Understanding and intervening in HIV-associated tuberculosis

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

The immune response in tuberculosis is responsible both for protecting us, but paradoxically can also contribute to symptoms of the disease. This research programme aims to determine the mechanisms by which the steroid hormone vitamin D might enhance protection and decrease tissue damage in tuberculosis. In addition we are interested in the mechanism by which corticosteroid therapy might decrease tissue damaging immune reactions

Technical Summary

The laboratory programme in the UK investigates in vitro the mechanisms by which vitamin D metabolites modulate immunity to M. tuberculosis infection, and the analysis of clinical samples obtained from an ongoing clinical trial of adjunctive vitamin D in tuberculosis treatment. The programme will evolve to additionally consider the mode of action of corticosteroids in suppressing aberrant M. tuberculosis specific immunity as exemplified by the HIV-TB associated immune reconstitution inflammatory syndrome (TB-IRIS). In Cape Town we have assembled the worlds largest (> 300 cases) case series and specimen collection of TB-IRIS in the context of a placebo-controlled trial of corticosteroid therapy.

Publications

10 25 50

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Bahr N (2013) Central nervous system immune reconstitution inflammatory syndrome. in Current infectious disease reports

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Bhaijee F (2010) Warfarin-induced skin necrosis in HIV-1-infected patients with tuberculosis and venous thrombosis. in South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde

 
Description A single dose of vitamin D enhances immunity to mycobacteria
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
Impact As documented elsewhere the work has led to investigation of vitamin D status becoming routine amongst tuberculosis patients and their contacts.
 
Guideline Title British HIV association guidelines for the management of TB/HIV co-infection in adults 2017
Description British HIV association guidelines for the management of TB/HIV co-infection in adults 2017
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
Impact Recommendation to provide preventive therapy against tuberculosis to people living with HIV
URL https://www.bhiva.org/file/wciyxvzCuTmjD/BHIVA-TB-HIV-co-infection-guidelines-consultation.pdf
 
Guideline Title WHO strategic advisory and technical group
Description Citation of meta-analysis
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact On the basis of meta-analysis we conducted The STAG-TB endorsed the 'findings of the WHO expert group and supports the strategic approach to develop negative WHO policy recommendations to discourage the use of commercial Interferon-gamma release assays in low-income and middle-income countries
 
Description Effect of HIV-1 infection on T-cell-based and skin test detection of tuberculosis infection
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
Impact Several jurisdictions have licensed interferon gamma release assays for the diagnosis of tuberculosis infection and clinical guidelines on their use in HIV infected persons are in evolution. We have established these tests have little advantage over the skin test in the high incidence environment of South Africa
 
Description Lancet review 2007
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
Impact The review concludes that overall health expenditure on tuberculosis will need to substantially increase if the goal of eliminating tuberculosis by 2050 is to be realised
 
Guideline Title South African HIV Society ART guidelines for adults
Description South African HIV Society ART guidelines for adults http://www.sahivsoc.org/Files/Adult_ART_2017.pdf
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
Impact IPT recommended to PLHIV on ART, to those TST positive as well as those TST negative Guidelines being updated. Recommendation based on our study results will be kept.
URL http://www.sahivsoc.org/Files/Adult_ART_2017.pdf
 
Guideline Title The South African antiretroviral treatment guidelines (2013)
Description The South African antiretroviral treatment guidelines (2013)
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
Impact IPT recommended to PLHIV on ART, to those TST positive as well as those TST negative Guidelines being updated. Recommendation based on our study results will be kept.
URL http://www.kznhealth.gov.za/medicine/2013_art_guidelines
 
Guideline Title Tuberculosis NICE guideline [NG33]
Description Tuberculosis NICE guideline [NG33] Published date: January 2016
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
Impact Recommendation to provide Isoniazid preventive therapy to HIV infected persons receiving antiretroviral therapy
URL https://www.nice.org.uk/guidance/ng33/chapter/Recommendations#preventing-tb
 
Guideline Title WHO Guidelines for the treatment of latent tuberculosis - 2018
Description WHO Guidelines for the treatment of latent tuberculosis - 2018 http://www.who.int/tb/publications/2018/latent-tuberculosis-infection/en/
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact a. Study results informed recommendations on: • Provision of IPT to ART patients regardless of CD4 • Individuals with negative LTBI results can be considered for IPT, considering other risk factors • Either TST or IGRA can be used to test for LTBI b. The number of PLHIV newly enrolled in care who are prescribed IPT is increasing. http://apps.who.int/iris/bitstream/handle/10665/274453/9789241565646-eng.pdf?ua=1 • See Chapter 5 on TB prevention
URL http://www.who.int/tb/publications/2018/latent-tuberculosis-infection/en/
 
Description corticosteroids for TB-IRIS
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Corticosteroid therapy reduces the duration of hospital admission and symptoms in TB-IRIS
 
Description Carnegie Corporation Early Career Fellowship (University of Cape Town)
Amount R 1,500,000 (ZAR)
Organisation Carnegie Corporation of New York 
Sector Charity/Non Profit
Country United States
Start 10/2017 
End 09/2020
 
Description Centres for Global Health Scheme
Amount £767,599 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2013 
End 08/2018
 
Description Developing the Next Generation of Academics
Amount R 500,000 (ZAR)
Organisation Carnegie Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
End 12/2014
 
Description EDCTP
Amount € 4,900,000 (EUR)
Funding ID RIA2017T-2004 
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country European Union (EU)
Start 01/2019 
End 12/2022
 
Description Fellowship
Amount R 370,000 (ZAR)
Organisation Claude Leon Foundation 
Sector Charity/Non Profit
Country South Africa
Start 01/2014 
End 12/2015
 
Description Financial Assistance Agreement to holders of FP7 awards
Amount R 649,055 (ZAR)
Organisation Department of Science and Technology 
Sector Public
Country South Africa
Start 06/2013 
End 12/2017
 
Description Incentive funding for rated researchers
Amount R 30,000 (ZAR)
Funding ID 96841 
Organisation South African National Research Foundation (NRF) 
Sector Public
Country South Africa
Start 01/2018 
End 12/2018
 
Description Master's Fellowship: Shepherd Nhamoyebonde
Amount £75,115 (GBP)
Funding ID 090677 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2010 
End 06/2012
 
Description Masters Fellowship in Public Health and Tropical Medicine
Amount R 1,891,000 (ZAR)
Funding ID 106360/Z/14/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 06/2017
 
Description Medical Research Council of South Africa Strategic Health Innovation partnerships
Amount R 15,959,010 (ZAR)
Organisation Medical Research Council of South Africa (MRC) 
Sector Public
Country South Africa
Start 10/2014 
End 09/2019
 
Description National Health Scholars Programme
Amount R 654,000 (ZAR)
Organisation Medical Research Council of South Africa (MRC) 
Sector Public
Country South Africa
Start 01/2015 
End 12/2017
 
Description Phase IIB vaccine trial
Amount £4,416,000 (GBP)
Funding ID IP.07.32080.002 
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country European Union (EU)
Start 09/2009 
End 12/2014
 
Description RCUK GCRF
Amount £6,336,136 (GBP)
Funding ID MR/P028071/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 12/2021
 
Description RIA - 2017-Treatment Innovations
Amount € 9,255,810 (EUR)
Funding ID RIA2017T-2019 109237 
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country European Union (EU)
Start 01/2019 
End 12/2022
 
Description Research Training Fellowship (DML)
Amount £326,500 (GBP)
Funding ID 087754 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2009 
End 03/2013
 
Description Research Training Fellowship: Hanif Esmail
Amount £302,638 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Research Training Fellowship
Sector Charity/Non Profit
Country United Kingdom
Start 10/2010 
End 03/2014
 
Description Research training Fellowship in Public HEalth and Tropical Medicine (SM)
Amount £379,275 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2012 
End 12/2015
 
Description Resesarch Training Fellowship: Naomi Walker
Amount £295,860 (GBP)
Funding ID 094000 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 12/2014
 
Description Senior Fellowship in Clinical Science (renewal)
Amount £2,520,809 (GBP)
Funding ID 104803 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2014 
End 09/2019
 
Description Strategic Award
Amount £1,209,295 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2013 
End 06/2015
 
Description Strategic primer grant
Amount € 616,102 (EUR)
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country European Union (EU)
Start 01/2013 
End 12/2014
 
Description Sydney Brenner Fellowship
Amount R 480,000 (ZAR)
Organisation Academy of Science of South Africa 
Sector Academic/University
Country South Africa
Start 01/2014 
End 12/2015
 
Description Wellcome Trust Senior fellowship Renewal (Quadruple intervention against tuberculosis)
Amount £1,328,024 (GBP)
Funding ID 088316 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2009 
End 09/2014
 
Description Wellcome Trust Strategic Award (Establishment of a Centre for Clinical Infectious Diseases Research at the University of Cape Town (Wellcome-UCT-CCIDR).
Amount £3,272,110 (GBP)
Funding ID 084323 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2008 
End 06/2013
 
Title Clinical Infectious Diseases Research Initiative 
Description This is funded by a strategic award from the Wellcome Trust and has led to infrastructure improvements at the Unviersity of Cape Town that include a Class III miscrobiological safety cabinet, freezers and liquid nitrogen storage and enhanced clinical research facilities 
Type Of Material Improvements to research infrastructure 
Year Produced 2009 
Provided To Others? Yes  
Impact The award also funds entry level Fellowship of approximately £100000 in value. 7 such awards were made in 2009 
URL http://www.cidri.uct.ac.za
 
Title ekhayavac.org 
Description www.ekhayavac.org eKhayaVac is the vaccine trial site in South Africa of the multicentre tuberculosis vaccine trial: A Phase II, Proof of Concept, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Protective Efficacy Against TB Disease, Safety, and Immunogenicity of MVA85A / AERAS-485 in Healthy, HIV-infected Adults 
Type Of Material Biological samples 
Provided To Others? No  
Impact This is a bespoke secure online data entry solution to a our data management needs. It could form a model for other studies and for other groups 
URL http://www.ekhayavac.org
 
Title ANIMA 
Description Deffur, A., Wilkinson, R.J., Mayosi, B.M. and Mulder, N.M. ANIMA: Association Network Integration for Multiscale Analysis Wellcome Open Research (2018) 3:27 PMID 30271886.2 PMCID PMC6134339 
Type Of Material Data analysis technique 
Year Produced 2018 
Provided To Others? Yes  
Impact None as yet 
URL https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134339/
 
Description Baylor microarray 
Organisation Baylor Scott & White Health
Department Baylor Institute for Immunology Research
Country United States 
Sector Academic/University 
PI Contribution We have suplpied clinical samples from carefully phenotyped patients
Collaborator Contribution performance of microarrays and assistance with their analayis
Impact Berry, M.P.R., Graham, C.M., McNab, F.W., Xu, Z., Bloch, S.J., Oni, T., Wilkinson, K.A., Banchereau, R., Skinner, J., Wilkinson, R.J., Quinn, C., Blankenship, D., Dhawan, R., Cush, J.J., Mejias, A., Ramilo, O., Kon, O.M., Pascual, V., Banchereau, J., Chaussabel, D., and O'Garra, A. An Interferon-Inducible Neutrophil-Driven blood transcriptional signature in Human Tuberculosis Nature (2010) 466: 973-977 PMID 20725040 Lai, R.P-J., Meintjes, G., Wilkinson, K.A., Graham, C.M., Marais, S., Van der Plas, H., Deffur, A., Schutz, C., Bloom, C., Munagala, I., Anguiano, E., Goliath, G., Maartens, G., Banchereau, J., Chaussabel, D., O'Garra, A., and Wilkinson, R.J. HIV-Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome Is Characterized by Toll-Like-Receptor And Inflammasome Signaling Nature Communications† 6: 8451 doi 10:1038/ncomms9451 PMID 26399326 PMCID PMC4595995 Bloom, C.I., Graham, C.M., Berry, M.P.R., Rozakeas, F., Redford, P.S., Wang, Y., Xu, Z., Wilkinson, K.A., Wilkinson, R.J., Kendrick, Y., Devouassoux, G., Ferry, T., Miyara, M., Bouvry, D., Valeyre, D., Gorochov, G., Blankenship, D., Saadatian, M., Vanhems, P., Beynon, H., Vancheeswaran, R., Wickremasinghe, M., Chaussabel, D., Banchereau, J., Pascual, V., Ho, L-P., Lipman, M., O'Garra, A. Transcriptional Blood Signatures Distinguish Pulmonary Tuberculosis, Pulmonary Sarcoidosis, Pneumonias and Lung Cancers. PLOS ONE (2013) 8(8):e70630 PMID 23940611 PMCID PMC3734176 Bloom, C.I., Graham, C.M., Berry, M.P.R., Wilkinson, K.A., Oni, T., Rozakeas, F., Xu, X., Rossello-Urgell, J., Chaussabel, D., Banchereau, J., Pascual, V., Lipman, M., Wilkinson, R.J., O'Garra, A. Detectable Changes in The Blood Transcriptome are Present after Two Weeks of Antituberculosis Therapy PLOS ONE (2012) 7(10): e46191 PMID 23056259 PMCID PMC3462772 McNab, F.W., Berry, M.P., Graham, C.M., Bloch, S.A., Oni, T., Wilkinson, K.A., Wilkinson, R.J., Kon, O.M., Banchereau, J., Chaussabel, D., O'Garra, A. Programmed Death Ligand 1 is over-expressed by neutrophils in the blood of patients with active Tuberculosis European Journal of Immunology (2011) 41(7):1941-7 PMID 21509782 PMCID PMC3179592
Start Year 2009
 
Description Crick African Network 
Organisation MRC/UVRI Uganda Research Unit on AIDS
Country Uganda 
Sector Public 
PI Contribution Crick is the lead and co-ordinating partner on this £6.3 million GCRF award
Collaborator Contribution They have helped us convene workshops and scientific symposia and contributed to management
Impact 4 workshops and scientific symposia
Start Year 2017
 
Description Crick African Network 
Organisation Medical Research Council (MRC)
Department MRC Unit, The Gambia
Country Gambia 
Sector Public 
PI Contribution Crick is the lead and co-ordinating partner on this £6.3 million GCRF award
Collaborator Contribution They have helped us convene workshops and scientific symposia and contributed to management
Impact 4 workshops and scientific symposia
Start Year 2017
 
Description Crick African Network 
Organisation University of Cape Town
Country South Africa 
Sector Academic/University 
PI Contribution Crick is the lead and co-ordinating partner on this £6.3 million GCRF award
Collaborator Contribution They have helped us convene workshops and scientific symposia and contributed to management
Impact 4 workshops and scientific symposia
Start Year 2017
 
Description Crick African Network 
Organisation University of Ghana
Country Ghana 
Sector Academic/University 
PI Contribution Crick is the lead and co-ordinating partner on this £6.3 million GCRF award
Collaborator Contribution They have helped us convene workshops and scientific symposia and contributed to management
Impact 4 workshops and scientific symposia
Start Year 2017
 
Description Crick African Network 
Organisation University of Stellenbosch
Country South Africa 
Sector Academic/University 
PI Contribution Crick is the lead and co-ordinating partner on this £6.3 million GCRF award
Collaborator Contribution They have helped us convene workshops and scientific symposia and contributed to management
Impact 4 workshops and scientific symposia
Start Year 2017
 
Description HIV co-infections IRSES 
Organisation Institute of Tropical Medicine Antwerp
Country Belgium 
Sector Academic/University 
PI Contribution This is a Marie Curie International Research staff exchange scheme award that will allow us to exchange staff with the University of Cape Town and the INstitute for Tropical Medicine in Antwerp
Collaborator Contribution The Institute of tropical medicine at the University of Antwerp was the co-ordinator of this project
Impact Mutiple: please refer to publications.
Start Year 2011
 
Description ILULU: Diagnostics for tuberculosis 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We administer a field site and provide RNA and serum samples from well-charactersied tuberculosis patients
Collaborator Contribution An MD student is registered at ImperialSeveral network meetings that have been informativeSeveral network meetings and proposed extension of collaboration in Malawi Anderson, S.T.B., Kaforou, M., Brent, A., Wright, V.J., Banwell, C.M., Chagaluka, G., Crampin, A.C., Dockrell, H.M., French, N., Hamilton, M.S., Hibberd, M.L., Kern, F., Langford, P.R., Ling, L., Mlotha, R., Ottenhoff, T.H.M., Pienaar, S., Pillay, V., Scott, J.A.G, Twahir, H., Wilkinson, R.J., Coin, L.J., Heyderman, R.S., Levin, M., Eley, B. Diagnosis of childhood tuberculosis and host RNA expression in Africa New England Journal of Medicine (2014) 370:1712-23 PMID 24785206 PMCID: PMC4069985 Kaforou, M., Wright, V.J., Oni, T., French, N., Anderson, S.T.B., Bangani, N., Banwell, C.M., Brent, A.J., Crampin, A.C., Dockrell, H.M., Eley, B., Heyderman, R.S., Hibberd, M.L., Kern, F., Langford, P.R., Ling, L., Mendelson, M., Ottenhoff, T.H.M., Zgambo, F., Wilkinson, R.J., Coin, L.J., Levin, M. Detection of tuberculosis in HIV-infected and -uninfected African adults using whole blood RNA expression signatures: a case-control study PLOS Medicine (2013) 10(10): e1001538 PMID 24167453 PMCID3805485
Impact A very large well characterised biobank of samples that will be invaluable for future diagnostic evaluations. A patent is pending.
Start Year 2007
 
Description ILULU: Diagnostics for tuberculosis 
Organisation Liverpool School of Tropical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We administer a field site and provide RNA and serum samples from well-charactersied tuberculosis patients
Collaborator Contribution An MD student is registered at ImperialSeveral network meetings that have been informativeSeveral network meetings and proposed extension of collaboration in Malawi Anderson, S.T.B., Kaforou, M., Brent, A., Wright, V.J., Banwell, C.M., Chagaluka, G., Crampin, A.C., Dockrell, H.M., French, N., Hamilton, M.S., Hibberd, M.L., Kern, F., Langford, P.R., Ling, L., Mlotha, R., Ottenhoff, T.H.M., Pienaar, S., Pillay, V., Scott, J.A.G, Twahir, H., Wilkinson, R.J., Coin, L.J., Heyderman, R.S., Levin, M., Eley, B. Diagnosis of childhood tuberculosis and host RNA expression in Africa New England Journal of Medicine (2014) 370:1712-23 PMID 24785206 PMCID: PMC4069985 Kaforou, M., Wright, V.J., Oni, T., French, N., Anderson, S.T.B., Bangani, N., Banwell, C.M., Brent, A.J., Crampin, A.C., Dockrell, H.M., Eley, B., Heyderman, R.S., Hibberd, M.L., Kern, F., Langford, P.R., Ling, L., Mendelson, M., Ottenhoff, T.H.M., Zgambo, F., Wilkinson, R.J., Coin, L.J., Levin, M. Detection of tuberculosis in HIV-infected and -uninfected African adults using whole blood RNA expression signatures: a case-control study PLOS Medicine (2013) 10(10): e1001538 PMID 24167453 PMCID3805485
Impact A very large well characterised biobank of samples that will be invaluable for future diagnostic evaluations. A patent is pending.
Start Year 2007
 
Description ILULU: Diagnostics for tuberculosis 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Country United Kingdom 
Sector Academic/University 
PI Contribution We administer a field site and provide RNA and serum samples from well-charactersied tuberculosis patients
Collaborator Contribution An MD student is registered at ImperialSeveral network meetings that have been informativeSeveral network meetings and proposed extension of collaboration in Malawi Anderson, S.T.B., Kaforou, M., Brent, A., Wright, V.J., Banwell, C.M., Chagaluka, G., Crampin, A.C., Dockrell, H.M., French, N., Hamilton, M.S., Hibberd, M.L., Kern, F., Langford, P.R., Ling, L., Mlotha, R., Ottenhoff, T.H.M., Pienaar, S., Pillay, V., Scott, J.A.G, Twahir, H., Wilkinson, R.J., Coin, L.J., Heyderman, R.S., Levin, M., Eley, B. Diagnosis of childhood tuberculosis and host RNA expression in Africa New England Journal of Medicine (2014) 370:1712-23 PMID 24785206 PMCID: PMC4069985 Kaforou, M., Wright, V.J., Oni, T., French, N., Anderson, S.T.B., Bangani, N., Banwell, C.M., Brent, A.J., Crampin, A.C., Dockrell, H.M., Eley, B., Heyderman, R.S., Hibberd, M.L., Kern, F., Langford, P.R., Ling, L., Mendelson, M., Ottenhoff, T.H.M., Zgambo, F., Wilkinson, R.J., Coin, L.J., Levin, M. Detection of tuberculosis in HIV-infected and -uninfected African adults using whole blood RNA expression signatures: a case-control study PLOS Medicine (2013) 10(10): e1001538 PMID 24167453 PMCID3805485
Impact A very large well characterised biobank of samples that will be invaluable for future diagnostic evaluations. A patent is pending.
Start Year 2007
 
Description ILULU: Diagnostics for tuberculosis 
Organisation University of Sussex
Department Brighton and Sussex Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution We administer a field site and provide RNA and serum samples from well-charactersied tuberculosis patients
Collaborator Contribution An MD student is registered at ImperialSeveral network meetings that have been informativeSeveral network meetings and proposed extension of collaboration in Malawi Anderson, S.T.B., Kaforou, M., Brent, A., Wright, V.J., Banwell, C.M., Chagaluka, G., Crampin, A.C., Dockrell, H.M., French, N., Hamilton, M.S., Hibberd, M.L., Kern, F., Langford, P.R., Ling, L., Mlotha, R., Ottenhoff, T.H.M., Pienaar, S., Pillay, V., Scott, J.A.G, Twahir, H., Wilkinson, R.J., Coin, L.J., Heyderman, R.S., Levin, M., Eley, B. Diagnosis of childhood tuberculosis and host RNA expression in Africa New England Journal of Medicine (2014) 370:1712-23 PMID 24785206 PMCID: PMC4069985 Kaforou, M., Wright, V.J., Oni, T., French, N., Anderson, S.T.B., Bangani, N., Banwell, C.M., Brent, A.J., Crampin, A.C., Dockrell, H.M., Eley, B., Heyderman, R.S., Hibberd, M.L., Kern, F., Langford, P.R., Ling, L., Mendelson, M., Ottenhoff, T.H.M., Zgambo, F., Wilkinson, R.J., Coin, L.J., Levin, M. Detection of tuberculosis in HIV-infected and -uninfected African adults using whole blood RNA expression signatures: a case-control study PLOS Medicine (2013) 10(10): e1001538 PMID 24167453 PMCID3805485
Impact A very large well characterised biobank of samples that will be invaluable for future diagnostic evaluations. A patent is pending.
Start Year 2007
 
Description ILULU: Diagnostics for tuberculosis 
Organisation Wellcome Trust
Department Malawi-Liverpool Wellcome Trust Clinical Research Programme
Country Malawi 
Sector Charity/Non Profit 
PI Contribution We administer a field site and provide RNA and serum samples from well-charactersied tuberculosis patients
Collaborator Contribution An MD student is registered at ImperialSeveral network meetings that have been informativeSeveral network meetings and proposed extension of collaboration in Malawi Anderson, S.T.B., Kaforou, M., Brent, A., Wright, V.J., Banwell, C.M., Chagaluka, G., Crampin, A.C., Dockrell, H.M., French, N., Hamilton, M.S., Hibberd, M.L., Kern, F., Langford, P.R., Ling, L., Mlotha, R., Ottenhoff, T.H.M., Pienaar, S., Pillay, V., Scott, J.A.G, Twahir, H., Wilkinson, R.J., Coin, L.J., Heyderman, R.S., Levin, M., Eley, B. Diagnosis of childhood tuberculosis and host RNA expression in Africa New England Journal of Medicine (2014) 370:1712-23 PMID 24785206 PMCID: PMC4069985 Kaforou, M., Wright, V.J., Oni, T., French, N., Anderson, S.T.B., Bangani, N., Banwell, C.M., Brent, A.J., Crampin, A.C., Dockrell, H.M., Eley, B., Heyderman, R.S., Hibberd, M.L., Kern, F., Langford, P.R., Ling, L., Mendelson, M., Ottenhoff, T.H.M., Zgambo, F., Wilkinson, R.J., Coin, L.J., Levin, M. Detection of tuberculosis in HIV-infected and -uninfected African adults using whole blood RNA expression signatures: a case-control study PLOS Medicine (2013) 10(10): e1001538 PMID 24167453 PMCID3805485
Impact A very large well characterised biobank of samples that will be invaluable for future diagnostic evaluations. A patent is pending.
Start Year 2007
 
Description Intense-TBM 
Organisation August Pi i Sunyer Biomedical Research Institute
Country Spain 
Sector Academic/University 
PI Contribution Mortality due to Tuberculous meningitis (TBM) reaches 30% in HIV-negative and up to 70% in HIV-positive individuals with drug resistant TB strains, with death occurring most frequently in the first 2 weeks after diagnosis. Amongst TBM survivors, 50% are disabled due to neurological sequelae. Treatment of TBM has remained unchanged for decades despite this high level of mortality. INTENSE-TBM aims to improve the prognosis of TBM in patients with or without HIV co-infection in sub- Saharan Africa by reducing TBM mortality and neurological sequelae as well as improving the clinical management of TBM-HIV co-infection. For this purpose, INTENSE-TBM will carry out a multicentre randomised controlled trial in 4 Sub-Saharan African countries (Madagascar, Ivory Coast, Uganda and South Africa). Patients with suspected TBM will be randomised 1:1:1:1 to standard WHO TBM therapy, versus an intensified treatment (INTENSE-TBM programme), and into aspirin versus placebo therapy in a factorial design. The intensified TBM programme will consist of: i) First 5-7 days: high dose intravenous (IV) rifampicin 20 mg/kg/d, IV linezolid 1200 mg/d, IV isoniazid 5 mg/kg/d, pyrazinamide 30 mg/kg/d and corticosteroids. ii) Up until 2 month (oral): rifampicin 35 mg/kg/d, linezolid 1200 mg/d, isoniazid, pyrazinamide, and corticosteroids. iii) Seven months: isoniazid 5 mg/kg/d and rifampicin 10 mg/kg/d Patients will also be randomised to receive either aspirin 150 mg per day or placebo for the first two months of treatment. If superiority of this experimental arm is demonstrated in terms of reduced mortality, INTENSE-TBM will become the first Phase III study to demonstrate survival benefit from intensified TBM treatment. HIV co-infected patients will start a generic formulation of tenofovir, lamivudine, and dolutegravir four weeks after TBM treatment initiation, and continue with dexamethasone for at least the first four weeks of antiretroviral treatment. Incidence and risk-factors for severe immune reconstitution inflammatory syndrome will be determined and the pharmacokinetics of the drug-drug interactions between standard and high dose rifampicin with dolutegravir analysed. INTENSE-TBM responds directly to the call by evaluating (i) the impact of an optimized drug regimen for TBM on mortality including high dose rifampicin and linezolid, a repurposed drug for the treatment of TBM, (ii) the impact of the addition of aspirin on TBM mortality, a drug that has not previously been authorised for use against any infectious disease (iii) an antiretroviral therapy strategy in TBM patient co-infected with HIV to specifically assess the risk of severe IRIS, and to study drug-drug interactions.
Collaborator Contribution INTENSE-TBM is a multidisciplinary international research project involving four Sub-Saharan countries around a large randomized controlled Phase III trial. The project has been structured within eight highly-interactive work packages (WP) each with a Sub-Saharan African lead or co-lead to ensure optimal implementation of all activities from project and trial coordination, to pre- and post-trial capacity building, to nested studies and of utmost importance, disseminating and exploiting results amongst all stakeholders. WP1 Project Coordination and Management will ensure that all project objectives are achieved according to the project workplan and within budget limits, and that all activities are implemented in conformity with the EDCTP contract and the consortium agreement. WP1 will interact closely with WP3 for all aspects of trial management. WP1 is led by Fabrice Bonnet at the University of Bordeaux (UBx) and supported by co-leader X. Anglaret (methodologist) a trial manager at the Mereva clinical trial unit (CTU) a joint structure of INSERM U1219 and PACCI, Ivory Coast. WP2 Capacity Building will ensure that all the participating clinical centres have the capacity (equipment, skills, know-how) to carry out the INTENSE-TBM trial as well as developing a long-term network of skilled clinical researchers, centres and microbiology laboratories in the Sub-Saharan countries beyond the duration of the current project to facilitate both roll-out of the trial regimen as well as capacity to carry out further clinical trials in PRDs. WP2 will interact with WP4 in preparing and rolling out the clinical training and with WP8 for developing the capacity and skills of medical staff outside the scope of the trial. This WP is led by IDIPABS (Barcelona) in close coordination with Pasteur Institute of Madagascar as regards lab implementation and evaluation and with UNIGE for training of PI (Principal Investigator) of each country and 'GCP local trainers' as well as infection control training of teams. WP3 Trial management, monitoring and analysis will provide the methodological support to the INTENSE-TBM clinical trial which will be implemented in WP4. WP3 will ensure that the trial is well designed, developed, conducted, managed, monitored and analysed according to international standards. This includes regulatory and ethics management as well as overseeing all aspects of trial implementation notably monitoring activities and quality control. WP3 will furthermore integrate all data from the trial (WP4) and associated studies (WP5, 6 & 7) and provide data analyses to the WPs to draw conclusions on the efficacy of the INTENSE-TBM regimen and potential for wide-scale roll out. This WP is led by PACCI, (an ANRS site), directed by Pr S. Eholié supported by ANRS (C Rekacewicz) as the trial sponsor. This organization and leadership has been proved to be efficient in previous international trials in the field of HIV and tuberculosis in Africa under the sponsorship of ANRS. WP4 Clinical Trial implementation will ensure the timely and efficient implementation of the randomized clinical trial closely monitored by WP3 in order to ensure that patients receive the best available care. Procedures and guidelines for clinical management of patients participating in the trial (covering the trial and sub studies WP5- 7) will be developed and implemented at all participating centres so as to ensure optimum patient safety and harmonization of data. This WP is led by M. Bonnet (IRD) and A. Calmy (UNIGE), clinician-researcher experimented in the leading and the management of controlled trials in the field of HIV and tuberculosis. WP5 Management of patients with HIV-TBM coinfection will ensure the appropriate management of HIV-TBM co-infected patients within the INTENSE-TBM trial and will carry out a sub study to deepen our understanding regarding prediction of Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) and its etiology including investigating the potential role of Xpert Ultra as a prediction tool for the development of IRIS. Diagnostic and management protocols (SOPs) for safe and effective management of patients with HIV-1 infection included within the study will be developed in collaboration with WP4. The regulatory aspects of this study will be dealt with in WP3 as well as the data analysis. WP5 is led by G Meintjes (UCT) and C Muzoora (MUST) who are opinion leaders in the field of HIV-TB coinfection and TB-IRIS. WP6 M. Tuberculosis diagnosis, resistance, and PK studies will carry out Mycobacterium tuberculosis diagnosis and resistance testing as well as perform pharmacokinetics studies of anti-TB drugs and antiretroviral drugs. The INTENSE-TBM project raises numerous questions regarding the issue of pharmacological interactions. IDIBAPS (Barcelona), through reference pharmacological laboratory will be able to provide new insights in short time regarding drug-drug interactions between rifampicin high-dose and other antitubercular drugs and DTG. IDIPAPS and Pasteur Institute will lead this work as they are both highly experimented in the field of TB resistance and able to describe the impact of high-dose rifampicin and linezolid on M tuberculosis . WP7 Neurological complications and disability will provide a comprehensive assessment of the clinical, neurological and sensorial complications of TBM as well as the impact of INTENSE-TBM treatment as regards these complications. Little is known on the reversibility of these complications with time and since we hypothesize that the use of aspirin, in addition to antitubercular treatment will reduce neurological sequalae and disability, clinical endpoints used to assess treatment effectiveness will be complemented with patient-centered measures of activities limitation (functioning), of quality of life (QoL) and of disability to provide a comprehensive picture of patients' situations and needs. This WP is led by P. Debeaudrap (IRD) who has already managed previous studies on disability in Sub-Saharan Africa and A Davis, neurologist from UCT. Implementation of neurologic evaluation and training of medical staff will be provided by WP2/4 and regulatory management and analysis will be performed by WP3. WP8 Dissemination and exploitation will ensure that the expected impacts of INTENSE-TBM are achieved by minimizing any potential barriers through an ambitious dissemination and communication programme. WP8 will interact closely with WP2 for all training and capacity building aspects and with WP3 for disseminating trial results as they become available. This WP is led by UBx and UCT in close collaboration with all participants and institutions.
Impact None so far
Start Year 2019
 
Description Intense-TBM 
Organisation French National Agency for Research on AIDS and Viral Hepatitis (ANRS)
Country France 
Sector Public 
PI Contribution Mortality due to Tuberculous meningitis (TBM) reaches 30% in HIV-negative and up to 70% in HIV-positive individuals with drug resistant TB strains, with death occurring most frequently in the first 2 weeks after diagnosis. Amongst TBM survivors, 50% are disabled due to neurological sequelae. Treatment of TBM has remained unchanged for decades despite this high level of mortality. INTENSE-TBM aims to improve the prognosis of TBM in patients with or without HIV co-infection in sub- Saharan Africa by reducing TBM mortality and neurological sequelae as well as improving the clinical management of TBM-HIV co-infection. For this purpose, INTENSE-TBM will carry out a multicentre randomised controlled trial in 4 Sub-Saharan African countries (Madagascar, Ivory Coast, Uganda and South Africa). Patients with suspected TBM will be randomised 1:1:1:1 to standard WHO TBM therapy, versus an intensified treatment (INTENSE-TBM programme), and into aspirin versus placebo therapy in a factorial design. The intensified TBM programme will consist of: i) First 5-7 days: high dose intravenous (IV) rifampicin 20 mg/kg/d, IV linezolid 1200 mg/d, IV isoniazid 5 mg/kg/d, pyrazinamide 30 mg/kg/d and corticosteroids. ii) Up until 2 month (oral): rifampicin 35 mg/kg/d, linezolid 1200 mg/d, isoniazid, pyrazinamide, and corticosteroids. iii) Seven months: isoniazid 5 mg/kg/d and rifampicin 10 mg/kg/d Patients will also be randomised to receive either aspirin 150 mg per day or placebo for the first two months of treatment. If superiority of this experimental arm is demonstrated in terms of reduced mortality, INTENSE-TBM will become the first Phase III study to demonstrate survival benefit from intensified TBM treatment. HIV co-infected patients will start a generic formulation of tenofovir, lamivudine, and dolutegravir four weeks after TBM treatment initiation, and continue with dexamethasone for at least the first four weeks of antiretroviral treatment. Incidence and risk-factors for severe immune reconstitution inflammatory syndrome will be determined and the pharmacokinetics of the drug-drug interactions between standard and high dose rifampicin with dolutegravir analysed. INTENSE-TBM responds directly to the call by evaluating (i) the impact of an optimized drug regimen for TBM on mortality including high dose rifampicin and linezolid, a repurposed drug for the treatment of TBM, (ii) the impact of the addition of aspirin on TBM mortality, a drug that has not previously been authorised for use against any infectious disease (iii) an antiretroviral therapy strategy in TBM patient co-infected with HIV to specifically assess the risk of severe IRIS, and to study drug-drug interactions.
Collaborator Contribution INTENSE-TBM is a multidisciplinary international research project involving four Sub-Saharan countries around a large randomized controlled Phase III trial. The project has been structured within eight highly-interactive work packages (WP) each with a Sub-Saharan African lead or co-lead to ensure optimal implementation of all activities from project and trial coordination, to pre- and post-trial capacity building, to nested studies and of utmost importance, disseminating and exploiting results amongst all stakeholders. WP1 Project Coordination and Management will ensure that all project objectives are achieved according to the project workplan and within budget limits, and that all activities are implemented in conformity with the EDCTP contract and the consortium agreement. WP1 will interact closely with WP3 for all aspects of trial management. WP1 is led by Fabrice Bonnet at the University of Bordeaux (UBx) and supported by co-leader X. Anglaret (methodologist) a trial manager at the Mereva clinical trial unit (CTU) a joint structure of INSERM U1219 and PACCI, Ivory Coast. WP2 Capacity Building will ensure that all the participating clinical centres have the capacity (equipment, skills, know-how) to carry out the INTENSE-TBM trial as well as developing a long-term network of skilled clinical researchers, centres and microbiology laboratories in the Sub-Saharan countries beyond the duration of the current project to facilitate both roll-out of the trial regimen as well as capacity to carry out further clinical trials in PRDs. WP2 will interact with WP4 in preparing and rolling out the clinical training and with WP8 for developing the capacity and skills of medical staff outside the scope of the trial. This WP is led by IDIPABS (Barcelona) in close coordination with Pasteur Institute of Madagascar as regards lab implementation and evaluation and with UNIGE for training of PI (Principal Investigator) of each country and 'GCP local trainers' as well as infection control training of teams. WP3 Trial management, monitoring and analysis will provide the methodological support to the INTENSE-TBM clinical trial which will be implemented in WP4. WP3 will ensure that the trial is well designed, developed, conducted, managed, monitored and analysed according to international standards. This includes regulatory and ethics management as well as overseeing all aspects of trial implementation notably monitoring activities and quality control. WP3 will furthermore integrate all data from the trial (WP4) and associated studies (WP5, 6 & 7) and provide data analyses to the WPs to draw conclusions on the efficacy of the INTENSE-TBM regimen and potential for wide-scale roll out. This WP is led by PACCI, (an ANRS site), directed by Pr S. Eholié supported by ANRS (C Rekacewicz) as the trial sponsor. This organization and leadership has been proved to be efficient in previous international trials in the field of HIV and tuberculosis in Africa under the sponsorship of ANRS. WP4 Clinical Trial implementation will ensure the timely and efficient implementation of the randomized clinical trial closely monitored by WP3 in order to ensure that patients receive the best available care. Procedures and guidelines for clinical management of patients participating in the trial (covering the trial and sub studies WP5- 7) will be developed and implemented at all participating centres so as to ensure optimum patient safety and harmonization of data. This WP is led by M. Bonnet (IRD) and A. Calmy (UNIGE), clinician-researcher experimented in the leading and the management of controlled trials in the field of HIV and tuberculosis. WP5 Management of patients with HIV-TBM coinfection will ensure the appropriate management of HIV-TBM co-infected patients within the INTENSE-TBM trial and will carry out a sub study to deepen our understanding regarding prediction of Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) and its etiology including investigating the potential role of Xpert Ultra as a prediction tool for the development of IRIS. Diagnostic and management protocols (SOPs) for safe and effective management of patients with HIV-1 infection included within the study will be developed in collaboration with WP4. The regulatory aspects of this study will be dealt with in WP3 as well as the data analysis. WP5 is led by G Meintjes (UCT) and C Muzoora (MUST) who are opinion leaders in the field of HIV-TB coinfection and TB-IRIS. WP6 M. Tuberculosis diagnosis, resistance, and PK studies will carry out Mycobacterium tuberculosis diagnosis and resistance testing as well as perform pharmacokinetics studies of anti-TB drugs and antiretroviral drugs. The INTENSE-TBM project raises numerous questions regarding the issue of pharmacological interactions. IDIBAPS (Barcelona), through reference pharmacological laboratory will be able to provide new insights in short time regarding drug-drug interactions between rifampicin high-dose and other antitubercular drugs and DTG. IDIPAPS and Pasteur Institute will lead this work as they are both highly experimented in the field of TB resistance and able to describe the impact of high-dose rifampicin and linezolid on M tuberculosis . WP7 Neurological complications and disability will provide a comprehensive assessment of the clinical, neurological and sensorial complications of TBM as well as the impact of INTENSE-TBM treatment as regards these complications. Little is known on the reversibility of these complications with time and since we hypothesize that the use of aspirin, in addition to antitubercular treatment will reduce neurological sequalae and disability, clinical endpoints used to assess treatment effectiveness will be complemented with patient-centered measures of activities limitation (functioning), of quality of life (QoL) and of disability to provide a comprehensive picture of patients' situations and needs. This WP is led by P. Debeaudrap (IRD) who has already managed previous studies on disability in Sub-Saharan Africa and A Davis, neurologist from UCT. Implementation of neurologic evaluation and training of medical staff will be provided by WP2/4 and regulatory management and analysis will be performed by WP3. WP8 Dissemination and exploitation will ensure that the expected impacts of INTENSE-TBM are achieved by minimizing any potential barriers through an ambitious dissemination and communication programme. WP8 will interact closely with WP2 for all training and capacity building aspects and with WP3 for disseminating trial results as they become available. This WP is led by UBx and UCT in close collaboration with all participants and institutions.
Impact None so far
Start Year 2019
 
Description Intense-TBM 
Organisation Institute of Development Research (IRD)
Department IRD Centre de Montpelier
Country France 
Sector Charity/Non Profit 
PI Contribution Mortality due to Tuberculous meningitis (TBM) reaches 30% in HIV-negative and up to 70% in HIV-positive individuals with drug resistant TB strains, with death occurring most frequently in the first 2 weeks after diagnosis. Amongst TBM survivors, 50% are disabled due to neurological sequelae. Treatment of TBM has remained unchanged for decades despite this high level of mortality. INTENSE-TBM aims to improve the prognosis of TBM in patients with or without HIV co-infection in sub- Saharan Africa by reducing TBM mortality and neurological sequelae as well as improving the clinical management of TBM-HIV co-infection. For this purpose, INTENSE-TBM will carry out a multicentre randomised controlled trial in 4 Sub-Saharan African countries (Madagascar, Ivory Coast, Uganda and South Africa). Patients with suspected TBM will be randomised 1:1:1:1 to standard WHO TBM therapy, versus an intensified treatment (INTENSE-TBM programme), and into aspirin versus placebo therapy in a factorial design. The intensified TBM programme will consist of: i) First 5-7 days: high dose intravenous (IV) rifampicin 20 mg/kg/d, IV linezolid 1200 mg/d, IV isoniazid 5 mg/kg/d, pyrazinamide 30 mg/kg/d and corticosteroids. ii) Up until 2 month (oral): rifampicin 35 mg/kg/d, linezolid 1200 mg/d, isoniazid, pyrazinamide, and corticosteroids. iii) Seven months: isoniazid 5 mg/kg/d and rifampicin 10 mg/kg/d Patients will also be randomised to receive either aspirin 150 mg per day or placebo for the first two months of treatment. If superiority of this experimental arm is demonstrated in terms of reduced mortality, INTENSE-TBM will become the first Phase III study to demonstrate survival benefit from intensified TBM treatment. HIV co-infected patients will start a generic formulation of tenofovir, lamivudine, and dolutegravir four weeks after TBM treatment initiation, and continue with dexamethasone for at least the first four weeks of antiretroviral treatment. Incidence and risk-factors for severe immune reconstitution inflammatory syndrome will be determined and the pharmacokinetics of the drug-drug interactions between standard and high dose rifampicin with dolutegravir analysed. INTENSE-TBM responds directly to the call by evaluating (i) the impact of an optimized drug regimen for TBM on mortality including high dose rifampicin and linezolid, a repurposed drug for the treatment of TBM, (ii) the impact of the addition of aspirin on TBM mortality, a drug that has not previously been authorised for use against any infectious disease (iii) an antiretroviral therapy strategy in TBM patient co-infected with HIV to specifically assess the risk of severe IRIS, and to study drug-drug interactions.
Collaborator Contribution INTENSE-TBM is a multidisciplinary international research project involving four Sub-Saharan countries around a large randomized controlled Phase III trial. The project has been structured within eight highly-interactive work packages (WP) each with a Sub-Saharan African lead or co-lead to ensure optimal implementation of all activities from project and trial coordination, to pre- and post-trial capacity building, to nested studies and of utmost importance, disseminating and exploiting results amongst all stakeholders. WP1 Project Coordination and Management will ensure that all project objectives are achieved according to the project workplan and within budget limits, and that all activities are implemented in conformity with the EDCTP contract and the consortium agreement. WP1 will interact closely with WP3 for all aspects of trial management. WP1 is led by Fabrice Bonnet at the University of Bordeaux (UBx) and supported by co-leader X. Anglaret (methodologist) a trial manager at the Mereva clinical trial unit (CTU) a joint structure of INSERM U1219 and PACCI, Ivory Coast. WP2 Capacity Building will ensure that all the participating clinical centres have the capacity (equipment, skills, know-how) to carry out the INTENSE-TBM trial as well as developing a long-term network of skilled clinical researchers, centres and microbiology laboratories in the Sub-Saharan countries beyond the duration of the current project to facilitate both roll-out of the trial regimen as well as capacity to carry out further clinical trials in PRDs. WP2 will interact with WP4 in preparing and rolling out the clinical training and with WP8 for developing the capacity and skills of medical staff outside the scope of the trial. This WP is led by IDIPABS (Barcelona) in close coordination with Pasteur Institute of Madagascar as regards lab implementation and evaluation and with UNIGE for training of PI (Principal Investigator) of each country and 'GCP local trainers' as well as infection control training of teams. WP3 Trial management, monitoring and analysis will provide the methodological support to the INTENSE-TBM clinical trial which will be implemented in WP4. WP3 will ensure that the trial is well designed, developed, conducted, managed, monitored and analysed according to international standards. This includes regulatory and ethics management as well as overseeing all aspects of trial implementation notably monitoring activities and quality control. WP3 will furthermore integrate all data from the trial (WP4) and associated studies (WP5, 6 & 7) and provide data analyses to the WPs to draw conclusions on the efficacy of the INTENSE-TBM regimen and potential for wide-scale roll out. This WP is led by PACCI, (an ANRS site), directed by Pr S. Eholié supported by ANRS (C Rekacewicz) as the trial sponsor. This organization and leadership has been proved to be efficient in previous international trials in the field of HIV and tuberculosis in Africa under the sponsorship of ANRS. WP4 Clinical Trial implementation will ensure the timely and efficient implementation of the randomized clinical trial closely monitored by WP3 in order to ensure that patients receive the best available care. Procedures and guidelines for clinical management of patients participating in the trial (covering the trial and sub studies WP5- 7) will be developed and implemented at all participating centres so as to ensure optimum patient safety and harmonization of data. This WP is led by M. Bonnet (IRD) and A. Calmy (UNIGE), clinician-researcher experimented in the leading and the management of controlled trials in the field of HIV and tuberculosis. WP5 Management of patients with HIV-TBM coinfection will ensure the appropriate management of HIV-TBM co-infected patients within the INTENSE-TBM trial and will carry out a sub study to deepen our understanding regarding prediction of Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) and its etiology including investigating the potential role of Xpert Ultra as a prediction tool for the development of IRIS. Diagnostic and management protocols (SOPs) for safe and effective management of patients with HIV-1 infection included within the study will be developed in collaboration with WP4. The regulatory aspects of this study will be dealt with in WP3 as well as the data analysis. WP5 is led by G Meintjes (UCT) and C Muzoora (MUST) who are opinion leaders in the field of HIV-TB coinfection and TB-IRIS. WP6 M. Tuberculosis diagnosis, resistance, and PK studies will carry out Mycobacterium tuberculosis diagnosis and resistance testing as well as perform pharmacokinetics studies of anti-TB drugs and antiretroviral drugs. The INTENSE-TBM project raises numerous questions regarding the issue of pharmacological interactions. IDIBAPS (Barcelona), through reference pharmacological laboratory will be able to provide new insights in short time regarding drug-drug interactions between rifampicin high-dose and other antitubercular drugs and DTG. IDIPAPS and Pasteur Institute will lead this work as they are both highly experimented in the field of TB resistance and able to describe the impact of high-dose rifampicin and linezolid on M tuberculosis . WP7 Neurological complications and disability will provide a comprehensive assessment of the clinical, neurological and sensorial complications of TBM as well as the impact of INTENSE-TBM treatment as regards these complications. Little is known on the reversibility of these complications with time and since we hypothesize that the use of aspirin, in addition to antitubercular treatment will reduce neurological sequalae and disability, clinical endpoints used to assess treatment effectiveness will be complemented with patient-centered measures of activities limitation (functioning), of quality of life (QoL) and of disability to provide a comprehensive picture of patients' situations and needs. This WP is led by P. Debeaudrap (IRD) who has already managed previous studies on disability in Sub-Saharan Africa and A Davis, neurologist from UCT. Implementation of neurologic evaluation and training of medical staff will be provided by WP2/4 and regulatory management and analysis will be performed by WP3. WP8 Dissemination and exploitation will ensure that the expected impacts of INTENSE-TBM are achieved by minimizing any potential barriers through an ambitious dissemination and communication programme. WP8 will interact closely with WP2 for all training and capacity building aspects and with WP3 for disseminating trial results as they become available. This WP is led by UBx and UCT in close collaboration with all participants and institutions.
Impact None so far
Start Year 2019
 
Description Intense-TBM 
Organisation Médecins Sans Frontières (MSF)
Department Epicentre - Médecins Sans Frontières (MSF Epicentre)
Country France 
Sector Charity/Non Profit 
PI Contribution Mortality due to Tuberculous meningitis (TBM) reaches 30% in HIV-negative and up to 70% in HIV-positive individuals with drug resistant TB strains, with death occurring most frequently in the first 2 weeks after diagnosis. Amongst TBM survivors, 50% are disabled due to neurological sequelae. Treatment of TBM has remained unchanged for decades despite this high level of mortality. INTENSE-TBM aims to improve the prognosis of TBM in patients with or without HIV co-infection in sub- Saharan Africa by reducing TBM mortality and neurological sequelae as well as improving the clinical management of TBM-HIV co-infection. For this purpose, INTENSE-TBM will carry out a multicentre randomised controlled trial in 4 Sub-Saharan African countries (Madagascar, Ivory Coast, Uganda and South Africa). Patients with suspected TBM will be randomised 1:1:1:1 to standard WHO TBM therapy, versus an intensified treatment (INTENSE-TBM programme), and into aspirin versus placebo therapy in a factorial design. The intensified TBM programme will consist of: i) First 5-7 days: high dose intravenous (IV) rifampicin 20 mg/kg/d, IV linezolid 1200 mg/d, IV isoniazid 5 mg/kg/d, pyrazinamide 30 mg/kg/d and corticosteroids. ii) Up until 2 month (oral): rifampicin 35 mg/kg/d, linezolid 1200 mg/d, isoniazid, pyrazinamide, and corticosteroids. iii) Seven months: isoniazid 5 mg/kg/d and rifampicin 10 mg/kg/d Patients will also be randomised to receive either aspirin 150 mg per day or placebo for the first two months of treatment. If superiority of this experimental arm is demonstrated in terms of reduced mortality, INTENSE-TBM will become the first Phase III study to demonstrate survival benefit from intensified TBM treatment. HIV co-infected patients will start a generic formulation of tenofovir, lamivudine, and dolutegravir four weeks after TBM treatment initiation, and continue with dexamethasone for at least the first four weeks of antiretroviral treatment. Incidence and risk-factors for severe immune reconstitution inflammatory syndrome will be determined and the pharmacokinetics of the drug-drug interactions between standard and high dose rifampicin with dolutegravir analysed. INTENSE-TBM responds directly to the call by evaluating (i) the impact of an optimized drug regimen for TBM on mortality including high dose rifampicin and linezolid, a repurposed drug for the treatment of TBM, (ii) the impact of the addition of aspirin on TBM mortality, a drug that has not previously been authorised for use against any infectious disease (iii) an antiretroviral therapy strategy in TBM patient co-infected with HIV to specifically assess the risk of severe IRIS, and to study drug-drug interactions.
Collaborator Contribution INTENSE-TBM is a multidisciplinary international research project involving four Sub-Saharan countries around a large randomized controlled Phase III trial. The project has been structured within eight highly-interactive work packages (WP) each with a Sub-Saharan African lead or co-lead to ensure optimal implementation of all activities from project and trial coordination, to pre- and post-trial capacity building, to nested studies and of utmost importance, disseminating and exploiting results amongst all stakeholders. WP1 Project Coordination and Management will ensure that all project objectives are achieved according to the project workplan and within budget limits, and that all activities are implemented in conformity with the EDCTP contract and the consortium agreement. WP1 will interact closely with WP3 for all aspects of trial management. WP1 is led by Fabrice Bonnet at the University of Bordeaux (UBx) and supported by co-leader X. Anglaret (methodologist) a trial manager at the Mereva clinical trial unit (CTU) a joint structure of INSERM U1219 and PACCI, Ivory Coast. WP2 Capacity Building will ensure that all the participating clinical centres have the capacity (equipment, skills, know-how) to carry out the INTENSE-TBM trial as well as developing a long-term network of skilled clinical researchers, centres and microbiology laboratories in the Sub-Saharan countries beyond the duration of the current project to facilitate both roll-out of the trial regimen as well as capacity to carry out further clinical trials in PRDs. WP2 will interact with WP4 in preparing and rolling out the clinical training and with WP8 for developing the capacity and skills of medical staff outside the scope of the trial. This WP is led by IDIPABS (Barcelona) in close coordination with Pasteur Institute of Madagascar as regards lab implementation and evaluation and with UNIGE for training of PI (Principal Investigator) of each country and 'GCP local trainers' as well as infection control training of teams. WP3 Trial management, monitoring and analysis will provide the methodological support to the INTENSE-TBM clinical trial which will be implemented in WP4. WP3 will ensure that the trial is well designed, developed, conducted, managed, monitored and analysed according to international standards. This includes regulatory and ethics management as well as overseeing all aspects of trial implementation notably monitoring activities and quality control. WP3 will furthermore integrate all data from the trial (WP4) and associated studies (WP5, 6 & 7) and provide data analyses to the WPs to draw conclusions on the efficacy of the INTENSE-TBM regimen and potential for wide-scale roll out. This WP is led by PACCI, (an ANRS site), directed by Pr S. Eholié supported by ANRS (C Rekacewicz) as the trial sponsor. This organization and leadership has been proved to be efficient in previous international trials in the field of HIV and tuberculosis in Africa under the sponsorship of ANRS. WP4 Clinical Trial implementation will ensure the timely and efficient implementation of the randomized clinical trial closely monitored by WP3 in order to ensure that patients receive the best available care. Procedures and guidelines for clinical management of patients participating in the trial (covering the trial and sub studies WP5- 7) will be developed and implemented at all participating centres so as to ensure optimum patient safety and harmonization of data. This WP is led by M. Bonnet (IRD) and A. Calmy (UNIGE), clinician-researcher experimented in the leading and the management of controlled trials in the field of HIV and tuberculosis. WP5 Management of patients with HIV-TBM coinfection will ensure the appropriate management of HIV-TBM co-infected patients within the INTENSE-TBM trial and will carry out a sub study to deepen our understanding regarding prediction of Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) and its etiology including investigating the potential role of Xpert Ultra as a prediction tool for the development of IRIS. Diagnostic and management protocols (SOPs) for safe and effective management of patients with HIV-1 infection included within the study will be developed in collaboration with WP4. The regulatory aspects of this study will be dealt with in WP3 as well as the data analysis. WP5 is led by G Meintjes (UCT) and C Muzoora (MUST) who are opinion leaders in the field of HIV-TB coinfection and TB-IRIS. WP6 M. Tuberculosis diagnosis, resistance, and PK studies will carry out Mycobacterium tuberculosis diagnosis and resistance testing as well as perform pharmacokinetics studies of anti-TB drugs and antiretroviral drugs. The INTENSE-TBM project raises numerous questions regarding the issue of pharmacological interactions. IDIBAPS (Barcelona), through reference pharmacological laboratory will be able to provide new insights in short time regarding drug-drug interactions between rifampicin high-dose and other antitubercular drugs and DTG. IDIPAPS and Pasteur Institute will lead this work as they are both highly experimented in the field of TB resistance and able to describe the impact of high-dose rifampicin and linezolid on M tuberculosis . WP7 Neurological complications and disability will provide a comprehensive assessment of the clinical, neurological and sensorial complications of TBM as well as the impact of INTENSE-TBM treatment as regards these complications. Little is known on the reversibility of these complications with time and since we hypothesize that the use of aspirin, in addition to antitubercular treatment will reduce neurological sequalae and disability, clinical endpoints used to assess treatment effectiveness will be complemented with patient-centered measures of activities limitation (functioning), of quality of life (QoL) and of disability to provide a comprehensive picture of patients' situations and needs. This WP is led by P. Debeaudrap (IRD) who has already managed previous studies on disability in Sub-Saharan Africa and A Davis, neurologist from UCT. Implementation of neurologic evaluation and training of medical staff will be provided by WP2/4 and regulatory management and analysis will be performed by WP3. WP8 Dissemination and exploitation will ensure that the expected impacts of INTENSE-TBM are achieved by minimizing any potential barriers through an ambitious dissemination and communication programme. WP8 will interact closely with WP2 for all training and capacity building aspects and with WP3 for disseminating trial results as they become available. This WP is led by UBx and UCT in close collaboration with all participants and institutions.
Impact None so far
Start Year 2019
 
Description Intense-TBM 
Organisation Pasteur Institute of Madagascar
Country Madagascar 
Sector Charity/Non Profit 
PI Contribution Mortality due to Tuberculous meningitis (TBM) reaches 30% in HIV-negative and up to 70% in HIV-positive individuals with drug resistant TB strains, with death occurring most frequently in the first 2 weeks after diagnosis. Amongst TBM survivors, 50% are disabled due to neurological sequelae. Treatment of TBM has remained unchanged for decades despite this high level of mortality. INTENSE-TBM aims to improve the prognosis of TBM in patients with or without HIV co-infection in sub- Saharan Africa by reducing TBM mortality and neurological sequelae as well as improving the clinical management of TBM-HIV co-infection. For this purpose, INTENSE-TBM will carry out a multicentre randomised controlled trial in 4 Sub-Saharan African countries (Madagascar, Ivory Coast, Uganda and South Africa). Patients with suspected TBM will be randomised 1:1:1:1 to standard WHO TBM therapy, versus an intensified treatment (INTENSE-TBM programme), and into aspirin versus placebo therapy in a factorial design. The intensified TBM programme will consist of: i) First 5-7 days: high dose intravenous (IV) rifampicin 20 mg/kg/d, IV linezolid 1200 mg/d, IV isoniazid 5 mg/kg/d, pyrazinamide 30 mg/kg/d and corticosteroids. ii) Up until 2 month (oral): rifampicin 35 mg/kg/d, linezolid 1200 mg/d, isoniazid, pyrazinamide, and corticosteroids. iii) Seven months: isoniazid 5 mg/kg/d and rifampicin 10 mg/kg/d Patients will also be randomised to receive either aspirin 150 mg per day or placebo for the first two months of treatment. If superiority of this experimental arm is demonstrated in terms of reduced mortality, INTENSE-TBM will become the first Phase III study to demonstrate survival benefit from intensified TBM treatment. HIV co-infected patients will start a generic formulation of tenofovir, lamivudine, and dolutegravir four weeks after TBM treatment initiation, and continue with dexamethasone for at least the first four weeks of antiretroviral treatment. Incidence and risk-factors for severe immune reconstitution inflammatory syndrome will be determined and the pharmacokinetics of the drug-drug interactions between standard and high dose rifampicin with dolutegravir analysed. INTENSE-TBM responds directly to the call by evaluating (i) the impact of an optimized drug regimen for TBM on mortality including high dose rifampicin and linezolid, a repurposed drug for the treatment of TBM, (ii) the impact of the addition of aspirin on TBM mortality, a drug that has not previously been authorised for use against any infectious disease (iii) an antiretroviral therapy strategy in TBM patient co-infected with HIV to specifically assess the risk of severe IRIS, and to study drug-drug interactions.
Collaborator Contribution INTENSE-TBM is a multidisciplinary international research project involving four Sub-Saharan countries around a large randomized controlled Phase III trial. The project has been structured within eight highly-interactive work packages (WP) each with a Sub-Saharan African lead or co-lead to ensure optimal implementation of all activities from project and trial coordination, to pre- and post-trial capacity building, to nested studies and of utmost importance, disseminating and exploiting results amongst all stakeholders. WP1 Project Coordination and Management will ensure that all project objectives are achieved according to the project workplan and within budget limits, and that all activities are implemented in conformity with the EDCTP contract and the consortium agreement. WP1 will interact closely with WP3 for all aspects of trial management. WP1 is led by Fabrice Bonnet at the University of Bordeaux (UBx) and supported by co-leader X. Anglaret (methodologist) a trial manager at the Mereva clinical trial unit (CTU) a joint structure of INSERM U1219 and PACCI, Ivory Coast. WP2 Capacity Building will ensure that all the participating clinical centres have the capacity (equipment, skills, know-how) to carry out the INTENSE-TBM trial as well as developing a long-term network of skilled clinical researchers, centres and microbiology laboratories in the Sub-Saharan countries beyond the duration of the current project to facilitate both roll-out of the trial regimen as well as capacity to carry out further clinical trials in PRDs. WP2 will interact with WP4 in preparing and rolling out the clinical training and with WP8 for developing the capacity and skills of medical staff outside the scope of the trial. This WP is led by IDIPABS (Barcelona) in close coordination with Pasteur Institute of Madagascar as regards lab implementation and evaluation and with UNIGE for training of PI (Principal Investigator) of each country and 'GCP local trainers' as well as infection control training of teams. WP3 Trial management, monitoring and analysis will provide the methodological support to the INTENSE-TBM clinical trial which will be implemented in WP4. WP3 will ensure that the trial is well designed, developed, conducted, managed, monitored and analysed according to international standards. This includes regulatory and ethics management as well as overseeing all aspects of trial implementation notably monitoring activities and quality control. WP3 will furthermore integrate all data from the trial (WP4) and associated studies (WP5, 6 & 7) and provide data analyses to the WPs to draw conclusions on the efficacy of the INTENSE-TBM regimen and potential for wide-scale roll out. This WP is led by PACCI, (an ANRS site), directed by Pr S. Eholié supported by ANRS (C Rekacewicz) as the trial sponsor. This organization and leadership has been proved to be efficient in previous international trials in the field of HIV and tuberculosis in Africa under the sponsorship of ANRS. WP4 Clinical Trial implementation will ensure the timely and efficient implementation of the randomized clinical trial closely monitored by WP3 in order to ensure that patients receive the best available care. Procedures and guidelines for clinical management of patients participating in the trial (covering the trial and sub studies WP5- 7) will be developed and implemented at all participating centres so as to ensure optimum patient safety and harmonization of data. This WP is led by M. Bonnet (IRD) and A. Calmy (UNIGE), clinician-researcher experimented in the leading and the management of controlled trials in the field of HIV and tuberculosis. WP5 Management of patients with HIV-TBM coinfection will ensure the appropriate management of HIV-TBM co-infected patients within the INTENSE-TBM trial and will carry out a sub study to deepen our understanding regarding prediction of Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) and its etiology including investigating the potential role of Xpert Ultra as a prediction tool for the development of IRIS. Diagnostic and management protocols (SOPs) for safe and effective management of patients with HIV-1 infection included within the study will be developed in collaboration with WP4. The regulatory aspects of this study will be dealt with in WP3 as well as the data analysis. WP5 is led by G Meintjes (UCT) and C Muzoora (MUST) who are opinion leaders in the field of HIV-TB coinfection and TB-IRIS. WP6 M. Tuberculosis diagnosis, resistance, and PK studies will carry out Mycobacterium tuberculosis diagnosis and resistance testing as well as perform pharmacokinetics studies of anti-TB drugs and antiretroviral drugs. The INTENSE-TBM project raises numerous questions regarding the issue of pharmacological interactions. IDIBAPS (Barcelona), through reference pharmacological laboratory will be able to provide new insights in short time regarding drug-drug interactions between rifampicin high-dose and other antitubercular drugs and DTG. IDIPAPS and Pasteur Institute will lead this work as they are both highly experimented in the field of TB resistance and able to describe the impact of high-dose rifampicin and linezolid on M tuberculosis . WP7 Neurological complications and disability will provide a comprehensive assessment of the clinical, neurological and sensorial complications of TBM as well as the impact of INTENSE-TBM treatment as regards these complications. Little is known on the reversibility of these complications with time and since we hypothesize that the use of aspirin, in addition to antitubercular treatment will reduce neurological sequalae and disability, clinical endpoints used to assess treatment effectiveness will be complemented with patient-centered measures of activities limitation (functioning), of quality of life (QoL) and of disability to provide a comprehensive picture of patients' situations and needs. This WP is led by P. Debeaudrap (IRD) who has already managed previous studies on disability in Sub-Saharan Africa and A Davis, neurologist from UCT. Implementation of neurologic evaluation and training of medical staff will be provided by WP2/4 and regulatory management and analysis will be performed by WP3. WP8 Dissemination and exploitation will ensure that the expected impacts of INTENSE-TBM are achieved by minimizing any potential barriers through an ambitious dissemination and communication programme. WP8 will interact closely with WP2 for all training and capacity building aspects and with WP3 for disseminating trial results as they become available. This WP is led by UBx and UCT in close collaboration with all participants and institutions.
Impact None so far
Start Year 2019
 
Description Intense-TBM 
Organisation University of Bordeaux
Country France 
Sector Academic/University 
PI Contribution Mortality due to Tuberculous meningitis (TBM) reaches 30% in HIV-negative and up to 70% in HIV-positive individuals with drug resistant TB strains, with death occurring most frequently in the first 2 weeks after diagnosis. Amongst TBM survivors, 50% are disabled due to neurological sequelae. Treatment of TBM has remained unchanged for decades despite this high level of mortality. INTENSE-TBM aims to improve the prognosis of TBM in patients with or without HIV co-infection in sub- Saharan Africa by reducing TBM mortality and neurological sequelae as well as improving the clinical management of TBM-HIV co-infection. For this purpose, INTENSE-TBM will carry out a multicentre randomised controlled trial in 4 Sub-Saharan African countries (Madagascar, Ivory Coast, Uganda and South Africa). Patients with suspected TBM will be randomised 1:1:1:1 to standard WHO TBM therapy, versus an intensified treatment (INTENSE-TBM programme), and into aspirin versus placebo therapy in a factorial design. The intensified TBM programme will consist of: i) First 5-7 days: high dose intravenous (IV) rifampicin 20 mg/kg/d, IV linezolid 1200 mg/d, IV isoniazid 5 mg/kg/d, pyrazinamide 30 mg/kg/d and corticosteroids. ii) Up until 2 month (oral): rifampicin 35 mg/kg/d, linezolid 1200 mg/d, isoniazid, pyrazinamide, and corticosteroids. iii) Seven months: isoniazid 5 mg/kg/d and rifampicin 10 mg/kg/d Patients will also be randomised to receive either aspirin 150 mg per day or placebo for the first two months of treatment. If superiority of this experimental arm is demonstrated in terms of reduced mortality, INTENSE-TBM will become the first Phase III study to demonstrate survival benefit from intensified TBM treatment. HIV co-infected patients will start a generic formulation of tenofovir, lamivudine, and dolutegravir four weeks after TBM treatment initiation, and continue with dexamethasone for at least the first four weeks of antiretroviral treatment. Incidence and risk-factors for severe immune reconstitution inflammatory syndrome will be determined and the pharmacokinetics of the drug-drug interactions between standard and high dose rifampicin with dolutegravir analysed. INTENSE-TBM responds directly to the call by evaluating (i) the impact of an optimized drug regimen for TBM on mortality including high dose rifampicin and linezolid, a repurposed drug for the treatment of TBM, (ii) the impact of the addition of aspirin on TBM mortality, a drug that has not previously been authorised for use against any infectious disease (iii) an antiretroviral therapy strategy in TBM patient co-infected with HIV to specifically assess the risk of severe IRIS, and to study drug-drug interactions.
Collaborator Contribution INTENSE-TBM is a multidisciplinary international research project involving four Sub-Saharan countries around a large randomized controlled Phase III trial. The project has been structured within eight highly-interactive work packages (WP) each with a Sub-Saharan African lead or co-lead to ensure optimal implementation of all activities from project and trial coordination, to pre- and post-trial capacity building, to nested studies and of utmost importance, disseminating and exploiting results amongst all stakeholders. WP1 Project Coordination and Management will ensure that all project objectives are achieved according to the project workplan and within budget limits, and that all activities are implemented in conformity with the EDCTP contract and the consortium agreement. WP1 will interact closely with WP3 for all aspects of trial management. WP1 is led by Fabrice Bonnet at the University of Bordeaux (UBx) and supported by co-leader X. Anglaret (methodologist) a trial manager at the Mereva clinical trial unit (CTU) a joint structure of INSERM U1219 and PACCI, Ivory Coast. WP2 Capacity Building will ensure that all the participating clinical centres have the capacity (equipment, skills, know-how) to carry out the INTENSE-TBM trial as well as developing a long-term network of skilled clinical researchers, centres and microbiology laboratories in the Sub-Saharan countries beyond the duration of the current project to facilitate both roll-out of the trial regimen as well as capacity to carry out further clinical trials in PRDs. WP2 will interact with WP4 in preparing and rolling out the clinical training and with WP8 for developing the capacity and skills of medical staff outside the scope of the trial. This WP is led by IDIPABS (Barcelona) in close coordination with Pasteur Institute of Madagascar as regards lab implementation and evaluation and with UNIGE for training of PI (Principal Investigator) of each country and 'GCP local trainers' as well as infection control training of teams. WP3 Trial management, monitoring and analysis will provide the methodological support to the INTENSE-TBM clinical trial which will be implemented in WP4. WP3 will ensure that the trial is well designed, developed, conducted, managed, monitored and analysed according to international standards. This includes regulatory and ethics management as well as overseeing all aspects of trial implementation notably monitoring activities and quality control. WP3 will furthermore integrate all data from the trial (WP4) and associated studies (WP5, 6 & 7) and provide data analyses to the WPs to draw conclusions on the efficacy of the INTENSE-TBM regimen and potential for wide-scale roll out. This WP is led by PACCI, (an ANRS site), directed by Pr S. Eholié supported by ANRS (C Rekacewicz) as the trial sponsor. This organization and leadership has been proved to be efficient in previous international trials in the field of HIV and tuberculosis in Africa under the sponsorship of ANRS. WP4 Clinical Trial implementation will ensure the timely and efficient implementation of the randomized clinical trial closely monitored by WP3 in order to ensure that patients receive the best available care. Procedures and guidelines for clinical management of patients participating in the trial (covering the trial and sub studies WP5- 7) will be developed and implemented at all participating centres so as to ensure optimum patient safety and harmonization of data. This WP is led by M. Bonnet (IRD) and A. Calmy (UNIGE), clinician-researcher experimented in the leading and the management of controlled trials in the field of HIV and tuberculosis. WP5 Management of patients with HIV-TBM coinfection will ensure the appropriate management of HIV-TBM co-infected patients within the INTENSE-TBM trial and will carry out a sub study to deepen our understanding regarding prediction of Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) and its etiology including investigating the potential role of Xpert Ultra as a prediction tool for the development of IRIS. Diagnostic and management protocols (SOPs) for safe and effective management of patients with HIV-1 infection included within the study will be developed in collaboration with WP4. The regulatory aspects of this study will be dealt with in WP3 as well as the data analysis. WP5 is led by G Meintjes (UCT) and C Muzoora (MUST) who are opinion leaders in the field of HIV-TB coinfection and TB-IRIS. WP6 M. Tuberculosis diagnosis, resistance, and PK studies will carry out Mycobacterium tuberculosis diagnosis and resistance testing as well as perform pharmacokinetics studies of anti-TB drugs and antiretroviral drugs. The INTENSE-TBM project raises numerous questions regarding the issue of pharmacological interactions. IDIBAPS (Barcelona), through reference pharmacological laboratory will be able to provide new insights in short time regarding drug-drug interactions between rifampicin high-dose and other antitubercular drugs and DTG. IDIPAPS and Pasteur Institute will lead this work as they are both highly experimented in the field of TB resistance and able to describe the impact of high-dose rifampicin and linezolid on M tuberculosis . WP7 Neurological complications and disability will provide a comprehensive assessment of the clinical, neurological and sensorial complications of TBM as well as the impact of INTENSE-TBM treatment as regards these complications. Little is known on the reversibility of these complications with time and since we hypothesize that the use of aspirin, in addition to antitubercular treatment will reduce neurological sequalae and disability, clinical endpoints used to assess treatment effectiveness will be complemented with patient-centered measures of activities limitation (functioning), of quality of life (QoL) and of disability to provide a comprehensive picture of patients' situations and needs. This WP is led by P. Debeaudrap (IRD) who has already managed previous studies on disability in Sub-Saharan Africa and A Davis, neurologist from UCT. Implementation of neurologic evaluation and training of medical staff will be provided by WP2/4 and regulatory management and analysis will be performed by WP3. WP8 Dissemination and exploitation will ensure that the expected impacts of INTENSE-TBM are achieved by minimizing any potential barriers through an ambitious dissemination and communication programme. WP8 will interact closely with WP2 for all training and capacity building aspects and with WP3 for disseminating trial results as they become available. This WP is led by UBx and UCT in close collaboration with all participants and institutions.
Impact None so far
Start Year 2019
 
Description Intense-TBM 
Organisation University of Cape Town
Department Institute of Infectious Disease and Molecular Medicine (IIDMM)
Country South Africa 
Sector Academic/University 
PI Contribution Mortality due to Tuberculous meningitis (TBM) reaches 30% in HIV-negative and up to 70% in HIV-positive individuals with drug resistant TB strains, with death occurring most frequently in the first 2 weeks after diagnosis. Amongst TBM survivors, 50% are disabled due to neurological sequelae. Treatment of TBM has remained unchanged for decades despite this high level of mortality. INTENSE-TBM aims to improve the prognosis of TBM in patients with or without HIV co-infection in sub- Saharan Africa by reducing TBM mortality and neurological sequelae as well as improving the clinical management of TBM-HIV co-infection. For this purpose, INTENSE-TBM will carry out a multicentre randomised controlled trial in 4 Sub-Saharan African countries (Madagascar, Ivory Coast, Uganda and South Africa). Patients with suspected TBM will be randomised 1:1:1:1 to standard WHO TBM therapy, versus an intensified treatment (INTENSE-TBM programme), and into aspirin versus placebo therapy in a factorial design. The intensified TBM programme will consist of: i) First 5-7 days: high dose intravenous (IV) rifampicin 20 mg/kg/d, IV linezolid 1200 mg/d, IV isoniazid 5 mg/kg/d, pyrazinamide 30 mg/kg/d and corticosteroids. ii) Up until 2 month (oral): rifampicin 35 mg/kg/d, linezolid 1200 mg/d, isoniazid, pyrazinamide, and corticosteroids. iii) Seven months: isoniazid 5 mg/kg/d and rifampicin 10 mg/kg/d Patients will also be randomised to receive either aspirin 150 mg per day or placebo for the first two months of treatment. If superiority of this experimental arm is demonstrated in terms of reduced mortality, INTENSE-TBM will become the first Phase III study to demonstrate survival benefit from intensified TBM treatment. HIV co-infected patients will start a generic formulation of tenofovir, lamivudine, and dolutegravir four weeks after TBM treatment initiation, and continue with dexamethasone for at least the first four weeks of antiretroviral treatment. Incidence and risk-factors for severe immune reconstitution inflammatory syndrome will be determined and the pharmacokinetics of the drug-drug interactions between standard and high dose rifampicin with dolutegravir analysed. INTENSE-TBM responds directly to the call by evaluating (i) the impact of an optimized drug regimen for TBM on mortality including high dose rifampicin and linezolid, a repurposed drug for the treatment of TBM, (ii) the impact of the addition of aspirin on TBM mortality, a drug that has not previously been authorised for use against any infectious disease (iii) an antiretroviral therapy strategy in TBM patient co-infected with HIV to specifically assess the risk of severe IRIS, and to study drug-drug interactions.
Collaborator Contribution INTENSE-TBM is a multidisciplinary international research project involving four Sub-Saharan countries around a large randomized controlled Phase III trial. The project has been structured within eight highly-interactive work packages (WP) each with a Sub-Saharan African lead or co-lead to ensure optimal implementation of all activities from project and trial coordination, to pre- and post-trial capacity building, to nested studies and of utmost importance, disseminating and exploiting results amongst all stakeholders. WP1 Project Coordination and Management will ensure that all project objectives are achieved according to the project workplan and within budget limits, and that all activities are implemented in conformity with the EDCTP contract and the consortium agreement. WP1 will interact closely with WP3 for all aspects of trial management. WP1 is led by Fabrice Bonnet at the University of Bordeaux (UBx) and supported by co-leader X. Anglaret (methodologist) a trial manager at the Mereva clinical trial unit (CTU) a joint structure of INSERM U1219 and PACCI, Ivory Coast. WP2 Capacity Building will ensure that all the participating clinical centres have the capacity (equipment, skills, know-how) to carry out the INTENSE-TBM trial as well as developing a long-term network of skilled clinical researchers, centres and microbiology laboratories in the Sub-Saharan countries beyond the duration of the current project to facilitate both roll-out of the trial regimen as well as capacity to carry out further clinical trials in PRDs. WP2 will interact with WP4 in preparing and rolling out the clinical training and with WP8 for developing the capacity and skills of medical staff outside the scope of the trial. This WP is led by IDIPABS (Barcelona) in close coordination with Pasteur Institute of Madagascar as regards lab implementation and evaluation and with UNIGE for training of PI (Principal Investigator) of each country and 'GCP local trainers' as well as infection control training of teams. WP3 Trial management, monitoring and analysis will provide the methodological support to the INTENSE-TBM clinical trial which will be implemented in WP4. WP3 will ensure that the trial is well designed, developed, conducted, managed, monitored and analysed according to international standards. This includes regulatory and ethics management as well as overseeing all aspects of trial implementation notably monitoring activities and quality control. WP3 will furthermore integrate all data from the trial (WP4) and associated studies (WP5, 6 & 7) and provide data analyses to the WPs to draw conclusions on the efficacy of the INTENSE-TBM regimen and potential for wide-scale roll out. This WP is led by PACCI, (an ANRS site), directed by Pr S. Eholié supported by ANRS (C Rekacewicz) as the trial sponsor. This organization and leadership has been proved to be efficient in previous international trials in the field of HIV and tuberculosis in Africa under the sponsorship of ANRS. WP4 Clinical Trial implementation will ensure the timely and efficient implementation of the randomized clinical trial closely monitored by WP3 in order to ensure that patients receive the best available care. Procedures and guidelines for clinical management of patients participating in the trial (covering the trial and sub studies WP5- 7) will be developed and implemented at all participating centres so as to ensure optimum patient safety and harmonization of data. This WP is led by M. Bonnet (IRD) and A. Calmy (UNIGE), clinician-researcher experimented in the leading and the management of controlled trials in the field of HIV and tuberculosis. WP5 Management of patients with HIV-TBM coinfection will ensure the appropriate management of HIV-TBM co-infected patients within the INTENSE-TBM trial and will carry out a sub study to deepen our understanding regarding prediction of Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) and its etiology including investigating the potential role of Xpert Ultra as a prediction tool for the development of IRIS. Diagnostic and management protocols (SOPs) for safe and effective management of patients with HIV-1 infection included within the study will be developed in collaboration with WP4. The regulatory aspects of this study will be dealt with in WP3 as well as the data analysis. WP5 is led by G Meintjes (UCT) and C Muzoora (MUST) who are opinion leaders in the field of HIV-TB coinfection and TB-IRIS. WP6 M. Tuberculosis diagnosis, resistance, and PK studies will carry out Mycobacterium tuberculosis diagnosis and resistance testing as well as perform pharmacokinetics studies of anti-TB drugs and antiretroviral drugs. The INTENSE-TBM project raises numerous questions regarding the issue of pharmacological interactions. IDIBAPS (Barcelona), through reference pharmacological laboratory will be able to provide new insights in short time regarding drug-drug interactions between rifampicin high-dose and other antitubercular drugs and DTG. IDIPAPS and Pasteur Institute will lead this work as they are both highly experimented in the field of TB resistance and able to describe the impact of high-dose rifampicin and linezolid on M tuberculosis . WP7 Neurological complications and disability will provide a comprehensive assessment of the clinical, neurological and sensorial complications of TBM as well as the impact of INTENSE-TBM treatment as regards these complications. Little is known on the reversibility of these complications with time and since we hypothesize that the use of aspirin, in addition to antitubercular treatment will reduce neurological sequalae and disability, clinical endpoints used to assess treatment effectiveness will be complemented with patient-centered measures of activities limitation (functioning), of quality of life (QoL) and of disability to provide a comprehensive picture of patients' situations and needs. This WP is led by P. Debeaudrap (IRD) who has already managed previous studies on disability in Sub-Saharan Africa and A Davis, neurologist from UCT. Implementation of neurologic evaluation and training of medical staff will be provided by WP2/4 and regulatory management and analysis will be performed by WP3. WP8 Dissemination and exploitation will ensure that the expected impacts of INTENSE-TBM are achieved by minimizing any potential barriers through an ambitious dissemination and communication programme. WP8 will interact closely with WP2 for all training and capacity building aspects and with WP3 for disseminating trial results as they become available. This WP is led by UBx and UCT in close collaboration with all participants and institutions.
Impact None so far
Start Year 2019
 
Description MRC-SHIP 
Organisation University of Stellenbosch
Country South Africa 
Sector Academic/University 
PI Contribution We are the principal investigators
Collaborator Contribution Intellectual collaboration and performance of research bronchoscopy
Impact None as yet: new collaboration
Start Year 2014
 
Description PRAVA-TB 
Organisation ETH Zurich
Department Molecular Health Sciences Platform
Country Switzerland 
Sector Public 
PI Contribution I am providing advice on clinical trials and capacity building
Collaborator Contribution University of Cape Town and University of Zurich are responsible for the clinical trial. All partners are responsible for capacity building and management.
Impact Noen so far
Start Year 2019
 
Description PRAVA-TB 
Organisation University of Cape Town
Department Institute of Infectious Disease and Molecular Medicine (IIDMM)
Country South Africa 
Sector Academic/University 
PI Contribution I am providing advice on clinical trials and capacity building
Collaborator Contribution University of Cape Town and University of Zurich are responsible for the clinical trial. All partners are responsible for capacity building and management.
Impact Noen so far
Start Year 2019
 
Description PRAVA-TB 
Organisation University of Namibia
Country Namibia 
Sector Academic/University 
PI Contribution I am providing advice on clinical trials and capacity building
Collaborator Contribution University of Cape Town and University of Zurich are responsible for the clinical trial. All partners are responsible for capacity building and management.
Impact Noen so far
Start Year 2019
 
Description PathCo 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution We are providing strains of M. tuberculosis and expertise in the tissue culture of HIV and tuberculosis
Collaborator Contribution Biochemical and Bioinformatic expertise
Impact We have sequenced 192 strains of M. tuberculosis. Please refer to publications.
Start Year 2012
 
Description Wellcome Centre for Infectious Diseases research in Africa 
Organisation University of Cape Town
Country South Africa 
Sector Academic/University 
PI Contribution I direct this centre as an Honorary employee of the University of Cape Town
Collaborator Contribution There are 12 principal investiagtors and 31 contributing investigators at the University of Cape Town
Impact We have strengthened human and laboratory capacity at the University of Cape Town substantially
Start Year 2017
 
Title DIAGNOSIS OF ACTIVE TUBERCULOSIS BY DETERMINING THE MRNA EXPRESSION LEVELS OF MARKER GENES IN BLOOD 
Description The present disclosure relates to a method of distinguishing active TB in the presence of a complicating factor, for example, latent TB and/ or co-morbidities, such as those that present similar symptoms to TB, such as HIV. The method employs a 27 gene signature to distinguish active tuberculosis from latent TB infection, a 44 gene signature to distinguish active TB from other diseases such as HIV and/or a 53 gene signature to discriminate active TB from latent TB and other diseases. The disclosure also relates to a gene signature employed in the method, a bespoke gene chip for use in the method and a disease risk score obtainable from the method. 
IP Reference WO2014019977 
Protection Patent application published
Year Protection Granted 2014
Licensed No
Impact None as yet
 
Title DIAGNOSIS OF ACTIVE TUBERCULOSIS BY DETERMINING THE MRNA EXPRESSION LEVELS OF MARKER GENES IN BLOOD 
Description The present disclosure relates to a method of distinguishing active TB in the presence of a complicating factor, for example, latent TB and/or co-morbidities, such as those that present similar symptoms to TB, such as HIV. The method employs a 27 gene signature to distinguish active tuberculosis from latent TB infection, a 44 gene signature to distinguish active TB from other diseases such as HIV and/or a 53 gene signature to discriminate active TB from latent TB and other diseases. The disclosure also relates to a gene signature employed in the method, a bespoke gene chip for use in the method and a disease risk score obtainable from the method. 
IP Reference US2015203899 
Protection Patent application published
Year Protection Granted 2015
Licensed No
Impact None as yet
 
Title DIAGNOSIS OF ACTIVE TUBERCULOSIS BY DETERMINING THE MRNA EXPRESSION LEVELS OF MARKER GENES IN BLOOD 
Description Use of patterns of RNA from peripheral blood to diagnose tuberculosis 
IP Reference EP2880178 
Protection Patent application published
Year Protection Granted 2015
Licensed No
Impact None as yet
 
Title EARLY DETECTION OF TUBERCULOSIS TREATMENT RESPONSE 
Description The present invention includes methods for early detection of a treatment response in a patient suspected of being infected with Mycobacterium tuberculosis. Changes in the blood transcriptome are detectable within two weeks of the initiation of antituberculosis therapy. 
IP Reference CA2867118 
Protection Patent granted
Year Protection Granted 2013
Licensed No
Impact None as yet
 
Title EARLY DETECTION OF TUBERCULOSIS TREATMENT RESPONSE 
Description The present invention includes methods for early detection of a treatment response in a patient suspected of being infected with Mycobacterium tuberculosis. Changes in the blood transcriptome are detectable within two weeks of the initiation of antituberculosis therapy. 
IP Reference US2015133469 
Protection Patent granted
Year Protection Granted 2015
Licensed No
Impact None as yet
 
Title EARLY DETECTION OF TUBERCULOSIS TREATMENT RESPONSE 
Description The present invention includes methods for early detection of a treatment response in a patient suspected of being infected with Mycobacterium tuberculosis. Changes in the blood transcriptome are detectable within two weeks of the initiation of antituberculosis therapy. 
IP Reference WO2013138497 
Protection Patent granted
Year Protection Granted 2013
Licensed No
Impact None as yet
 
Title EARLY DETECTION OF TUBERCULOSIS TREATMENT RESPONSE 
Description Use of RNA blood biosignature to monitor the efficacy of tuberculosis treatment 
IP Reference EP2825671 
Protection Patent granted
Year Protection Granted 2015
Licensed No
Impact Approach adopted by many others, including commercial entities
 
Title METHOD OF DETECTING ACTIVE TUBERCULOSIS USING MINIMAL GENE SIGNATURE 
Description A method of detecting active TB in the presence of a complicating factor, for example, latent TB and/or co-morbidities, such as those that present similar symptoms to TB. The disclosure also relates to a minimal gene signature employed in the said method and to a bespoke gene chip for use in the method. The disclosure further relates to use of gene chips and primer sets in the methods of the disclosure and kits comprising the elements required for performing the method. The disclosure also relates to use of the method to provide a composite expression score which can be used in the diagnosis of TB, particularly in a low resource setting. 
IP Reference WO2018037031 
Protection Patent application published
Year Protection Granted 2018
Licensed No
Impact None as yet
 
Title A phase IIb, double-blind, randomised, placebo-controlled study to evaluate the efficacy, safety and immunogenicity of GSK Biologicals' candidate tuberculosis (TB) vaccine GSK 692342 against TB disease, in adults aged 18-50 years, living in a TB endemic region 
Description A novel subunit tuberculosis vaccine 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2018
Development Status Actively seeking support
Clinical Trial? Yes
Impact Van Der Meeren, O., Hatherill, M., Nduba, V., Wilkinson, R.J., Muyoyeta, M., Van Brakel, E., Ayles, H.M., Henostroza, G., Thienemann, F., Scriba, T.J., Diacon, A., Blatner, G.L., Demoitié, M-A., Tameris, M., Malahleha, M., Innes, J.C., Hellstrom, E., Martinson, N., Singh, T., Akite, E.J., Azam, A.K., Bollaerts, A., Ginsberg, A.M., Evans, T.G., Gillard, P., Tait, D.R. Phase 2b Controlled Trial of M72/AS01E Vaccine to Prevent Tuberculosis New England Journal of Medicine† (2018) 379:1621-1634 PMID 30280651 PMCID PMC6151253 
 
Title Prednisone 
Description A randomised controlled trial of prednisone versus placebo for HIV-tuberculosis associated immune reconstitution inflammatory syndrome (TB-IRIS) 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2008
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Corticosteroid thereapy reduced the need for hospitalisation and medical intervention and improved radiographic and symptom scores. However the occurrence of TB-IRIS in the context of drug resistant isolates of M. tuberculosis is a relative contraindication to corticosteroid therapy 
 
Title Preventing Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome in High-Risk Patients: a Randomized Placebo-Controlled Trial of Prednisone (PredART Trial) 
Description Background: Early initiation of antiretroviral therapy (ART) in patients with tuberculosis reduces mortality in those with low CD4 counts, but increases the risk of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS). We determined whether prophylactic prednisone safely reduces the incidence of paradoxical TB-IRIS in patients at high risk. Methods: Randomized, double-blind, placebo-controlled trial of prednisone (40 mg/day for 14 days then 20 mg/day for 14 days) started with ART in ART-naïve adults at high risk of TB-IRIS (within 30 days of antituberculosis treatment initiation and CD4 count =100 cells/µL). Primary endpoint was development of TB-IRIS within 12 weeks, adjudicated by an independent committee. Results: Among 240 participants median age was 36.8 (IQR=30-42.8), 60% male, and median CD4 49 cells/µL (IQR=24-86). 18 were lost to follow-up or withdrew. TB-IRIS was diagnosed in 56 in the placebo arm (46.7%) and 39 in the prednisone arm (32.5%) (relative risk (RR)=0.70 (95%CI=0.51-0.96)). Open-label corticosteroids to treat TB-IRIS were prescribed to 34 of the placebo arm (28.3%) and 16 (13.3%) of the prednisone arm (RR=0.47 (95%CI=0.27-0.83)). 4 deaths occurred in the placebo arm; 5 in the prednisone arm (p=1.0). Severe infections (AIDS-defining or invasive bacterial) occurred in 18 in the placebo arm; 11 in the prednisone arm (p=0.17). One Kaposi's sarcoma case occurred (placebo arm). Conclusions: In patients at high risk, prednisone during the first 4 weeks of ART reduced paradoxical TB-IRIS incidence by 30% and reduced corticosteroid treatment required for TB-IRIS by 53%. There was no excess risk of infection or malignancy. 
Type Preventative Intervention - Physical/Biological risk modification
Current Stage Of Development Small-scale adoption
Year Development Stage Completed 2017
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Meintjes, G., Stek, C., Blumenthal, L., Thienemann, F., Schutz, C., Buyze, J., Ravinetto, R., van Loen, H., Nair, A., Jackson, A., Colebunders, R., Maartens, G., Wilkinson, R.J., Lynen, L. on behalf of the PredART trial team Prednisone for prevention of paradoxical tuberculosis-associated IRIS New England Journal of Medicine† (2018) 379:1915-25 PMID 30428290 
 
Title Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome 
Description OBJECTIVE: Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of antiretroviral therapy in resource-limited countries. We aimed to assess whether a 4-week course of prednisone would reduce morbidity in patients with paradoxical TB-IRIS without excess adverse events. DESIGN: A randomized, double-blind, placebo-controlled trial of prednisone (1.5 mg/kg per day for 2 weeks then 0.75 mg/kg per day for 2 weeks). Patients with immediately life-threatening TB-IRIS manifestations were excluded. METHODS: The primary combined endpoint was days of hospitalization and outpatient therapeutic procedures, which were counted as one hospital day. RESULTS: One hundred and ten participants were enrolled (55 to each arm). The primary combined endpoint was more frequent in the placebo than the prednisone arm {median hospital days 3 [interquartile range (IQR) 0-9] and 0 (IQR 0-3), respectively; P = 0.04}. There were significantly greater improvements in symptoms, Karnofsky score, and quality of life (MOS-HIV) in the prednisone vs. the placebo arm at 2 and 4 weeks, but not at later time points. Chest radiographs improved significantly more in the prednisone arm at weeks 2 (P = 0.002) and 4 (P = 0.02). Infections on study medication occurred in more participants in prednisone than in placebo arm (27 vs. 17, respectively; P = 0.05), but there was no difference in severe infections (2 vs. 4, respectively; P = 0.40). Isolates from 10 participants were found to be resistant to rifampicin after enrolment. CONCLUSION: Prednisone reduced the need for hospitalization and therapeutic procedures and hastened improvements in symptoms, performance, and quality of life. It is important to investigate for drug-resistant tuberculosis and other causes for deterioration before administering glucocorticoids. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Wide-scale adoption
Year Development Stage Completed 2010
Development Status Under active development/distribution
Clinical Trial? Yes
Impact This is the only randomised trial to be conducted in this condition and, as such, is the best evidence base for treatment 
 
Title Safety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial 
Description BACKGROUND: HIV-1 infection is associated with increased risk of tuberculosis and a safe and effective vaccine would assist control measures. We assessed the safety, immunogenicity, and efficacy of a candidate tuberculosis vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in adults infected with HIV-1. METHODS: We did a randomised, double-blind, placebo-controlled, phase 2 trial of MVA85A in adults infected with HIV-1, at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. Eligible participants were aged 18-50 years, had no evidence of active tuberculosis, and had baseline CD4 counts greater than 350 cells per µL if they had never received antiretroviral therapy or greater than 300 cells per µL (and with undetectable viral load before randomisation) if they were receiving antiretroviral therapy; participants with latent tuberculosis infection were eligible if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. Participants were randomly assigned (1:1) in blocks of four by randomly generated sequence to receive two intradermal injections of either MVA85A or placebo. Randomisation was stratified by antiretroviral therapy status and study site. Participants, nurses, investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6-12 months after the first vaccination. The primary study outcome was safety in all vaccinated participants (the safety analysis population). Safety was assessed throughout the trial as defined in the protocol. Secondary outcomes were immunogenicity and vaccine efficacy against Mycobacterium tuberculosis infection and disease, assessed in the per-protocol population. Immunogenicity was assessed in a subset of participants at day 7 and day 28 after the first and second vaccination, and M tuberculosis infection and disease were assessed at the end of the study. The trial is registered with ClinicalTrials.gov, number NCT01151189. FINDINGS: Between Aug 4, 2011, and April 24, 2013, 650 participants were enrolled and randomly assigned; 649 were included in the safety analysis (324 in the MVA85A group and 325 in the placebo group) and 645 in the per-protocol analysis (320 and 325). 513 (71%) participants had CD4 counts greater than 300 cells per µL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per µL and had never received antiretroviral therapy. 277 (43%) had received isoniazid prophylaxis before enrolment. Solicited adverse events were more frequent in participants who received MVA85A (288 [89%]) than in those given placebo (235 [72%]). 34 serious adverse events were reported, 17 (5%) in each group. MVA85A induced a significant increase in antigen 85A-specific T-cell response, which peaked 7 days after both vaccinations and was primarily monofunctional. The number of participants with negative QuantiFERON-TB Gold In-Tube findings at baseline who converted to positive by the end of the study was 38 (20%) of 186 in the MVA85A group and 40 (23%) of 173 in the placebo group, for a vaccine efficacy of 11·7% (95% CI -41·3 to 44·9). In the per-protocol population, six (2%) cases of tuberculosis disease occurred in the MVA85A group and nine (3%) occurred in the placebo group, for a vaccine efficacy of 32·8% (95% CI -111·5 to 80·3). INTERPRETATION: MVA85A was well tolerated and immunogenic in adults infected with HIV-1. However, we detected no efficacy against M tuberculosis infection or disease, although the study was underpowered to detect an effect against disease. Potential reasons for the absence of detectable efficacy in this trial include insufficient induction of a vaccine-induced immune response or the wrong type of vaccine-induced immune response, or both. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2015
Development Status Closed
Clinical Trial? Yes
Impact This was a very large trial of a novel tuberculosis vaccine in HIV infected persons. Unfortunately no efficacy was demonstrated 
 
Title vitamin D 
Description A single dose of vitamin D 
Type Preventative Intervention - Nutrition and Chemoprevention
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2007
Development Status Under active development/distribution
Impact Improved the ability of contacts of tuberculosis to restrict the growth of mycobacteria in a whole blood assay. As vitamin D deficiency was found to be common in the study and supplementation has other beneficial effects this has led to the suggestion that all tuberculosis contacts in the UK should be tested for deficiency and treated as necessary 
 
Title vitamin D therapy 
Description High dose vitamin D 
Type Therapeutic Intervention - Complementary
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2010
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Reduced the median time to sputum clearance in tuberculosis patients from 43.5 to 36 days 
 
Title ANIMA: Association Network Integration for Multiscale Analysis 
Description Contextual functional interpretation of -omics data derived from clinical samples is a classical and difficult problem in computational systems biology. The measurement of thousands of data points on single samples has become routine but relating 'big data' datasets to the complexities of human pathobiology is an area of ongoing research. Complicating this is the fact that many publically available datasets use bulk transcriptomics data from complex tissues like blood. The most prevalent analytic approaches derive molecular 'signatures' of disease states or apply modular analysis frameworks to the data. Here we describe ANIMA (association network integration for multiscale analysis), a network-based data integration method using clinical phenotype and microarray data as inputs. ANIMA is implemented in R and Neo4j and runs in Docker containers. In short, the build algorithm iterates over one or more transcriptomics datasets to generate a large, multipartite association network by executing multiple independent analytic steps (differential expression, deconvolution, modular analysis based on co-expression, pathway analysis) and integrating the results. Once the network is built, it can be queried directly using Cypher, or via custom functions that communicate with the graph database via language-specific APIs. We developed a web application using Shiny, which provides fully interactive, multiscale views of the data. Using our approach, we show that we can reconstruct multiple features of disease states at various scales of organization, from transcript abundance patterns of individual genes through co-expression patterns of groups of genes to patterns of cellular behaviour in whole blood samples, both in single experiments as well as in a meta-analysis of multiple datasets. 
Type Of Technology Webtool/Application 
Year Produced 2018 
Open Source License? Yes  
Impact None yet 
 
Description Aberdeen visit May 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 'The breath, heart and mind of HIV-associated tuberculosis' Institute of Immunology and Infection, University of Aberdeen, 30th May 2013

I spoke with many students and postdocs about their research and in particular with a joint student between Aberdeen and the University of Cape Town
Year(s) Of Engagement Activity 2013
 
Description Advancing host directed therapy for tuberculosis workshop 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact HIV associated tuberculosis: role of host directed therapies to reduce early mortality and TB-IRIS' Sponsored by NIH DAIDS as speaker at Advancing host directed therapy for tuberculosis workshop, 16th April 2014, Rockville, MD, USA
Year(s) Of Engagement Activity 2014
 
Description Aspects of the Clinical Immunology of tuberculosis and HIV-tuberculosis 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 15th Key Symposium: Innate Immunity Thursday 27th September 2018, Exeter College, Oxford, UK
Year(s) Of Engagement Activity 2018
 
Description Cape Times 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact A newspaper article about the start of a Phase IIB clinical trial of a novel antituberculosis vaccine in HIV infected people

We hope that recruitment to the trial will thereby be enhanced
Year(s) Of Engagement Activity 2011
 
Description Convener and Session chair, 4th South African tuberculosis conference, Durban 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact 'The Immunology of HIV associated tuberculosis' Convener and Session chair, 4th South African tuberculosis conference, Durban, 12th June 2014
Year(s) Of Engagement Activity 2014
 
Description Factors controlling susceptibility to tuberculosis disease progression 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact NIH sponsored travel and plenary presentation at TB Science 2018, Wednesday 24th October 2018, Den Haag, Netherlands
Year(s) Of Engagement Activity 2018
 
Description Factors influencing tuberculosis progression 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited plenary at London Infection and Immunity Meeting, 5th November 2018, Francis Crick Institute, London
Year(s) Of Engagement Activity 2018
 
Description Film for BBC 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The BBC made a film on location at our study site in Khayelitsha site B. This was screened globally and multiply.

Increased awareness of the association between HIV and TB and of drug resistant tuberculosis
Year(s) Of Engagement Activity 2008
 
Description How latent is latent tuberculosis? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited seminar at Institut de Pharmacologie et de Biologie Structurale, Toulouse, France Friday 26th October 2018
Year(s) Of Engagement Activity 2018
 
Description How latent is latent tuberculosis? 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited plenary at HCAI symposium, University of Manchester, UK, Friday 9th November 2018
Year(s) Of Engagement Activity 2018
 
Description Insights into the host response and the potential for HDT from studies of HIV-TB associated TBM-IRIS 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Tuberculosis Meningitis: Advancing Immunopathogenesis, Diagnosis, and Treatment, Tuesday 23rd May 2017, Invited plenary speaker National Institutes of Allergy and Infectious Diseases, Rockville, MD
Year(s) Of Engagement Activity 2017
 
Description Invited opening plenary speaker Host response to TB-HIV infection: a genomic perspective, National Institutes of Health 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The application of, and opportunities for, genomics to improve understanding of HIV-TB interaction in the context of global health' Invited opening plenary speaker Host response to TB-HIV infection: a genomic perspective, National Institutes of Health, Rockville, MD, January 13-14th 2015
Year(s) Of Engagement Activity 2015
 
Description Invited plenary (final talk) Keystone symposium on Host response in tuberculosis 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 'Safety, immunogenicity and efficacy of the candidate tuberculosis vaccine MVA85A in healthy HIV-1-infected adults: a randomized, placebo-controlled phase 2 trial' Invited plenary (final talk) Keystone symposium on Host response in tuberculosis, Santa FE, NM, January 26th 2015
Year(s) Of Engagement Activity 2015
 
Description Invited plenary speaker 16th International Congress of Infectious Diseases 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Interaction between antimicrobial and adjunctive therapies and the immune response to tuberculosis
Year(s) Of Engagement Activity 2014
 
Description Invited speaker KwaZuluNatal Research institute for tuberculosis and HIV, Durban, South Africa 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact 'Transcriptional profiling in human tuberculosis' Invited speaker KwaZuluNatal Research institute for tuberculosis and HIV, Durban, South Africa, 10th October 2014
Year(s) Of Engagement Activity 2014
 
Description Invited speaker and plenary, 11th European Federation of Immunology Societies-European Journal of Immunology Tatra Immunology conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 'Transcriptional profiling in human tuberculosis' Invited speaker and plenary, 11th European Federation of Immunology Societies-European Journal of Immunology Tatra Immunology conference, Strbské Pleso, Slovakia, 7th September 2014
Year(s) Of Engagement Activity 2014
 
Description Invited speaker, Advanced Medicine, Royal College of Physicians of London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact 'Understanding and intervening in HIV-associated tuberculosis' Invited speaker, Advanced Medicine, Royal College of Physicians of London, February 9th 2015
Year(s) Of Engagement Activity 2015
 
Description Ker Memorial Lecture University of Edinburgh 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Attended by 100 plus delegates

New collaboration
Year(s) Of Engagement Activity 2013
 
Description Keystone Symposium plenary 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 700 attendees at conference. Feedback was generally positive

New collaboration
Year(s) Of Engagement Activity 2013
URL http://www.keystonesymposia.org
 
Description News Feature Nature: A tale of two centres 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact An article comparing the work of the Institute of Infectious Diseases and Molecular Medicine with that of the Africa Centre

A much better relationship with the Africa centre such that Wilkinson now serves on the ISAB of the Africa Centre
Year(s) Of Engagement Activity 2007
 
Description News Item Daily Express Monday May 14th 2007 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Newspaper article on the potential benefits of vitamin D supplementation in preventing tuberculosis

Increased awareness of the widespread prevalence of vitamin D deficiency in the UK, especially amongst ethnic minorities
Year(s) Of Engagement Activity 2007
 
Description News item Leicester Mercury 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Item in local newspaper

Raised awareness of tuberculosis as a potential problem amongst schoolchildren
Year(s) Of Engagement Activity 2006
 
Description PET/CT: a window into incipient tuberculosis 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited plenary at American Thoracic Society 2017 symposium A89 Sunday 21st May 2017 Washington DC
Year(s) Of Engagement Activity 2017
 
Description Plenary talk Keystone symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact 'Interaction between antimicrobial and adjunctive therapies and the immune response to tuberculosis' Invited plenary speaker Keystone symposium: Novel therapeutic approaches to tuberculosis 1rd April 2014, Keystone, CO

Increased requests for collaboration and further funding
Year(s) Of Engagement Activity 2014
 
Description Plenary talk, American Thoracic Society, San Diego, CA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 'The potential impact of genomics on tuberculosis control' Plenary talk, American Thoracic Society, San Diego, CA, 1030 Sunday 18th May 2014, Scientific symposium A15
Year(s) Of Engagement Activity 2014
 
Description Press release and subsequent media coverage (Vit D anti-inflammatory) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact 5 print or online articles resulted from the press release.

Increased awareness of the extent of vitamin D deficiency and its immunomodulatory potential in tuberculosis
Year(s) Of Engagement Activity 2012
 
Description Press release and subsequent press coverage 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact A number of articles appeared in the lay media

The profile of tuberculosis research was increased
Year(s) Of Engagement Activity 2010
 
Description Second Plenary talk, American Thoracic Society, San Diego, CA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 'Images of the new spectrum of tuberculosis' Plenary talk, American Thoracic Society, San Diego, CA, 1400 Sunday 18th May 2014, Scientific symposium A87
Year(s) Of Engagement Activity 2014
 
Description Southampton July 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 'The breath, heart and mind of HIV-associated tuberculosis' Department of Medicine, University of Southampton, 3rd July 2013

Potential new collaboration
Year(s) Of Engagement Activity 2013
 
Description The Pathogenesis of progressive HIV-associated tuberculosis 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker at Federation of African Immunological Societies, 10th African Congress of Immunology, Hammamet, Tunisia, 4th December 2017
Year(s) Of Engagement Activity 2017
 
Description The cause and management of HIV-associated tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited plenary at ID week 2017 (IDSA/HIVMA/PIDSA/SHEA) Thursday 5th October 2017, San Diego, CA, United States of America
Year(s) Of Engagement Activity 2017
 
Description The role in research of imaging and biomarkers in tuberculosis 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker in Symposium on hot topics in tuberculosis research, 28th European Congress of Clinical Microbiology, Madrid, Spain 24th April 2018
Year(s) Of Engagement Activity 2018
 
Description Transcriptomic profiling of hyperinflammatory tuberculosis 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Symposium on Infection, Lee Kong Chian School of Medicine, 1130, 1st February 2019, Singapore
Year(s) Of Engagement Activity 2019
 
Description Tuberculosis biomarker research at the Wellcome Centre for Infectious Diseases Research in Africa, Cape Town 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact 5th SA TB conference, Durban, Republic of South Africa, June 12th 2018
Year(s) Of Engagement Activity 2018
 
Description Tuberculous meningitis 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited plenary at Tuberculosis workshop: ID week 2017 (IDSA/HIVMA/PIDSA/SHEA) Wednesday 4th October 2017, San Diego, CA
Year(s) Of Engagement Activity 2017
 
Description Ugandan televison appearance 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Interview on Ugandan television
Year(s) Of Engagement Activity 2018
URL https://t.co/qaoJLbmAju
 
Description Understanding and intervening in HIV-associated tuberculosis 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Wednesday 20th September 2017, invited plenary speaker, HIV-tuberculosis workshop Providence/Boston Center for AIDS Research, Boston MA
Year(s) Of Engagement Activity 2017
 
Description Vaccination against tuberculosis 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited plenary at UCL/NIHR Mucosal Pathogens Research Unit, 14 November 2018, Muldersdrift, Republic of South Africa
Year(s) Of Engagement Activity 2018
 
Description Visit of British High Commissioner to South Africa 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact We hosted a visit of the British High Commissioner to South Africa Mr Nigel Casey to our research facilities
Year(s) Of Engagement Activity 2017
 
Description Visit of Sir Simon McDonald, Permanent Under-Secretary at the Foreign and Commonwealth Office and Head of the Diplomatic Service 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact We hosted a visit as above to the Research clinic in Khayelitsha South Africa
Year(s) Of Engagement Activity 2018
 
Description Wellcome Trust College of Peer reviewers 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact peer review

None as yet
Year(s) Of Engagement Activity 2012
 
Description World Tuberculosis day Vancouver 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 'Understanding and intervening in HIV-associated tuberculosis' Plenary speaker at University of British Columbia world TB day programme, Vancouver 18th March 2013

Networking with international colleagues
Year(s) Of Engagement Activity 2013