Maya Ronse

In 2024, the WHO’s Division on Access to Medicines and Health Products issued a call to action for sustainability in the pharmaceutical sector. The initiative, ‘Greener Pharmaceuticals’ Regulatory Highway’, underscored the need to reduce the environmental footprint of medical products. It explicitly called on the regulatory community to adopt initiatives towards ‘innovative approaches in the manufacturing, distribution, and usage of medical products.’ 1 This timely initiative aligns with the growing recognition of interconnectedness between climate change, pollution—including ‘pharmaceutical pollution’—and public health. However, the need to decrease greenhouse gas emissions should not overshadow other relevant areas for action in the pharmaceutical sector. Here, we focus on the negative environmental impact of the inappropriate elimination of pharmaceutical waste generated at the last mile in healthcare.

Background: To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double dose of rifampicin led to a similar reduction in incident leprosy, prompting the need for stronger PEP. The objective of this Phase 2 trial was to assess safety of a bedaquiline-enhanced PEP regimen (intervention arm, bedaquiline 800 mg with rifampicin 600 mg, BE-PEP), relative to the WHO recommended PEP with rifampicin 600 mg alone (control arm, SDR-PEP). Methods and findings: From July 2022 to January 2023, consenting participants were screened for eligibility, including a heart rate-corrected QT interval (QTc) <450 ms and liver enzyme tests (ALT/AST) below 3× the upper limit of normal (ULN), before they were individually randomized 1:1 in an open-label design. Recruitment was sequential, by age group. Pediatric dosages were weight adjusted. Follow-up was done at day 1 post-dose (including ECG) and day 14 (including ALT/AST), with repeat of ALT/AST on the last follow-up at day 30 in case of elevation on day 14. The primary outcome was non-inferiority of BE-PEP based on a 50 ms or exceeded 450 ms after PEP administration. Per protocol, all children were analyzed together, with no significant difference in mean QTc increase for BE-PEP compared to SDR-PEP, although non-inferiority of BE-PEP in children was not demonstrated in unadjusted analysis, as the upper limit of the 95% CI of 10.4 ms exceeded the predefined margin of 10 ms. Adjusting for baseline QTc, the regression coefficient and 95% CI (3.3; −1.4, 8.0) met the 10 ms non-inferiority margin. No significant differences in ALT or AST levels were noted between the intervention and control arms, although a limitation of the study was false elevation of ALT/AST during adult recruitment due to a technical error. In both study arms, one serious adverse event was reported, both considered unlikely related to the study drugs. Dizziness, nausea, headache, and diarrhea among adults, and headaches in children, were nonsignificantly more frequently observed in the BE-PEP group. Conclusions: In this study, we observed that safety of single-dose bedaquiline 800 mg in combination with rifampicin is comparable to rifampicin alone, although non-inferiority of QTc changes was demonstrated in children only after adjusting for the baseline QTc measurements. A Phase 3 cluster randomized efficacy trial is currently ongoing in the Comoros. Trial Registration: ClinicalTrials.gov NCT05406479.

Despite the global threat of antimicrobial resistance (AMR), evidence on the use and quality of medicines at community level is limited, particularly in impoverished, rural areas where prevalence of (bacterial) infections is high. To better understand the processes that drive vulnerability to AMR’ effects, this study aimed to assess social factors underpinning access to–and use of–medical products and healthcare, among people from the Raglai ethnic minority in Ninh Thuan Province, Vietnam. We conducted ethnographic research in eight villages in 2018–2019, using interviewing and participant observation methods for data collection. Different types of informants (including community members and healthcare providers) were selected using purposive sampling strategies and analysis was retroductive. Our findings show that, despite the existence of a government-funded health insurance scheme, Raglai people’s flexible therapeutic itineraries did not systematically start with formal healthcare. Different types of care (private/informal, public, shamanic) were combined in parallel or in alternation, determined by distance to the provider, cost, workload, perceived diagnostic capacity, perceived severity and aetiology of the illness, and trust in the provider. Available medicines were often tablets dispensed in plastic bags containing labelled tablets, unlabelled tablets (in bulk) or tablets ground to powder. Treatment was often considered effective when it relieved symptoms, which led to abandonment of the treatment course. When symptoms did not speedily abate, the illness aetiology would be reinterpreted, and “stronger” medicines would be sought. The precarious socio-economic status of some Raglai drove them in cycles of severe poverty when additional unforeseen factors such as illness, animal disease or loss of crops arose, hampering access to (in)formal healthcare providers and/or appropriate diagnosis and treatment. We conclude that Raglai communities are structurally unable to buffer themselves against the threat and consequences of AMR. Despite this vulnerability, they are among the least targeted by efforts to optimize antibiotic use, which are concentrated in secondary and tertiary healthcare facilities targeted at urban populations.

Despite difficulties to document transmission pathways (assumed to be airborne), increased risk of leprosy infection has been shown for individuals living in close contact with patients. However, variations in the concept of ‘close contacts’ are used in different settings and studies. We conduct this review to identify criteria of space (location, geographical variables, distance, indoor vs outdoor), time (including frequency and duration), physical exposure (skin to skin, sexual), and relationship (familial, occupational, social) involved in the definition of ‘close contacts’ in leprosy studies. We expect this review to provide an overview of the (lack of) conceptualization of this term and its variations across settings. Primary studies and reviews are eligible for inclusion in this review. The main source of records will be the PubMed interface. Secondary searches will be conducted in Google Scholar, as well as through the reference lists of selected publications. The search strategy is based on the combination of the condition of interest (leprosy) and the concept under study (‘contact’). The findings of this review will be presented using thematic narrative synthesis, tables, and figures. The protocol is written in line with the Prisma Extension for Scoping reviews (PRISMA-ScR).

Background: A high prevalence of epilepsy has been observed in several onchocerciasis-endemic villages in the Sanaga River basin, Cameroon. Recent studies suggest that ivermectin, a drug that is distributed annually with the aim of eliminating onchocerciasis, may have a protective effect against acquiring onchocerciasis-associated epilepsy (OAE). This study, therefore, provides an in-depth understanding of both the complex therapeutic landscape for epilepsy as well as the experiences related to the ‘community-directed treatment with ivermectin’ (CDTI) campaign in order to identify a more trenchant path forward in the fight against epilepsy. Methodology/Principal findings: Based on a mixed methods study combining a qualitative strand with a quantitative survey, we found that epilepsy was perceived to have had an epidemic emergence in the past and was still considered an important health issue in the study area. Socio-economic status, availability and accessibility of drugs and practitioners, as well as perceived aetiology shaped therapeutic itineraries for epilepsy, which included frequenting (in)formal biomedical health care providers, indigenous and/or faith healing practitioners. Ivermectin uptake for onchocerciasis was generally well known and well regarded. The CDTI faced structural and logistical bottlenecks undermining equal access and optimal adherence to the drug. Conclusions/Significance: Locally accessible, uninterrupted, sustainable and comprehensive health-service delivery is essential to help alleviate the epilepsy burden on afflicted households. Addressing structural challenges of CDTI and communicating the potential link with epilepsy to local populations at risk could optimize the uptake of this potentially significant tool in OAE prevention.

Malaria elimination in the Greater Mekong Sub-Region is challenged by a rising proportion of malaria attributable to P. vivax. Primaquine (PQ) is effective in eliminating the parasite’s dormant liver stages and can prevent relapsing infections, but it induces severe haemolysis in patients with Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency, highlighting the importance of testing enzyme activity prior to treatment. A mixed-method study was conducted in south-central Vietnam to explore the factors that affect acceptability of G6PD testing, treatment-seeking behaviors, and adherence to current regimens. The majority of respondents (75.7%) were unaware of the different parasite species and rather differentiated malaria by perceived severity. People sought a diagnosis if suspected of malaria fever but not if they perceived their fevers as mild. Most respondents agreed to take prescribed medication to treat asymptomatic infection (94.1%) and to continue medication even if they felt better (91.5%). Health professionals did not have G6PD diagnostic tools nor the means to prescribe PQ safely. Adherence to treatment was linked to trust in public providers, who were perceived to make therapeutic decisions in the interest of the patient. Greater focus on providing acceptable ways of assessing G6PD deficiency will be needed to ensure the timely elimination of malaria in Vietnam.

In onchocerciasis-endemic areas, particularly in those with a sub-optimal onchocerciasis control programme, a high prevalence of epilepsy is observed. Both onchocerciasis and epilepsy are stigmatizing conditions. The first international workshop on onchocerciasis-associated epilepsy (OAE) was held in Antwerp, Belgium (12–14 October 2017) and during this meeting, an OAE alliance was established. In this paper, we review what is known about epilepsy-associated stigma in onchocerciasis-endemic regions, and present the recommendations of the OAE alliance working group on stigma. For this scoping review, literature searches were performed on the electronic databases PubMed, Scopus and Science Direct using the search terms “epilepsy AND onchocerciasis AND stigma”. Hand searches were also undertaken using Google Scholar, and in total seven papers were identified that addressed epilepsy-related stigma in an onchocercisasis-endemic area. Due to the limited number of published research papers on epilepsy-associated stigma in onchocerciasis-endemic areas, other relevant literature that describes important aspects related to stigma is discussed. The thematic presentation of this scoping review follows key insights on the barriers to alleviating the social consequences of stigma in highly affected onchocerciasis-endemic areas, which were established by experts during the working group on stigma and discrimination at the first international workshop on OAE. These themes are: knowledge gaps, perceived disease aetiology, access to education, marriage restrictions, psycho-social well-being, burden on the care-giver and treatment seeking behaviour. Based on the literature and expert discussions during the OAE working group on stigma, this paper describes important issues regarding epilepsy-related stigma in onchocerciasis-endemic regions and recommends interventions that are needed to reduce stigma and discrimination for the improvement of the psycho-social well-being of persons with epilepsy. Educating healthcare workers and communities about OAE, strengthening onchocerciasis elimination programs, decreasing the anti-epileptic treatment gap, improving the care of epilepsy-related injuries, and prioritising epilepsy research is the way forward to decreasing the stigma associated with epilepsy in onchocerciasis-endemic regions.

During the 2014 Ebola Virus Disease (EVD) epidemic, the Ebola-Tx trial evaluated the use of convalescent plasma (CP) in Guinea. The effectiveness of plasmapheresis trials depends on the recruitment of plasma donors. This paper describes what motivated or deterred EVD survivors to donate CP, providing insights for future plasmapheresis trials and epidemic preparedness. This qualitative study, part of Ebola-Tx, researched and addressed emergent trial difficulties through interviewing, participant observation and focus group discussions. Sampling was theoretical and retroductive analysis was done in NVivo 10. Willingness or hesitance to participate in plasma donation depended on factors at the interface of pre-existing social dynamics; the impact of the disease and the consequent emergency response including the trial set-up. For volunteers, motivation to donate was mainly related to the feeling of social responsibility inspired by having survived EVD and to positive perceptions of plasmapheresis technology despite still unknown trial outcomes. Conversely, confidentiality concerns when volunteering due to stigmatization of survivors and perceived decrease in vital strength and in antibodies when donating, leading to fears of loss in protection against EVD, were main deterrents. The dynamic (dis)trust in Ebola Response Actors and in other survivors further determined willingness to participate and lead to the emergence/decline of rumours related to blood stealing and treatment effectiveness. Historic inter-ethnic relations in the health care setting further defined volunteering along socio-economic and ethnic lines. Finally, lack of follow-up and of dedicated care further impacted on motivation to volunteer. Ebola-Tx was the first trial to solicit and evaluate blood-product donation as an experimental treatment on a large scale in Sub-Saharan Africa. An effective donation system requires directly engaging with emergent social barriers and providing an effective ethical response, including improved and transparent communication, effective follow-up after donation, assuring confidentiality and determining ethical incentives. During the 2014 West-African Ebola Virus Disease epidemic, the Ebola-Tx clinical trial in Guinea aimed to determine whether the administration of Ebola antibodies from the blood plasma of Ebola survivors could increase Ebola patients’ survival rate. Ebola-Tx was the first trial to solicit and evaluate blood-product donation as an experimental treatment on a large scale in Sub-Saharan Africa. In this qualitative study, part of the Ebola-Tx study, we report on factors of motivation and demotivation influencing Ebola survivors to donate their plasma. Understanding these factors is essential as the successful recruitment of this specific subgroup, providing the therapy itself, directly impacts the effectiveness of such a trial. We show that organizing an effective and ethical donation system requires directly engaging with emerging social barriers at the interface between pre-existing social dynamics, the impact of the disease, and the consequent emergency response including the trial set-up. These results provide insights that can be useful for future plasma trials but also for emergency clinical trials as part of general epidemic preparedness.

### Summary box How prepared were we for this most recent Ebola outbreak? Real-time emergent research is imperative for successful response to global health emergencies. While innovative biomedical interventions are certainly important,1 local on-the-ground realities during the 2014–2015 West African Ebola epidemic demanded a different though complementary set of research skills. Effective response required deep, sensitive understandings of emergent local dynamics and flexible, emergent solution. Emergency intervention called for evolving, flexible emergent methods that produced and translated rapid knowledge throughout the crisis. Yet, the need for emergent theory methodologies such as ethnography that actively witness and document the unforeseen consequences of emergencies and their response receives little attention in preparedness strategies.2 Global health community preparedness and response largely hinges on the rapid financialisation and development of innovative …

Although convalescent plasma (CP) transfusion was prioritized among potential Ebola treatments by the World Health Organization, there were concerns on the feasibility of its implementation. We report on the successful organization of donor mobilization and plasma collection as part of the Ebola-Tx clinical trial from November 2014 to July 2015 in Conakry, Guinea. Project implementation registers, tools and reports, mission reports, and minutes of research team meetings were used to reconstruct the sequence of events on how donor mobilization was organized, plasmapheresis was set up, and how effective this approach was in collecting CP. An initial needs assessment of the Guinean National Blood Transfusion Center resulted in targeted training of staff on site, resulting in autonomy and independent production of CP within 3 months. The Conakry Ebola Survivors Association played a direct role in donor mobilization and organization of CP donations. A total of 98 Ebola survivors were screened for plasma donation, of which 84 were found eligible for plasmapheresis. Of these, 26 (30.9%) were excluded. The remaining 58 donors made a total of 90 donations, corresponding to 50.9 L of CP. This sufficed to treat the 99 eligible patients enrolled in the trial. Within a poor resource emergency context, transfusion capacity could be rapidly improved through the strengthening of local capacities and gradual transfer of skills coupled with active involvement of Ebola survivors. However, large-scale plasma collection or multisite studies may require further adaptations of both strategy and logistics. The Ebola-Tx trial was funded by the European Union and others.