A Smartphone App for Real-Time Assessment of Malaria Prophylaxis Adverse Events.

Background: Growth of international travel to malarial areas over the last decades has contributed to more travelers taking malaria prophylaxis. Travel-related symptoms may be wrongly attributed to malaria prophylaxis and hinder compliance. Here, we aimed to assess the frequency of real-time reporting of symptoms by travelers following malaria prophylaxis using a smartphone app. Method: Adult international travelers included in this single-center study (Barcelona, Spain) used the smartphone Trip Doctor® app developed by our group for real-time tracking of symptoms and adherence to prophylaxis. Results: Six hundred four (n = 604) international travelers were included in the study; 74.3% (449) used the app daily, and for one-quarter of travelers, malaria prophylaxis was prescribed. Participants from the prophylaxis group traveled more to Africa (86.7% vs. 4.3%; p < 0.01) and to high travel medical risk countries (60.8% vs. 18%; p < 0.01) and reported more immunosuppression (30.8% vs. 23.1% p < 0.01). Regarding symptoms, no significant intergroup differences were observed, and no relationship was found between the total number of malarial pills taken and reported symptoms. Conclusions: In our cohort, the number of symptoms due to malaria prophylaxis was not significantly higher than in participants for whom prophylaxis was not prescribed, and the overall proportion of symptoms is higher compared with other studies.

Tafenoquine exposure assessment, safety, and relapse prevention efficacy in children with Plasmodium vivax malaria: open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 trial.

BACKGROUND: Single-dose tafenoquine 300 mg is approved for Plasmodium vivax malaria relapse prevention in patients at least 16 years old. We aimed to determine appropriate oral tafenoquine paediatric dosing regimens, including a dispersible formulation, and evaluated tafenoquine efficacy and safety in children infected with P vivax. METHODS: This open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 study enrolled children (2-15 years) who weighed 5 kg or more, with glucose-6-phosphate dehydrogenase activity more than 70% of the local population median, and P vivax malaria infection, from three community health centres in Vietnam and one in Colombia. Patients received 3-day chloroquine plus oral single-dose tafenoquine as dispersible tablets (50 mg) or film-coated tablets (150 mg). Dosing groups were assigned by body weight, predicted to achieve similar median exposures as the approved 300 mg dose for adults: patients who weighed 5 kg or more to 10 kg received 50 mg, those who weighed more than 10 to 20 kg received 100 or 150 mg, those who weighed more than 20 to 35 kg received 200 mg, and patients who weighed more than 35 kg received 300 mg. Population pharmacokinetic analysis was done to develop a paediatric population pharmacokinetic model. The primary outcome was the tafenoquine area under the concentration-time curve extrapolated to infinity (AUC[0-∞]) by patient body weight in the pharmacokinetic population (all patients who received tafenoquine with at least one valid pharmacokinetic sample) estimated from a paediatric population pharmacokinetic model. A key prespecified secondary outcome was 4-month recurrence-free efficacy. This trial is registered with ClinicalTrials.gov, NCT02563496. FINDINGS: Between Feb 6, 2017, and Feb 17, 2020, 60 patients were enrolled into the study: 14 (23%) received tafenoquine 100 mg, five (8%) 150 mg, 22 (36%) 200 mg, and 19 (32%) 300 mg. The paediatric population pharmacokinetic model predicted adequate tafenoquine exposure at all doses. The predicted median AUC(0-∞) was 73·8 (90% prediction interval [PI] 46·9-117·0) µg × h/mL with the 50 mg dose for patients who weighed 5 kg or more to 10 kg, 87·5 (55·4-139·0) µg × h/mL with the 100 mg dose for body weight more than 10 to 20 kg, 110·7 (70·9-174·0) µg × h/mL with the 200 mg dose for body weight more than 20 to 35 kg, and 85·7 (50·6-151·0) µg × h/mL with the 300 mg dose for body weight more than 35 kg. 4-month recurrence-free efficacy was 94·7% (95% CI 84·6-98·3). Adverse events were consistent with previous studies, except for the seven (12%) of 60 patients who had post-dose vomiting or spitting with the 50 mg dispersed tablet. Following mitigation strategies, there were no additional occurrences of this adverse event. There were no deaths during the study. INTERPRETATION: For the prevention of P vivax relapse in children, single-dose tafenoquine, including a dispersible formulation, had exposure, safety, and efficacy consistent with observations in adolescents and adults, notwithstanding post-dose vomiting. FUNDING: GlaxoSmithKline and Medicines for Malaria Venture. TRANSLATIONS: For the Vietnamese and Spanish translations of the abstract see Supplementary Materials section.

Model-based assessment of the safety of community interventions with primaquine in sub-Saharan Africa.

BACKGROUND: Single low-dose primaquine (SLD-PQ) is recommended in combination with artemisinin-based combination therapy to reduce Plasmodium falciparum transmission in areas threatened by artemisinin resistance or aiming for malaria elimination. SLD-PQ may be beneficial in mass drug administration (MDA) campaigns to prevent malaria transmission but uptake is limited by concerns of hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The aim of this study was to improve the evidence on the safety of MDA with SLD-PQ in a sub-Saharan African setting. METHODS: A nonlinear mixed-effects model describing the pharmacokinetics and treatment-induced hemolysis of primaquine was developed using data from an adult (n = 16, G6PD deficient) and pediatric study (n = 38, G6PD normal). The relationship between primaquine pharmacokinetics and hemolysis was modeled using an established erythrocyte lifespan model. The safety of MDA with SLD-PQ was explored through Monte Carlo simulations for SLD-PQ at 0.25 or 0.4 mg/kg using baseline data from a Tanzanian setting with detailed information on hemoglobin concentrations and G6PD status. RESULTS: The predicted reduction in hemoglobin levels following SLD-PQ was small and returned to pre-treatment levels after 25 days. G6PD deficiency (African A- variant) was associated with a 2.5-fold (95% CI 1.2-8.2) larger reduction in hemoglobin levels. In the Tanzanian setting where 43% of the population had at least mild anemia (hemoglobin < 11-13 g/dl depending on age and sex) and 2.73% had severe anemia (hemoglobin < 7-8 g/dl depending on age and sex), an additional 3.7% and 6.0% of the population were predicted to develop at least mild anemia and 0.25% and 0.41% to develop severe anemia after 0.25 and 0.4 mg/kg SLD-PQ, respectively. Children < 5 years of age and women ≥ 15 years of age were found to have a higher chance to have low pre-treatment hemoglobin. CONCLUSIONS: This study supports the feasibility of MDA with SLD-PQ in a sub-Saharan African setting by predicting small and transient reductions in hemoglobin levels. In a setting where a substantial proportion of the population had low hemoglobin concentrations, our simulations suggest treatment with SLD-PQ would result in small increases in the prevalence of anemia which would most likely be transient.

Decomposition of socioeconomic inequalities in the uptake of intermittent preventive treatment of malaria in pregnancy in Nigeria: evidence from Demographic Health Survey.

BACKGROUND: Although malaria in pregnancy is preventable with the use of intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP), it still causes maternal morbidity and mortality, in sub-Saharan Africa and Nigeria in particular. Socioeconomic inequality leads to limited uptake of IPTp-SP by pregnant women and is, therefore, a public health challenge in Nigeria. This study aimed to measure and identify factors explaining socioeconomic inequality in the uptake of IPTp-SP in Nigeria. METHODS: The study re-analysed dataset of 12,294 women aged 15-49 years from 2018 Nigeria Demographic Health Survey (DHS). The normalized concentration index (Cn) and concentration curve were used to quantify and graphically present socioeconomic inequalities in the uptake of IPTp-SP among pregnant women in Nigeria. The Cn was decomposed to identify key factors contributing to the observed socioeconomic inequality in the uptake of adequate (≥ 3) IPTp-SP. RESULTS: The study showed a higher concentration of the adequate uptake of IPTp-SP among socioeconomically advantaged women (Cn = 0.062; 95% confidence interval [CI] 0.048 to 0.076) in Nigeria. There is a pro-rich inequality in the uptake of IPTp-SP in urban areas (Cn = 0.283; 95%CI 0.279 to 0.288). In contrast, a pro-poor inequality in the uptake of IPTp-SP was observed in rural areas (Cn = - 0.238; 95%CI - 0.242 to - 0.235). The result of the decomposition analysis indicated that geographic zone of residence and antenatal visits were the two main drivers for the concentration of the uptake of IPTp-SP among wealthier pregnant women in Nigeria. CONCLUSION: The pro-rich inequalities in the uptake of IPTp-SP among pregnant women in Nigeria, particularly in urban areas, warrant further attention. Strategies to improve the uptake of IPTp-SP among women residing in socioeconomically disadvantaged geographic zones (North-East and North-West) and improving antenatal visits among the poor women may reduce pro-rich inequality in the uptake of IPTp-SP among pregnant women in Nigeria.

Trends in access to anti-malarial treatment in the formal private sector in Uganda: an assessment of availability and affordability of first-line anti-malarials and diagnostics between 2007 and 2018.

BACKGROUND: Malaria is the single largest cause of illness in Uganda. Since the year 2008, the Global Fund has rolled out several funding streams for malaria control in Uganda. Among these are mechanisms aimed at increasing the availability and affordability of artemisinin-based combination therapy (ACT). This paper examines the availability and affordability of first-line malaria treatment and diagnostics in the private sector, which is the preferred first point of contact for 61% of households in Uganda between 2007 and 2018. METHODS: Cross-sectional surveys were conducted between 2007 and 2018, based on a standardized World Health Organization/Health Action International (WHO/HAI) methodology adapted to assess availability, patient prices, and affordability of ACT medicines in private retail outlets. A minimum of 30 outlets were surveyed per year as prescribed by the standardized methodology co-developed by the WHO and Health Action International. Availability, patient prices, and affordability of malaria rapid diagnostic tests (RDTs) was also tracked from 2012 following the rollout of the test and treat policy in 2010. The median patient prices for the artemisinin-based combinations and RDTs was calculated in US dollars (USD). Affordability was assessed by computing the number of days' wages the lowest-paid government worker (LPGW) had to pay to purchase a treatment course for acute malaria. RESULTS: Availability of artemether/lumefantrine (A/L), the first-line ACT medicine, increased from 85 to100% in the private sector facilities during the study period. However, there was low availability of diagnostic tests in private sector facilities ranging between 13% (2012) and 37% (2018). There was a large reduction in patient prices for an adult treatment course of A/L from USD 8.8 in 2007 to USD 1.1 in 2018, while the price of diagnostics remained mostly stagnant at USD 0.5. The affordability of ACT medicines and RDTs was below one day's wages for LPGW. CONCLUSIONS: Availability of ACT medicines in the private sector medicines retail outlets increased to 100% while the availability of diagnostics remained low. Although malaria treatment was affordable, the price of diagnostics remained stagnant and increased the cumulative cost of malaria management. Malaria stakeholders should consolidate the gains made and consider the inclusion of diagnostic kits in the subsidy programme.

Rapid ethnographic assessment for potential anti-malarial mass drug administration in an outbreak area of Santo Domingo, Dominican Republic.

BACKGROUND: In the Dominican Republic, a recent outbreak of malaria in the capital, Santo Domingo, threatens efforts to eliminate the disease. Mass drug administration (MDA) has been proposed as one strategy to reduce transmission. The success of MDA is contingent upon high levels of acceptance among the target population. To inform the design of future MDA campaigns, this rapid ethnographic assessment examined malaria-related knowledge and attitudes toward malaria MDA among residents of a transmission focus in Santo Domingo. METHODS: In October 2019, a rapid ethnographic assessment was conducted in the Los Tres Brazos transmission focus, which had not previously received MDA. National malaria programme staff conducted 61 structured interviews with key informants, recorded observations, and held 72 informal conversations. Using a grounded theory approach, data were analysed during three workshop sessions with research team members. RESULTS: Among those who had heard of malaria in the structured interviews (n = 39/61; 64%), understanding of the disease was largely based on personal experience from past outbreaks or through word-of-mouth. Community health workers (promotores) were trusted for health information and malaria diagnosis more so than professional clinicians. No participant (0%) was familiar with malaria MDA. After learning about MDA, almost all study participants (92%) said that they would participate, seeing it as a way to care for their community. Reasons for not participating in future MDA included not trusting drug administrators, feeling reluctant to take unprescribed medicine, and fear of missing work. Additional identified challenges to MDA included reaching specific demographic groups, disseminating effective MDA campaign messages, and managing misinformation and political influence. CONCLUSION: Residents appear accepting of MDA despite a lack of prior familiarity. Successful MDA will depend on several factors: fostering relationships among community-based health workers, clinicians, community leaders, and others; developing clear health messages that use local terms and spreading them through a variety of media and social networks; and contextualizing MDA as part of a broader effort to promote community health.

Safety assessment of MEFAS: an innovative hybrid salt of mefloquine and artesunate for malaria treatment.

Malaria is a global public health problem that causes approximately 445 000 deaths annually worldwide, especially in underdeveloped countries. Because of the high prevalence and mortality of the disease, new and less toxic therapeutic agents need to be developed, such as MEFAS, a low-cost hybrid salt that consists of artesunate and mefloquine. However, the efficacy of MEFAS has been systematically demonstrated, its safety requires further investigation. This study investigated the acute toxicity of MEFAS and its precursors, artesunate, and mefloquine. A total of 42 female Swiss mice were divided into seven groups (n = 6/group) that were treated orally by gavage with vehicle (filtered water, negative control), MEFAS (50, 500, and 1000 mg/kg), and 1:1 concentrations of artesunate + mefloquine (50, 500, and 1000 mg/kg). Clinical signs of toxicity were observed for 14 d after treatment. On day 15, the animals were weighed, deeply anesthetized with isoflurane, and euthanized for subsequent collection of the liver, spleen, and kidneys. The relative organ weights were determined, followed by histopathological analysis. Artesunate + mefloquine produced toxic effects compared with the negative control group, reflected by changes in clinical signs, relative organ weights, and histopathological alterations. In MEFAS-treated animals, no changes were observed compared with the negative control group. These findings demonstrate that MEFAS is safer than artesunate + mefloquine after acute administration in mice.

Effectiveness of seasonal malaria chemoprevention at scale in west and central Africa: an observational study.

BACKGROUND: Seasonal malaria chemoprevention (SMC) aims to prevent malaria in children during the high malaria transmission season. The Achieving Catalytic Expansion of SMC in the Sahel (ACCESS-SMC) project sought to remove barriers to the scale-up of SMC in seven countries in 2015 and 2016. We evaluated the project, including coverage, effectiveness of the intervention, safety, feasibility, drug resistance, and cost-effectiveness. METHODS: For this observational study, we collected data on the delivery, effectiveness, safety, influence on drug resistance, costs of delivery, impact on malaria incidence and mortality, and cost-effectiveness of SMC, during its administration for 4 months each year (2015 and 2016) to children younger than 5 years, in Burkina Faso, Chad, The Gambia, Guinea, Mali, Niger, and Nigeria. SMC was administered monthly by community health workers who visited door-to-door. Drug administration was monitored via tally sheets and via household cluster-sample coverage surveys. Pharmacovigilance was based on targeted spontaneous reporting and monitoring systems were strengthened. Molecular markers of resistance to sulfadoxine-pyrimethamine and amodiaquine in the general population before and 2 years after SMC introduction was assessed from community surveys. Effectiveness of monthly SMC treatments was measured in case-control studies that compared receipt of SMC between patients with confirmed malaria and neighbourhood-matched community controls eligible to receive SMC. Impact on incidence and mortality was assessed from confirmed outpatient cases, hospital admissions, and deaths associated with malaria, as reported in national health management information systems in Burkina Faso and The Gambia, and from data from selected outpatient facilities (all countries). Provider costs of SMC were estimated from financial costs, costs of health-care staff time, and volunteer opportunity costs, and cost-effectiveness ratios were calculated as the total cost of SMC in each country divided by the predicted number of cases averted. FINDINGS: 12 467 933 monthly SMC treatments were administered in 2015 to a target population of 3 650 455 children, and 25 117 480 were administered in 2016 to a target population of 7 551 491. In 2015, among eligible children, mean coverage per month was 76·4% (95% CI 74·0-78·8), and 54·5% children (95% CI 50·4-58·7) received all four treatments. Similar coverage was achieved in 2016 (74·8% [72·2-77·3] treated per month and 53·0% [48·5-57·4] treated four times). In 779 individual case safety reports over 2015-16, 36 serious adverse drug reactions were reported (one child with rash, two with fever, 31 with gastrointestinal disorders, one with extrapyramidal syndrome, and one with Quincke's oedema). No cases of severe skin reactions (Stevens-Johnson or Lyell syndrome) were reported. SMC treatment was associated with a protective effectiveness of 88·2% (95% CI 78·7-93·4) over 28 days in case-control studies (2185 cases of confirmed malaria and 4370 controls). In Burkina Faso and The Gambia, implementation of SMC was associated with reductions in the number of malaria deaths in hospital during the high transmission period, of 42·4% (95% CI 5·9 to 64·7) in Burkina Faso and 56·6% (28·9 to 73·5) in The Gambia. Over 2015-16, the estimated reduction in confirmed malaria cases at outpatient clinics during the high transmission period in the seven countries ranged from 25·5% (95% CI 6·1 to 40·9) in Nigeria to 55·2% (42·0 to 65·3) in The Gambia. Molecular markers of resistance occurred at low frequencies. In individuals aged 10-30 years without SMC, the combined mutations associated with resistance to amodiaquine (pfcrt CVIET haplotype and pfmdr1 mutations [86Tyr and 184Tyr]) had a prevalence of 0·7% (95% CI 0·4-1·2) in 2016 and 0·4% (0·1-0·8) in 2018 (prevalence ratio 0·5 [95% CI 0·2-1·2]), and the quintuple mutation associated with resistance to sulfadoxine-pyrimethamine (triple mutation in pfdhfr and pfdhps mutations [437Gly and 540Glu]) had a prevalence of 0·2% (0·1-0·5) in 2016 and 1·0% (0·6-1·6) in 2018 (prevalence ratio 4·8 [1·7-13·7]). The weighted average economic cost of administering four monthly SMC treatments was US$3·63 per child. INTERPRETATION: SMC at scale was effective in preventing morbidity and mortality from malaria. Serious adverse reactions were rarely reported. Coverage varied, with some areas consistently achieving high levels via door-to-door campaigns. Markers of resistance to sulfadoxine-pyrimethamine and amodiaquine remained uncommon, but with some selection for resistance to sulfadoxine-pyrimethamine, and the situation needs to be carefully monitored. These findings should support efforts to ensure high levels of SMC coverage in west and central Africa. FUNDING: Unitaid.

Cost-effectiveness of intermittent preventive treatment with dihydroartemisinin-piperaquine versus single screening and treatment for the control of malaria in pregnancy in Papua, Indonesia: a provider perspective analysis from a cluster-randomised trial.

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.

Cost-effectiveness of intermittent preventive treatment with dihydroartemisinin-piperaquine for malaria during pregnancy: an analysis using efficacy results from Uganda and Kenya, and pooled data.

BACKGROUND: Prevention of malaria infection during pregnancy in HIV-negative women currently relies on the use of long-lasting insecticidal nets together with intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP). Increasing sulfadoxine-pyrimethamine resistance in Africa threatens current prevention of malaria during pregnancy. Thus, a replacement for IPTp-SP is urgently needed, especially for locations with high sulfadoxine-pyrimethamine resistance. Dihydroartemisinin-piperaquine is a promising candidate. We aimed to estimate the cost-effectiveness of intermittent preventive treatment in pregnancy with dihydroartemisinin-piperaquine (IPTp-DP) versus IPTp-SP to prevent clinical malaria infection (and its sequelae) during pregnancy. METHODS: We did a cost-effectiveness analysis using meta-analysis and individual trial results from three clinical trials done in Kenya and Uganda. We calculated disability-adjusted life-years (DALYs) arising from stillbirths, neonatal death, low birthweight, mild and moderate maternal anaemia, and clinical malaria infection, associated with malaria during pregnancy. Cost estimates were obtained from data collected in observational studies, health-facility costings, and from international drug procurement databases. The cost-effectiveness analyses were done from a health-care provider perspective using a decision tree model with a lifetime horizon. Deterministic and probabilistic sensitivity analyses using appropriate parameter ranges and distributions were also done. Results are presented as the incremental cost per DALY averted and the likelihood that an intervention is cost-effective for different cost-effectiveness thresholds. FINDINGS: Compared with three doses of sulfadoxine-pyrimethamine, three doses of dihydroartemisinin-piperaquine, delivered to a hypothetical cohort of 1000 pregnant women, averted 892 DALYs (95% credibility interval 274 to 1517) at an incremental cost of US$7051 (2653 to 13 038) generating an incremental cost-effectiveness ratio (ICER) of $8 (2 to 29) per DALY averted. Compared with monthly doses of sulfadoxine-pyrimethamine, monthly doses of dihydroartemisinin-piperaquine averted 534 DALYS (-141 to 1233) at a cost of $13 427 (4994 to 22 895), resulting in an ICER of $25 (-151 to 224) per DALY averted. Both results were highly robust to most or all variations in the deterministic sensitivity analysis. INTERPRETATION: Our findings suggest that among HIV-negative pregnant women with high uptake of long-lasting insecticidal nets, IPTp-DP is cost-effective in areas with high malaria transmission and high sulfadoxine-pyrimethamine resistance. These data provide a comprehensive overview of the current evidence on the cost-effectiveness of IPTp-DP. Nevertheless, before a policy change is advocated, we recommend further research into the effectiveness and costs of different regimens of IPTp-DP in settings with different underlying sulfadoxine-pyrimethamine resistance. FUNDING: Malaria in Pregnancy Consortium, which is funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Hygiene and Tropical Medicine.

Cost-Effectiveness of Focal Mass Drug Administration and Mass Drug Administration with Dihydroartemisinin-Piperaquine for Malaria Prevention in Southern Province, Zambia: Results of a Community-Randomized Controlled Trial.

Community-wide administration of antimalarial drugs in therapeutic doses is a potential tool to prevent malaria infection and reduce the malaria parasite reservoir. To measure the effectiveness and cost of using the antimalarial drug combination dihydroartemisinin-piperaquine (DHAp) through different community-wide distribution strategies, Zambia's National Malaria Control Centre conducted a three-armed community-randomized controlled trial. The trial arms were as follows: 1) standard of care (SoC) malaria interventions, 2) SoC plus focal mass drug administration (fMDA), and 3) SoC plus MDA. Mass drug administration consisted of offering all eligible individuals DHAP, irrespective of a rapid diagnostic test (RDT) result. Focal mass drug administration consisted of offering DHAP to all eligible individuals who resided in a household where anyone tested positive by RDT. Results indicate that the costs of fMDA and MDA per person targeted and reached are similar (US$9.01 versus US$8.49 per person, respectively, P = 0.87), but that MDA was superior in all cost-effectiveness measures, including cost per infection averted, cost per case averted, cost per death averted, and cost per disability-adjusted life year averted. Subsequent costing of the MDA intervention in a non-trial, operational setting yielded significantly lower costs per person reached (US$2.90). Mass drug administration with DHAp also met the WHO thresholds for "cost-effective interventions" in the Zambian setting in 90% of simulations conducted using a probabilistic sensitivity analysis based on trial costs, whereas fMDA met these criteria in approximately 50% of simulations. A sensitivity analysis using costs from operational deployment and trial effectiveness yielded improved cost-effectiveness estimates. Mass drug administration may be a cost-effective intervention in the Zambian context and can help reduce the parasite reservoir substantially. Mass drug administration was more cost-effective in relatively higher transmission settings. In all scenarios examined, the cost-effectiveness of MDA was superior to that of fMDA.

Pharmacogenetic assessment of tafenoquine efficacy in patients with Plasmodium vivax malaria.

Plasmodium vivax has the largest geographic range of human malaria species and is challenging to manage and eradicate due to its ability to establish a dormant liver stage, the hypnozoite, which can reactivate leading to relapse. Until recently, the only treatment approved to kill hypnozoites was the 8-aminoquinoline, primaquine, requiring daily treatment for 14 days. Tafenoquine, an 8-aminoquinoline single-dose treatment with activity against P. vivax hypnozoites, has recently been approved by the US Food and Drug Administration and Australian Therapeutic Goods Administration for the radical cure of P. vivax malaria in patients 16 years and older. We conducted an exploratory pharmacogenetic analysis (GSK Study 208099) to assess the role of host genome-wide variation on tafenoquine efficacy in patients with P. vivax malaria using data from three GSK clinical trials, GATHER and DETECTIVE Part 1 and Part 2. Recurrence-free efficacy at 6 and 4 months and time to recurrence up to 6 months postdosing were analyzed in 438 P. vivax malaria patients treated with tafenoquine. Among the approximately 10.6 million host genetic variants analyzed, two signals reached genome-wide significance (P value ≤ 5 × 10). rs62103056, and variants in a chromosome 12 intergenic region, were associated with recurrence-free efficacy at 6 and 4 months, respectively. Neither of the signals has an obvious biological rationale and would need replication in an independent population. This is the first genome-wide association study to evaluate genetic influence on response to tafenoquine in P. vivax malaria.

Cost-Effectiveness Analysis of Sex-Stratified Plasmodium vivax Treatment Strategies Using Available G6PD Diagnostics to Accelerate Access to Radical Cure.

Tafenoquine has been licensed for the single-dose radical cure of Plasmodium vivax in adults; however, it is only recommended in patients with > 70% of normal glucose-6-phosphate dehydrogenase (G6PD) activity. Because this may hinder widespread use, we investigated sex-based treatment strategies in which all adult patients are tested with a qualitative G6PD rapid diagnostic test (RDT). Glucose-6-phosphate dehydrogenase normal males are prescribed tafenoquine in all three strategies, whereas G6PD normal females are prescribed either a low-dose 14-day primaquine regimen (PQ14, total dose 3.5 mg/kg) or a high-dose 7-day primaquine regimen (PQ7, total dose 7 mg/kg), or referred to a healthcare facility for quantitative G6PD testing before prescribing tafenoquine. Patients testing G6PD deficient are prescribed a weekly course of primaquine for 8 weeks. We compared the cost-effectiveness of these three strategies to usual care in four countries using a decision tree model. Usual care in Ethiopia does not include radical cure, whereas Afghanistan, Indonesia, and Vietnam prescribe PQ14 without G6PD screening. The cost per disability-adjusted life-year (DALY) averted was expressed through incremental cost-effectiveness ratios (ICERs). Compared with usual care, the ICERs for a sex-based treatment strategy with PQ7 for females from a healthcare provider perspective were $127 per DALY averted in Vietnam, $466 in Ethiopia, $1,089 in Afghanistan, and $4,443 in Indonesia. The PQ14 and referral options cost more while averting fewer DALYs than PQ7. This study provides an alternative cost-effective mode of rolling out tafenoquine in areas where initial testing with only a G6PD RDT is feasible.

[Evaluation of the operational capacity of first-line health facilities in the management of malaria in Ivory Coast]. / Evaluation de la capacité opérationnelle des établissements sanitaires de première ligne dans la prise en charge du paludisme en Côte d'Ivoire.

INTRODUCTION: Do health facilities (HF) have basic resources needed to manage malaria? The purpose of our study was to analyze the operational capacity (OC) of first-line health facilities in Ivory Coast in the management of malaria. METHODS: SARA methodology was used to conduct a descriptive cross-sectional study from 10 to 30 July 2016. The operational capacity in the management showed an average availability of 9 identification tracers divided in 3 areas: (i) staff and guidelines; (ii) capacity of diagnosis; (iii) drugs and products. This operational capacity was assessed through the calculation of an index and then compared with the health facilities according to the management authority and the geographical area using Chi-square test with p-values α fixed at 0.05. RESULTS: Out of 818 HFs, 651(79.6%) were in the public sector and 487(59.5%) were located in the rural area. The operational capacity of first line health facilities was 74.5%. This OC was higher in the public sector (81.3%) than in the private sector (48.8%) (p < 10-3) as well as in the rural area (82.7%) compared to the urban area (62.9%) (p < 10-3). CONCLUSION: In 2016, first line health facilities in Ivory Coast had basic resources needed to manage malaria. It is necessary to focus on the need to strengthen health facility services in addition to prevention.

The effect of subsidized malaria treatment among under-five children in the Buea Health District, Cameroon.

INTRODUCTION: Access to free diagnoses and treatments has been shown to be a major determinant in malaria control. The Cameroon government launched in 2011 and 2014 the exemption of the under-fives' simple and severe malaria treatment policy to increase access to health care and reduce inequality, so as to reduce the mortality related to malaria among the under-fives. This study assessed the effect of providing free malaria treatment in the Buea health district. METHODS: This retrospective and cross sectional study was carried out in the Buea health district. Aggregated monthly data from (2008-2010) before and (2012-2014) after the implementation of free malaria treatment was compared, to assess the attributable outcomes of free treatment. A semi-structure questionnaire was also used to assess barriers faced in providing free malaria treatment services by health care workers. Data was collected using a semi-structure questionnaire and a data review summary sheet. The data was analysed using Epi-Info 7, Excel and SPSS (Statistical Package for the Social Sciences) version 20.0 for Windows. All statistical tests were performed at 95% confidence interval (significance level of 0.05). RESULTS: Increase utilisation of health care; as general and malaria related consultations (by 5.7% (p=0.001) witnessed an increase after the implementation of free malaria treatment services. Severe malaria hospitalisation also increased, indicating that most caregivers used the health facility when complications had already set in, which could have led to no significant reduction in mortality due to malaria among under-five children (4.4%, p=0.533). CONCLUSION: Utilisation of health care increased; as consultation and morbidity rate increased after the implementation of free malaria treatment services. Communication strategy should therefore be strengthened so as to better disseminate information, so as to enhance the effectiveness of the program. There is the need to make a large-scale study to assess the impact of subsidized malaria treatment.

The role of monitoring and evaluation to ensure functional access to community-based early diagnosis and treatment in a malaria elimination programme in Eastern Myanmar.

BACKGROUND: Improving access to early diagnosis and treatment (EDT) has increasingly proven to be a major contributor to decreasing malaria incidence in low-transmission settings. The Malaria Elimination Task Force (METF) has deployed malaria posts set up in Eastern Myanmar, providing free uninterrupted community-based access to EDT in more than 1200 villages. Ensuring high quality services are provided by these malaria posts is essential to reaching elimination targets. The present study aimed to determine the functionality of the malaria posts in the METF programme. METHODS: This report analysed routinely collected data (weekly reports, individual consultation, diagnostic test quality control) and data collected specifically during monitoring and evaluation visits using descriptive statistics and univariate logistic regression. The presence of major dysfunctions (stock-outs and reported closing; likely to impair the ability of the population to access EDT) or minor dysfunctions (no formal METF training, lack of regular salary, forms and manual not on-site, and low frequency of supervisor visits) and the ability to anticipate dysfunctions through analysis of weekly reports were assessed. RESULTS: A total of 65% of malaria posts had no major dysfunction identified during monitoring and evaluation visits, while 86% of malaria posts were fully stocked with tests and medicines used for treatment. Diagnosis was correctly conducted with few false positives and rare mis-speciation of results. Malaria post worker knowledge of malaria treatments showed few gaps, mostly in the treatment of more complex presentations. Malaria posts were well utilized in the population, with 94% of consultations occurring within the first 3 days of fever. In the regression analysis, reported stock-outs and delayed weekly reports were associated with observed major and minor dysfunctions in monitoring and evaluation visits, emphasizing the need to reinforce support to malaria post supervisors, who were responsible for the local logistics of supply and data transmission and day-to-day supervision. CONCLUSION: The malaria posts operating under the METF programme perform to a high standard, with the majority offering uninterrupted access to diagnosis and treatment, and high service uptake in the villages serviced by the programme. However, programme operations can be strengthened by increasing malaria post supervisor visits and re-training malaria post workers.

Effectiveness of antimalarial interventions in Nigeria: Evidence from facility-level longitudinal data.

OBJECTIVE: To evaluate the effectiveness of a program of antimalarial interventions implemented in 2010-2013 in Niger State, Nigeria. DATA SOURCES: Utilization reports from 99 intervention and 51 non-intervention health facilities from the Niger State Malaria Elimination Program, supplemented by data on facility-level characteristics from the Niger State Primary Health Care Development Agency and Local Government Malaria Control units. STUDY DESIGN: Estimated with mixed-effects negative binomial modeling, a difference-in-differences method was used to quantify the impact of the program on the number of febrile illness cases and confirmed malaria cases. Potential confounding factors, non-stationarity, seasonality, and autocorrelation were explicitly accounted for. DATA EXTRACTION METHODS: Data were retrieved from hard copies of utilization reports and manually inputted to create a panel of 5550 facility-month observations. PRINCIPAL FINDINGS: The program was implemented in two phases. The first phase (August 2010-June 2012) involved the provision of free artemisinin-based combination therapies, long-lasting insecticidal nets, and intermittent preventive treatments. In the second phase (July 2012-March 2013), the program introduced an additional intervention: free parasite-based rapid diagnostic tests. Compared to the pre-intervention period, the average number of monthly febrile illness and malaria cases increased by 20.876 (P < 0.01) and 22.835 (P < 0.01) in the first phase, and by 19.007 (P < 0.05) and 19.681 (P < 0.05) in the second phase, respectively. The results are consistent across different evaluation methods. CONCLUSIONS: This study suggests that user-fee removal leads to increased utilization of antimalarial services. It motivates future studies to cautiously select their investigative methods.

Access to and use of preventive intermittent treatment for Malaria during pregnancy: A qualitative study in the Chókwè district, Southern Mozambique.

BACKGROUND: Malaria remains a significant health problem in Mozambique, particularly in the case of pregnant women and children less than five years old. Intermittent preventive treatment with sulfadoxine-pyrimethamine (IPT-SP) is recommended for preventing malaria in pregnancy (MiP). Despite the widespread use and cost-effectiveness of IPTp-SP, coverage remains low. In this study, we explored factors limiting access to and use of IPTp-SP in a rural part of Mozambique. METHODS AND FINDINGS: We performed a qualitative study using semi-structured interviews to collect data from 46 pregnant women and four health workers in Chókwè, a rural area of southern Mozambique. Data were transcribed, translated where appropriate, manually coded, and the content analyzed according to key themes. The women interviewed were not aware of the risks of MiP or the benefits of its prevention. Delays in accessing antenatal care, irregular attendance of visits, and insufficient time for proper antenatal care counselling by health workers were driving factors for inadequate IPTp delivery. CONCLUSIONS: Pregnant women face substantial barriers in terms of optimal IPTp-SP uptake. Health system barriers and poor awareness of the risks and consequences of MiP and of the measures available for its prevention were identified as the main factors influencing access to and use of IPTp-SP. Implementation of MiP prevention strategies must be improved through intensive community health education and increased access to other sources of information. Better communication between health workers and ANC clients and better knowledge of national ANC and IPTp policies are important.

In vitro assessment of cytotoxic, genotoxic and mutagenic effects of antimalarial drugs artemisinin and artemether in human lymphocytes.

Artemisinin is a substance extracted from the Chinese plant Artemisia annua L. widely used in natural medicine for the treatment of various diseases. Artemether is a substance synthesized from artemisinin, and both drugs are commonly administered in the treatment of malaria. Although considered effective antimalarial drugs, very little is known about the genotoxic, cytotoxic and mutagenic effects of these drugs. Therefore, in the present study, we evaluated the genotoxic, mutagenic and cytotoxic effects of artemisinin (12.5, 25 and 50 µg/mL) and artemether (7.46; 14.92 and 29.84 µg/mL) in cultured human lymphocytes using the comet assay, the micronucleus test and the cytotoxicity assay for detection of necrosis and apoptosis by acridine orange/ethidium bromide staining. Our results showed a significant increase (p < 0.05) in the rate of DNA damage measured by comet assay and in the micronucleus frequency after treatment with both drugs. It was also observed that only artemisinin induced a statistically significant increase (p < 0.05) in the number of lymphocytes with death by necrosis 48 h after treatment. The results demonstrated that these two drugs induce mutagenic, genotoxic and cytotoxic effects in cultured human lymphocytes. Our data indicate the need for caution in the use of such drugs, since genotoxic/mutagenic effects may increase the risk of carcinogenesis.