1. Dr Angela Loyse CI
Dr Sayoki Mfinanga PI-National Institute Medical Research Tanzania
Dr Cecilia Kanyama PI-UNC Project Malawi
Dr Charles Kouanfack PI-Hôpital Central Yaoundé, Cameroon
Dr Sile Molloy PI/Epidemiologist
Ms Aude Sturny-Leclerc-Ingénieure Institut Pasteur

2. The road less travelled?
Implementation project centred around hard clinical mortality end point.
Integrated approach to diagnosis and treatment of HIV-associated meningo-encephalitis using latest rapid diagnostic tests and optimised treatment regimens.
Routine care hospital staff implementing algorithmic approach.

3. Second generation cryptococcal antigen lateral flow assays (CrAg LFAs)
Immy FDA-approved LFA

4. Bedside / POC tests
Implementation of ACTA

5. Outline DREAMM study
Multi-centre study with evaluation done using a before-after design.
3 representative and geographically distinct African sites:
-Dar Es Salaam, Tanzania.
-Yaoundé, Cameroon.
-Lilongwe, Malawi.
Triad: Local African researcher principal investigator led.
Local hospital physician leadership.
Ministry of Health (MOH) backing from the outset.
Institut Pasteur & Centers for Disease Prevention and Control (CDC) backing.

6. Aims-DREAMM study Reduce all cause 2 and 10 week mortality.
Reduce time to lumbar puncture (LP) & effective treatment.
Improve sustainable access to:
-rapid diagnostic tests (CrAg LFA, urinary lipoarabinomannan (LAM), S.pneumoniae)
-essential antifungal medicines (Amphotericin B (AmB), flucytosine (5-FC)).
Implement study findings (rapid diagnostic tests including CrAg LFA; diagnostic/treatment algorithm; open access training aides) locally and regionally.
Develop new international guidelines for the management HIV-associated meningitis in Africa.

7. Study design Observation Training phase:
-Laboratory & clinical training
Routine care staff +
Optimised local patient & laboratory pathways defined
Implementation of diagnostic/treatment algorithm

8. DREAMM study Endpoints
Clinical
-Time to LP
-Time to appropriate therapy
-2 week & 10 week mortality
Epidemiological
-Prevalence of suspected and microbiologically proven cryptococcal
meningitis
-Prevalence of suspected and microbiologically proven bacterial
meningitis, tuberculous meningitis, bacterial toxoplasmosis
-Proportion of patients presenting with meningitis that are HIV +

9. Diagnostic tests-Tuberculous meningitis
Xpert MTB/RIF Ultra-
Urine & cerebrospinal fluid (CSF) samples
TB-LAM.
Smear-large volume (>7mL) CSF and 30 minute examination significantly improve sensitivity.
Culture (60% sensitivity).
Lawn SD et al BMC Medicine 2013; 11: 231.
Lawn SD et al BMC Medicine 2015; 13: 192.
Maynard-Smith et al BMC Infectious Diseases 2014; 14:709.
Cox JA et al Journal Clinical Microbiology 2015; 53:

10. Public health impact
Three study sites will work as test sites within each country.
Audit and implementation phase data fed back to MOHs.
Key role of MOHs in:
-Access to essential medicines and rapid diagnostic tests (drug registration etc…).
-Funding applications (Global Fund Concept notes).
-Developing new HIV-associated meningo-encephalitis guidelines for Africa.
Pasteur, ANRS and CDC backing.
Dissemination study findings, rapid diagnostic tests, training program and teaching aides and validation of devised guidelines.

11. Polyvalent tests (CrAg/HIV & CrAg/S.pneumoniae)
Work with Institut Pasteur
Conceived idea of polyvalent CrAg LFA/HIV point of care test.
Impact for integration of CrAg screening into WHO’s ‘test and treat programs’ where in a number of LMICs baseline CD4 counts not being done.
Health economics and social science evaluation within WHO ‘test & treat’ programs
Evaluation of CrAg/S. pneumoniae LFA & CrAg/HIV LFA within DREAMM
Both at prototype phase of development

12. Future options? Nanopore technology
Single-molecule nanopore genome
sequencing.
Simple and robust technology.
Used as point of care genomic surveillance.
Translate technology for diagnosis of HIV-associated meningitis in Africa.
Identify and track the dynamics of key mutations, such as those conferring virulence and/or drug resistance in vivo and in situ.

13. DREAMM Team UNC Project Lilongwe, Malawi Institut Pasteur
Dr Cecilia Kanyama-PI
Dr Tarsizio Chikaonda
Prof Mina Hosseinipour
NIMR Tanzania
Dr Sayoki Mfinanga-PI
Dr Sokoine Lesikari
Hôpital Central Yaoundé, Cameroon/ANRS
Dr Charles Kouanfack-PI
Prof Sinata Koulla-Shiro
M. Calice Talom (patient representative)
CDC
Dr Tom Chiller
Clinton Health Access Initiative (CHAI)
Ms Vivienne Mulema
Edendale Hospital
Dr Douglas Wilson
University of Douala
Prof Yacouba Mapoure
Institut Pasteur
Ms Aude Sturny-Leclerc
Prof Olivier Lortholary
Prof Francoise Dromer
St George’s University of London
Dr Sile Molloy
M Muirgen Stack
Ms Claire Robb
M Jack Adams
Ms Sarah Burton
Prof Tom Harrison
Prof Anne-Marie Reid (Dean of Education)
Dr Tariq Sadiq (optimisation of nanopore technology)
Dr Sebastian Fuller
LSTM
Prof Shabbar Jaffar
LSHTM
Prof Robin Bailey
National Institute Communicable Diseases
Dr Nelesh Govender