Dr Angela Loyse CI Dr Sayoki Mfinanga PINational

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 meningoencephalitis using latest rapid diagnostic tests and optimised treatment regimens. • Routine care hospital staff implementing algorithmic approach.

Second generation cryptococcal antigen lateral flow assays (Cr. Ag 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 (Cr. Ag LFA, urinary lipoarabinomannan (LAM), S. pneumoniae) -essential antifungal medicines (Amphotericin B (Am. B), flucytosine (5 -FC)). • Implement study findings (rapid diagnostic tests including Cr. Ag 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 (>7 m. L) CSF and 30 minute examination • Culture (60% sensitivity). significantly improve 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 (Cr. Ag/HIV & Cr. Ag/S. pneumoniae) • Work with Institut Pasteur • Conceived idea of polyvalent Cr. Ag LFA/HIV point of care test. • Impact for integration of Cr. Ag screening into WHO’s ‘test and treat programs’ where in a number of LMICs baseline CD 4 counts not being done. • Health economics and social science evaluation within WHO ‘test & treat’ programs • Evaluation of Cr. Ag/S. pneumoniae LFA & Cr. Ag/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 Ms Aude Sturny-Leclerc Prof Olivier Lortholary Prof Francoise Dromer • NIMR Tanzania • St George’s University of London Dr Sayoki Mfinanga-PI Dr Sokoine Lesikari 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 • 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 • LSTM Prof Shabbar Jaffar • LSHTM Prof Robin Bailey • National Institute Communicable Diseases Dr Nelesh Govender