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

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.

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

Bedside / POC tests Implementation of ACTA

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.

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.

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

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 +

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: 2267-2673.

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.

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

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.

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