Conference Material > Abstract
Ahortor E, Mahazu S, Manful T, Erber A, Ablordey A
MSF Scientific Days International 2024. 2024 May 16
INTRODUCTION
Buruli ulcer caused by Mycobacterium ulcerans is a devastating necrotic skin disease. PCR, recommended for confirmation of Buruli ulcer by WHO, requires an adequately equipped laboratory, often delaying diagnosis and treatment of patients in remote or humanitarian settings. We aimed to assess loop- mediated isothermal amplification (LAMP), which is a molecular assay for isothermal amplification of DNA suggested for timely diagnosis of Buruli ulcer in low-resource settings.
METHODS
This study combines quantitative and qualitative methods. First, we evaluated a simple rapid syringe DNA extraction method (SM) in comparison with a conventional extraction method (CM), followed by a LAMP assay targeting IS2404 for the detection of M ulcerans, either using a pocket warmer (pw) or a heat block (hb) for incubation of the reaction. 83 clinical specimens (swabs and fine-needle aspirates from different centres in Ghana) were tested. We assessed sensitivity, specificity, and positive and negative predictive value (PPV and NPV). Second, we explored the diagnostic workflow for Buruli ulcer at a community-based health centre in rural Ghana, a potential target setting. We used observations and interviews with researchers and healthcare workers (HCWs) and community-based surveillance volunteers. We discuss evaluation results in relation to the target setting and requirements of a target product profile for Buruli ulcer diagnosis.
RESULTS
DNA extraction using SM followed by IS2404 PCR (IS2404 PCRSM) identified M ulcerans DNA in 73 of 83 clinical specimens. The sensitivity, specificity, PPV, and NPV of IS2404 PCRSM were 90.12%, 100%, 100%, and 65.21%, respectively, compared
with the reference standard IS2404 PCR with the CM protocol. Evaluation of the LAMP assay on 64 SM DNA extracts showed a sensitivity, specificity, PPV, and NPV of 83.6%, 100%, 100%, and 50%, respectively, using either pw (pwLAMPSM) or hb (hbLAMPSM) for incubation, compared with the same reference standard. The limit of detection of both pwLAMPSM and hbLAMPSM was 30 target copies. Interviews confirmed that, despite great engagement from HCWs and volunteers, patients met challenges regarding transport and costs for initial diagnosis and follow- up and often sought alternative treatments first. Diagnostic confirmation via PCR in a reference laboratory led to a delay in the initiation of treatment. A diagnosis at the point of care, following clinical screening, was considered advantageous to prevent delays and loss to follow-up, therefore ensuring timely patient treatment.
CONCLUSION
Our findings support the potential use of pwLAMP for rapid diagnosis of Buruli Ulcer in patients with a suspected infection at the community or primary health-care level, with limited equipment and without reliable electricity supply such as found in humanitarian settings.
Buruli ulcer caused by Mycobacterium ulcerans is a devastating necrotic skin disease. PCR, recommended for confirmation of Buruli ulcer by WHO, requires an adequately equipped laboratory, often delaying diagnosis and treatment of patients in remote or humanitarian settings. We aimed to assess loop- mediated isothermal amplification (LAMP), which is a molecular assay for isothermal amplification of DNA suggested for timely diagnosis of Buruli ulcer in low-resource settings.
METHODS
This study combines quantitative and qualitative methods. First, we evaluated a simple rapid syringe DNA extraction method (SM) in comparison with a conventional extraction method (CM), followed by a LAMP assay targeting IS2404 for the detection of M ulcerans, either using a pocket warmer (pw) or a heat block (hb) for incubation of the reaction. 83 clinical specimens (swabs and fine-needle aspirates from different centres in Ghana) were tested. We assessed sensitivity, specificity, and positive and negative predictive value (PPV and NPV). Second, we explored the diagnostic workflow for Buruli ulcer at a community-based health centre in rural Ghana, a potential target setting. We used observations and interviews with researchers and healthcare workers (HCWs) and community-based surveillance volunteers. We discuss evaluation results in relation to the target setting and requirements of a target product profile for Buruli ulcer diagnosis.
RESULTS
DNA extraction using SM followed by IS2404 PCR (IS2404 PCRSM) identified M ulcerans DNA in 73 of 83 clinical specimens. The sensitivity, specificity, PPV, and NPV of IS2404 PCRSM were 90.12%, 100%, 100%, and 65.21%, respectively, compared
with the reference standard IS2404 PCR with the CM protocol. Evaluation of the LAMP assay on 64 SM DNA extracts showed a sensitivity, specificity, PPV, and NPV of 83.6%, 100%, 100%, and 50%, respectively, using either pw (pwLAMPSM) or hb (hbLAMPSM) for incubation, compared with the same reference standard. The limit of detection of both pwLAMPSM and hbLAMPSM was 30 target copies. Interviews confirmed that, despite great engagement from HCWs and volunteers, patients met challenges regarding transport and costs for initial diagnosis and follow- up and often sought alternative treatments first. Diagnostic confirmation via PCR in a reference laboratory led to a delay in the initiation of treatment. A diagnosis at the point of care, following clinical screening, was considered advantageous to prevent delays and loss to follow-up, therefore ensuring timely patient treatment.
CONCLUSION
Our findings support the potential use of pwLAMP for rapid diagnosis of Buruli Ulcer in patients with a suspected infection at the community or primary health-care level, with limited equipment and without reliable electricity supply such as found in humanitarian settings.
Conference Material > Abstract
Sterk E, Schramm B, Riccio E, Gabut M, Fontana L, et al.
MSF Scientific Days International 2024. 2024 May 16
INTRODUCTION
The 2014 West Africa Ebola outbreak underlined inadequacies of current personal protective equipment (PPE), such as being uncomfortable and hot, causing excessive sweating and rapid exhaustion, and limiting interactions between health workers and patients. The smartPPE development project responded to the urgent need for a more comfortable, simpler, and sustainable PPE solution for filovirus-outbreak front-line workers. A one- piece, reusable smartPPE with ventilation system was developed to address these challenges. We assessed ease-of-use, comfort, functionality, and perceived doffing-safety of the smartPPE prototype compared with currently used PPE (current-PPE) under simulated field conditions.
METHODS
In June 2023, we conducted a mixed-methods crossover usability study in a controlled high-heat/high-humidity indoor site in Brindisi, Italy. Ten test users (three female, seven with filovirus-front-line experience) assessed smartPPE and current- PPE in four guided sessions covering donning, (emergency) doffing, clinical tasks, and heavy physical WATSAN activities. User feedback was collected through structured questionnaires. Temperature, humidity, session duration, and vital signs were measured, and perceived exertion was assessed using Borg- scores (scale 6–20).
RESULTS
Median temperature and humidity were higher inside current- PPE than inside smartPPE (difference: 2.3°C [IQR 1.8–3.0] and 12.6 percentage points [8.8–19.6], respectively). Users endured heavy work sessions for significantly longer in smartPPE than in current-PPE (80.0 min [IQR 75–84] vs 49.5 min [45–56]). Median increases in body temperature (1.1°C [IQR 0.7–1.6] vs 0.7°C [0.3–0.9]; p<0.001) and respiratory rate (3.5 rpm [1–5] vs 1.5 rpm [0–3]; p=0.034), and reductions in O2 saturation (–2% [–5 to –1] vs –1.5% [–3 to 0]; p=0.027) were higher with current-PPE than with smartPPE. Peripheral vision was similarly rated, but hearing was compromised with smartPPE at ≥5 m. Median exertion- scores were lower for smartPPE (clinical tasks 8.5 [IQR 7–11] vs 15.5 [14–16] p<0.01; heavy physical activities 14 [13–17] vs 18 [17–20] p=0.035). All users preferred smartPPE for overall and thermal comfort, breathing, and doffing-safety; nine (90%) favoured it for non-verbal communication, eight (80%) for vision or longer-interval heavy WATSAN activities, six (60%) for longer- interval patient care, six (60%) for short-term clinical activities, and six (60%) for emergency doffing. Reported concerns were airflow obstruction while bending, hearing difficulties attributed to ventilation noise, and adjustments for headgear, ventilation, and suit fitting.
CONCLUSION
Test users confirmed the usability of smartPPE and favoured it, especially for doffing-safety, longer-interval clinical or physical work, and improved non-verbal interactions, whereas hearing was challenged by the ventilation. Adjustments are currently underway before design freeze. Stakeholder commitment will be crucial to ensure production at scale.
The 2014 West Africa Ebola outbreak underlined inadequacies of current personal protective equipment (PPE), such as being uncomfortable and hot, causing excessive sweating and rapid exhaustion, and limiting interactions between health workers and patients. The smartPPE development project responded to the urgent need for a more comfortable, simpler, and sustainable PPE solution for filovirus-outbreak front-line workers. A one- piece, reusable smartPPE with ventilation system was developed to address these challenges. We assessed ease-of-use, comfort, functionality, and perceived doffing-safety of the smartPPE prototype compared with currently used PPE (current-PPE) under simulated field conditions.
METHODS
In June 2023, we conducted a mixed-methods crossover usability study in a controlled high-heat/high-humidity indoor site in Brindisi, Italy. Ten test users (three female, seven with filovirus-front-line experience) assessed smartPPE and current- PPE in four guided sessions covering donning, (emergency) doffing, clinical tasks, and heavy physical WATSAN activities. User feedback was collected through structured questionnaires. Temperature, humidity, session duration, and vital signs were measured, and perceived exertion was assessed using Borg- scores (scale 6–20).
RESULTS
Median temperature and humidity were higher inside current- PPE than inside smartPPE (difference: 2.3°C [IQR 1.8–3.0] and 12.6 percentage points [8.8–19.6], respectively). Users endured heavy work sessions for significantly longer in smartPPE than in current-PPE (80.0 min [IQR 75–84] vs 49.5 min [45–56]). Median increases in body temperature (1.1°C [IQR 0.7–1.6] vs 0.7°C [0.3–0.9]; p<0.001) and respiratory rate (3.5 rpm [1–5] vs 1.5 rpm [0–3]; p=0.034), and reductions in O2 saturation (–2% [–5 to –1] vs –1.5% [–3 to 0]; p=0.027) were higher with current-PPE than with smartPPE. Peripheral vision was similarly rated, but hearing was compromised with smartPPE at ≥5 m. Median exertion- scores were lower for smartPPE (clinical tasks 8.5 [IQR 7–11] vs 15.5 [14–16] p<0.01; heavy physical activities 14 [13–17] vs 18 [17–20] p=0.035). All users preferred smartPPE for overall and thermal comfort, breathing, and doffing-safety; nine (90%) favoured it for non-verbal communication, eight (80%) for vision or longer-interval heavy WATSAN activities, six (60%) for longer- interval patient care, six (60%) for short-term clinical activities, and six (60%) for emergency doffing. Reported concerns were airflow obstruction while bending, hearing difficulties attributed to ventilation noise, and adjustments for headgear, ventilation, and suit fitting.
CONCLUSION
Test users confirmed the usability of smartPPE and favoured it, especially for doffing-safety, longer-interval clinical or physical work, and improved non-verbal interactions, whereas hearing was challenged by the ventilation. Adjustments are currently underway before design freeze. Stakeholder commitment will be crucial to ensure production at scale.
Conference Material > Abstract
Rapoud D, Cramer E, Al Asmar M, Sagara F, Ndiaye B, et al.
MSF Scientific Days International 2024. 2024 May 16
INTRODUCTION
Antimicrobial resistance (AMR) is a major threat to public health and could cause 10 million deaths per year by 2050. Access to high-quality diagnostic tests is a key intervention to tackle AMR, leading to better patient care, provision of data for global surveillance, and more rational use of antibiotics. Despite technological advances, antimicrobial susceptibility testing (AST) interpretation is complex and requires expert clinical microbiologists, which are lacking in low- and middle-income countries (LMIC). To fill the gap, The Médecins Sans Frontières (MSF) Foundation developed Antibiogo, a smartphone-based application to support laboratory technicians with AST interpretation. We aimed to assess the clinical performance of Antibiogo in intended use settings as per European regulations for in-vitro diagnostic medical devices.
METHODS
Antibiogo combines image processing, machine learning, and expert system technologies for the provision of final results (S/I/R: Susceptible, Intermediate, or Resistant). In 2022, we assessed the clinical performance of Antibiogo according to European regulations in three microbiology laboratories in Jordan (MSF Reconstructive Surgery Hospital, Amman), Mali (MSF Paediatric Hospital, Koutiala), and Senegal (Pasteur Institute, Dakar). In each site, clinical AST performed for routine purposes was processed in parallel with Antibiogo. AST pictures and inhibition zone diameter values measured with Antibiogo were interpreted by an expert microbiologist who was masked to Antibiogo interpretation. We calculated S/I/R category agreement between the microbiologist and Antibiogo, as well as minor (mD), major (MD) and very major discrepancies (VMD).
RESULTS
We included 378 fresh isolates in the study, representing 11 different pathogens. The overall category agreement was 88.8% (95% CI 87.9–89.7), ranging per pathogen from 67.1% (63.2–70.8) (for Pseudomonas aeruginosa) to 98.1% (94.4–99.6) (for Haemophilus influenzae), with 10.2% (9.4–11.1) mD, 1.6% MD (1.2–2.3), and 0.25% VMD (0.08–0.59). From these results, Antibiogo was validated for 11 WHO priority pathogens. From an operational need identified, to proof of concept and evaluation, it became the first MSF CE-marked in-vitro diagnostic (IVD) test in May 2022. As of January 2024, it has been implemented in five MSF laboratories (in Central African Republic, Democratic Republic of the Congo, Jordan, Mali, and Yemen), and in public laboratories in Mali upon request from the Ministry of Health.
CONCLUSION
It will take 400 years to address the shortfall of microbiologists in LMIC at the present rate of training. In the meantime, technology can help fill the gap. In parallel to deployment of Antibiogo in additional countries and regions, developments are ongoing, and an improved version of the app will be released in 2024.
Antimicrobial resistance (AMR) is a major threat to public health and could cause 10 million deaths per year by 2050. Access to high-quality diagnostic tests is a key intervention to tackle AMR, leading to better patient care, provision of data for global surveillance, and more rational use of antibiotics. Despite technological advances, antimicrobial susceptibility testing (AST) interpretation is complex and requires expert clinical microbiologists, which are lacking in low- and middle-income countries (LMIC). To fill the gap, The Médecins Sans Frontières (MSF) Foundation developed Antibiogo, a smartphone-based application to support laboratory technicians with AST interpretation. We aimed to assess the clinical performance of Antibiogo in intended use settings as per European regulations for in-vitro diagnostic medical devices.
METHODS
Antibiogo combines image processing, machine learning, and expert system technologies for the provision of final results (S/I/R: Susceptible, Intermediate, or Resistant). In 2022, we assessed the clinical performance of Antibiogo according to European regulations in three microbiology laboratories in Jordan (MSF Reconstructive Surgery Hospital, Amman), Mali (MSF Paediatric Hospital, Koutiala), and Senegal (Pasteur Institute, Dakar). In each site, clinical AST performed for routine purposes was processed in parallel with Antibiogo. AST pictures and inhibition zone diameter values measured with Antibiogo were interpreted by an expert microbiologist who was masked to Antibiogo interpretation. We calculated S/I/R category agreement between the microbiologist and Antibiogo, as well as minor (mD), major (MD) and very major discrepancies (VMD).
RESULTS
We included 378 fresh isolates in the study, representing 11 different pathogens. The overall category agreement was 88.8% (95% CI 87.9–89.7), ranging per pathogen from 67.1% (63.2–70.8) (for Pseudomonas aeruginosa) to 98.1% (94.4–99.6) (for Haemophilus influenzae), with 10.2% (9.4–11.1) mD, 1.6% MD (1.2–2.3), and 0.25% VMD (0.08–0.59). From these results, Antibiogo was validated for 11 WHO priority pathogens. From an operational need identified, to proof of concept and evaluation, it became the first MSF CE-marked in-vitro diagnostic (IVD) test in May 2022. As of January 2024, it has been implemented in five MSF laboratories (in Central African Republic, Democratic Republic of the Congo, Jordan, Mali, and Yemen), and in public laboratories in Mali upon request from the Ministry of Health.
CONCLUSION
It will take 400 years to address the shortfall of microbiologists in LMIC at the present rate of training. In the meantime, technology can help fill the gap. In parallel to deployment of Antibiogo in additional countries and regions, developments are ongoing, and an improved version of the app will be released in 2024.
Conference Material > Abstract
Gotham D, Martin M, Barber M, Kazounis E, Batts C, et al.
MSF Scientific Days International 2024. 2024 May 16
INTRODUCTION
Clinical trials are a cornerstone of medical innovation. Nonetheless, little information on the cost of conducting clinical trials is available, especially for clinical trials in the global south. This lack of data and transparency hinders the creation of reliable cost estimates and adequate funding of clinical trials in resource- limited settings. Following the recent adoption of the Médecins Sans Frontières (MSF) Clinical Trial Transparency Policy, we present a detailed cost report for TB-PRACTECAL.
METHODS
TB-PRACTECAL was an open-label, phase 2–3, multicentre randomised trial of all-oral regimens for the treatment of drug- resistant tuberculosis. Trial planning began in 2013 and work on publications continued into 2023. The trial took place in six sites across Belarus, South Africa, and Uzbekistan, and enrolled 552 patients. We analysed accounting data for the TB-PRACTECAL project, comprehensively including different costs, presented into 27 categories, by site, and by year, and at the per-patient level.
RESULTS
Total costs for TB-PRACTECAL were €33.9 million, of which 26% were at central level (costs incurred by the UK clinical trial team including trial planning, management, quality assurance, and analysis of results), while 72% were at the trial site level (across all six sites) and 2% were uncategorisable. At trial sites, the largest cost category was staff (43%), followed by external diagnostic services (11%), medicines (9%), other medical consumables (7%), external non-medical services (6%), and transport and travel (6%). Among medicines, the costliest were bedaquiline (46% of medicine costs), linezolid (16%), imipenem/ cilastatin (10%), and delamanid (9%). The mean cost per patient enrolled was €61,460 across the whole trial (including trial management overhead). When only site-level costs were considered, per-patient costs ranged between €19,998 and €45,942 across the six sites.
CONCLUSION
The costs of TB-PRACTECAL were similar to previously reported estimates for comparable clinical trials. However, TB- PRACTECAL included additional costs that would not typically be incurred in a commercial trial, such as investments in clinical research infrastructure and purchase of investigative medical products. To our knowledge, this is the first time MSF, or any other entity, published and analysed the disaggregated costs of a specific clinical trial. These data could help generate reliable predictions for future clinical trials and support planning and involvement, particularly in low-resource settings. Additionally, this study highlights the role of clinical trial cost disclosure in supporting both practical and policy discussions around the development of a more equitable system of biomedical R&D and fairer medicine pricing. Additionally, we developed a financial reporting template to facilitate future reporting of clinical trial cost by MSF and other entities investing in research.
Clinical trials are a cornerstone of medical innovation. Nonetheless, little information on the cost of conducting clinical trials is available, especially for clinical trials in the global south. This lack of data and transparency hinders the creation of reliable cost estimates and adequate funding of clinical trials in resource- limited settings. Following the recent adoption of the Médecins Sans Frontières (MSF) Clinical Trial Transparency Policy, we present a detailed cost report for TB-PRACTECAL.
METHODS
TB-PRACTECAL was an open-label, phase 2–3, multicentre randomised trial of all-oral regimens for the treatment of drug- resistant tuberculosis. Trial planning began in 2013 and work on publications continued into 2023. The trial took place in six sites across Belarus, South Africa, and Uzbekistan, and enrolled 552 patients. We analysed accounting data for the TB-PRACTECAL project, comprehensively including different costs, presented into 27 categories, by site, and by year, and at the per-patient level.
RESULTS
Total costs for TB-PRACTECAL were €33.9 million, of which 26% were at central level (costs incurred by the UK clinical trial team including trial planning, management, quality assurance, and analysis of results), while 72% were at the trial site level (across all six sites) and 2% were uncategorisable. At trial sites, the largest cost category was staff (43%), followed by external diagnostic services (11%), medicines (9%), other medical consumables (7%), external non-medical services (6%), and transport and travel (6%). Among medicines, the costliest were bedaquiline (46% of medicine costs), linezolid (16%), imipenem/ cilastatin (10%), and delamanid (9%). The mean cost per patient enrolled was €61,460 across the whole trial (including trial management overhead). When only site-level costs were considered, per-patient costs ranged between €19,998 and €45,942 across the six sites.
CONCLUSION
The costs of TB-PRACTECAL were similar to previously reported estimates for comparable clinical trials. However, TB- PRACTECAL included additional costs that would not typically be incurred in a commercial trial, such as investments in clinical research infrastructure and purchase of investigative medical products. To our knowledge, this is the first time MSF, or any other entity, published and analysed the disaggregated costs of a specific clinical trial. These data could help generate reliable predictions for future clinical trials and support planning and involvement, particularly in low-resource settings. Additionally, this study highlights the role of clinical trial cost disclosure in supporting both practical and policy discussions around the development of a more equitable system of biomedical R&D and fairer medicine pricing. Additionally, we developed a financial reporting template to facilitate future reporting of clinical trial cost by MSF and other entities investing in research.
Conference Material > Abstract
Wardley T, West KP, Tesfay B, Robinson N, Parry L, et al.
MSF Scientific Days International 2024. 2024 May 16
INTRODUCTION
Climate and environmental conditions are critical factors in malaria transmission. Médecins Sans Frontières (MSF) teams in South Sudan have seen changes in the timing and intensity of malaria seasonal peaks over the past decade. The Malaria Anticipation Project (MAP) aims to develop predictive early warning systems to better predict and act upon any expected rise in malaria cases, through routine surveillance.
METHODS
Predictive models were developed using environmental data collected from climate and space agencies and weekly outpatient department (OPD) malaria case count in Lankien hospital (Jonglei State, South Sudan) as the epidemiological input and output. An ensemble modelling approach was developed using linear regression and extreme gradient boosting (XGBoost) models in a recursive modelling framework. The models were developed using data from 2012–2020, verified with data from 2020–2022, and then monitored in real time in the 2022/23 season. To assess model performance, observed OPD malaria cases were compared with the monthly average cases and classified into categories to assess how often the model prediction was in the same category as the observed number of cases. We
also conducted a qualitative survey to explore community understanding of malaria and its relationship to climate.
RESULTS
During model development, the predictive performance was very high at 2 weeks’ lead time (75% classification accuracy). Model performance remained satisfactory at up to 8 weeks’ lead time (70% classification accuracy), while beyond this, it became increasingly susceptible to large prediction errors. In the 2020/21 and 2021/22 malaria seasons, the predictive performance at 2 weeks’ lead time was good, but it overpredicted for both seasons at 4–8 weeks. The 2022–23 season saw the lowest number of malaria cases of any year in the data used to train the model. The models predicted that the number of cases would be below the long-term average for Lankien hospital, but overpredicted the burden. Across all models, the shorter the lead time of the models, the greater their predictive performance.
CONCLUSION
This modelling approach has the potential to inform anticipatory action within an operationally useful timeframe. Given the models are trained on historical data and cannot include all factors affecting malaria transmission, if relationships between malaria and other conditions change over time, this will impact model performance, demonstrating the limits of forecasting approaches. The next stage of the MAP project will focus on replicability in other settings and pilot implementation to understand operational feasibility and improve performance.
Climate and environmental conditions are critical factors in malaria transmission. Médecins Sans Frontières (MSF) teams in South Sudan have seen changes in the timing and intensity of malaria seasonal peaks over the past decade. The Malaria Anticipation Project (MAP) aims to develop predictive early warning systems to better predict and act upon any expected rise in malaria cases, through routine surveillance.
METHODS
Predictive models were developed using environmental data collected from climate and space agencies and weekly outpatient department (OPD) malaria case count in Lankien hospital (Jonglei State, South Sudan) as the epidemiological input and output. An ensemble modelling approach was developed using linear regression and extreme gradient boosting (XGBoost) models in a recursive modelling framework. The models were developed using data from 2012–2020, verified with data from 2020–2022, and then monitored in real time in the 2022/23 season. To assess model performance, observed OPD malaria cases were compared with the monthly average cases and classified into categories to assess how often the model prediction was in the same category as the observed number of cases. We
also conducted a qualitative survey to explore community understanding of malaria and its relationship to climate.
RESULTS
During model development, the predictive performance was very high at 2 weeks’ lead time (75% classification accuracy). Model performance remained satisfactory at up to 8 weeks’ lead time (70% classification accuracy), while beyond this, it became increasingly susceptible to large prediction errors. In the 2020/21 and 2021/22 malaria seasons, the predictive performance at 2 weeks’ lead time was good, but it overpredicted for both seasons at 4–8 weeks. The 2022–23 season saw the lowest number of malaria cases of any year in the data used to train the model. The models predicted that the number of cases would be below the long-term average for Lankien hospital, but overpredicted the burden. Across all models, the shorter the lead time of the models, the greater their predictive performance.
CONCLUSION
This modelling approach has the potential to inform anticipatory action within an operationally useful timeframe. Given the models are trained on historical data and cannot include all factors affecting malaria transmission, if relationships between malaria and other conditions change over time, this will impact model performance, demonstrating the limits of forecasting approaches. The next stage of the MAP project will focus on replicability in other settings and pilot implementation to understand operational feasibility and improve performance.
Conference Material > Abstract
Jamaluddine Z, Chen Z, Abukmail H, Aly S, Elnakib S, et al.
MSF Scientific Days International 2024. 2024 May 16
INTRODUCTION
Since 7 October 2023, large-scale military operations in the Gaza Strip have resulted in an escalating public health crisis. Residents of Gaza are mostly displaced from their homes and living in overcrowded conditions with insufficient access to water, sanitation, and food, and health services have been considerably disrupted. To inform humanitarian and decision-making efforts, we aimed to estimate the project excess mortality from traumatic injuries, infectious diseases, maternal and newborn complications, and non-communicable diseases (NCDs) under different future scenarios.
METHODS
We used five different models to project excess deaths from February to August 2024, considering three scenarios: (1) an immediate and permanent ceasefire; (2) the status quo, reflecting conditions from mid-October 2023 to mid-January 2024; and (3) a further escalation of the conflict. Using publicly available data and expert consultations, our analysis projected excess deaths resulting under each scenario. A model was developed to determine increased malnutrition (as an underlying cause).
RESULTS
Without epidemics, the ceasefire scenario would result in 6550 excess deaths, rising to 58,260 under the status quo, and 74,290 under escalation. With epidemics, these projections rise to 11,580, 66,720, and 85,750, respectively. Under the ceasefire scenario, infectious diseases would be the main cause of excess deaths (1,520 excess deaths without epidemics and 6,550 with epidemics). Traumatic injuries followed by infectious diseases would be the main causes of excess deaths in both the status quo (53,450 due to traumatic injuries; 2,120 due to infectious diseases without epidemics and 10,590 including epidemics) and escalation scenarios (68,650 due to traumatic injuries; 2,720 due to infectious diseases without epidemics and 14,180 with epidemics). Our projections indicate that, even in the best-case ceasefire scenario, thousands of excess deaths would continue to occur, mainly due to the time it would take to improve water, sanitation, shelter conditions, and malnutrition, and restore functioning healthcare services in Gaza. While the total number of estimated excess deaths from maternal and neonatal causes are relatively small (100–330 excess deaths), every loss of a mother has severe consequences for family health and wellbeing. NCDs are projected to cause more deaths (1,680 (ceasefire) –2,680 (escalation) excess deaths) due to a heavily disrupted specialised health services and impeded access to treatment and medications.
CONCLUSION
These projections underscore the critical and urgent need for an immediate ceasefire to mitigate the alarming excess mortality in Gaza. The severity of the ceasefire scenario cannot be understated, with over 6–11 thousand excess deaths projected. Decision-makers must act swiftly to prevent further loss of life and address the dire humanitarian situation in Gaza.
Since 7 October 2023, large-scale military operations in the Gaza Strip have resulted in an escalating public health crisis. Residents of Gaza are mostly displaced from their homes and living in overcrowded conditions with insufficient access to water, sanitation, and food, and health services have been considerably disrupted. To inform humanitarian and decision-making efforts, we aimed to estimate the project excess mortality from traumatic injuries, infectious diseases, maternal and newborn complications, and non-communicable diseases (NCDs) under different future scenarios.
METHODS
We used five different models to project excess deaths from February to August 2024, considering three scenarios: (1) an immediate and permanent ceasefire; (2) the status quo, reflecting conditions from mid-October 2023 to mid-January 2024; and (3) a further escalation of the conflict. Using publicly available data and expert consultations, our analysis projected excess deaths resulting under each scenario. A model was developed to determine increased malnutrition (as an underlying cause).
RESULTS
Without epidemics, the ceasefire scenario would result in 6550 excess deaths, rising to 58,260 under the status quo, and 74,290 under escalation. With epidemics, these projections rise to 11,580, 66,720, and 85,750, respectively. Under the ceasefire scenario, infectious diseases would be the main cause of excess deaths (1,520 excess deaths without epidemics and 6,550 with epidemics). Traumatic injuries followed by infectious diseases would be the main causes of excess deaths in both the status quo (53,450 due to traumatic injuries; 2,120 due to infectious diseases without epidemics and 10,590 including epidemics) and escalation scenarios (68,650 due to traumatic injuries; 2,720 due to infectious diseases without epidemics and 14,180 with epidemics). Our projections indicate that, even in the best-case ceasefire scenario, thousands of excess deaths would continue to occur, mainly due to the time it would take to improve water, sanitation, shelter conditions, and malnutrition, and restore functioning healthcare services in Gaza. While the total number of estimated excess deaths from maternal and neonatal causes are relatively small (100–330 excess deaths), every loss of a mother has severe consequences for family health and wellbeing. NCDs are projected to cause more deaths (1,680 (ceasefire) –2,680 (escalation) excess deaths) due to a heavily disrupted specialised health services and impeded access to treatment and medications.
CONCLUSION
These projections underscore the critical and urgent need for an immediate ceasefire to mitigate the alarming excess mortality in Gaza. The severity of the ceasefire scenario cannot be understated, with over 6–11 thousand excess deaths projected. Decision-makers must act swiftly to prevent further loss of life and address the dire humanitarian situation in Gaza.
Conference Material > Abstract
Fahal AH, Ahmed ES, Bakhiet SM, Bakheet OE, Fahal LA, et al.
MSF Scientific Days International 2024. 2024 May 16
INTRODUCTION
Treatment options for the highly neglected fungal tropical disease eumycetoma are limited and poorly adapted to patients’ contexts, with surgery often required. The first-line treatment, itraconazole, thought to be 40% effective, must be taken twice daily for ≥12 months with food, making adherence difficult. An effective, affordable, context-appropriate treatment is urgently needed. The Drugs for Neglected Diseases Initiative (DNDi) repurposed the broad-spectrum antifungal agent fosravuconazole, developed by Eisai Ltd for onychomycosis. We aimed to compare two different doses of weekly fosravuconazole with standard-of-care daily itraconazole in patients with eumycetoma.
METHODS
This phase 2, randomised, double-blind, active-controlled, superiority trial was done at the Mycetoma Research Centre, Soba University Hospital, Sudan. Patients aged ≥15 years with a small-to-medium lesion (≥2 to <16 cm) caused by M mycetomatis requiring surgery were randomly assigned (1:1:1) to receive either 300 mg fosravuconazole weekly (group 1), 200 mg fosravuconazole weekly (group 2), or 400 mg itraconazole daily (group 3), for 12 months, together with surgery at 6 months in all groups. The primary efficacy endpoint, assessed in all patients receiving at least one dose of study drug (modified intention to treat), was complete cure at 12 months (absence of eumycetoma mass and sinuses and discharge with normal imaging; or a negative fungal culture if mass present). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03086226).
RESULTS
Between 9 May, 2017, and 10 June, 2021, 104 patients were randomised (34 to group 1, 34 to group 2, and 36 to group 3).Median age was 29.0 (IQR22.0–33.0), 23.0 (20.0–29.0) and 24.5 (19.5–33.0) years for Groups 1, 2, and 3 respectively. Complete cure rates at end of treatment were 50.0% (95% CI 32.4–67.6), 64.7% (46.5–80.3), and 75.0% (57.8–87.9) with Groups 1, 2 and 3, respectively, showing no superiority of fosravuconazole over the standard-of-care (p=0.030 for Group 2 vs Group 3; and p=0.347 for Group 1 vs Group 3; with significance level set at 0.022). Treatment-emergent adverse drug reactions were reported in one (3%) of 34 patients in group 2 (nausea or vomiting) and three (8%) of 36 patients in group 3 (cortisol decreased, QT prolonged).
CONCLUSION
Although not superior, fosravuconazole 200 mg seemed to have similar efficacy to itraconazole, coupled with advantages such as a weekly, not daily, administration, no food effect, and low risk for drug-drug interactions. An early access programme is under review by authorities in Sudan and a regulatory dossier and global access plan are under preparation.
Treatment options for the highly neglected fungal tropical disease eumycetoma are limited and poorly adapted to patients’ contexts, with surgery often required. The first-line treatment, itraconazole, thought to be 40% effective, must be taken twice daily for ≥12 months with food, making adherence difficult. An effective, affordable, context-appropriate treatment is urgently needed. The Drugs for Neglected Diseases Initiative (DNDi) repurposed the broad-spectrum antifungal agent fosravuconazole, developed by Eisai Ltd for onychomycosis. We aimed to compare two different doses of weekly fosravuconazole with standard-of-care daily itraconazole in patients with eumycetoma.
METHODS
This phase 2, randomised, double-blind, active-controlled, superiority trial was done at the Mycetoma Research Centre, Soba University Hospital, Sudan. Patients aged ≥15 years with a small-to-medium lesion (≥2 to <16 cm) caused by M mycetomatis requiring surgery were randomly assigned (1:1:1) to receive either 300 mg fosravuconazole weekly (group 1), 200 mg fosravuconazole weekly (group 2), or 400 mg itraconazole daily (group 3), for 12 months, together with surgery at 6 months in all groups. The primary efficacy endpoint, assessed in all patients receiving at least one dose of study drug (modified intention to treat), was complete cure at 12 months (absence of eumycetoma mass and sinuses and discharge with normal imaging; or a negative fungal culture if mass present). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03086226).
RESULTS
Between 9 May, 2017, and 10 June, 2021, 104 patients were randomised (34 to group 1, 34 to group 2, and 36 to group 3).Median age was 29.0 (IQR22.0–33.0), 23.0 (20.0–29.0) and 24.5 (19.5–33.0) years for Groups 1, 2, and 3 respectively. Complete cure rates at end of treatment were 50.0% (95% CI 32.4–67.6), 64.7% (46.5–80.3), and 75.0% (57.8–87.9) with Groups 1, 2 and 3, respectively, showing no superiority of fosravuconazole over the standard-of-care (p=0.030 for Group 2 vs Group 3; and p=0.347 for Group 1 vs Group 3; with significance level set at 0.022). Treatment-emergent adverse drug reactions were reported in one (3%) of 34 patients in group 2 (nausea or vomiting) and three (8%) of 36 patients in group 3 (cortisol decreased, QT prolonged).
CONCLUSION
Although not superior, fosravuconazole 200 mg seemed to have similar efficacy to itraconazole, coupled with advantages such as a weekly, not daily, administration, no food effect, and low risk for drug-drug interactions. An early access programme is under review by authorities in Sudan and a regulatory dossier and global access plan are under preparation.
Conference Material > Abstract
Baudin E, Mordt OV, Alves D, Seixas J, Lemerani M, et al.
MSF Scientific Days International 2024. 2024 May 16; DOI:10.57740/6ss9-0934
INTRODUCTION
Trypanosoma brucei rhodesiense human African trypanosomiasis (r-HAT), the zoonotic, acute form of sleeping sickness in eastern Africa, is lethal if untreated. Today, only one arsenic- based, neurotoxic drug, melarsoprol, is available for treatment of the advanced meningo-encephalitic stage. A new oral treatment would simplify HAT elimination as proposed by WHO. Fexinidazole was recommended by the European Medicines Agency (EMA) in 2018 as the first oral treatment for Trypanosoma brucei gambiense HAT, but it was not yet evaluated for r-HAT.
METHODS
This single-arm clinical trial, sponsored by DNDi, began in October 2019 and tested fexinidazole treatment in patients with r-HAT as an alternative to existing treatment in Malawi and Uganda. Patients (aged ≥6 years) with both stages of the disease were recruited up to the target of 34 patients with stage 2 disease evaluable at the end of hospitalization. Patients were hospitalised during the 10 days of treatment and followed up to 12 months after hospital discharge. The primary outcome was r-HAT-related or treatment-related fatality at the end of hospitalisation in patients with stage 2 disease and was compared with an unacceptable fatality rate of 8.5%, a threshold defined according to results from a previous clinical trial with melarsoprol. This trial is registered with ClinicalTrials.gov, NCT03974178.
RESULTS
45 patients received treatment between 1 October 2019 and 28 November 2021 (35 [78%] had stage 2 disease and ten [22%] stage 1, 31 [69%] were male and 14 [31%] female, with median age of 24 years). The primary efficacy result of the clinical trial, analysed among the 34 evaluable patients, was achieved, with no r-HAT-related or treatment-related deaths during hospitalisation (0.0%, 95% CI 0.0–8.4), compared with a benchmark of 8.5% lethality attributable to melarsoprol. Safety was acceptable, with no severe adverse events related to fexinidazole; and one patient relapsed.
CONCLUSION
Fexinidazole, an oral treatment, was shown to be a good alternative to existing injectable and toxic drugs. Results were submitted for EMA regulatory review in preparation for use in endemic countries, and a positive scientific opinion was received in December 2023 to extend the indication of fexinidazole for the treatment of r-HAT. Fexinidazole is expected to be deployed in 2024 as a new r-HAT therapeutic.
Trypanosoma brucei rhodesiense human African trypanosomiasis (r-HAT), the zoonotic, acute form of sleeping sickness in eastern Africa, is lethal if untreated. Today, only one arsenic- based, neurotoxic drug, melarsoprol, is available for treatment of the advanced meningo-encephalitic stage. A new oral treatment would simplify HAT elimination as proposed by WHO. Fexinidazole was recommended by the European Medicines Agency (EMA) in 2018 as the first oral treatment for Trypanosoma brucei gambiense HAT, but it was not yet evaluated for r-HAT.
METHODS
This single-arm clinical trial, sponsored by DNDi, began in October 2019 and tested fexinidazole treatment in patients with r-HAT as an alternative to existing treatment in Malawi and Uganda. Patients (aged ≥6 years) with both stages of the disease were recruited up to the target of 34 patients with stage 2 disease evaluable at the end of hospitalization. Patients were hospitalised during the 10 days of treatment and followed up to 12 months after hospital discharge. The primary outcome was r-HAT-related or treatment-related fatality at the end of hospitalisation in patients with stage 2 disease and was compared with an unacceptable fatality rate of 8.5%, a threshold defined according to results from a previous clinical trial with melarsoprol. This trial is registered with ClinicalTrials.gov, NCT03974178.
RESULTS
45 patients received treatment between 1 October 2019 and 28 November 2021 (35 [78%] had stage 2 disease and ten [22%] stage 1, 31 [69%] were male and 14 [31%] female, with median age of 24 years). The primary efficacy result of the clinical trial, analysed among the 34 evaluable patients, was achieved, with no r-HAT-related or treatment-related deaths during hospitalisation (0.0%, 95% CI 0.0–8.4), compared with a benchmark of 8.5% lethality attributable to melarsoprol. Safety was acceptable, with no severe adverse events related to fexinidazole; and one patient relapsed.
CONCLUSION
Fexinidazole, an oral treatment, was shown to be a good alternative to existing injectable and toxic drugs. Results were submitted for EMA regulatory review in preparation for use in endemic countries, and a positive scientific opinion was received in December 2023 to extend the indication of fexinidazole for the treatment of r-HAT. Fexinidazole is expected to be deployed in 2024 as a new r-HAT therapeutic.
Conference Material > Abstract
Wilson JM, Chowdhury F, Hassan S, Harriss E, Alves F, et al.
MSF Scientific Days International 2024. 2024 May 16; DOI:10.57740/9SthRqK
INTRODUCTION
Visceral leishmaniasis (VL) is a neglected tropical disease prevalent in populations affected by poverty, war, and famine. Without effective treatment, death is the norm. Prognostic models, as used by Médecins Sans Frontières (MSF) in East Africa, are used to identify high-risk patients for intensive management, including hospital admission, treatment with liposomal amphotericin B, broad-spectrum antibiotics, and blood transfusions. We provide a comprehensive and objective resource for policymakers, healthcare providers, and investigators, by identifying, summarising, and appraising the available prognostic models predicting clinical outcomes in patients with VL.
METHODS
We performed a systematic review of published studies that developed, validated, or updated models predicting future clinical outcomes in patients diagnosed with VL. We searched five bibliographic databases (Ovid Embase, Ovid MEDLINE, Web of Science Core Collection, SciELO, and LILACS) on March 1, 2023, for papers published from database inception, with no language restriction. Screening, data extraction, and risk of bias assessment were performed in duplicate. This study is registered with PROSPERO (ID: CRD42023417226).
RESULTS
Eight prognostic model studies, published between 2003 and 2021, were identified describing 12 prognostic model developments and 19 external validations. Nine models were developed in Brazil and three in East Africa by MSF investigators (two developed in South Sudan and one in Ethiopia). In-hospital mortality was the outcome for all but two Brazilian models, which predicted registry-reported mortality. Three models were developed exclusively in adolescents or children. Risk of bias was assessed as high for all model evaluations. Model overfitting due to small sample sizes, leading to optimistic model performance measures and exaggerated risk estimates, was identified for all but one model development. Only half of the presented risk scores were reproducible by following the authors’ methodology.
CONCLUSION
A poorly developed model can result in inaccurate risk estimation, potentially leading to harmful and inequitable decision making. With half of all risk scores incorrectly calculated, and a high risk of bias identified across all model evaluations, caution must be exercised when using these models to guide patient management. In the first systematic review of VL prognostic models, we show that no models predicted treatment failure and relapse, and despite South Asia representing the highest VL burden before 2010, no models were developed in this population. These represent important evidence gaps, which should be prioritised when developing new models. Using the Infectious Diseases Data Observatory repository of VL individual patient data from clinical trials, we are currently building a prognostic model for VL relapse in South Asia, which we hope to serve the ongoing elimination campaign.
Visceral leishmaniasis (VL) is a neglected tropical disease prevalent in populations affected by poverty, war, and famine. Without effective treatment, death is the norm. Prognostic models, as used by Médecins Sans Frontières (MSF) in East Africa, are used to identify high-risk patients for intensive management, including hospital admission, treatment with liposomal amphotericin B, broad-spectrum antibiotics, and blood transfusions. We provide a comprehensive and objective resource for policymakers, healthcare providers, and investigators, by identifying, summarising, and appraising the available prognostic models predicting clinical outcomes in patients with VL.
METHODS
We performed a systematic review of published studies that developed, validated, or updated models predicting future clinical outcomes in patients diagnosed with VL. We searched five bibliographic databases (Ovid Embase, Ovid MEDLINE, Web of Science Core Collection, SciELO, and LILACS) on March 1, 2023, for papers published from database inception, with no language restriction. Screening, data extraction, and risk of bias assessment were performed in duplicate. This study is registered with PROSPERO (ID: CRD42023417226).
RESULTS
Eight prognostic model studies, published between 2003 and 2021, were identified describing 12 prognostic model developments and 19 external validations. Nine models were developed in Brazil and three in East Africa by MSF investigators (two developed in South Sudan and one in Ethiopia). In-hospital mortality was the outcome for all but two Brazilian models, which predicted registry-reported mortality. Three models were developed exclusively in adolescents or children. Risk of bias was assessed as high for all model evaluations. Model overfitting due to small sample sizes, leading to optimistic model performance measures and exaggerated risk estimates, was identified for all but one model development. Only half of the presented risk scores were reproducible by following the authors’ methodology.
CONCLUSION
A poorly developed model can result in inaccurate risk estimation, potentially leading to harmful and inequitable decision making. With half of all risk scores incorrectly calculated, and a high risk of bias identified across all model evaluations, caution must be exercised when using these models to guide patient management. In the first systematic review of VL prognostic models, we show that no models predicted treatment failure and relapse, and despite South Asia representing the highest VL burden before 2010, no models were developed in this population. These represent important evidence gaps, which should be prioritised when developing new models. Using the Infectious Diseases Data Observatory repository of VL individual patient data from clinical trials, we are currently building a prognostic model for VL relapse in South Asia, which we hope to serve the ongoing elimination campaign.
Conference Material > Abstract
Finger F, Mimbu N, Ratnayake R, Meakin S, Bahati JB, et al.
MSF Scientific Days International 2024. 2024 May 16
INTRODUCTION
The risk of cholera outbreaks spreading rapidly and extensively is substantial. Case-area targeted interventions (CATI) are based on the premise that early detection can trigger a rapid, localised response in the high-risk radius around case-households to reduce transmission sufficiently to extinguish the outbreak or reduce its spread, as opposed to relying on resource-intensive mass interventions. Current evidence supports intervention in a high-risk spatiotemporal zone of up to 200 m around case- households for 5 days after case presentation. Médecins Sans Frontières (MSF) started delivering CATI to people living within these high-risk rings during outbreaks in the Democratic Republic of the Congo in April 2022. We present the results of a prospective observational study designed to evaluate the CATI strategy, measuring effectiveness, feasibility, timeliness, and resource requirements, and we extract operational learnings.
METHODS
Between April 2022 and April 2023, MSF delivered the holistic CATI package in five cholera-affected regions. The package incorporated key interventions combining household-level water, sanitation, and hygiene measures, health promotion, antibiotic chemoprophylaxis, and single-dose oral cholera vaccination (OCV). We conducted a survey in each ring roughly 3 weeks after the intervention to estimate coverage and uptake of the different components. We measured effectiveness by comparing cholera incidence in the first 30 days between rings with different delays from primary case presentation to CATI implementation, using a Bayesian regression model and adjusting for covariates such as population density, age, and access to water and sanitation.
RESULTS
During the study, four MSF operational sections implemented 118 CATI rings in five sites. The median number of households per ring was 70, the median OCV coverage was 85%, and the median time from presentation of the primary case to CATI implementation and to vaccination was 2 days and 3 days, respectively. These characteristics varied widely across sites and between rings. No secondary cases were observed in 81 (78%) of 104 rings included in the analysis, and we noted a (non- significant) decreasing trend in the number of secondary cases with decreasing delay to CATI implementation, e.g. 1.3 cases [95% CrI 0.01–4.9] for CATI implementation starting within 5 days from primary case presentation, and 0.5 cases [0.03–2.0] for CATI starting within 2 days.
CONCLUSION
Our results show that rapid implementation of CATI with vaccination is feasible in complex contexts. The number of secondary cases was low when CATI was implemented promptly. This highly targeted approach may be an effective strategy to quickly protect people most at risk and is resource- efficient if implemented early to extinguish localised outbreaks before they require mass interventions.
The risk of cholera outbreaks spreading rapidly and extensively is substantial. Case-area targeted interventions (CATI) are based on the premise that early detection can trigger a rapid, localised response in the high-risk radius around case-households to reduce transmission sufficiently to extinguish the outbreak or reduce its spread, as opposed to relying on resource-intensive mass interventions. Current evidence supports intervention in a high-risk spatiotemporal zone of up to 200 m around case- households for 5 days after case presentation. Médecins Sans Frontières (MSF) started delivering CATI to people living within these high-risk rings during outbreaks in the Democratic Republic of the Congo in April 2022. We present the results of a prospective observational study designed to evaluate the CATI strategy, measuring effectiveness, feasibility, timeliness, and resource requirements, and we extract operational learnings.
METHODS
Between April 2022 and April 2023, MSF delivered the holistic CATI package in five cholera-affected regions. The package incorporated key interventions combining household-level water, sanitation, and hygiene measures, health promotion, antibiotic chemoprophylaxis, and single-dose oral cholera vaccination (OCV). We conducted a survey in each ring roughly 3 weeks after the intervention to estimate coverage and uptake of the different components. We measured effectiveness by comparing cholera incidence in the first 30 days between rings with different delays from primary case presentation to CATI implementation, using a Bayesian regression model and adjusting for covariates such as population density, age, and access to water and sanitation.
RESULTS
During the study, four MSF operational sections implemented 118 CATI rings in five sites. The median number of households per ring was 70, the median OCV coverage was 85%, and the median time from presentation of the primary case to CATI implementation and to vaccination was 2 days and 3 days, respectively. These characteristics varied widely across sites and between rings. No secondary cases were observed in 81 (78%) of 104 rings included in the analysis, and we noted a (non- significant) decreasing trend in the number of secondary cases with decreasing delay to CATI implementation, e.g. 1.3 cases [95% CrI 0.01–4.9] for CATI implementation starting within 5 days from primary case presentation, and 0.5 cases [0.03–2.0] for CATI starting within 2 days.
CONCLUSION
Our results show that rapid implementation of CATI with vaccination is feasible in complex contexts. The number of secondary cases was low when CATI was implemented promptly. This highly targeted approach may be an effective strategy to quickly protect people most at risk and is resource- efficient if implemented early to extinguish localised outbreaks before they require mass interventions.