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Background Ebola 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 Findings Inclusion 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, In the context the recent Ebola outbreak, Xavier Anglaret and colleagues test an experimental treatment, favipiravir, for Ebola virus disease in a multicenter non-randomized trial., Editors' Summary Background In 2014 and 2015, an Ebola virus outbreak larger than any known before occurred in West Africa. Ebola virus disease (EVD) is highly contagious, and many infected people die. Central to the emergency response to the recent outbreak were local Ebola treatment centers where patients were diagnosed, were isolated, and received supportive care. With thousands of patients dying and many health workers contracting the disease, fear was ubiquitous and distrust abundant. While conducting research in this environment was extremely challenging, the urgent need for treatments and the opportunity to conduct studies that could bring such treatments closer to reality was also recognized. In September 2014, WHO released a short list of existing drugs that were candidates for clinical trials among patients infected in the outbreak. Favipiravir, an antiviral drug developed in Japan for patients with severe influenza, was on the list. Why Was This Study Done? Because of the urgent need to find drugs that could reduce deaths caused by Ebola, the researchers decided to conduct a clinical trial using favipiravir in patients with EVD in Guinea. In view of the circumstances, they decided against a randomized controlled trial and instead designed a study where all participants would receive the same treatment. In randomized controlled trials only some participants receive the treatment in addition to standard care, while others serve as a control group and receive standard care only, or standard care plus a placebo. Such studies allow stronger conclusions to be drawn about whether a treatment is safe and whether it works or not. The researchers had two main reasons for this decision. First, patients from the same family or village often sought EVD treatment at the same time, and the researchers felt that it was ethically unacceptable to randomize such groups, with only some of them receiving the experimental drug. Second, the strict isolation procedures imposed to interrupt virus transmission had intensified fear in affected communities and fueled rumors of illicit drug experimentation and organ theft at the treatment centers. In this context, the researchers worried that a randomized study might increase distrust among the community and the reluctance of patients to seek care. Rather than seeking definitive answers about the safety and efficacy of favipiravir in patients with EVD, the objectives of the study as it was designed were to test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak and to learn lessons from the experience. In addition, the researchers planned to collect data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with EVD in the hope that their preliminary findings could improve the design of subsequent trials and the chance to provide conclusive answers. What Did the Researchers Do and Find? After 13 weeks of preparation, the trial took place from December 2014 to April 2015 at four separate Ebola treatment centers, three in rural areas and one in an urban setting. In addition to standard care (which included rehydration, antimalarial and antibacterial therapies, and medication to reduce fever, pain, and nausea), all participants were given favipiravir by mouth for ten days, at doses substantially higher than those recommended for patients with influenza. Outcomes measured were mortality, viral load changes over time (based on blood samples), and adverse events. EVD was confirmed with an assay that used patient blood and provided an estimate of the viral load, that is, of how much virus the blood contained. Because viral load was known to influence the course of EVD, the researchers analyzed the participants in two groups, namely, those with a viral load estimate above a certain threshold and those with viral load estimate below the threshold. They also used existing data from Guinean patients diagnosed with Ebola earlier in the outbreak who had received only standard care and calculated an expected mortality rate for patients above and below the viral load threshold. The researchers were able to enroll 126 participants in the trial. Of these, 111 were included in the final analysis. Of 99 adult and adolescent participants 13 years and older, 55 were in the lower viral load group and 44 in the higher viral load group. Mortality was 20% in the former and 91% in the latter. Neither mortality rate was significantly different from that of earlier patients who had received only standard care. The researchers also found that favipiravir was well tolerated. None of the patients stopped the course of treatment, vomiting following drug intake was rare, and no severe adverse events were attributed to the drug. The researchers did not see a difference in mortality between patients who reported onset of symptoms less than three days before the start of treatment and those whose symptoms had started more than three days the start of treatment. What Do these Findings Mean? The report shows that it is possible to conduct an emergency trial during an outbreak in a low-resource setting. In fact, at the time of its acceptance, this paper reported on an Ebola treatment trial larger than any other yet published. The experience described should be useful for similar undertakings in the future. The following conditions contributed to the success of the trial: close collaboration between researchers, local health officials, and affected communities on one hand, and flexibility in design, conduct, and analysis based on close monitoring and interim assessments on the other. Besides using interim results to influence the conduct and analysis of their own trial, the researchers also shared these results with the scientific community in real time, and this feedback influenced other research during the outbreak. The trial could not answer definitively whether favipiravir treatment was safe or reduced mortality in patients with EVD. The results suggest that the drug is unlikely to be beneficial for patients with very high viral loads, at least when given by itself. They also suggest that favipiravir is safe in patients with lower viral loads, and that in such patients additional efficacy studies are warranted. Intermediate analysis of various measurements in trial participants showed that the estimate of viral load from the field EVD diagnosis test is a good proxy for the actual viral load (determined after the samples were shipped to and analyzed in a reference laboratory in France) and suitable as a surrogate marker. The results also confirm that viral load is a strong predictor of mortality. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001967. The World Health Organization has pages on Ebola virus disease, trials of Ebola treatments and vaccines, and the current update of the list of suitable drugs for testing or use in patients infected with Ebola (originally compiled in September 2014) US Centers for Disease Control and Prevention has information on the Ebola outbreak in West Africa The European Centre for Disease Prevention and Control also has information on the Ebola outbreak in West Africa

International audience; Objectives: To evaluate the virological response and to describe the resistance profiles in the case of failure after 6 months of first-line highly active antiretroviral therapy (HAART) in HIV-1-infected children living in resource-limited settings.Patients and methods: Ninety-seven HIV-1-infected children who started two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) (mainly zidovudine/lamivudine/nevirapine) in Mali were prospectively studied. Virological failure (VF) was defined as loss to follow-up, death or HIV-1 RNA viral load (VL) of >400 copies/mL at 6 months. When VL was >50 copies/mL, a genotypic resistance test was performed.Results: Among the 97 children, median age at antiretroviral initiation was 31 months and the majority were in WHO clinical (77.3%) and immunological (70.1%) stage III or IV. At month 6, 44% of children had VL > 400 copies/mL (61% VF). Among the children with detectable VL, 30/37 genotypic resistance tests were available, 8 with wild-type viruses and 22 with resistance mutations (73%): 19 M184V/I, 21 NNRTI mutations and only 3 thymidine analogue mutations (TAMs) (K70R, D67N and L210W in three distinct viruses). At failure, 6/8 children with wild-type viruses had a VL of 1000 copies/mL.Conclusions: Under NNRTI-based regimens, early detection of VF could allow the reinforcement of adherence when VL was 1000 copies/mL. The low frequency of TAMs suggests that most NRTIs can be used in a second-line regimen after early failure.

Background: In West Africa, female sex workers are at increased risk of HIV acquisition and transmission. HIV self-testing could be an effective tool to improve access to and frequency of HIV testing to female sex workers, their clients and partners. This article explores their perceptions regarding HIV self-testing use and the redistribution of HIV self-testing kits to their partners and clients. Methods: Embedded within ATLAS, a qualitative study was conducted in Côte-d’Ivoire, Mali, and Senegal in 2020. Nine focus group discussions were conducted. A thematic analysis was performed. Results: A total of 87 participants expressed both positive attitudes toward HIV self-testing and their willingness to use or reuse HIV self-testing. HIV self-testing was perceived to be discreet, confidential, and convenient. HIV self-testing provides autonomy from testing by providers and reduces stigma. Some perceived HIV self-testing as a valuable tool for testing their clients who are willing to offer a premium for condomless sex. While highlighting some potential issues, overall, female sex workers were optimistic about linkage to confirmatory testing following a reactive HIV self-testing. Female sex workers expressed positive attitudes toward secondary distribution to their partners and clients, although it depended on relationship types. They seemed more enthusiastic about secondary distribution to their regular/emotional partners and regular clients with whom they had difficulty using condoms, and whom they knew enough to discuss HIV self-testing. However, they expressed that it could be more difficult with casual clients; the duration of the interaction being too short to discuss HIV self-testing, and they fear violence and/or losing them. Conclusion: Overall, female sex workers have positive attitudes toward HIV self-testing use and are willing to redistribute to their regular partners and clients. However, they are reluctant to promote such use with their casual clients. HIV self-testing can improve access to HIV testing for female sex workers and the members of their sexual and social network.

International audience; Objectives: We estimate the effects of ATLAS's HIV self-testing (HIVST) kit distribution on conventional HIV testing, diagnoses, and antiretroviral treatment (ART) initiations in Cote d'Ivoire. Design: Ecological study using routinely collected HIV testing services program data. Methods: We used the ATLAS's programmatic data recorded between the third quarter of 2019 and the first quarter of 2021, in addition to data from the President's Emergency Plan for AIDS Relief dashboard. We performed ecological time series regression using linear mixed models. Results are presented per 1000 HIVST kits distributed through ATLAS. Results: We found a negative but nonsignificant effect of the number of ATLAS' distributed HIVST kits on conventional testing uptake (-190 conventional tests; 95% confidence interval [CI]: -427 to 37). The relationship between the number of HIVST kits and HIV diagnoses was significant and positive (+8 diagnosis; 95% CI: 0 to 15). No effect was observed on ART initiation (-2 ART initiations; 95% CI: -8 to 5). Conclusions: ATLAS' HIVST kit distribution had a positive impact on HIV diagnoses. Despite the negative signal on conventional testing, even if only 20% of distributed kits are used, HIVST would increase access to testing. The methodology used in this paper offers a promising way to leverage routinely collected programmatic data to estimate the effects of HIVST kit distribution in real-world programs.

International audience; Background: The ATLAS program promotes and implements HIVST in Côte d'Ivoire, Mali, and Senegal. Priority groups include members of key populations—female sex workers (FSW), men having sex with men (MSM), and people who use drugs (PWUD)—and their partners and relatives. HIVST distribution activities, which began in mid-2019, were impacted in early 2020 by the COVID-19 pandemic.Methods: This article, focusing only on outreach activities among key populations, analyzes quantitative, and qualitative program data collected during implementation to examine temporal trends in HIVST distribution and their evolution in the context of the COVID-19 health crisis. Specifically, we investigated the impact on, the adaptation of and the disruption of field activities.Results: In all three countries, the pre-COVID-19 period was marked by a gradual increase in HIVST distribution. The period corresponding to the initial emergency response (March-May 2020) witnessed an important disruption of activities: a total suspension in Senegal, a significant decline in Côte d'Ivoire, and a less pronounced decrease in Mali. Secondary distribution was also negatively impacted. Peer educators showed resilience and adapted by relocating from public to private areas, reducing group sizes, moving night activities to the daytime, increasing the use of social networks, integrating hygiene measures, and promoting assisted HIVST as an alternative to conventional rapid testing. From June 2020 onward, with the routine management of the COVID-19 pandemic, a catch-up phenomenon was observed with the resumption of activities in Senegal, the opening of new distribution sites, a rebound in the number of distributed HIVST kits, a resurgence in larger group activities, and a rebound in the average number of distributed HIVST kits per primary contact.Conclusions: Although imperfect, the program data provide useful information to describe changes in the implementation of HIVST outreach activities over time. The impact of the COVID-19 pandemic on HIVST distribution among key populations was visible in the monthly activity reports. Focus groups and individual interviews allowed us to document the adaptations made by peer educators, with variations across countries and populations. These adaptations demonstrate the resilience and learning capacities of peer educators and key populations.

International audience; Despite significant progress on the proportion of individuals who know their HIV status in 2020, Côte d'Ivoire (76%), Senegal (78%), and Mali (48%) remain far below, and key populations (KP) including female sex workers (FSW), men who have sex with men (MSM), and people who use drugs (PWUD) are the most vulnerable groups with a HIV prevalence at 5–30%. HIV self-testing (HIVST), a process where a person collects his/her own specimen, performs a test, and interprets the result, was introduced in 2019 as a new testing modality through the ATLAS project coordinated by the international partner organisation Solthis (IPO). We estimate the costs of implementing HIVST through 23 civil society organisations (CSO)-led models for KP in Côte d'Ivoire (N = 7), Senegal (N = 11), and Mali (N = 5). We modelled costs for programme transition (2021) and early scale-up (2022–2023). Between July 2019 and September 2020, a total of 51,028, 14,472, and 34,353 HIVST kits were distributed in Côte d'Ivoire, Senegal, and Mali, respectively. Across countries, 64–80% of HIVST kits were distributed to FSW, 20–31% to MSM, and 5–8% to PWUD. Average costs per HIVST kit distributed were $15 for FSW (Côte d'Ivoire: $13, Senegal: $17, Mali: $16), $23 for MSM (Côte d'Ivoire: $15, Senegal: $27, Mali: $28), and $80 for PWUD (Côte d'Ivoire: $16, Senegal: $144), driven by personnel costs (47–78% of total costs), and HIVST kits costs (2–20%). Average costs at scale-up were $11 for FSW (Côte d'Ivoire: $9, Senegal: $13, Mali: $10), $16 for MSM (Côte d'Ivoire: $9, Senegal: $23, Mali: $17), and $32 for PWUD (Côte d'Ivoire: $14, Senegal: $50). Cost reductions were mainly explained by the spreading of IPO costs over higher HIVST distribution volumes and progressive IPO withdrawal at scale-up. In all countries, CSO-led HIVST kit provision to KP showed relatively high costs during the study period related to the progressive integration of the programme to CSO activities and contextual challenges (COVID-19 pandemic, country safety concerns). In transition to scale-up and integration of the HIVST programme into CSO activities, this model shows large potential for substantial economies of scale. Further research will assess the overall cost-effectiveness of this model.

Background The ATLAS programme aims to promote and implement HIV self-testing (HIVST) in three West African countries: Côte d’Ivoire, Mali, and Senegal. During 2019–2021, in close collaboration with the national AIDS implementing partners and communities, ATLAS plans to distribute 500,000 HIVST kits through eight delivery channels, combining facility-based, community-based strategies, primary and secondary distribution of HIVST. Considering the characteristics of West African HIV epidemics, the targets of the ATLAS programme are hard-to-reach populations: key populations (female sex workers, men who have sex with men, and drug users), their clients or sexual partners, partners of people living with HIV and patients diagnosed with sexually transmitted infections and their partners. The ATLAS programme includes research support implementation to generate evidence for HIVST scale-up in West Africa. The main objective is to describe, analyse and understand the social, health, epidemiological effects and cost-effectiveness of HIVST introduction in Côte d’Ivoire, Mali and Senegal to improve the overall HIV testing strategy (accessibility, efficacy, ethics). Methods ATLAS research is organised into five multidisciplinary workpackages (WPs): Key Populations WP: qualitative surveys (individual in-depth interviews, focus group discussions) conducted with key actors, key populations, and HIVST users.Index testing WP: ethnographic observation of three HIV care services introducing HIVST for partner testing.Coupons survey WP: an anonymous telephone survey of HIVST users.Cost study WP: incremental economic cost analysis of each delivery model using a top-down costing with programmatic data, complemented by a bottom-up costing of a representative sample of HIVST distribution sites, and a time-motion study for health professionals providing HIVST.Modelling WP: Adaptation, parameterisation and calibration of a dynamic compartmental model that considers the varied populations targeted by the ATLAS programme and the different testing modalities and strategies. Discussion ATLAS is the first comprehensive study on HIV self-testing in West Africa. The ATLAS programme focuses particularly on the secondary distribution of HIVST. This protocol was approved by three national ethic committees and the WHO’s Ethical Research Committee. Supplementary Information The online version contains supplementary material available at 10.1186/s12889-021-10212-1.

System resilience has long been an area of study, and the term has become increasingly used across different sectors. Studies on resilience in health systems are more recent, multiplying particularly since the 2014 Ebola epidemic in West Africa. The World Health Organization (WHO) is calling for national governments to increase the resilience of their health systems. Concepts help define research objects and guide the analysis. Yet, to be useful, concepts need to be clear and precise. We aimed to improve the conceptual understanding of health systems resilience by conducting a scoping review to describe the state of knowledge in this area. We searched for literature in 10 databases, and analyzed data using a list of themes. We evaluated the clarity and the precision of the concept of health systems resilience using Daigneault & Jacob's three dimensions of a concept: term, sense, and referent. Of the 1091 documents initially identified, 45 met the inclusion criteria. Term: multiple terms are used, switching from one to the other to speak about the same subject. Sense: there is no consensus yet on a unique definition. Referent: the magnitude and nature of events that resilient health systems face differ with context, covering a broad range of situations from sudden crisis to everyday challenges. The lack of clarity in this conceptualization hinders the expansion of knowledge, the creation of reliable analytical tools, and the effectiveness of communication. The current conceptualization of health systems resilience is too scattered to enable the enhancement of this concept with great potential, opening a large avenue for future research.

Correction:15 Apr 2014: The PLOS ONE Staff (2014) Correction: Persistent Difficulties in Switching to Second-Line ART in Sub-Saharan Africa — A Systematic Review and Meta-Analysis. PLOS ONE 9(4): e95820. https://doi.org/10.1371/journal.pone.0095820; International audience; Objectives: Switching to second-line antiretroviral therapy (ART) largely depends on careful clinical assessment and access to biological measurements. We performed a systematic review and meta-analysis to estimate the incidence of switching to second-line ART in sub-Saharan Africa and its main programmatic determinants.Methods: We searched 2 databases for studies reporting the incidence rate of switching to second-line ART in adults living in sub-Saharan Africa. Data on the incidence rate of switching were pooled, and random-effect models were used to evaluate the effect of factors measured at the programme level on this incidence rate.Results: Nine studies (157,340 patients) in 21 countries were included in the meta-analysis. All studies considered patients under first-line ART and conditions to initiate ART were similar across studies. Overall, 3,736 (2.4%) patients switched to second-line ART. Incidence rate of switch was in mean 2.65 per 100 person-years (PY) (95% confidence interval: 2.01-3.30); it ranged from 0.42 to 4.88 per 100 PY and from 0 to 4.80 per 100 PY in programmes with and without viral load monitoring, respectively. No factors measured at the programme level were associated with the incidence rate of switching to second-line ART.Conclusion: The low incidence rate of switching to second-line ART suggests that the monitoring of patients under ART is challenging and that access to second-line ART is ineffective; efforts should be made to increase access to second-line ART to those in need by providing monitoring tools, education and training, as well as a more convenient regimen.

International audience; In sub-Saharan Africa, while antiretroviral therapy (ART) becomes widely available, access to biological measurements to monitor patients under ART remains scarce, making the management of ART difficult. We described the management of switching to second-line ART where HIV care is provided mainly in secondary health-care structures, in the region of Segou, Mali. Of 865 patients, followed under ART for a median time of 15 months, 40 switched to second-line ART (3.3 switches/100 person years). Reason for switching was failure in 18 patients (after 21 months in median) and severe intolerance in 13 (after three months in median). Switching to second-line ART occurred earlier when motivated by intolerance than by failure. The low rate of switch compares well with other studies, but was low compared to the expected rate of failure, and may indicate that physicians are reluctant to switch ART when treatment options are limited.

BackgroundIn developing countries, malnutrition is a contributing factor in over 50% of child deaths. Mortality rates are higher in underweight children, and HIV-infection is known to increase underweight. Our goals were to evaluate the prevalence of HIV among children hospitalised for severe malnutrition (SM) at the Niamey national hospital (Niger), and to compare renutrition and mortality by HIV-status.MethodsRetrospective study based on all children ResultsDuring the study period, 477 children were hospitalised for SM. HIV testing was accepted in 470 (98.5%), of which 40 were HIV+ (HIV prevalence (95% confidence interval) of 8.6% (6.2-11.5)). Duration of renutrition was longer in HIV+ than HIV- children (mean: 22 vs. 15 days; p = 0.003). During renutrition, 8 (20%) and 61 (14%) HIV+ and HIV- children died, respectively (p = 0.81).ConclusionAround 9% of children hospitalised for severe malnutrition were HIV infected, while in Niger HIV prevalence in adults is estimated at 0.8%. This pleads for wider access to HIV testing in this population.