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As part of our ongoing scaffold-hopping work on an antikinetoplastid 3-nitroimidazo[1,2-a]pyridine scaffold, we explored 3-nitroimidazo[1,2-b]pyridazine as a potential new antikinetoplastid series. Using conditions previously described by our lab, we obtained 6-chloro-3-nitro-2-[(phenylsulfonyl)methyl]imidazo[1,2-b]pyridazine with 54% yield. In vitro activity of this compound was evaluated against both the promastigote form of Leishmania donovani, the axenic amastigote form of Leishmania infantum and the trypomastigote blood stream form of Trypanosomabrucei brucei, and its influence on cell viability was assessed on the HepG2 cell line. However, despite good activity against the trypomastigote blood stream form of T. b. brucei (EC50 = 0.38 µM), it showed poor solubility in both HepG2 (CC50 > 7.8 µM) and L. infantum axenic amastigotes (EC50 > 1.6 µM) culture media, associated with a loss of activity against the promastigote form of L. infantum (EC50 > 15.6 µM).

Background In the last decade, an innovative approach has emerged for arthropod identification based on matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Increasing interest in applying the original technique for arthropod identification has led to the development of a variety of procedures for sample preparation and selection of body parts, among others. However, the absence of a consensual strategy hampers direct inter-study comparisons. Moreover, these different procedures are confusing to new users. Establishing optimized procedures and standardized protocols for mosquito identification by MALDI-TOF MS is therefore a necessity, and would notably enable the sharing of reference MS databases. Here, we assess the optimal conditions for mosquito identification using MALDI-TOF MS profiling. Methods Three homogenization methods, two of which were manual and one automatic, were used on three distinct body parts (legs, thorax, head) of two mosquito laboratory strains, Anopheles coluzzii and Aedes aegypti, and the results evaluated. The reproducibility of MS profiles, identification rate with relevant scores and the suitability of procedures for high-throughput analyses were the main criteria for establishing optimized guidelines. Additionally, the consequences of blood-feeding and geographical origin were evaluated using both laboratory strains and field-collected mosquitoes. Results Relevant score values for mosquito identification were obtained for all the three body parts assayed using MALDI-TOF MS profiling; however, the thorax and legs were the most suitable specimens, independently of homogenization method or species. Although the manual homogenization methods were associated with a high rate of identification on the three body parts, this homogenization mode is not adaptable to the processing of a large number of samples. Therefore, the automatic homogenization procedure was selected as the reference homogenization method. Blood-feeding status did not hamper the identification of mosquito species, despite the presence of MS peaks from original blood in the MS profiles of the three body parts tested from both species. Finally, a significant improvement in identification scores was obtained for field-collected specimens when MS spectra of species from the same geographical area were added to the database. Conclusion The results of the current study establish guidelines for the selection of mosquito anatomic parts and modality of sample preparation (e.g. homogenization) for future specimen identification by MALDI-TOF MS profiling. These standardized operational protocols could be used as references for creating an international MS database.

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.

Jean-Christophe Lagier,1,2 Matthieu Million,1,2 Sébastien Cortaredona,1,3 Léa Delorme,1 Philippe Colson,1,2 Pierre-Edouard Fournier,1,3 Philippe Brouqui,1,2 Didier Raoult,1,2 Philippe Parola1,3 On behalf of the IHU Task Force1IHU-Méditerranée Infection, Marseille, France; 2MEPHI, Aix Marseille Université, Institut de Recherche pour le Développement, Assistance Publique Hôpitaux de Marseille, Marseille, France; 3VITROME, Aix Marseille Université, Institut de Recherche pour le Développement, Assistance Publique Hôpitaux de Marseille, Service de Santé des Armées, Marseille, FranceCorrespondence: Philippe Parola, Institut Hospitalo-Universitaire Méditerranée Infection, 19-21 Boulevard Jean Moulin, Marseille, 13005, France, Tel + 33 0 4 13 73 24 01, Fax + 33 0 4 13 73 24 02, Email philippe.parola@univ-amu.fr Jean-Christophe Lagier, Email jeanchristophe.lagier@ap-hm.frObjectives: We evaluated the 6-week mortality of SARS-CoV-2 hospitalized patients treated using a standardized protocol in 2020 in Marseille, France.Methods: A retrospective monocentric cohort study was conducted in the standard hospital wards at the Institut Hospitalo-Universitaire Méditerranée Infection, between March and December 2020 in adults with SARS-CoV-2 PCR-proven infection.Results: Of the 2111 hospitalized patients (median age, 67 [IQR 55– 79] years; 1154 [54.7%] men), 271 were transferred to the intensive care unit (12.8%) and 239 died (11.3%; the mean age of patients who died was 81.2 (± 9.9)). Treatment with hydroxychloroquine plus azithromycin (HCQ-AZ), used in 1270 patients, was an independent protective factor against death (0.68 [0.52 – 0.88]). This effect was consistent for all subgroups of age, comorbidities, severity of the disease and comedications with zinc or corticosteroids. Zinc was independently protective against death (0.39 [0.23 – 0.67]), in a subgroup analysis of patients treated with HCQ-AZ without dexamethasone. The use of high-flow oxygen therapy in elderly patients who were not eligible for intensive care unit transfer saved 19 patients (33.9%).Conclusions: In our 2020 cohort, treating COVID-19 with HCQ-AZ was associated with lower mortality. These results need to be analyzed in the context of academic discussions about observational studies versus randomized clinical trials. More data will deserve to be analyzed in the SARS-Cov 2 variants, vaccination and post-vaccination era.Keywords: SARS-CoV-2, COVID-19, hydroxychloroquine, azithromycin

International audience; Abstract Background Due to the discreet and private nature of HIV self-testing (HIVST), it is particularly challenging to monitor and assess the impacts of this testing strategy. To overcome this challenge, we conducted a study in Côte d’Ivoire to characterize the profile of end users of HIVST kits distributed through the ATLAS project ( AutoTest VIH, Libre d’Accéder à la connaissance de son Statut ). Feasibility was assessed using a pilot phone-based survey. Methods The ATLAS project aims to distribute 221300 HIVST kits in Côte d’Ivoire from 2019 to 2021 through both primary (e.g., direct distribution to primary users) and secondary distribution (e.g., for partner testing). The pilot survey used a passive recruitment strategy—whereby participants voluntarily called a toll-free survey phone number—to enrol participants. The survey was promoted through a sticker on the HIVST instruction leaflet and hotline invitations and informal promotion by HIVST kit-dispensing agents. Importantly, participation was not financially incentivized, even though surveys focussed on key populations usually use incentives in this context. Results After a 7-month period in which 25,000 HIVST kits were distributed, only 42 questionnaires were completed. Nevertheless, the survey collected data from users receiving HIVST kits via both primary and secondary distribution (69% and 31%, respectively). Conclusion This paper provides guidance on how to improve the design of future surveys of this type. It discusses the need to financial incentivize participation, to reorganize the questionnaire, the importance of better informing and training stakeholders involved in the distribution of HIVST, and the use of flyers to increase the enrolment of users reached through secondary distribution.

International audience; The close phylogenetic relationship between humans and other primates creates exceptionally high potential for pathogen exchange. The surveillance of pathogens in primates plays an important role in anticipating possible outbreaks. In this study, we conducted a molecular investigation of pathogenic bacteria in feces from African nonhuman primates (NHPs). We also investigated the pathogens shared by the human population and gorillas living in the same territory in the Republic of Congo. In total, 93% of NHPs (n=176) and 95% (n=38) of humans were found to carry at least one bacterium. Non-pallidum Treponema spp. (including T. succinifaciens, T. berlinense, and several potential new species) were recovered from stools of 70% of great apes, 88% of monkeys, and 79% of humans. Non-tuberculosis Mycobacterium spp. were also common in almost all NHP species as well as in humans. In addition, Acinetobacter spp., members of the primate gut microbiota, were mainly prevalent in human and gorilla. Pathogenic Leptospira spp. were highly present in humans (82%) and gorillas (66%) stool samples in Congo, but were absent in the other NHPs, therefore suggesting a possible gorillas-humans exchange. Particular attention will be necessary for enteropathogenic bacteria detected in humans such as Helicobacter pylori, Salmonella spp. (including S. typhi/paratyphi), Staphyloccocus aureus, and Tropheryma whipplei, some of which were also present in gorillas in the same territory (S. aureus and T. whipplei). This study enhances our knowledge of pathogenic bacteria that threaten African NHPs and humans by using a non-invasive sampling technique. Contact between humans and NHPs results in an exchange of pathogens. Ongoing surveillance, prevention, and treatment strategies alone will limit the spread of these infectious agents.

International audience; Filarioid nematodes are parasites of the tissues and tissue spaces of all vertebrates except fish. Females produce microfilariae that enter the host's blood circulation or skin and may cause ocular and neurological pathology, leading to important implications in veterinary and public health. The present work is the first investigation on Setaria labiatopapillosa conducted in Morocco to characterize the morphological features of both adult and microfilaria forms. Two adult female nematodes were found free in the thoracic cavity of a slaughtered 3.5-year-old (6 teeth) Moroccan enhanced cross-breed bull which was born and raised in Morocco. The worms were identified as S. labiatopapillosa by light microscope (LM) and scanning electron microscopy (SEM) on the basis of their characteristic features of the anterior and posterior parts of the worms. The two S. labiatopapillosa worms measured 90 mm and 105 mm in length and 0.55 and 0.64 mm in width, respectively. Microfilariae were detected in the fully developed eggs contained in the uterus of both nematodes. A detailed morphology of both the adult females and larvae of S. labiatopapillosa is described using LM and SEM. Although the origin of S. labiatopapillosa analyzed in the present study is unknown and there is currently no evidence that Setaria spp. have invaded Morocco, further surveillance is warranted to determine the incidence of setariasis, identify its vectors, and take appropriate measures to protect the livestock and cattle industry of the country.

International audience; Equine vector-borne diseases (EVBDs) are emerging and re-emerging diseases, and most of them are zoonotic. This study aimed to investigate EVBDs in equines and associated arthropods (ticks and flies) from Egypt using molecular analyses, in addition to a preliminary characterization of associated ticks and flies by the matrixassisted laser desorption/ionization time of flight (MALDI-TOF) and molecular techniques. In this study, 335 blood samples were obtained from equines that appeared to be in good health (320 horses and 15 donkeys) in Cairo and Beni Suef provinces, Egypt. From the same animals, 166 arthropods (105 sucking flies and 61 ticks) were collected. Ticks and flies were preliminary characterized by the MALDI-TOF and molecular tools. Quantitative PCR (qPCR) and standard PCR coupled with sequencing were performed on the DNA of equines, ticks, and flies to screen multiple pathogens. The MALDI-TOF and molecular characterization of arthropods revealed that louse fly (Hippobosca equina) and cattle tick (Rhipicephalus annulatus) infesting equines. Anaplasma platys-like (1.6%), Anaplasma marginale (1.6%), Candidatus Ehrlichia rustica (6.6%), a new Ehrlichia sp. (4.9%), and Borrelia theileri (3.3%) were identified in R. annulatus. Anaplasma sp. and Borrelia sp. DNAs were only detected in H. equina by qPCR. A. marginale, Anaplasma ovis, and Theileria ovis recorded the same low infection rate (0.6%) in donkeys, while horses were found to be infected with Theileria equi and a new Theileria sp. Africa with recorded prevalence rates of 1.2% and 2.7%, respectively. In conclusion, different pathogens were first detected such as A. platys-like, Candidatus E. rustica, and a new Ehrlichia sp. in R. annulatus; A. marginale, A. ovis, and T. ovis in donkeys; and a new Theileria sp. "Africa" in horses.

Author(s): Havlir, Diane; Lockman, Shahin; Ayles, Helen; Larmarange, Joseph; Chamie, Gabriel; Gaolathe, Tendani; Iwuji, Collins; Fidler, Sarah; Kamya, Moses; Floyd, Sian; Moore, Janet; Hayes, Richard; Petersen, Maya; Dabis, Francois; (Universal Test, Treat Trials) UT3 Consortium | Abstract: IntroductionAchieving HIV epidemic control globally will require new strategies to accelerate reductions in HIV incidence and mortality. Universal test and treat (UTT) was evaluated in four randomized population-based trials (BCPP/Ya Tsie, HPTN 071/PopART, SEARCH, ANRS 12249/TasP) conducted in sub-Saharan African(SSA) during expanded antiretroviral treatment (ART) eligibility by World Health Organization guidelines and the UNAIDS 90-90-90 campaign.DiscussionThese three-year studies were conducted in Botswana, Zambia, Uganda, Kenya and South Africa in settings with baseline HIV prevalence from 4% to 30%. Key observations across studies were: (1) Universal testing (implemented via a variety of home and community-based testing approaches) achieved g90% coverage in all studies. (2) When coupled with robust linkage to HIV care, rapid ART start and patient-centred care, UTT achieved among the highest reported population levels of viral suppression in SSA. Significant gains in population-level viral suppression were made in regions with both low and high baseline population viral load; however, viral suppression gains were not uniform across all sub-populations and were lower among youth. (3) UTT resulted innmarked reductions in community HIV incidence when universal testing and robust linkage were present. However, HIV elimination targets were not reached. In BCPP and HPTN 071, annualized HIV incidence was approximately 20% to 30% lower in the intervention (which included universal testing) compared to control arms (no universal testing). In SEARCH (where both arms had universal testing), incidence declined 32% over three years. (4) UTT reduced HIV associated mortality by 23% in the intervention versus control communities in SEARCH, a study in whichnmortality was comprehensively measured.ConclusionsThese trials provide strong evidence that UTT inclusive of universal testing increases population-level viral suppression and decreases HIV incidence and mortality faster than the status quo in SSA and should be adapted at a sub-country level as a public health strategy. However, more is needed, including integration of new prevention interventions into UTT, in order to reach UNAIDS HIV elimination targets.

Objectives Research on men who have sex with men (MSM) in sub-Saharan Africa was neglected for a long time. The objective of this study was to understand factors associated with unprotected anal intercourse (UAI) with male partners among a group of MSM living in the city of Douala, Cameroon. Methods In 2008, a survey on the sexual activity and practices of MSM was set up in Douala in collaboration with a local community-based organisation. Data were collected among a convenience sample of 168 MSM during face-to-face interviews with trained interviewers. Results A total of 142 individuals reported sexual activity during the previous 6 months, among whom 80 (57%) reported UAI with male partners. In a multivariate logistic regression model adjusted for the frequency of sexual intercourse, not having had access to prevention interventions and not knowing any HIV-infected person were both independently associated with a higher risk of UAI. Other factors associated with this higher risk included having had a stable male partnership at some point in one’s life and not having been out of Douala for more than 4 weeks during the previous year. Conclusions This community-based research is the first study of MSM in Cameroon and the HIV transmission risks they face. Results show the importance of HIV prevention interventions from peers, and underline the need to maintain efforts to develop specific interventions targeting MSM more efficiently in the African context. Research on men who have sex with men (MSM) in sub-Saharan Africa was neglected for a long time. Criminalisation of male-to-male sex in many countries, social denial and difficulty in reaching this population were the explanations given for the weak involvement of researchers in this area. However, recent literature describing MSM in Africa, 1e3 and the assumption that this population could be significantly vulnerable to HIV and sexually transmitted infections (STI) 45 has encouraged

International audience; Population-based HIV surveillance is crucial to inform understanding of the HIV pandemic and evaluate HIV interventions, but little is known about longitudinal participation patterns in such settings. We investigated the dynamics of longitudinal participation patterns in a high HIV prevalence surveillance setting in rural South Africa between 2003 and 2012, taking into account demographic dynamics. At any given survey round, 22,708 to 30,495 persons were eligible. Although the yearly participation rates were relatively modest (26% to 46%), cumulative rates increased substantially with multiple recruitment opportunities: 68% of eligible persons participated at least once, 48% at least twice and 31% at least three times after five survey rounds. We identified two types of study fatigue: at the individual level, contact and consent rates decreased with multiple recruitment opportunities and, at the population level, these rates also decreased over calendar time, independently of multiple recruitment opportunities. Using sequence analysis and hierarchical clustering, we identified three broad individual participation profiles: consenters (20%), switchers (43%) and refusers (37%). Men were over represented among refusers, women among consenters, and temporary non-residents among switchers. The specific subgroup of persons who were systemically not contacted or refusers constitutes a challenge for population-based surveillance and interventions.

Les progrès observés ces dix dernières années dans le champ de la prévention du VIH, en particulier la place croissante prise par le traitement antirétroviral, ont amené certains leaders politiques et scientifiques à évoquer la « fin du sida », à savoir un contrôle des nouvelles infections et de la mortalité liée au VIH. Dans cet article, nous revenons en particulier sur l’objectif de contrôle de la transmission sexuelle. Le traitement antirétroviral précoce des personnes infectées permet de réduire fortement la charge virale plasmatique et, par conséquent, la probabilité de transmettre le virus (treatment as prevention ou TasP). De même, la prise d’antirétroviraux par des personnes non infectées permet également de les prémunir contre l’infection (prophylaxie préexposition ou PrEP). La question aujourd’hui n’est plus de savoir quand utiliser ces médicaments mais comment. Une stratégie de prévention combinée pourrait réduire significativement les nouvelles infections, mais à condition d’atteindre des niveaux de mise à l’échelle non encore atteints à ce jour. L’objectif de la fin du sida est atteignable, à condition de ne pas succomber aux sirènes d’un ‘tout biomédical’ et de mesurer pleinement les enjeux programmatiques, opérationnels, sociaux, comportementaux et politiques qui nous font face. Over the past decade, progress made in the field of HIV prevention, particularly the growing role of antiretroviral drugs, has led some political and scientific leaders to envision the “end of AIDS”, i.e. the control of new HIV infections and HIV-related deaths. In this paper, we address in particular the issue of preventing sexual transmission. Early antiretroviral treatment of infected persons can almost always deeply reduce plasma viral load and therefore the probability of transmitting the virus (treatment as prevention or TasP). Similarly, antiretroviral drugs for non-infected people also protect them against HIV acquisition (pre-exposure prophylaxis or PrEP). The question today is no longer when to use antiretroviral drugs but how. A combined prevention strategy could significantly reduce new HIV infections, but only if the corresponding health programs are scaled up at a level not yet sustained. The goal of ending AIDS is achievable, if we do not succumb to the sirens of a 'biomedical-only' approach and fully measure the programmatic, operational, social, behavioural and political challenges that we do face.