy. Patients ≥ 6 months of age with microscopy confirmed Plasmodium falciparum or Plasmodium vivax mono-infections were enrolled, treated with AL or DHA-PPQ, and followed up for 42 days. Study endpoints were adequate clinical and parasitological response (ACPR) on days 28 and 42. The in vitro efficacy of anti-malarials and the prevalence of selected molecular markers of resistance were also determined. RESULTS: A total of 274 P. falciparum and 70 P. vivax cases were enrolled. The day-42 PCR-corrected ACPR for P. falciparum was 98.1% (104/106) for AL and 100% (135/135) for DHA-PPQ. The day-42 PCR-corrected ACPR for P. vivax was 79.0% (15/19) for AL and 92.3% (36/39) for DHA-PPQ. Day 3 parasite clearance of P. falciparum was 99.2% with AL and 100% with DHA-PPQ. In vitro testing of 96 samples revealed low susceptibility to chloroquine (34% of samples above IC50 threshold) but not to lumefantrine (0%). Molecular markers assessed in a sub-set of the study population indicated high rates of chloroquine resistance in P. falciparum (pfcrt SVMNT: 94.2%, n = 104) and in P. vivax (pvmdr1 Y976F: 64.8%, n = 54). CONCLUSIONS: AL and DHA-PPQ were efficacious as first- and second-line treatments for uncomplicated malaria in PNG. Continued in vivo efficacy monitoring is warranted considering the threat of resistance to artemisinin and partner drugs in the region and scale-up of artemisinin-based combination therapy in PNG.
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    Mathematical modelling of the impact of expanding levels of malaria control interventions on Plasmodium vivax
    White, MT ; Walker, P ; Karl, S ; Hetzel, MW ; Freeman, T ; Waltmann, A ; Laman, M ; Robinson, LJ ; Ghani, A ; Mueller, I (NATURE PUBLISHING GROUP, 2018-08-17)
    Plasmodium vivax poses unique challenges for malaria control and elimination, notably the potential for relapses to maintain transmission in the face of drug-based treatment and vector control strategies. We developed an individual-based mathematical model of P. vivax transmission calibrated to epidemiological data from Papua New Guinea (PNG). In many settings in PNG, increasing bed net coverage is predicted to reduce transmission to less than 0.1% prevalence by light microscopy, however there is substantial risk of rebounds in transmission if interventions are removed prematurely. In several high transmission settings, model simulations predict that combinations of existing interventions are not sufficient to interrupt P. vivax transmission. This analysis highlights the potential options for the future of P. vivax control: maintaining existing public health gains by keeping transmission suppressed through indefinite distribution of interventions; or continued development of strategies based on existing and new interventions to push for further reduction and towards elimination.
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    Sustained Malaria Control Over an 8-Year Period in Papua New Guinea: The Challenge of Low-Density Asymptomatic Plasmodium Infections
    Koepfli, C ; Ome-Kaius, M ; Jally, S ; Malau, E ; Maripal, S ; Ginny, J ; Timinao, L ; Kattenberg, JH ; Obadia, T ; White, M ; Rarau, P ; Senn, N ; Barry, AE ; Kazura, JW ; Mueller, I ; Robinson, LJ (OXFORD UNIV PRESS INC, 2017-12-01)
    Background: The scale-up of effective malaria control in the last decade has resulted in a substantial decline in the incidence of clinical malaria in many countries. The effects on the proportions of asymptomatic and submicroscopic infections and on transmission potential are yet poorly understood. Methods: In Papua New Guinea, vector control has been intensified since 2008, and improved diagnosis and treatment was introduced in 2012. Cross-sectional surveys were conducted in Madang Province in 2006 (with 1280 survey participants), 2010 (with 2117 participants), and 2014 (with 2516 participants). Infections were quantified by highly sensitive quantitative polymerase chain reaction (PCR) analysis, and gametocytes were quantified by reverse-transcription qPCR analysis. Results: Plasmodium falciparum prevalence determined by qPCR decreased from 42% in 2006 to 9% in 2014. The P. vivax prevalence decreased from 42% in 2006 to 13% in 2010 but then increased to 20% in 2014. Parasite densities decreased 5-fold from 2006 to 2010; 72% of P. falciparum and 87% of P. vivax infections were submicroscopic in 2014. Gametocyte density and positivity correlated closely with parasitemia, and population gametocyte prevalence decreased 3-fold for P. falciparum and 29% for P. vivax from 2010 to 2014. Conclusions: Sustained control has resulted in reduced malaria transmission potential, but an increasing proportion of gametocyte carriers are asymptomatic and submicroscopic and represent a challenge to malaria control.
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    Dosing pole recommendations for lymphatic filariasis elimination: A height-weight quantile regression modeling approach
    Goss, CW ; O'Brian, K ; Dubray, C ; Fischer, PU ; Hardy, M ; Jambulingam, P ; King, CL ; Laman, M ; Lemoine, JF ; Robinson, LJ ; Samuela, J ; Subramanian, S ; Supali, T ; Weil, GJ ; Schechtman, KB ; Samy, AM (PUBLIC LIBRARY SCIENCE, 2019-07-01)
    BACKGROUND: The World Health Organization (WHO) currently recommends height or age-based dosing as alternatives to weight-based dosing for mass drug administration lymphatic filariasis (LF) elimination programs. The goals of our study were to compare these alternative dosing strategies to weight-based dosing and to develop and evaluate new height-based dosing pole scenarios. METHODOLOGY/PRINCIPAL FINDINGS: Age, height and weight data were collected from >26,000 individuals in five countries during a cluster randomized LF clinical trial. Weight-based dosing for diethylcarbamazine (DEC; 6 mg/kg) and ivermectin (IVM; 200 ug/kg) with tablet numbers derived from a table of weight intervals was treated as the "gold standard" for this study. Following WHO recommended age-based dosing of DEC and height-based dosing of IVM would have resulted in 32% and 27% of individuals receiving treatment doses below those recommended by weight-based dosing for DEC and IVM, respectively. Underdosing would have been especially common in adult males, who tend to have the highest LF prevalence in many endemic areas. We used a 3-step modeling approach to develop and evaluate new dosing pole cutoffs. First, we analyzed the clinical trial data using quantile regression to predict weight from height. We then used weight predictions to develop new dosing pole cutoff values. Finally, we compared different dosing pole cutoffs and age and height-based WHO dosing recommendations to weight-based dosing. We considered hundreds of scenarios including country- and sex-specific dosing poles. A simple dosing pole with a 6-tablet maximum for both DEC and IVM reduced the underdosing rate by 30% and 21%, respectively, and was nearly as effective as more complex pole combinations for reducing underdosing. CONCLUSIONS/SIGNIFICANCE: Using a novel modeling approach, we developed a simple dosing pole that would markedly reduce underdosing for DEC and IVM in MDA programs compared to current WHO recommended height or age-based dosing.
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    The safety of double- and triple-drug community mass drug administration for lymphatic filariasis: A multicenter, open-label, cluster-randomized study
    Weil, GJ ; Bogus, J ; Christian, M ; Dubray, C ; Djuardi, Y ; Fischer, PU ; Goss, CW ; Hardy, M ; Jambulingam, P ; King, CL ; Kuttiat, VS ; Krishnamoorthy, K ; Laman, M ; Lemoine, JF ; O'Brian, KK ; Robinson, LJ ; Samuela, J ; Schechtman, KB ; Sircar, A ; Srividya, A ; Steer, AC ; Supali, T ; Subramanian, S ; Pomat, W ; Tavul, L ; Kotty, B ; Howard, SC ; Maure, T ; Kerry, Z ; Samuel, A ; Kumai, S ; Makita, L ; John, L ; Bieb, S ; Rahi, M ; Basker, N ; Raju, HKK ; Britto, RLJ ; Somani, R ; Dwivedi, GP ; Dr, S ; Gaded, S ; Lefevre, R ; Thys, F ; Jasmin, R ; Fayette, C ; Javell, A ; Ernest, JR ; Pavilus, G ; Dereny, A ; de Rochard, MB ; Ciceron, M ; Iskandar, E ; Maylasari, R ; Sudirman, ; Lomiga, A ; Sili, Y ; Jenga, M ; Sogara, PU ; Mezza, L ; Ngongo, Y ; Kama, M ; Tuicakau, M ; Romani, L ; Kaldor, J ; Whitfeld, M ; Naidu, R ; Lutumailagi, M ; Ravula, L ; Koroivueti, A ; Budge, P ; Rao, R ; Klenke, J ; Bjerum, C ; Tisch, D ; Tobon, J ; Howard, SC ; Rigney, A ; Lenhard, K ; Krentel, A ; Garner, P (PUBLIC LIBRARY SCIENCE, 2019-06-01)
    BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) provides antifilarial medications to hundreds of millions of people annually to treat filarial infections and prevent elephantiasis. Recent trials have shown that a single-dose, triple-drug treatment (ivermectin with diethylcarbamazine and albendazole [IDA]) is superior to a two-drug combination (diethylcarbamazine plus albendazole [DA]) that is widely used in LF elimination programs. This study was performed to assess the safety of IDA and DA in a variety of endemic settings. METHODS AND FINDINGS: Large community studies were conducted in five countries between October 2016 and November 2017. Two studies were performed in areas with no prior mass drug administration (MDA) for filariasis (Papua New Guinea and Indonesia), and three studies were performed in areas with persistent LF despite extensive prior MDA (India, Haiti, and Fiji). Participants were treated with a single oral dose of IDA (ivermectin, 200 μg/kg; diethylcarbamazine, 6 mg/kg; plus albendazole, a fixed dose of 400 mg) or with DA alone. Treatment assignment in each study site was randomized by locality of residence. Treatment was offered to residents who were ≥5 years of age and not pregnant. Adverse events (AEs) were assessed by medical teams with active follow-up for 2 days and passive follow-up for an additional 5 days. A total of 26,836 persons were enrolled (13,535 females and 13,300 males). A total of 12,280 participants were treated with DA, and 14,556 were treated with IDA. On day 1 or 2 after treatment, 97.4% of participants were assessed for AEs. The frequency of all AEs was similar after IDA and DA treatment (12% versus 12.1%, adjusted odds ratio for IDA versus DA 1.15, 95% CI 0.87-1.52, P = 0.316); 10.9% of participants experienced mild (grade 1) AEs, 1% experienced moderate (grade 2) AEs, and 0.1% experienced severe (grade 3) AEs. Rates of serious AEs after DA and IDA treatment were 0.04% (95% CI 0.01%-0.1%) and 0.01% (95% CI 0.00%-0.04%), respectively. Severity of AEs was not significantly different after IDA or DA. Five of six serious AEs reported occurred after DA treatment. The most common AEs reported were headache, dizziness, abdominal pain, fever, nausea, and fatigue. AE frequencies varied by country and were higher in adults and in females. AEs were more common in study participants with microfilaremia (33.4% versus 11.1%, P < 0.001) and more common in microfilaremic participants after IDA than after DA (39.4% versus 25.6%, P < 0.001). However, there was no excess of severe or serious AEs after IDA in this subgroup. The main limitation of the study was that it was open-label. Also, aggregation of AE data from multiple study sites tends to obscure variability among study sites. CONCLUSIONS: In this study, we observed that IDA was well tolerated in LF-endemic populations. Posttreatment AE rates and severity did not differ significantly after IDA or DA treatment. Thus, results of this study suggest that IDA should be as safe as DA for use as a MDA regimen for LF elimination in areas that currently receive DA. TRIAL REGISTRATION: Clinicaltrials.gov registration number: NCT02899936.