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Abstract The need for novel antibiotics to combat emerging multi-drug resistant bacterial strains is widely acknowledged. The development of new therapeutic agents relies on small and medium-sized biotechnology enterprises (SMEs), representing 75% of the late-stage pipeline. However, most SME sponsors of an antibacterial approved by the FDA since 2010 have gone bankrupt, or exited at a loss, below investment cost. Uncovering financial flows related to the development and commercialisation of a single drug is complex and typically untransparent. There is therefore a lack of empirical research on the financial vulnerabilities of these critical SMEs. The development of plazomicin by Achaogen (2004–2019) entailed financial disclosures as a public company enabling application of financial analysis methods to: determine quantum and timing of public and private investments; quantify development costs; and provide a deeper understanding of the role of capital market dependency in exacerbating pipeline fragility. Achaogen’s widely cited bankruptcy, and plazomicin’s commercialisation failure, created a perception that novel antibiotics have zero market value, causing investors to question the SME developer business model. Our analysis of Achaogen’s inability to fund commercialisation suggests three key implications for the antibiotic investment ecosystem: (1) novel antibiotics with narrow approval for small patient populations affected by severe resistant infections cannot be successfully commercialised in the current US antibiotic market; (2) SMEs need incentive payments structured to enable them to survive the commercialisation cashflow drought, and (3) these changes are necessary to restore industry and financial investor confidence in the antibiotic SME development model. Achaogen’s demise demonstrates that proposals to incentivise innovation, e.g. by providing one-off payments at registration, may be insufficient to ensure access to novel antibiotics developed by SMEs. In plazomicin’s case, moreover, US government biosecurity investments have not resulted in access, as the Indian and Chinese companies which bought post-bankruptcy rights have not widely commercialised the drug. This study is timely as new market-based incentives are currently being proposed by the US, EU, Canada and Japan. In order to make further government funding effective, ensuring access, not only innovation, these must support sustainable financial models for the SMEs critical to novel antibiotic development.

Background An explosion in a Chinese factory in 2016 caused a global shortage of essential broad-spectrum antibiotic piperacillin-tazobactam. Hitherto, no detailed, policy-relevant analysis has been conducted on this major shortage event. Thus, we aimed to (1) investigate causes; (2) describe supply chain challenges; and (3) uncover policy gaps to support possible mitigation actions.Methods Applying an analytical framework for security of medical supply chains, we investigated the changing roles of Pfizer-led and Chinese API suppliers. We identified demand surge, capacity reduction and co-ordination failures. Triangulating between scientific literature, corporate, and regulatory documents, we analysed the impact of Western and Chinese policy contexts on supply chain resilience.Results We uncovered ‘red flags’: geographically dispersed manufacturing failures due to complexity of sterile production; undetected supply chain concentration and interlinkages; and Chinese policy-led API supplier consolidation. We found these warning signals were ignored in the absence of a co-ordinated policy framework to identify and mitigate emerging global supply risks. Firstly, policy makers lacked visibility on growing ‘volume dependency’ in the chain. Secondly, national policy makers lacked a global view of supply risk. Thirdly, we show antibiotic API manufacturing economics were impacted by a number of non-pharmaceutical policy decisions (e.g. state aid, environmental standards, procurement rules) which contributed to supply chain vulnerability.Conclusions Our findings suggest possible policy gaps in governance of supply chain resilience. Firstly, disclosure of API suppliers including degree of dependency may better pre-empt bottlenecks, facilitating priority setting for public investments in re-shoring where global API supply currently relies on few, or single plants; secondly, a whole-of-government approach may counter the potential impact of non-pharmaceutical policies on supply chain resilience. Our findings confirm suggestions from previous studies that international data sharing would be beneficial considering the global shortage effects which can emerge from a single point of failure.

Abstract Background A functioning Viral Haemorrhagic Fever (VHF) surveillance system in countries at risk for outbreaks can reduce early transmission in case of an outbreak. Surveillance performance depends on the application of suspect case definitions in daily clinical practice. Recommended suspect case criteria during outbreaks are designed for high sensitivity and include general symptoms, pyrexia, haemorrhage, epidemiological link and unexplained death in patients. Non-outbreak criteria are narrower, relying on the persistence of fever and the presence of haemorrhagic signs. Methods This study ascertains VHF suspect case prevalence based on outbreak and non-outbreak criteria in a Guinean regional hospital for a period of three months. The study further describes clinical trajectories of patients who meet non-outbreak VHF suspect case criteria in order to discuss challenges in their identification. We used cross-sectional data collection at triage and emergency room to record demographic and clinical data of all admitted patients during the study period. For the follow-up study with description of diagnostic trajectories of VHF suspect cases, we used retrospective chart review. Results The most common symptoms of all patients upon admission were fever, tiredness/weakness and abdominal pain. 686 patients met EVD outbreak criteria, ten adult patients and two paediatric patients met study-specific non-outbreak VHF suspect case criteria. None of the suspect cases was treated as VHF suspect case and none tested positive for malaria upon admission. Their most frequent discharge diagnosis was unspecific gastrointestinal infection. The most common diagnostic measures were haemoglobin level and glycaemia for both adults and for children; of the requested examinations for hospitalized suspect cases, 36% were not executed or obtained. Half of those patients self-discharged against medical advice. Conclusions Our study shows that the number of VHF suspect cases may vary greatly depending on which suspect case criteria are applied. Identification of VHF suspect cases seems challenging in clinical practice. We suggest that this may be due to the low use of laboratory diagnostics to support certain diagnoses and the non-application of VHF suspect case definitions in clinical practice. Future VHF suspect case management should aim to tackle such challenges in comparable hospital settings.

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The provision of gifts and payments for healthy volunteer subjects remains an important topic in global health research ethics. This paper provides empirical insights into theoretical debates by documenting participants' perspectives on an Ebola vaccine trial in West Africa. This trial provided hundreds of Africans with regular payments, food packages and certificates for participation. The researchers conducting the trials considered these socioeconomic provisions to be gifts in accordance with contemporary ethical standards and principles. Trial participants viewed them differently, however, approaching trial participation as a means for training and employment in what was from their perspective a new job market: the post-Ebola expansion of research and health care systems. This paper analyses participation in contemporary research by viewing the context-specific histories of trial participants through the lens of prior interventions, specifically participatory reintegration programmes conducted in Anglophone West Africa to overcome civil war crises. In particular, we argue that participation in the Ebola vaccine trial was inadvertently shaped by the design and outcomes of past reintegration programmes. Our results highlight the need to investigate existing socioeconomic landscapes which surround and indeed permeate clinical research as a prerequisite for understanding the participatory motives of vulnerable participants in West Africa and elsewhere.

Acinetobacter baumannii has become increasingly resistant to leading antimicrobial agents since the 1970s. Increased resistance appears linked to armed conflicts, notably since widespread media stories amplified clinical reports in the wake of the American invasion of Iraq in 2003. Antimicrobial resistance is usually assumed to arise through selection pressure exerted by antimicrobial treatment, particularly where treatment is inadequate, as in the case of low dosing, substandard antimicrobial agents, or shortened treatment course. Recently attention has focused on an emerging pathogen, multi-drug resistant A. baumannii (MDRAb). MDRAb gained media attention after being identified in American soldiers returning from Iraq and treated in US military facilities, where it was termed “Iraqibacter.” However, MDRAb is strongly associated in the literature with war injuries that are heavily contaminated by both environmental debris and shrapnel from weapons. Both may harbor substantial amounts of toxic heavy metals. Interestingly, heavy metals are known to also select for antimicrobial resistance. In this review we highlight the potential causes of antimicrobial resistance by heavy metals, with a focus on its emergence in A. baumanni in war zones.

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PurposeThe l’Actuel PrEP Cohort was established to monitor the uptake, effectiveness, safety and changes in sexual risk behaviours among individuals receiving pre-exposure prophylaxis (PrEP) for the prevention of HIV. This prospective dynamic cohort is based at Clinique médicale l’Actuel, a large sexual health clinic located in Montreal, Canada.ParticipantsSince the cohort inception in January of 2013 through June 2018, 2156 individuals consulted for PrEP as participants in the l’Actuel PrEP Cohort. Median age was 35 years (IQR: 29–44 years) and the majority (96%) were men who have sex with men. Among 1551 individuals who initiated PrEP care, the median duration of follow-up was 9.2 months (IQR: 3.7–19.6), with substantial variation based on year of cohort entry. The l’Actuel PrEP Cohort contains both daily and intermittent ‘on-demand’ PrEP users and has the largest reported population of intermittent PrEP users (n=406) in North America.Findings to dateNo incident HIV infections have occurred among individuals using PrEP over 1637 person-years of follow-up. However, retention in PrEP care is essential as three individuals who discontinued PrEP subsequently acquired HIV, translating to an HIV incidence of 3.9 cases per 100 person-years (95% CI: 1.3 to 12.1). Among a sample of participants with 1 year of follow-up before and after PrEP initiation (n=109), a moderate increase in sexually transmitted infections was observed following PrEP start.Future plansThe l’Actuel PrEP Cohort continues to grow with new participants starting PrEP monthly and extended follow-up for existing users. The cohort data will be used for ongoing monitoring of PrEP and for population-level modelling of the impact of PrEP on HIV incidence in Montreal.

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Pre-exposure prophylaxis (PrEP) with antiretroviral medication is an effective, evidence-based option for HIV prevention. In England, issues of cost-effectiveness and of responsibility for commissioning prevention services have so far led National Health Service (NHS) England to decide not to commission PrEP. Given the significant lag between the awareness of PrEP efficacy and the opportunity to obtain PrEP through traditional health care routes, many gay and other men who have sex with men (MSM) have turned to 'DIY PrEP', purchasing generic formulations of PrEP for themselves on the internet or via other alternative routes. However, there is very little research on DIY PrEP practices and no qualitative study with DIY PrEP users in the UK. A formative qualitative study was conducted in 2017 to inform the development of an intervention (PrEP Club) to support DIY PrEP users and improve the safety and experience of this prevention strategy. Focus groups were held with 20 MSM who are based in London and are obtaining PrEP through means other than clinical trials, to explore their accounts of sourcing and using PrEP and the experiential meanings of these. In this article, we report findings from this first, formative study and present the different practices involved in finding out about PrEP, buying it and ascertaining legitimacy of sellers and products. We reflect on the uncertainties participants described related to actually using PrEP, including deciding on drug dosing and monitoring their health. Finally, we present the results of the discussions participants had about the kind of support they had received, the help they would have liked, and their views on proposed interventions to support DIY PrEP users, such as PrEP Club.

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[This corrects the article DOI: 10.1371/journal.pmed.1001967.].

BackgroundEbola virus disease (EVD) is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for EVD research. Favipiravir, an antiviral developed for the treatment of severe influenza, was one of these. In late 2014, the conditions for starting a randomized Ebola trial were not fulfilled for two reasons. One was the perception that, given the high number of patients presenting simultaneously and the very high mortality rate of the disease, it was ethically unacceptable to allocate patients from within the same family or village to receive or not receive an experimental drug, using a randomization process impossible to understand by very sick patients. The other was that, in the context of rumors and distrust of Ebola treatment centers, using a randomized design at the outset might lead even more patients to refuse to seek care. Therefore, we chose to conduct a multicenter non-randomized trial, in which all patients would receive favipiravir along with standardized care. The objectives of the trial were to test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak, and to collect data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with EVD. The trial was not aimed at directly informing future guidelines on Ebola treatment but at quickly gathering standardized preliminary data to optimize the design of future studies.Methods and findingsInclusion criteria were positive Ebola virus reverse transcription PCR (RT-PCR) test, age ≥ 1 y, weight ≥ 10 kg, ability to take oral drugs, and informed consent. All participants received oral favipiravir (day 0: 6,000 mg; day 1 to day 9: 2,400 mg/d). Semi-quantitative Ebola virus RT-PCR (results expressed in "cycle threshold" [Ct]) and biochemistry tests were performed at day 0, day 2, day 4, end of symptoms, day 14, and day 30. Frozen samples were shipped to a reference biosafety level 4 laboratory for RNA viral load measurement using a quantitative reference technique (genome copies/milliliter). Outcomes were mortality, viral load evolution, and adverse events. The analysis was stratified by age and Ct value. A "target value" of mortality was defined a priori for each stratum, to guide the interpretation of interim and final analysis. Between 17 December 2014 and 8 April 2015, 126 patients were included, of whom 111 were analyzed (adults and adolescents, ≥13 y, n = 99; young children, ≤6 y, n = 12). Here we present the results obtained in the 99 adults and adolescents. Of these, 55 had a baseline Ct value ≥ 20 (Group A Ct ≥ 20), and 44 had a baseline Ct value < 20 (Group A Ct < 20). Ct values and RNA viral loads were well correlated, with Ct = 20 corresponding to RNA viral load = 7.7 log10 genome copies/ml. Mortality was 20% (95% CI 11.6%-32.4%) in Group A Ct ≥ 20 and 91% (95% CI 78.8%-91.1%) in Group A Ct < 20. Both mortality 95% CIs included the predefined target value (30% and 85%, respectively). Baseline serum creatinine was ≥110 μmol/l in 48% of patients in Group A Ct ≥ 20 (≥300 μmol/l in 14%) and in 90% of patients in Group A Ct < 20 (≥300 μmol/l in 44%). In Group A Ct ≥ 20, 17% of patients with baseline creatinine ≥110 μmol/l died, versus 97% in Group A Ct < 20. In patients who survived, the mean decrease in viral load was 0.33 log10 copies/ml per day of follow-up. RNA viral load values and mortality were not significantly different between adults starting favipiravir within ConclusionsIn the context of an outbreak at its peak, with crowded care centers, randomizing patients to receive either standard care or standard care plus an experimental drug was not felt to be appropriate. We did a non-randomized trial. This trial reaches nuanced conclusions. On the one hand, we do not conclude on the efficacy of the drug, and our conclusions on tolerance, although encouraging, are not as firm as they could have been if we had used randomization. On the other hand, we learned about how to quickly set up and run an Ebola trial, in close relationship with the community and non-governmental organizations; we integrated research into care so that it improved care; and we generated knowledge on EVD that is useful to further research. Our data illustrate the frequency of renal dysfunction and the powerful prognostic value of low Ct values. They suggest that drug trials in EVD should systematically stratify analyses by baseline Ct value, as a surrogate of viral load. They also suggest that favipiravir monotherapy merits further study in patients with medium to high viremia, but not in those with very high viremia.Trial registrationClinicalTrials.gov NCT02329054.

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Nel 1994, due anni dopo aver scoperto di essere sieropositivo, Dominique Esmel, un giovane studente di legge di Abidjan, fondò uno dei primi gruppi per persone sieropositive in Africa, Lumière-Action, “Abbiamo scelto questo nome perché sentivamo di vivere nelle tenebre”, Dominique mi disse; “Volevamo uscire dall’ombra del nostro isolamento e vivere alla luce della solidarietà”.

Starting from a contextualization of Cindy Patton’s text, the authors invite consideration of the timeliness of these questions in light of contemporary issues related to the production of identities and communities that helps us see of the establishment of the « targets » of the prevention and treatment of HIV, as well as the effects of the depoliticization secured by the medicalization of the fight against the epidemic.