MEMBERS NEWS Keeping you updated!

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1 MEMBERS NEWS Keeping you updated! The GABRIEL Network Research Committee A research committee has been recently set up by the GABRIEL network. It has gained momentum this year with the assignment of specific new tasks: followup of articles for publication, review of manuscripts before submission, recommendations of journals for publication, evaluation of research projects, review of research projects before submission. The committee members include renowned specialists in the field of HIV, TB, virology, diagnostic methods, host markers, tropical diseases, fevers, and clinical medicine: Dr. Delia Goletti, Dr. Glaucia Paranhos-Baccalà, Dr. Werner Albrich, Dr. Robert Friedman, Prof. William Carman, Prof. François Simon. To apply to the committee, please contact Glaucia Paranhos-Baccalà or Florence Komurian-Pradel. Glaucia Paranhos-Baccalà, Emerging Pathogens Laboratory (EPL), Fondation Mérieux (France) Pneumonia Multi-centric Pilot Study The Pilot Pneumonia Multicentric Study, now being run on a case-control group of 2,200 children recruited in ten countries, is the largest-scale multi-country study to have ever been conducted at Fondation Mérieux. It represents a challenge in that it provides the opportunity to set up research platforms with procedures that will ultimately be standardised to facilitate the launch of future research projects. It is also the second largest study of its kind in the last two decades on the etiology of pneumonia and as a result, the study is gradually gaining greater attention and recognition internationally. Contents The GABRIEL Network Research Committee Pneumonia Multi-centric Pilot Study Compensation mutation in a TB isolate New test for Typhoid fever Laos : Workshop on The improvement of management and follow up treatment of hepatitis infected patients Expert meeting on diagnosis and detection of antimicrobial resistance in developing countries October 2011, Les Pensières (France) In brief This year, four sites have been designated to reach the recruitment process s planned target numbers: Cambodia, China, Madagascar, and Paraguay. Each site will progressively incorporate the lockout and closing procedures of the study. Specific SOPs are being drawn up and the closing procedures are expected to be officially launched. Global Approach for Biological Research on Infectious Epidemics in Low income countries 1/6

2 India, a country that entered the study at the end of last year, has successfully completed the site selection processes and IEC submissions. The two sites in India have now obtained their respective IEC approvals and are in the final stages of setting up procedures to begin recruitment. Looking ahead, we are pleased to announce that the Experts Committee, composed of volunteers and set up especially for this study, will take part in the 5th Annual GABRIEL meeting (in December 2012). The Committee members include Prof. Keith Klugman, (Emory University, USA), Prof. Ron Dagan (Soroka University Medical Center, Israel), Prof. Samir Saha (Sabin Vaccine Institute Bangladesh). Valentina Picot, Fondation Mérieux (France) Compensation mutation in a TB isolate In a study on TB resistance in three hospitals in Laos, CICM identified one isolate whose katg locus was not amplified in a MTBDRplus test. Such a deletion signifies that this isolate is highly resistant to Isoniazid. To overcome the oxidative stress that is usually counteracted by the catalase enzyme coded by the katg gene, a compensation mutation occurs within the promoter of bacterial ahpc, which results in regulating the alkylhydroperoxide reductase coded by ahpc. The Lyon-sud bacteriology laboratory sequenced the ahpc promoter of this isolate to determine whether it had mutated. A wild type sequence was retrieved on all but 3 positions, on which the base call between the wild type and the mutant was undistinguishable. To dispel any doubt, we cloned, at the EPL, PCR amplicons derived from this locus, and then sequenced 20 clones from among those obtained. The results revealed no wild type, but rather a mix of three population types, divided into equivalent numbers of -51g/a, -52c/t, and -57c/t mutations. Each clone carried only a single mutation, such that no double mutated clones were retrieved. We can therefore conclude that among resistant isolates, sequential polymorphism can occur. By typing this isolate, we will obtain greater knowledge on its extent in Laos. Jean-Luc Berland, Emerging Pathogens Laboratory (EPL), Fondation Mérieux (France) New test for Typhoid fever Thanks to the support of the Bill & Melinda Gates Foundation, Fondation Mérieux has launched a project to develop a sensitive molecular diagnostic test for the detection of Salmonella as the cause of Typhoid fever. Typhoid fever continues to be a major public health problem, especially amongst children in developing countries. The World Health Organization estimates that 17 to 22 million people are infected per year with a mortality rate of 600,000 each year. Typhoid and Paratyphoid fevers are caused by a bacteria named Salmonella (Salmonella typhi, Salmonella paratyphi A; Salmonella typhimurium and Salmonella enteritidis) and the bacteria is transmitted by contaminated food and water. Current diagnostic techniques are not very sensitive and are not all adapted to developing countries, this means that there is little data concerning the exact global prevalence rate of this disease. Global Approach for Biological Research on Infectious Epidemics in Low income countries 2/6

3 Given this situation, the Bill & Melinda Gates Foundation has asked Fondation Mérieux to develop a sensitive diagnostic test for the detection of S.typhi, S.paratyphi A, Salmonella spp. in blood. This ambitious project will last for a year and will involve four partners: Reference Centre for Salmonella at the Pasteur Institute (Paris) Fast Track Diagnostics (Luxembourg), Kemri-CDC (Kenya) Child Health Foundation (Bangladesh) Fondation Mérieux s Emerging Pathogens Laboratory, in addition to the coordination of the project, will have the role of developing the enrichment and purification of the nucleic acid of Salmonella from blood samples. Jean-Noel Telles, Emerging Pathogens Laboratory (EPL), Fondation Mérieux (France) Laos : Workshop on The improvement of management and follow up treatment of hepatitis infected patients 29 February March 2012, Vientiane (Laos) In Laos, as in many other South East Asian countries, viral hepatitis B and C represent a major public health problem, more so in terms of screening than patient management. Furthermore, medical knowledge amongst staff is still limited. Vaccination against hepatitis B has been integrated in the Laotian national programme since 2001 while the problems of HIV /HBV or HIV / HCV co-infections remain unexplored. The viral load of around 2,000 HIV infected patients is followed at the Christophe Mérieux Centre for Infectiology in Laos. These 1,890 people represent 88,5% of HIV infected patients in the country; conversely, only 1.5% of them are declared as being coinfected with HBV and very few with HCV. A possible hypothesis is that there is no systematic screening of hepatitis infections within the HIV positive population. At a diagnostic level, the majority of regional hospital laboratories look for the AgHBs serum (qualitative approach) and the anti-hcv antibody. However, other virological markers evaluating the evolution of Hepatitis B (AgHBe & Ac anti-hbe), the study of the HCV genotype and the quantification of viral loads (HBV and HCV), are done in Thailand, creating a major expenditure for patients to which the cost of treatment must be added. Even if certain patients have access to imported treatment (Lamivudine, Adéfovir, Ténofovir et Global Approach for Biological Research on Infectious Epidemics in Low income countries 3/6

4 Peg-IFN alfa-2a), the therapeutic follow up from specialised doctors is limited. In January 2010, the CICML set up an HBV and HCV viral load quantification technique to evaluate the effectiveness of treatment, however, clinicians also require continued training in patient management and treatment follow up. Thanks to the collaboration with Pr. Paul Dény (University of Paris 13), the University of Medicine and Pharmacy in Cluj-Napoca (Romania), and the University of Health Sciences in Vientiane (Laos), the CICML organised the 1st national workshop on The improvement of patient management and follow-up treatment of hepatitis infected patients with the financial support of Fondation Mérieux and the Association of Universities of the Francophonie. This workshop took place in Vientiane from 29 February to 2 March 2012 and was introduced by the Deputy Minister of Health of Laos Associated Professor Bounkong Syhavong, Nicolas Steenkeste (Fondation Mérieux, Asia) and Bernard Vanthomme (Association of Universities of the Francophonie in Laos). This workshop brought together, for the first time, health professionals from different provinces of Laos involved in diagnostics and follow up clinics, and treatment of patients infected with viral hepatitis. During three days of seminars, speakers covered news concerning hepatitis viruses, in particular, chronic viral infection and their treatment uptake, under the direction of Dr Phimpha Paboriboune (CICML) and Professor Paul Dény. The situation regarding hepatitis in South East Asia and in Laos was addressed by Dr G. Jourdain and Associate Professor Bouachanh Rasacheck, respectively, underlining the importance of the major public health problem of HBV infection in the country, as in other South and South East Asian countries, where more than 8,5% of the population is chronically infected, as shown by the HBs antigen (AgHBs). HCV infection seems to be less widespread: 1% of the population, at present 6.8 million inhabitants (2009). The natural history and evolution of HBV and HCV infections has been redefined by Professor C. Trépo, in particular in terms of the difficulty of treatment decisions in the absence of anatomopathology, underlining the need for non-invasive fibrosis evaluation. Professor P. Dény reintroduced diagnostic virology concepts ; particular points of concern were, firstly, the fact that in Laos, at the heart of the cause of clinical jaundice, and on the contrary in Western countries, the presence of anti-hav IgM was not pathognomonic for acute HAV infection. Secondly, quantification of viremia, available at the Rodolphe Mérieux Laboratory, was made as an integrated part of diagnostic virology also placing HBV and HCV viremia alongside the prognosis of HIV viremia as in infection by the Human Immunodeficiency Virus. The hepatitis D virus was discussed, but there is no information relating to Laos. Professor Y. Buisson recounted the natural history and epidemiology of HEV infection, which carries a grave risk for pregnant women and their foetus. Dr W. Khamduang then specified the work carried out in Thailand on the evaluation of residual transmission from HBV infected mother to the babies. After this first part of the workshop redefining the knowledge around hepatitis, the clinical aspect of patient management was discussed under the advice and recommendations of Professor C. Trépo this covered the diagnosis and use of biological markers, and treatment. Clinical cases were also presented and discussed between speakers and the public. Priority research themes were identified for public health in Laos, in particular thanks to the drive that brought the implementing of HIV viral load at the CICML. More federal research projects between Laos, Vietnam, Cambodia and Thailand, to create a real South East Asian consortium, were brought to attention, and the themes were identified, mainly hepato-cellular-carcinoma and preventative vaccination. Global Approach for Biological Research on Infectious Epidemics in Low income countries 4/6

5 Under the impetus of the deputy minister, the wish to repeat this type of event was put forward to more significantly share knowledge and good practices for managing hepatitis in Laos by allowing a true quality control of treatment practices through close cooperation with local bodies and health authorities. Paul Deny, University of Paris 13 (France), Christian Trépo, University of Paris 13 (France), Phimpha Paporiboune, Christophe Mérieux Centre of Infectiology (Laos) Expert meeting on diagnosis and detection of antimicrobial resistance in developing countries October 2011, Les Pensières (France) Antimicrobials have been used and abused everywhere around the world. Antimicrobial resistance (AMR) has now become a global concern, and this topic was the focus of World Health Day on 7 April 2012, organized by the World Health Organization. Whereas antimicrobial resistance is well mapped out and tightly monitored in developed countries, this problem is yet to be recognised in developing countries. An increasing body of evidence, however, reveals that antimicrobial resistance has been accelerating in developing countries. Resistance manifests itself in rural settings where surveillance is lacking, and its resulting increase has put into jeopardy the attainment of the Millenium goal of reducing maternal and infant mortality. Resistance is implicated in all the leading infectious disease killers that include lower respiratory tract infections, HIV, tuberculosis, diarrheal diseases, malaria, and Staphylococcus aureus infections. The problem is all the more pressing in that, in a globalized world, microorganisms and their resistance genes are carried faster and farther, and that the pipeline of new drugs is running dry. There is thus an urgent need to map out the problem of antimicrobial resistance in developing countries, so that appropriate steps can be taken to remedy it. Such mapping must rely on reliable and comprehensive surveillance networks, endowed with adequate laboratory capacities that are equipped with up-to-date technologies for diagnostics. What is the extent of our current knowledge on antibiotic resistance in developing countries? What are the most immediate threats that need to be addressed? What are the lessons to be taken from the successful examples of surveillance networks in developing countries? What are the most critical needs in terms of laboratory capacities? To what extent can molecular methods be integrated to conduct surveillance, and for which diseases? What type of framework should be deployed to create reliable and sustainable networks for antimicrobial surveillance? These were the questions that were examined in depth and debated on at the first Expert meeting on diagnosis and detection of antimicrobial resistance in developing countries, organized by the Fondation Mérieux, Wellcome Trust, and European Union at the Les Pensières Conference Centre in France, on October This meeting gathered together 45 experts from developed and developing countries. Presentations were given on existing capacities for the mapping of antimicrobial resistance in emerging and developing countries, on the gaps regarding diagnosis and surveillance, and on innovative laboratory tools. There were two workshops on the initiatives to be proposed and supported dealing with capacity building, the setting up of new networks, and R & D recommendations from the group will be soon published. Guy Vernet, Emerging Pathogens Laboratory, (EPL) Fondation Mérieux (France) Global Approach for Biological Research on Infectious Epidemics in Low income countries 5/6

6 In brief In February 2012, Thomas Baudry joined Fondation Mérieux to work as the Laos project coordinator based at the Centre d Infectiologie Christophe Mérieux of Laos. He is a medical doctor specialising in infectious diseases trained at the Croix Rousse hospital in Lyon. Thanks to the support of the Emerging Pathogen Laboratory (EPL), he has been trained in molecular biology and the use of Line Probe assay for TB drug resistance detection. He now participates actively in projects connected to the strengthening of capabilities regarding Tuberculosis. Milen Milenkov joined the team of the Emerging Pathogen Laboratory (EPL) in March His mission is to develop bacteriology in the laboratory and to work more particularly on the Pneumonia project by setting up techniques for molecular biology and for bacterial culture identification. In 2012, Marc-Ghislain Antoni joined the GHESKIO team in Port-au Prince (Haïti) as a International Volunteer. After one month of training at the Emerging Pathogen Laboratory (EPL), he provides technical support for the multicentric study on pneumonia which was set up in Haiti. Global Approach for Biological Research on Infectious Epidemics in Low income countries 6/6