Piperaquine Pharmacokinetics during Intermittent Preventive Treatment for Malaria in Pregnancy.

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.).

Malaria Chemoprevention in the Postdischarge Management of Severe Anemia.

BACKGROUND: Children who have been hospitalized with severe anemia in areas of Africa in which malaria is endemic have a high risk of readmission and death within 6 months after discharge. No prevention strategy specifically addresses this period. METHODS: We conducted a multicenter, two-group, randomized, placebo-controlled trial in nine hospitals in Kenya and Uganda to determine whether 3 months of malaria chemoprevention could reduce morbidity and mortality after hospital discharge in children younger than 5 years of age who had been admitted with severe anemia. All children received standard in-hospital care for severe anemia and a 3-day course of artemether-lumefantrine at discharge. Two weeks after discharge, children were randomly assigned to receive dihydroartemisinin-piperaquine (chemoprevention group) or placebo, administered as 3-day courses at 2, 6, and 10 weeks after discharge. Children were followed for 26 weeks after discharge. The primary outcome was one or more hospital readmissions for any reason or death from the time of randomization to 6 months after discharge. Conditional risk-set modeling for recurrent events was used to calculate hazard ratios with the use of the Prentice-Williams-Peterson total-time approach. RESULTS: From May 2016 through May 2018, a total of 1049 children underwent randomization; 524 were assigned to the chemoprevention group and 525 to the placebo group. From week 3 through week 26, a total of 184 events of readmission or death occurred in the chemoprevention group and 316 occurred in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.54 to 0.78; P<0.001). The lower incidence of readmission or death in the chemoprevention group than in the placebo group was restricted to the intervention period (week 3 through week 14) (hazard ratio, 0.30; 95% CI, 0.22 to 0.42) and was not sustained after that time (week 15 through week 26) (hazard ratio, 1.13; 95% CI, 0.87 to 1.47). No serious adverse events were attributed to dihydroartemisinin-piperaquine. CONCLUSIONS: In areas with intense malaria transmission, 3 months of postdischarge malaria chemoprevention with monthly dihydroartemisinin-piperaquine in children who had recently received treatment for severe anemia prevented more deaths or readmissions for any reason after discharge than placebo. (Funded by the Research Council of Norway and the Centers for Disease Control and Prevention; ClinicalTrials.gov number, NCT02671175.).

Intermittent screening and treatment with dihydroartemisinin-piperaquine for the prevention of malaria in pregnancy: implementation feasibility in a routine healthcare system setting in western Kenya.

BACKGROUND: Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for preventing malaria in pregnancy in areas of moderate-to-high transmission in sub-Saharan Africa. However, due to increasing parasite resistance to SP, research on alternative strategies is a priority. The study assessed the implementation feasibility of intermittent screening and treatment (ISTp) in the second and third trimester at antenatal care (ANC) with malaria rapid diagnostic tests (RDTs) and treatment of positive cases with dihydroartemisinin-piperaquine (DP) compared to IPTp-SP in western Kenya. METHODS: A 10-month implementation study was conducted in 12 government health facilities in four sub-counties. Six health facilities were assigned to either ISTp-DP or IPTp-SP. Evaluation comprised of facility audits, ANC observations, and exit interviews. Intermediate and cumulative effectiveness analyses were performed on all processes involved in delivery of ISTp-DP including RDT proficiency and IPTp-SP ± directly observed therapy (DOT, standard of care). Logistic regression was used to identify predictors of receiving each intervention. RESULTS: A total of 388 and 389 women were recruited in the ISTp-DP and IPTp-SP arms, respectively. For ISTp-DP, 90% (289/320) of eligible women received an RDT. Of 11% (32/289) who tested positive, 71% received the correct dose of DP and 31% the first dose by DOT, and only 6% were counselled on subsequent doses. Women making a sick visit and being tested in a facility with a resident microscopist were more likely to receive ISTp-DP (AOR 1.78, 95% CI 1.31, 2.41; and AOR 3.75, 95% CI 1.31, 2.40, respectively). For IPTp-SP, only 57% received a dose of SP by DOT. Payment for a laboratory test was independently associated with receipt of SP by DOT (AOR 6.43, 95% CI 2.07, 19.98). CONCLUSIONS: The findings indicate that the systems effectiveness of ANC clinics to deliver ISTp-DP under routine conditions was poor in comparison to IPTp-SP. Several challenges to integration of ISTp with ANC were identified that may need to be considered by countries that have introduced screening at first ANC visit and, potentially, for future adoption of ISTp with more sensitive RDTs. Understanding the effectiveness of ISTp-DP will require additional research on pregnant women's adherence to ACT.

Modelling the incremental benefit of introducing malaria screening strategies to antenatal care in Africa.

Plasmodium falciparum in pregnancy is a major cause of adverse pregnancy outcomes. We combine performance estimates of standard rapid diagnostic tests (RDT) from trials of intermittent screening and treatment in pregnancy (ISTp) with modelling to assess whether screening at antenatal visits improves upon current intermittent preventative therapy with sulphadoxine-pyrimethamine (IPTp-SP). We estimate that RDTs in primigravidae at first antenatal visit are substantially more sensitive than in non-pregnant adults (OR = 17.2, 95% Cr.I. 13.8-21.6), and that sensitivity declines in subsequent visits and with gravidity, likely driven by declining susceptibility to placental infection. Monthly ISTp with standard RDTs, even with highly effective drugs, is not superior to monthly IPTp-SP. However, a hybrid strategy, recently adopted in Tanzania, combining testing and treatment at first visit with IPTp-SP may offer benefit, especially in areas with high-grade SP resistance. Screening and treatment in the first trimester, when IPTp-SP is contraindicated, could substantially improve pregnancy outcomes.

Measuring Goal-Concordant Care: Results and Reflections From Secondary Analysis of a Trial to Improve Serious Illness Communication.

CONTEXT: Many consider goal-concordant care (GCC) to be the most important of advance care planning and palliative care. Researchers face significant challenges in attempting to measure this outcome. We conducted a randomized controlled trial to assess the effects of a system-level intervention to improve serious illness communication on GCC and other outcomes. OBJECTIVES: To describe our measurement approach to GCC, present findings from a post-hoc analysis of trial data, and discuss lessons learned about measuring GCC. METHODS: Using trial data collected to measure GCC, we analyzed ratings and rankings from a nonvalidated survey of patient priorities in the setting of advanced cancer, the Life Priorities Scale, and compared outcomes with correlative measures. RESULTS: Participants commonly rated several predetermined and literature-derived priorities as important but did so in ways that were commonly incongruent with rankings. Ratings were frequently stable over time; rankings less so. Rankings are more likely to help assess the degree to which care is goal concordant but may be best augmented by corollary measures that signal achievement of a given priority. CONCLUSION: Measuring GCC remains a fundamental challenge to palliative care researchers. Ratings attest to the fact that many things matter to patients; however, rankings can better determine what matters most. Insights gained from our experience may guide future research aiming to use this outcome to assess the effect of intervention to improve serious illness care.

Impact of Intermittent Mass Testing and Treatment on Incidence of Malaria Infection in a High Transmission Area of Western Kenya.

Progress with malaria control in western Kenya has stagnated since 2007. Additional interventions to reduce the high burden of malaria in this region are urgently needed. We conducted a two-arm, community-based, cluster-randomized, controlled trial of active case detection and treatment of malaria infections in all residents mass testing and treatment (MTaT) of 10 village clusters (intervention clusters) for two consecutive years to measure differences in the incidence of clinical malaria disease and malaria infections compared with 20 control clusters where MTaT was not implemented. All residents of intervention clusters, irrespective of history of fever or other malaria-related symptoms, were tested three times per year before the peak malaria season using malaria rapid diagnostic tests. All positive cases were treated with dihydroartemisinin-piperaquine. The incidence of clinical malaria was measured through passive surveillance, whereas the cumulative incidence of malaria infection was measured using active surveillance in a cohort comprising randomly selected residents. The incidence of clinical malaria was 0.19 cases/person-year (p-y, 95% CI: 0.13-0.28) in the intervention arm and 0.24 cases/p-y (95% CI: 0.15-0.39) in the control arm (incidence rate ratio [IRR] 0.79, 95% CI: 0.61-1.02). The cumulative incidence of malaria infections was similar between the intervention (2.08 infections/p-y, 95% CI: 1.93-2.26) and control arms (2.19 infections/p-y, 95% CI: 2.02-2.37) with a crude IRR of 0.95 (95% CI: 0.87-1.04). Six rounds of MTaT over 2 years did not have a significant impact on the incidence of clinical malaria or the cumulative incidence of malaria infection in this area of high malaria transmission.

Earlier identification of seriously ill patients: an implementation case series.

OBJECTIVE: To describe the strategies used by a collection of healthcare systems to apply different methods of identifying seriously ill patients for a targeted palliative care intervention to improve communication around goals and values. METHODS: We present an implementation case series describing the experiences, challenges and best practices in applying patient selection strategies across multiple healthcare systems implementing the Serious Illness Care Program (SICP). RESULTS: Five sites across the USA and England described their individual experiences implementing patient selection as part of the SICP. They employed a combination of clinician screens (such as the 'Surprise Question'), disease-specific criteria, existing registries or algorithms as a starting point. Notably, each describes adaptation and evolution of their patient selection methodology over time, with several sites moving towards using more advanced machine learning-based analytical approaches. CONCLUSIONS: Involving clinical and programme staff to choose a simple initial method for patient identification is the ideal starting place for selecting patients for palliative care interventions. However, improving and refining methods over time is important and we need ongoing research into better patient selection methodologies that move beyond mortality prediction and instead focus on identifying seriously ill patients-those with poor quality of life, worsening functional status and medical care that is negatively impacting their families.

Blood cytokine, chemokine and growth factor profiling in a cohort of pregnant women from tropical countries.

The immune status of women changes during and after pregnancy, differs between blood compartments at delivery and is affected by environmental factors particularly in tropical areas endemic for multiple infections. We quantified the plasma concentration of a set of thirty-one TH1, TH2, TH17 and regulatory cytokines, pro-inflammatory and anti-inflammatory cytokines and chemokines, and growth factors (altogether biomarkers), in a cohort of 540 pregnant women from five malaria-endemic tropical countries. Samples were collected at recruitment (first antenatal visit), delivery (periphery, cord and placenta) and postpartum, allowing a longitudinal analysis. We found the lowest concentration of biomarkers at recruitment and the highest at postpartum, with few exceptions. Among them, IL-6, HGF and TGF-ß had the highest levels at delivery, and even higher concentrations in the placenta compared to peripheral blood. Placental concentrations were generally higher than peripheral, except for eotaxin that was lower. We also compared plasma biomarker concentrations between the tropical cohort and a control group from Spain at delivery, presenting overall higher biomarker levels the tropical cohort, particularly pro-inflammatory cytokines and growth factors. Only IL-6 presented lower levels in the tropical group. Moreover, a principal component analysis of biomarker concentrations at delivery showed that women from Spain grouped more homogenously, and that IL-6 and IL-8 clustered together in the tropical cohort but not in the Spanish one. Plasma cytokine concentrations correlated with Plasmodium antibody levels at postpartum but not during pregnancy. This basal profiling of immune mediators over gestation and in different compartments at delivery is important to subsequently understand response to infections and clinical outcomes in mothers and infants in tropical areas.

Community-based intermittent mass testing and treatment for malaria in an area of high transmission intensity, western Kenya: development of study site infrastructure and lessons learned.

BACKGROUND: Malaria transmission is high in western Kenya and the asymptomatic infected population plays a significant role in driving the transmission. Mathematical modelling and simulation programs suggest that interventions targeting asymptomatic infections through mass testing and treatment (MTaT) or mass drug administration (MDA) have the potential to reduce malaria transmission when combined with existing interventions. OBJECTIVE: This paper describes the study site, capacity development efforts required, and lessons learned for implementing a multi-year community-based cluster-randomized controlled trial to evaluate the impact of MTaT for malaria transmission reduction in an area of high transmission in western Kenya. METHODS: The study partnered with Kenya's Ministry of Health (MOH) and other organizations on community sensitization and engagement to mobilize, train and deploy community health volunteers (CHVs) to deliver MTaT in the community. Within the health facilities, the study availed staff, medical and laboratory supplies and strengthened health information management system to monitor progress and evaluate impact of intervention. RESULTS: More than 80 Kenya MOH CHVs, 13 clinical officers, field workers, data and logistical staff were trained to carry out MTaT three times a year for 2 years in a population of approximately 90,000 individuals. A supply chain management was adapted to meet daily demands for large volumes of commodities despite the limitation of few MOH facilities having ideal storage conditions. Modern technology was adapted more to meet the needs of the high daily volume of collected data. CONCLUSIONS: In resource-constrained settings, large interventions require capacity building and logistical planning. This study found that investing in relationships with the communities, local governments, and other partners, and identifying and equipping the appropriate staff with the skills and technology to perform tasks are important factors for success in delivering an intervention like MTaT.

Evaluating an Intervention to Improve Communication Between Oncology Clinicians and Patients With Life-Limiting Cancer: A Cluster Randomized Clinical Trial of the Serious Illness Care Program.

IMPORTANCE: Earlier clinician-patient conversations about patients' values, goals, and preferences in serious illness (ie, serious illness conversations) are associated with better outcomes but occur inconsistently in cancer care. OBJECTIVE: To evaluate the efficacy of a communication quality-improvement intervention in improving the occurrence, timing, quality, and accessibility of documented serious illness conversations between oncology clinicians and patients with advanced cancer. DESIGN, SETTING, PARTICIPANTS: This cluster randomized clinical trial in outpatient oncology was conducted at the Dana-Farber Cancer Institute and included physicians, advanced-practice clinicians, and patients with cancer who were at high risk of death. MAIN OUTCOMES AND MEASURES: The primary outcomes (goal-concordant care and peacefulness at the end of life) are published elsewhere. Secondary outcomes are reported herein, including (1) documentation of at least 1 serious illness conversation before death, (2) timing of the initial conversation before death, (3) quality of conversations, and (4) their accessibility in the electronic medical record (EMR). RESULTS: We enrolled 91 clinicians (48 intervention, 43 control) and 278 patients (134 intervention, 144 control). Of enrolled patients, 58% died during the study (n=161); mean age was 62.3 years (95% CI, 58.9-65.6 years); 55% were women (n=88). These patients were cared for by 76 of the 91 enrolled clinicians (37 intervention, 39 control); years in practice, 11.5 (95% CI, 9.2-13.8); 57% female (n=43). Medical record review after patients' death demonstrated that a significantly higher proportion of intervention patients had a documented discussion compared with controls (96% vs 79%, P = .005) and intervention conversations occurred a median of 2.4 months earlier (median, 143 days vs 71 days, P < .001). Conversation documentation for intervention patients was significantly more comprehensive and patient centered, with a greater focus on values or goals (89% vs 44%, P < .001), prognosis or illness understanding (91% vs 48%, P < .001), and life-sustaining treatment preferences (63% vs 32%, P = .004). Documentation about end-of-life care planning did not differ between arms (80% intervention vs 68% control, P = .08). Significantly more intervention patients had documentation that was accessible in the EMR (61% vs 11%, P < .001). CONCLUSIONS AND RELEVANCE: This communication quality-improvement intervention resulted in more, earlier, better, and more accessible serious illness conversations documented in the EMR. To our knowledge, this is the first such study to demonstrate improvement in all 4 of these outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01786811.

Malaria chemoprevention with monthly dihydroartemisinin-piperaquine for the post-discharge management of severe anaemia in children aged less than 5 years in Uganda and Kenya: study protocol for a multi-centre, two-arm, randomised, placebo-controlled, superiority trial.

BACKGROUND: Children hospitalised with severe anaemia in malaria endemic areas in Africa are at high risk of readmission or death within 6 months post-discharge. Currently, no strategy specifically addresses this period. In Malawi, 3 months of post-discharge malaria chemoprevention (PMC) with monthly treatment courses of artemether-lumefantrine given at discharge and at 1 and 2 months prevented 30% of all-cause readmissions by 6 months post-discharge. Another efficacy trial is needed before a policy of malaria chemoprevention can be considered for the post-discharge management of severe anaemia in children under 5 years of age living in malaria endemic areas. OBJECTIVE: We aim to determine if 3 months of PMC with monthly 3-day treatment courses of dihydroartemisinin-piperaquine is safe and superior to a single 3-day treatment course with artemether-lumefantrine provided as part of standard in-hospital care in reducing all-cause readmissions and deaths (composite primary endpoint) by 6 months in the post-discharge management of children less than 5 years of age admitted with severe anaemia of any or undetermined cause. METHODS/DESIGN: This is a multi-centre, two-arm, placebo-controlled, individually randomised trial in children under 5 years of age recently discharged following management for severe anaemia. Children in both arms will receive standard in-hospital care for severe anaemia and a 3-day course of artemether-lumefantrine at discharge. At 2 weeks after discharge, surviving children will be randomised to receive either 3-day courses of dihydroartemisinin-piperaquine at 2, 6 and 10 weeks or an identical placebo and followed for 26 weeks through passive case detection. The trial will be conducted in hospitals in malaria endemic areas in Kenya and Uganda. The study is designed to detect a 25% reduction in the incidence of all-cause readmissions or death (composite primary outcome) from 1152 to 864 per 1000 child years (power 80%, α = 0.05) and requires 520 children per arm (1040 total children). RESULTS: Participant recruitment started in May 2016 and is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02671175 . Registered on 28 January 2016.

Prevention of malaria in pregnancy.

Malaria remains one of the most preventable causes of adverse birth outcomes. Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine is used to prevent malaria, but resistance to this drug combination has decreased its efficacy and new alternatives are needed. In Africa, a meta-analysis showed three-course or monthly IPTp with sulfadoxine-pyrimethamine to be safe and more effective than the original two-course sulfadoxine-pyrimethamine strategy, prompting WHO to update its policy in 2012. Although resistance to sulfadoxine-pyrimethamine reduces the parasitological efficacy of IPTp, this drug combination remains associated with reduced incidence of low birthweight in areas where prevalence of parasites with quintuple Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthetase (Pfdhps) mutations is greater than 90%. Nevertheless, its effectiveness is compromised in women infected with sextuple mutant parasites. Six trials of IPTp showed that neither amodiaquine, mefloquine, nor chloroquine-azithromycin are suitable replacements for sulfadoxine-pyrimethamine because of poor tolerability. Furthermore, four trials showed that intermittent screening and treatment with the current generation of malaria rapid diagnostic tests was not a suitable alternative strategy to IPTp with sulfadoxine-pyrimethamine, even in areas with high prevalence of quintuple mutations. Two trials showed that IPTp with dihydroartemisinin-piperaquine was well tolerated, effective, and acceptable for IPTp, with monthly regimens being the most effective. Coverage of IPTp and insecticide-treated nets continues to lag behind targets. The key barriers to uptake are well documented, and many are open to intervention. Outside of Africa, a single trial suggests a potential role for integrated approaches that combine sulfadoxine-pyrimethamine with azithromycin for IPTp in areas of Papua New Guinea where malaria transmission is high. Modelling analysis suggests the importance of the prevention of malaria early in pregnancy and the need to protect pregnant women declines more slowly than the rate at which transmission declines. Improved funding has led to an increase in the number of prevention trials in the past decade, showing the value of more sustained protection with monthly IPTp regimens. There is a need for confirmatory trials of the safety, efficacy, and feasibility of IPTp with dihydroartemisinin-piperaquine, for studies of intermittent screening and treatment with more sensitive rapid diagnostic tests, for studies of integrated strategies for malaria and other co-infections, and for studies of prevention strategies for malaria in pregnant women who are HIV-positive and living outside of Africa. Additional research is required on how to improve uptake of WHO's updated policy on IPTp with sulfadoxine-pyrimethamine and insecticide-treated nets.

Non-Seminomatous Germ Cell Tumor Presenting with Superior Vena Cava Syndrome.

BACKGROUND Primary mediastinal non-seminomatous germ cell tumors (NSGCTs) are aggressive and carry a poor five-year disease free survival rate even with aggressive treatment. We describe a young adult male with primary mediastinal NSGCT presenting with airway obstruction and superior vena cava syndrome (SVCS). CASE REPORT The patient presented with four weeks of nonproductive cough, weight loss, and right-sided pleuritic chest pain. Chest computed topography (CT) imaging demonstrated a right-sided mediastinal mass determined as a yolk sac tumor on biopsy. The patient underwent induction chemotherapy with etoposide and cisplatin for stage III NSGCT. In the interim, he developed SVCS warranting a second cycle of chemotherapy along with intravenous steroids, with notable improvement in symptoms. However, serial alpha-fetoprotein (AFP) measurements showed progressively increasing levels up to a maximum of 18,781 ng/mL indicating treatment failure. He is currently on salvage chemotherapy. CONCLUSIONS Obstruction of the SVC by external compression is often a manifestation of a malignant process in the thorax. SVCS is a medical emergency and occurs in 6% of patients with mediastinal GCTs. Historically, irradiation was initiated without a histologic diagnosis to relieve the life-threatening obstruction. However, newer data suggest that it is acceptable to defer therapy until a full diagnostic workup is completed. This case highlights the malignant nature of primary mediastinal NSGCTs. In addition, inasmuch as SVCS is dramatic in presentation, it is important to recognize that symptomatic obstruction often develops over weeks or longer. In a hemodynamically stable patient, an accurate histologic diagnosis prior to starting treatment is essential in guiding therapy.

Community-based intermittent mass testing and treatment for malaria in an area of high transmission intensity, western Kenya: study design and methodology for a cluster randomized controlled trial.

Most human Plasmodium infections in western Kenya are asymptomatic and are believed to contribute importantly to malaria transmission. Elimination of asymptomatic infections requires active treatment approaches, such as mass testing and treatment (MTaT) or mass drug administration (MDA), as infected persons do not seek care for their infection. Evaluations of community-based approaches that are designed to reduce malaria transmission require careful attention to study design to ensure that important effects can be measured accurately. This manuscript describes the study design and methodology of a cluster-randomized controlled trial to evaluate a MTaT approach for malaria transmission reduction in an area of high malaria transmission. Ten health facilities in western Kenya were purposively selected for inclusion. The communities within 3 km of each health facility were divided into three clusters of approximately equal population size. Two clusters around each health facility were randomly assigned to the control arm, and one to the intervention arm. Three times per year for 2 years, after the long and short rains, and again before the long rains, teams of community health volunteers visited every household within the intervention arm, tested all consenting individuals with malaria rapid diagnostic tests, and treated all positive individuals with an effective anti-malarial. The effect of mass testing and treatment on malaria transmission was measured through population-based longitudinal cohorts, outpatient visits for clinical malaria, periodic population-based cross-sectional surveys, and entomological indices.

Community perceptions of mass screening and treatment for malaria in Siaya County, western Kenya.

BACKGROUND: Intermittent mass screening and treatment (iMSaT) is currently being evaluated as a possible additional tool for malaria control and prevention in western Kenya. The literature identifying success and/or barriers to drug trial compliance and acceptability on malaria treatment and control interventions is considerable, especially as it relates to specific target groups, such as school-aged children and pregnant women, but there is a lack of such studies for mass screening and treatment and mass drug administration in the general population. METHODS: A qualitative study was conducted to explore community perceptions of the iMSaT intervention, and specifically of testing and treatment in the absence of symptoms, before and after implementation in order to identify aspects of iMSaT that should be improved in future rounds. Two rounds of qualitative data collection were completed in six randomly selected study communities: a total of 36 focus group discussions (FGDs) with men, women, and opinion leaders, and 12 individual or small group interviews with community health workers. All interviews were conducted in the local dialect Dholuo, digitally recorded, and transcribed into English. English transcripts were imported into the qualitative software programme NVivo8 for content analysis. RESULTS: There were mixed opinions of the intervention. In the pre-implementation round, respondents were generally positive and willing to participate in the upcoming study. However, there were concerns about testing in the absence of symptoms including fear of covert HIV testing and issues around blood sampling. There were fewer concerns about treatment, mostly because of the simpler dosing regimen of the study drug (dihydroartemisinin-piperaquine) compared to the current first-line treatment (artemether-lumefantrine). After the first implementation round, there was a clear shift in perceptions with less common concerns overall, although some of the same issues around testing and general misconceptions about research remained. CONCLUSIONS: Although iMSaT was generally accepted throughout the community, proper sensitization activities-and arguably, a more long-term approach to community engagement-are necessary for dispelling fears, clarifying misconceptions, and educating communities on the consequences of asymptomatic malaria.

Intermittent screening and treatment or intermittent preventive treatment with dihydroartemisinin-piperaquine versus intermittent preventive treatment with sulfadoxine-pyrimethamine for the control of malaria during pregnancy in western Kenya: an open-label, three-group, randomised controlled superiority trial.

BACKGROUND: Every year, more than 32 million pregnancies in sub-Saharan Africa are at risk of malaria infection and its adverse consequences. The effectiveness of the intermittent preventive treatment with sulfadoxine-pyrimethamine strategy recommended by WHO is threatened by high levels of parasite resistance. We aimed to assess the efficacy and safety of two alternative strategies: intermittent screening with malaria rapid diagnostic tests and treatment of women who test positive with dihydroartemisinin-piperaquine, and intermittent preventive treatment with dihydroartemisinin-piperaquine. METHODS: We did this open-label, three-group, randomised controlled superiority trial at four sites in western Kenya with high malaria transmission and sulfadoxine-pyrimethamine resistance. HIV-negative pregnant women between 16 and 32 weeks' gestation were randomly assigned (1:1:1), via computer-generated permuted-block randomisation (block sizes of three, six, and nine), to receive intermittent screening and treatment with dihydroartemisinin-piperaquine, intermittent preventive treatment with dihydroartemisinin-piperaquine, or intermittent preventive treatment with sulfadoxine-pyrimethamine. Study participants, study clinic nurses, and the study coordinator were aware of treatment allocation, but allocation was concealed from study investigators, delivery unit nurses, and laboratory staff. The primary outcome was malaria infection at delivery, defined as a composite of peripheral or placental parasitaemia detected by placental histology, microscopy, or rapid diagnostic test. The primary analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01669941. FINDINGS: Between Aug 21, 2012, and June 19, 2014, we randomly assigned 1546 women to receive intermittent screening and treatment with dihydroartemisinin-piperaquine (n=515), intermittent preventive treatment with dihydroartemisinin-piperaquine (n=516), or intermittent preventive treatment with sulfadoxine-pyrimethamine (n=515); 1368 (88%) women comprised the intention-to-treat population for the primary endpoint. Prevalence of malaria infection at delivery was lower in the intermittent preventive treatment with dihydroartemisinin-piperaquine group than in the intermittent preventive treatment with sulfadoxine-pyrimethamine group (15 [3%] of 457 women vs 47 [10%] of 459 women; relative risk 0·32, 95% CI 0·18-0·56; p<0·0001), but not in the intermittent screening and treatment with dihydroartemisinin-piperaquine group (57 [13%] of 452 women; 1·23, 0·86-1·77; p=0·26). Compared with intermittent preventive treatment with sulfadoxine-pyrimethamine, intermittent preventive treatment with dihydroartemisinin-piperaquine was associated with a lower incidence of malaria infection during pregnancy (192·0 vs 54·4 events per 100 person-years; incidence rate ratio [IRR] 0·28, 95% CI 0·22-0·36; p<0·0001) and clinical malaria during pregnancy (37·9 vs 6·1 events; 0·16, 0·08-0·33; p<0·0001), whereas intermittent screening and treatment with dihydroartemisinin-piperaquine was associated with a higher incidence of malaria infection (232·0 events; 1·21, 1·03-1·41; p=0·0177) and clinical malaria (53·4 events; 1·41, 1·00-1·98; p=0·0475). We recorded 303 maternal and infant serious adverse events, which were least frequent in the intermittent preventive treatment with dihydroartemisinin-piperaquine group. INTERPRETATION: At current levels of rapid diagnostic test sensitivity, intermittent screening and treatment is not a suitable alternative to intermittent preventive treatment with sulfadoxine-pyrimethamine in the context of high sulfadoxine-pyrimethamine resistance and malaria transmission. However, dihydroartemisinin-piperaquine is a promising alternative drug to replace sulfadoxine-pyrimethamine for intermittent preventive treatment. Future studies should investigate the efficacy, safety, operational feasibility, and cost-effectiveness of intermittent preventive treatment with dihydroartemisinin-piperaquine. FUNDING: The Malaria in Pregnancy Consortium, which is funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Tropical Medicine.

Daily iron supplementation is more efficacious than twice weekly iron supplementation for the treatment of childhood anemia in western Kenya.

A recent meta-analysis of 14 clinical trials indicated that daily compared with intermittent iron supplementation resulted in significantly greater hematological improvement in pregnant women. No such definitive beneficial effect was demonstrated in preschool children. We compared the efficacy of daily and twice weekly iron supplementation for 6 wk under supervised and unsupervised conditions in the treatment of mild and moderate anemia [hemoglobin (Hb) 50-109 g/L] in children aged 2-59 mo living in a malaria-endemic area of western Kenya. The study was a cluster-randomized trial using a factorial design; participants were aware of the treatment assigned. All children (n = 1049) were administered a single dose of sulfadoxine-pyrimethamine at enrollment followed by 6 wk of daily supervised iron supplementation [3-6 mg/(kg.d)], twice weekly supervised iron supplementation [6-12 mg/(kg.wk)], daily unsupervised iron supplementation, or twice weekly unsupervised iron supplementation. In the supervised groups, Hb concentrations at 6 and 12 wk (6 wk postsupplementation) were significantly higher in children given iron daily rather than twice weekly [mean (95% CI) difference at 6-wk: 4.2 g/L (2.1, 6.4); 12-wk: 4.4 g/L (1.8, 7.0)]. Among the unsupervised groups, Hb concentrations were not different at 6 wk [mean (95% CI) difference: 0.86 g/L (-1.4, 3.1)], but significantly higher at 12 wk for those assigned daily iron [mean (95% CI) difference: 3.4 g/L (0.79, 6.0), P = 0.02]. In this malarious area and after initial antimalarial treatment, 6 wk of daily iron supplementation results in better hematological responses than twice weekly iron supplementation in the treatment of anemia in preschool children, regardless of whether adherence can be ensured.

Relation between the response to iron supplementation and sickle cell hemoglobin phenotype in preschool children in western Kenya.

BACKGROUND: Iron supplementation has been associated with greater susceptibility to malaria and lower hematologic responses in pregnant Gambian women with sickle cell trait (HbAS) than in similar women with the normal (HbAA) phenotype. It is not known whether a similar interaction exists in children. OBJECTIVE: Our aim was to determine the influence of the HbAS phenotype on hematologic responses and malaria after iron supplementation in anemic (hemoglobin: 70-109 g/L) children aged 2-35 mo. DESIGN: We conducted a double-blind, randomized, placebo-controlled trial (HbAS, n = 115; HbAA, n = 408) of intermittent preventive treatment with sulfadoxine pyrimethamine (IPT-SP) at 4 and 8 wk and daily supervised iron for 12 wk. RESULTS: The mean difference in hemoglobin concentrations at 12 wk between children assigned iron and placebo iron, after adjustment for the effect of IPT-SP, was 9.1 g/L (95% CI: 6.4, 11.8) and 8.2 g/L (4.0, 12.4) in HbAA and HbAS children, respectively (P for interaction = 0.68). Although malaria parasitemia and clinical malaria occurred more often in HbAS children in the iron group than in those in the placebo iron group, this difference was not significant; incidence rate ratios were 1.23 (95% CI: 0.64, 2.34) and 1.41 (0.39, 5.00), respectively. The corresponding incidence rate ratios in HbAA children in the same groups were 1.07 (95% CI: 0.77, 1.48) and 0.59 (0.35, 1.01), respectively. The corresponding interactions between the effects of iron and hemoglobin phenotype were not significant. CONCLUSIONS: There was no evidence for a clinically relevant modification by the hemoglobin S phenotype of the effects of iron supplementation in the treatment of mild anemia. The benefits of iron supplementation are likely to outweigh possible risks associated with malaria in children with the HbAA or HbAS phenotype.

Randomized, controlled trial of daily iron supplementation and intermittent sulfadoxine-pyrimethamine for the treatment of mild childhood anemia in western Kenya.

A randomized, placebo-controlled treatment trial was conducted among 546 anemic (hemoglobin concentration, 7-11 g/dL) children aged 2-36 months in an area with intense malaria transmission in western Kenya. All children used bednets and received a single dose of sulfadoxine-pyrimethamine (SP) on enrollment, followed by either intermittent preventive treatment (IPT) with SP at 4 and 8 weeks and daily iron for 12 weeks, daily iron and IPT with SP placebo, IPT and daily iron placebo, or daily iron placebo and IPT with SP placebo (double placebo). The mean hemoglobin concentration at 12 weeks, compared with that for the double-placebo group, was 1.14 g/dL (95% confidence interval [CI], 0.82-1.47 g/dL) greater for the IPT+iron group, 0.79 g/dL (95% CI, 0.46-1.10 g/dL) greater for the iron group, and 0.17 g/dL (95% CI, -0.15-0.49 g/dL) greater for the IPT group. IPT reduced the incidence of malaria parasitemia and clinic visits, but iron did not. The combination of IPT and iron supplementation was most effective in the treatment of mild anemia. Although IPT prevented malaria, the hematological benefit it added to that of a single dose of SP and bednet use was modest.