Impact of a package of point-of-care diagnostic tests, a clinical diagnostic algorithm and adherence training on antibiotic prescriptions for the management of non-severe acute febrile illness in primary health facilities during the COVID-19 pandemic in Burkina Faso.

OBJECTIVE: To assess the impact of an intervention package on the prescription of antibiotic and subsequently the rate of clinical recovery for non-severe acute febrile illnesses at primary health centers. METHODS: Patients over 6 months of age presenting to primary health care centres with fever or history of fever within the past 7 days were randomized to receive either the intervention package constituted of point-of-care tests including COVID-19 antigen tests, a diagnostic algorithm and training and communication packages, or the standard practice. The primary outcomes were antibiotic prescriptions at Day 0 (D0) and the clinical recovery at Day 7 (D7). Secondary outcomes were non-adherence of participants and parents/caregivers to prescriptions, health workers' non-adherence to the algorithm, and the safety of the intervention. RESULTS: A total of 1098 patients were enrolled. 551 (50.2%) were randomized to receive the intervention versus 547 (49.8%) received standard care. 1054 (96.0%) completed follow-up and all of them recovered at D7 in both arms. The proportion of patients with antibiotic prescriptions at D0 were 33.2% (183/551) in the intervention arm versus 58.1% (318/547) under standard care, risk difference (RD) -24.9 (95% CI -30.6 to -19.2, p < 0.001), corresponding to one more antibiotic saved every four (95% CI: 3 to 5) consultations. This reduction was also statistically significant in children from 6 to 59 months (RD -34.5; 95% CI -41.7 to -27.3; p < 0.001), patients over 18 years (RD -35.9; 95%CI -58.5 to -13.4; p = 0.002), patients with negative malaria test (RD -46.9; 95% CI -53.9 to -39.8; p < 0.001), those with a respiratory diagnosis (RD -48.9; 95% CI -56.9 to -41.0, p < 0.001) and those not vaccinated against COVID-19 (-24.8% 95%CI -30.7 to -18.9, p-value: <0.001). A significant reduction in non-adherence to prescription by patients was reported (RD -7.1; 95% CI -10.9 to -3.3; p < 0.001). CONCLUSION: The intervention was associated with significant reductions of antibiotic prescriptions and non-adherence, chiefly among patients with non-malaria fever, those with respiratory symptoms and children below 5 years of age. The addition of COVID-19 testing did not have a major impact on antibiotic use at primary health centers. TRIAL REGISTRATION: Clinitrial.gov; NCT04081051 registered on 06/09/2019.

Antibiotic use by clinical presentation across all healthcare providers in rural Burkina Faso: a healthcare visit exit survey.

BACKGROUND: To guide antibiotic stewardship interventions, understanding for what indications antibiotics are used is essential. METHODS: In rural Burkina Faso, we measured antibiotic dispensing across all healthcare providers. From October 2021 to February 2022, we surveyed patients in Nanoro district, Burkina Faso, following visits to health centres (3), pharmacies (2), informal medicine vendors (5) and inpatients in health centres. We estimated prevalence of antibiotic use and the proportion of Watch group antibiotics by provider type and by clinical presentation, assessing compliance with WHO's AWaRe Antibiotic Book. We estimated per capita antibiotic use by multiplying prevalence of antibiotic use, mean DDD per adult treatment course, and the rate of healthcare visits per 1000 inhabitants per day, estimated from a prior household survey. RESULTS: Outpatient antibiotic use was more frequent after health centre visits (54.8%, of which 16.5% Watch, n = 1249) than after visits to pharmacies (26.2%, 16.3% Watch, n = 328) and informal medicine vendors (26.9%, 50.0% Watch, n = 349). The frequency of antibiotic use was highest for bronchitis (79.9% antibiotic use, of which 12.6% Watch), malaria (31.9%, 23.1% Watch), gastroenteritis (76.0%, 31.7% Watch), rhinopharyngitis (40.4%, 8.3% Watch) and undifferentiated fever (77.0%, 44.8% Watch). Compliance with WHO AWaRe guidance could have averted at least 68.4% of all Watch antibiotic use in outpatients at health centres. Community-wide, 2.9 DDD (95% CI 1.9-3.9) were used per 1000 adult inhabitants per day. CONCLUSIONS: Most Watch antibiotic use at community level or primary care deviated from WHO guidance. Antibiotic stewardship should focus on key clinical presentations and include primary care and self-medication.

A Randomized Trial to Assess the Impact of a Package of Diagnostic Tools and Diagnostic Algorithm on Antibiotic Prescriptions for the Management of Febrile Illnesses Among Children and Adolescents in Primary Health Facilities in Burkina Faso.

BACKGROUND: Low- and middle-income countries face significant challenges in differentiating bacterial from viral causes of febrile illnesses, leading to inappropriate use of antibiotics. This trial aimed to evaluate the impact of an intervention package comprising diagnostic tests, a diagnostic algorithm, and a training-and-communication package on antibiotic prescriptions and clinical outcomes. METHODS: Patients aged 6 months to 18 years with fever or history of fever within the past 7 days with no focus, or a suspected respiratory tract infection, arriving at 2 health facilities were randomized to either the intervention package or standard practice. The primary outcomes were the proportions of patients who recovered at day 7 (D7) and patients prescribed antibiotics at day 0. RESULTS: Of 1718 patients randomized, 1681 (97.8%; intervention: 844; control: 837) completed follow-up: 99.5% recovered at D7 in the intervention arm versus 100% in standard practice (P = .135). Antibiotics were prescribed to 40.6% of patients in the intervention group versus 57.5% in the control arm (risk ratio: 29.3%; 95% CI: 21.8-36.0%; risk difference [RD]: -16.8%; 95% CI: -21.7% to -12.0%; P < .001), which translates to 1 additional antibiotic prescription saved every 6 (95% CI: 5-8) consultations. This reduction was significant regardless of test results for malaria, but was greater in patients without malaria (RD: -46.0%; -54.7% to -37.4%; P < .001), those with a respiratory diagnosis (RD: -38.2%; -43.8% to -32.6%; P < .001), and in children 6-59 months old (RD: -20.4%; -26.0% to -14.9%; P < .001). Except for the period July-September, the reduction was consistent across the other quarters (P < .001). CONCLUSIONS: The implementation of the package can reduce inappropriate antibiotic prescription without compromising clinical outcomes. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov; NCT04081051.

Healthcare seeking outside healthcare facilities and antibiotic dispensing patterns in rural Burkina Faso: A mixed methods study.

OBJECTIVE: Optimising antibiotic use is important to limit increasing antibiotic resistance. In rural Burkina Faso, over-the-counter dispensing of antibiotics in community pharmacies and non-licensed medicine retail outlets facilitates self-medication. We investigated its extent, reasons and dispensing patterns. METHODS: In an exploratory mixed-method design conducted between October 2020 and December 2021, this study first explored illness perceptions, the range of healthcare providers in communities, antibiotics knowledge and reasons for seeking healthcare outside healthcare facilities. Second, frequencies of illness and healthcare utilisation in the last 3 months were quantitatively measured. RESULTS: Participants distinguished between natural and magico-religious illnesses, according to origins. For illnesses considered to be 'natural', healthcare was mainly sought at healthcare facilities, private pharmacies and informal drug outlets. For illnesses considered as magico-religious, traditional healers were mainly visited. Antibiotics were perceived in the community as medicines similar to painkillers. Healthcare-seeking outside healthcare facilities was reported by 660/1973 (33.5%) participants reporting symptoms, including 315 (47.7%) to informal vendors. Healthcare seeking outside facilities was less common for 0-4-year-olds (58/534, 10.9% vs. 379/850, 44.1% for ≥5-year-olds) and decreased with improving socio-economic status (108/237, 45.6% in the lowest quintile; 96/418, 23.0% in the highest). Reported reasons included financial limitation, and also proximity to informal drug vendors, long waiting times at healthcare facilities, and health professionals' non-empathetic attitudes towards their patients. CONCLUSION: This study highlights the need to facilitate and promote access to healthcare facilities through universal health insurance and patient-centred care including reducing patients' waiting time. Furthermore, community-level antibiotic stewardship programmes should include community pharmacies and informal vendors.

Phase 3 evaluation of an innovative simple molecular test for the diagnosis of malaria in different endemic and health settings in sub-Saharan Africa (DIAGMAL).

BACKGROUND: Rapid Diagnostic Tests (RDTs) have become the cornerstone for the management of malaria in many endemic settings, but their use is constrained for several reasons: (i) persistent malaria antigen (histidine-rich protein 2; HRP2) leading to false positive test results; (ii) hrp2 deletions leading to false negative PfHRP2 results; and (iii) limited sensitivity with a detection threshold of around 100 parasites/µl blood (pLDH- and HRP2-based) leading to false negative tests. Microscopy is still the gold standard for malaria diagnosis, and allows for species determination and quantitation, but requires trained microscopists, maintained microscopes and has detection limit issues. Consequently, there is a pressing need to develop and evaluate more sensitive and accurate diagnostic tests. To address this need we have developed a direct on blood mini PCR-NALFIA test that combines the benefits of molecular biology with low infrastructural requirements and extensive training. METHODS: This is a Phase 3 diagnostic evaluation in 5 African countries. Study sites (Sudan, Ethiopia, Burkina, Kenya and Namibia) were selected to ensure wide geographical coverage of Africa and to address various malaria epidemiological contexts ranging from high transmission to near elimination settings with different clinical scenarios and diagnostic challenges. Study participants will be enrolled at the study health facilities after obtaining written informed consent. Diagnostic accuracy will be assessed following the WHO/TDR guidelines for the evaluation of diagnostics and reported according to STARD principles. Due to the lack of a 100% specific and sensitive standard diagnostic test for malaria, the sensitivity and specificity of the new test will be compared to the available diagnostic practices in place at the selected sites and to quantitative PCR as the reference test. DISCUSSION: This phase 3 study is designed to validate the clinical performance and feasibility of implementing a new diagnostic tool for the detection of malaria in real clinical settings. If successful, the proposed technology will improve the diagnosis of malaria. Enrolment started in November 2022 (Kenya) with assessment of long term outcome to be completed by 2023 at all recruitment sites. TRIAL REGISTRATION: Pan African Clinical Trial Registry (www.pactr.org) PACTR202202766889963 on 01/02/2022 and ISCRTN (www.isrctn.com/) ISRCTN13334317 on 22/02/2022.

Phase 3 Evaluation of an Innovative Simple Molecular Test for the Diagnosis of Malaria and Follow-Up of Treatment Efficacy in Pregnant Women in Sub-Saharan Africa (Preg-Diagmal).

The malaria parasite Plasmodium falciparum (Pf) can sequester in the placenta resulting in low density of peripheral parasitemia and consequently in false negative malaria diagnosis (by microscopy) in pregnant women. Moreover, the use of rapid diagnostic tests (RDTs) in diagnostic strategies, including those for the detection of a malaria infection during pregnancy, is constrained by either persistent malaria antigen (histidine-rich protein 2; HRP2) after successful treatment, leading to false positive test results, or by false negative results as previously mentioned due to parasite sequestration (which is further exacerbated due to the low limited of detection [LoD] of conventional RDTs) or to HRP2 deletion. Recently, a direct blood polymerase chain reaction combined with a nucleic acid lateral flow immunoassay (dbPCR-NALFIA) has been developed, which circumvents these challenges and has demonstrated its diagnostic potential in phase 1 and 2 studies. The PREG-DIAGMAL trial presented in this manuscript will assess the diagnostic performance of dbPCR-NALFIA for the diagnostic of malaria in pregnant women and its potential to monitor treatment efficacy in these subjects. The work is ancillary embedded in an ongoing EDCTP funded trial, the PyraPreg project (PACTR202011812241529) in which the safety and efficacy of a newly registered Artemisinin-Based Combination (Pyronaridine-Artesunate) is being evaluated in pregnant women. This is a Phase 3 diagnostic evaluation conducted in 2 African countries: Democratic Republic of the Congo (DRC) and Burkina Faso. Pregnant women fulfilling the inclusion criteria of the PyraPreg study will be also invited to participate in the PREG-DIAGMAL study. Diagnostic accuracy will be assessed following the WHO/TDR guidelines for the evaluation of diagnostics and reported according to STARD principles. Due to the lack of a 100% specific and sensitive standard diagnostic test for malaria, the sensitivity and specificity of the new test will be compared to the available diagnostic practice in place at the selected settings (microscopy and/or RDT) and to quantitative PCR as the reference test. This phase 3 diagnostic study is designed towards the evaluation of the performance of a new diagnostic tool for the screening of malaria and the monitoring of treatment in pregnant women under real conditions life. If successful, the dbPCR-NALFIA could be a valuable tool to add to the diagnostic arsenal for malaria, in particular during pregnancy. Trial registration: Pan African Clinical Trial Registry database (PACTR202203780981413). Registered on 17 March 2022.

Development and evaluation of an electronic algorithm using a combination of a two-step malaria RDT and other rapid diagnostic tools for the management of febrile illness in children under 5 attending outpatient facilities in Burkina Faso.

BACKGROUND: In Sub-Saharan Africa (SSA), febrile illnesses remain a major public health problem in children. However, the persistence of hrp2 antigen and the low sensitivity of pLDH RDT negatively affect antimalarials and antibiotics prescription practices. These limitations lead to poor management of febrile diseases and antimicrobial resistance (AMR). To improve the diagnosis of these febrile diseases and subsequent prescription of antimicrobials, it is hypothesized that the implementation of an algorithm including a two-step malaria RDT PfHRP2/pLDH supported by point-of-care (PoC) tests for bacterial infections could significantly improve the management of febrile diseases and thereby tackling AMR. METHODS: To assess the value of the proposed algorithm, an open-label randomized controlled trial with three arms, enrolling febrile children from 6 to 59 months is proposed. In the control arm, febrile children will be managed according to the Integrated Management of Childhood Illnesses (IMCI), which is part of the standard of care in Burkina Faso. Treatment will be done according to national guidelines. In the RDT decisional algorithm (RDT-DA) arm (intervention), the clinical examination based on IMIC will be supported by a two-step malaria RDT and bacterial infections RDTs. Prescription will be left to the discretion of the healthcare workers based on clinical examination and PoC test results. In the e-algorithm arm (intervention), artificial intelligence integrating multiple layers of clinical information such as clinical examination, signs/symptoms and medical history, and biological information such as biomarkers (CRP and WBC) and pathogen-specific PoC tests, and oximetry will be developed. The e-algorithm will serve to guide the diagnostic and management of febrile infections in children. In the 3 arms, the case report forms will be digitalized. A final follow-up visit (day 7) will be scheduled for all participants. Patients will be asked to come back to the health facilities before the scheduled visit if the symptoms persist or in case of health condition worsening. DISCUSSION: If successful, this study could contribute to improve the management of febrile diseases and reduce inappropriate use of antimicrobials. TRIAL REGISTRATION: The trial is registered at ClinicalTrial.gov, NCT05285657. Enrolment started on 4 March 2022 with long-term outcome being assessed completely by 2023.

Efficacy and immunogenicity of R21/Matrix-M vaccine against clinical malaria after 2 years' follow-up in children in Burkina Faso: a phase 1/2b randomised controlled trial.

BACKGROUND: Malaria is a leading cause of morbidity and mortality worldwide. We previously reported the efficacy of the R21/Matrix-M malaria vaccine, which reached the WHO-specified goal of 75% or greater efficacy over 12 months in the target population of African children. Here, we report the safety, immunogenicity, and efficacy results at 12 months following administration of a booster vaccination. METHODS: This double-blind phase 1/2b randomised controlled trial was done in children aged 5-17 months in Nanoro, Burkina Faso. Eligible children were enrolled and randomly assigned (1:1:1) to receive three vaccinations of either 5 µg R21/25 µg Matrix-M, 5 µg R21/50 µg Matrix-M, or a control vaccine (the Rabivax-S rabies vaccine) before the malaria season, with a booster dose 12 months later. Children were eligible for inclusion if written informed consent could be provided by a parent or guardian. Exclusion criteria included any existing clinically significant comorbidity or receipt of other investigational products. A random allocation list was generated by an independent statistician by use of block randomisation with variable block sizes. A research assistant from the University of Oxford, independent of the trial team, prepared sealed envelopes using this list, which was then provided to the study pharmacists to assign participants. All vaccines were prepared by the study pharmacists by use of the same type of syringe, and the contents were covered with an opaque label. Vaccine safety, efficacy, and a potential correlate of efficacy with immunogenicity, measured as anti-NANP antibody titres, were evaluated over 1 year following the first booster vaccination. The population in which the efficacy analyses were done comprised all participants who received the primary series of vaccinations and a booster vaccination. Participants were excluded from the efficacy analysis if they withdrew from the trial within the first 2 weeks of receiving the booster vaccine. This trial is registered with ClinicalTrials.gov (NCT03896724), and is continuing for a further 2 years to assess both the potential value of additional booster vaccine doses and longer-term safety. FINDINGS: Between June 2, and July 2, 2020, 409 children returned to receive a booster vaccine. Each child received the same vaccination for the booster as they received in the primary series of vaccinations; 132 participants received 5 µg R21 adjuvanted with 25 µg Matrix-M, 137 received 5 µg R21 adjuvanted with 50 µg Matrix-M, and 140 received the control vaccine. R21/Matrix-M had a favourable safety profile and was well tolerated. Vaccine efficacy remained high in the high adjuvant dose (50 µg) group, similar to previous findings at 1 year after the primary series of vaccinations. Following the booster vaccination, 67 (51%) of 132 children who received R21/Matrix-M with low-dose adjuvant, 54 (39%) of 137 children who received R21/Matrix-M with high-dose adjuvant, and 121 (86%) of 140 children who received the rabies vaccine developed clinical malaria by 12 months. Vaccine efficacy was 71% (95% CI 60 to 78) in the low-dose adjuvant group and 80% (72 to 85) in the high-dose adjuvant group. In the high-dose adjuvant group, vaccine efficacy against multiple episodes of malaria was 78% (95% CI 71 to 83), and 2285 (95% CI 1911 to 2568) cases of malaria were averted per 1000 child-years at risk among vaccinated children in the second year of follow-up. Among these participants, at 28 days following their last R21/Matrix-M vaccination, titres of malaria-specific anti-NANP antibodies correlated positively with protection against malaria in both the first year of follow-up (Spearman's ρ -0·32 [95% CI -0·45 to -0·19]; p=0·0001) and second year of follow-up (-0·20 [-0·34 to -0·06]; p=0·02). INTERPRETATION: A booster dose of R21/Matrix-M at 1 year following the primary three-dose regimen maintained high efficacy against first and multiple episodes of clinical malaria. Furthermore, the booster vaccine induced antibody concentrations that correlated with vaccine efficacy. The trial is ongoing to assess long-term follow-up of these participants and the value of further booster vaccinations. FUNDING: European and Developing Countries Clinical Trials Partnership 2 (EDCTP2), Wellcome Trust, and NIHR Oxford Biomedical Research Centre. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Use of WATCH antibiotics prior to presentation to the hospital in rural Burkina Faso.

BACKGROUND: In low- and middle-income countries, the prevalence of antimicrobial resistance (AMR) is increasing. To control AMR, WHO recommends monitoring antibiotic use, in particular Watch antibiotics. These are critically important antibiotics, with restricted use because at risk of becoming ineffective due to increasing AMR. We investigated pre-hospital antibiotic use in rural Burkina Faso. METHODS: During 2016-2017, we collected data from patients aged > 3 months presenting with severe acute fever to the rural hospital of Nanoro Health District, Burkina Faso, including antibiotic use in the two weeks prior to consultation or hospitalization. We analysed reported antibiotic use by applying the WHO Access, Watch, Reserve classification. RESULTS: Of 920 febrile participants (63.0% ≤ 14 years), pre-hospital antibiotic use was reported by 363 (39.5%). Among these 363, microbiological diagnoses were available for 275 (75.8%) patients, of whom 162 (58.9%) were non-bacterial infections. Use of more than one antibiotic was reported by 58/363 (16.0%) participants. Of 491 self-referred patients who did not previously visit a primary health care center, 131 (26.7%) reported antibiotic use. Of 424 antibiotics reported, 265 (62.5%) were Access and 159 (37.5%) Watch antibiotics. Watch antibiotic use was more frequent among patients > 14 year olds (51.1%) compared to those 0-14 year old (30.7%, p < 0.001) and among referrals from the primary health care centers (42.2%) compared to self-referred patients (28.1%, p = 0.004). Most frequently reported Watch antibiotics were ceftriaxone (114, 71.7%) and ciprofloxacin (32, 20.1%). CONCLUSION: The reported frequent use of Watch group antibiotics among febrile patients prior to presentation to the hospital in rural Burkina Faso highlights the need to develop targeted interventions to improve antibiotic use in community settings as part of strengthening antibiotic stewardship in low- and middle-income countries. This should include facilitating referral, access to qualified prescribers and diagnostic tools in rural primary health care centers. Trial registration ClinicalTrials.gov identifier: NCT02669823. Registration date was February 1, 2016.

Magnitude of low birthweight in malaria endemic settings of Nanoro, rural Burkina Faso: a secondary data analysis.

Low birthweight (LBW) is a worldwide problem that particularly affects developing countries. However, limited information is available on its magnitude in rural area of Burkina Faso. This study aimed to estimate the prevalence of low birthweight and to identify its associated factors in Nanoro health district. A secondary analysis of data collected during a cross-sectional survey was conducted to assess the prevalence of low birthweight in Nanoro health and demographic surveillance system area (HDSS). Maternal characteristics extracted from antenatal care books or by interview, completed by malaria diagnosis were examined through a multi-level logistic regression to estimate odd-ratios of association with low birthweight. Significance level was set at 5%. Of the 291 neonates examined, the prevalence of low birthweight was 12%. After adjustment for socio-demographic, obstetric and malaria prevention variables, being primigravid (OR = 8.84, [95% CI: 3.72-21.01]), or multigravid with history of stillbirth (OR = 5.03, [95% CI: 1.54-16.40]), as well as the lack of long-lasting insecticide treated bed net use by the mother the night preceding the admission for delivery (OR = 2.5, [95% CI: 1.1-5.9]) were significantly associated with neonate low birthweight. The number of antenatal visits however did not confer any direct benefit on birthweight status within this study area. The prevalence of low birthweight was high in the study area and represents an important public health problem in Burkina Faso. In light of these results, a redefinition of the content of the antenatal care package is needed.

Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial.

BACKGROUND: Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy over 12 months in African children. We therefore assessed a new candidate vaccine for safety and efficacy. METHODS: In this double-blind, randomised, controlled, phase 2b trial, the low-dose circumsporozoite protein-based vaccine R21, with two different doses of adjuvant Matrix-M (MM), was given to children aged 5-17 months in Nanoro, Burkina Faso-a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals before the malaria season, with a fourth dose 1 year later. All vaccines were administered intramuscularly into the thigh. Group 1 received 5 µg R21 plus 25 µg MM, group 2 received 5 µg R21 plus 50 µg MM, and group 3, the control group, received rabies vaccinations. Children were randomly assigned (1:1:1) to groups 1-3. An independent statistician generated a random allocation list, using block randomisation with variable block sizes, which was used to assign participants. Participants, their families, and the local study team were all masked to group allocation. Only the pharmacists preparing the vaccine were unmasked to group allocation. Vaccine safety, immunogenicity, and efficacy were evaluated over 1 year. The primary objective assessed protective efficacy of R21 plus MM (R21/MM) from 14 days after the third vaccination to 6 months. Primary analyses of vaccine efficacy were based on a modified intention-to-treat population, which included all participants who received three vaccinations, allowing for inclusion of participants who received the wrong vaccine at any timepoint. This trial is registered with ClinicalTrials.gov, NCT03896724. FINDINGS: From May 7 to June 13, 2019, 498 children aged 5-17 months were screened, and 48 were excluded. 450 children were enrolled and received at least one vaccination. 150 children were allocated to group 1, 150 children were allocated to group 2, and 150 children were allocated to group 3. The final vaccination of the primary series was administered on Aug 7, 2019. R21/MM had a favourable safety profile and was well tolerated. The majority of adverse events were mild, with the most common event being fever. None of the seven serious adverse events were attributed to the vaccine. At the 6-month primary efficacy analysis, 43 (29%) of 146 participants in group 1, 38 (26%) of 146 participants in group 2, and 105 (71%) of 147 participants in group 3 developed clinical malaria. Vaccine efficacy was 74% (95% CI 63-82) in group 1 and 77% (67-84) in group 2 at 6 months. At 1 year, vaccine efficacy remained high, at 77% (67-84) in group 1. Participants vaccinated with R21/MM showed high titres of malaria-specific anti-Asn-Ala-Asn-Pro (NANP) antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to peak titres after the primary series of vaccinations after a fourth dose administered 1 year later. INTERPRETATION: R21/MM appears safe and very immunogenic in African children, and shows promising high-level efficacy. FUNDING: The European & Developing Countries Clinical Trials Partnership, Wellcome Trust, and National Institute for Health Research Oxford Biomedical Research Centre.

Long-term incidence of severe malaria following RTS,S/AS01 vaccination in children and infants in Africa: an open-label 3-year extension study of a phase 3 randomised controlled trial.

BACKGROUND: Results from a previous phase 3 study showed efficacy of the RTS,S/AS01 vaccine against severe and clinical malaria in children (in 11 sites in Africa) during a 3-4-year follow-up. We aimed to investigate malaria incidence up to 7 years postvaccination in three of the sites of the initial study. METHODS: In the initial phase 3 study, infants aged 6-12 weeks and children aged 5-17 months were randomly assigned (1:1:1) to receive four RTS,S/AS01 doses (four-dose group), three RTS,S/AS01 doses and a comparator dose (three-dose group), or four comparator doses (control group). In this open-label extension study in Korogwe (Tanzania), Kombewa (Kenya), and Nanoro (Burkina Faso), we assessed severe malaria incidences as the primary outcome for 3 additional years (January, 2014, to December, 2016), up to 6 years (younger children) or 7 years (older children) postprimary vaccination in the modified intention-to-treat population (ie, participants who received at least one dose of the study vaccine). As secondary outcomes, we evaluated clinical malaria incidences and serious adverse events. This trial is registered with ClinicalTrials.gov, number NCT02207816. FINDINGS: We enrolled 1739 older children (aged 5-7 years) and 1345 younger children (aged 3-5 years). During the 3-year extension, 66 severe malaria cases were reported, resulting in severe malaria incidence of 0·004 cases per person-years at risk (PPY; 95% CI 0-0·033) in the four-dose group, 0·007 PPY (0·001-0·052) in the three-dose group, and 0·009 PPY (0·001-0·066) in the control group in the older children category and a vaccine efficacy against severe malaria that did not contribute significantly to the overall efficacy (four-dose group 53·7% [95% CI -13·7 to 81·1], p=0·093; three-dose group 23·3% [-67·1 to 64·8], p=0·50). In younger children, severe malaria incidences were 0·007 PPY (0·001-0·058) in the four-dose group, 0·007 PPY (0·001-0·054) in the three-dose group, and 0·011 PPY (0·001-0·083) in the control group. Vaccine efficacy against severe malaria also did not contribute significantly to the overall efficacy (four-dose group 32·1% [-53·1 to 69·9], p=0·35; three-dose group 37·6% [-44·4 to 73·0], p=0·27). Malaria transmission was still occurring as evidenced by an incidence of clinical malaria ranging from 0·165 PPY to 3·124 PPY across all study groups and sites. In older children, clinical malaria incidence was 1·079 PPY (95% CI 0·152-7·662) in the four-dose group, 1·108 PPY (0·156-7·868) in the three-dose group, and 1·016 PPY (0·14-7·213) in the control group. In younger children, malaria incidence was 1·632 PPY (0·23-11·59), 1·563 PPY (0·22-11·104), and 1·686 PPY (0·237-11·974), respectively. In the older age category in Nanoro, clinical malaria incidence was higher in the four-dose (2·444 PPY; p=0·011) and three-dose (2·411 PPY; p=0·034) groups compared with the control group (1·998 PPY). Three cerebral malaria episodes and five meningitis cases, but no vaccine-related severe adverse events, were reported. INTERPRETATION: Overall, severe malaria incidence was low in all groups, with no evidence of rebound in RTS,S/AS01 recipients, despite an increased incidence of clinical malaria in older children who received RTS,S/AS01 compared with the comparator group in Nanoro. No safety signal was identified. FUNDING: GlaxoSmithKline Biologicals SA.

High adherence level to artemisinin-based combination therapies in rural settlement 11 years after their introduction in the health system, Nanoro, Burkina Faso.

PURPOSE: In 2005, Burkina Faso changed its first-line treatment for uncomplicated malaria from chloroquine to artemisinin-based combination therapies (ACTs). Patient adherence to ACTs regimen is a keystone to achieve the expected therapeutic outcome and prevent the emergence and spread of parasite resistance. Eleven years after the introduction of ACTs in the health system, this study aimed to measure adherence level of patients in rural settlement and investigate the determinants of nonadherence. PATIENTS AND METHODS: The study was carried out at public peripheral health facilities from May 2017 to August 2017 in Nanoro health district, Burkina Faso. An electronic semi-structured questionnaire was used for data collection from patients with an ACT prescription at their medical consultation exit visit and during home visit at day 5±2. Adherence level was measured through self-report and pill counts. Logistic regression was performed to identify factors for nonadherence. RESULTS: The analysis was conducted on 199 outpatients who received ACT as prescription. About 92.5% of ACT prescriptions included artemether-lumefantrine tablets. Adherence level was measured in 97.0% of included patients at day 5±2. Of these, 86.0% were classified as "complete adherent" and 14.0% as "nonadherent". In univariate analysis, patients/caregivers who considered that affordability of ACTs was easy seemed to be less adherent to the treatment regimen (OR: 0.26; 95% CI: 0.07-0.70). In univariate and multivariable analyses, patients/caregivers who did not receive advices from health care workers (HCWs) were more likely to be nonadherent to the prescribed ACTs (adjusted OR: 3.21; 95% CI: 1.13-9.12). CONCLUSION: This study demonstrates that majority of those who get an ACT prescription comply with the recommended regimen. This emphasizes that in rural settings where ACTs are provided free of charge or at a subsidized price, patient adherence to ACTs is high, thus minimizing the risk of subtherapeutic concentrations of the drug in blood which is known to increase resistance and susceptibility to new infections. Therefore, to address the problem of patient nonadherence, strategy to strengthen communication between HCWs and patients should be given greater consideration.

Gender differences in sociodemographic and behavioural factors associated with BMI in an adult population in rural Burkina Faso - an AWI-Gen sub-study.

BACKGROUND: The global health transition is linked with an increased burden of non-communicable diseases with cardiovascular diseases leading the epidemic. In sub-Saharan Africa (SSA), the prevalence of obesity has increased during the past decades and there is a need to investigate the associated driving factors. In Burkina Faso obesity remains low, especially in rural areas. In this study we recruited middle-aged adults, as part of a larger study on genetic and environmental contributions to cardiometabolic disease among Africans. OBJECTIVES: To investigate the distribution of BMI and prevalence of obesity in a cross-sectional population-based study and to determine the sociodemographic and behavioural correlates with BMI. METHODS: Participants (N = 2,076) were recruited from the Nanoro Health and Demographic Surveillance System area and were aged 40-60 years. We applied hierarchical modelling to identify factors associated with BMI and structural equation modelling to identify mediated effects of sociodemographic and behavioural variables on BMI. RESULTS: Data are presented on 2,076 participants (49.9% female). Men had significantly higher BMI than women with medians of 21.1 (19.2 - 23.4) vs 19.8 (18.1 - 21.6) (p < 0.001), and there were significantly more underweight women compared to men (31.0% vs 17.4%) (p < 0.001). More men were overweight and obese than women (11.9% vs 5.2% and 2.2% vs 1.4%). Socioeconomic status was the major contributor to increased BMI for men, and education was the main contributor in women. Tobacco smoking and chewing, and problematic alcohol consumption were associated with a decrease in BMI in men and women. CONCLUSION: Overweight and obesity are relatively low among adults in rural Burkina Faso, and men had a higher median BMI than women. Behavioural factors, including tobacco use and alcohol consumption, contributed to a decrease in BMI, whereas socioeconomic status and education (which were both generally low in this community) contributed to an increase in BMI.