Thèse de doctorat en Sciences de la vie et de la santé
Sous la direction de Olivier Lortholary.
Soutenue le 20-10-2017
à Sorbonne Paris Cité , dans le cadre de École doctorale Bio Sorbonne Paris Cité (Paris) , en partenariat avec Université Paris Descartes (1970-2019) (établissement de préparation) et de Mycologie moléculaire (laboratoire) .
Le président du jury était François Dabis.
Épidémiologie et prise en charge optimale de la méningo-encéphalite à cryptocoque associée au sida au Cameroun
Pas de résumé
Cryptococcal meningitis (CM), caused by an encapsulated yeast is a leading cause of AIDS related opportunistic infection in adults in sub-Saharan Africa and a major driver of mortality, second to tuberculosis. We aimed at optimising the management of AIDS-related cryptococcal meningitis in Cameroon through interventional studies. As such, we designed and performed three studies on the role of cryptococcal antigen (CrAg) in CM diagnosis, contributed in a major phase III non-inferiority clinical trial for inductive treatment of CM in the African setting and analysed the trial participants’ tolerability of the antifungals used in the trial. We also contributed in a review on the long-term prognosis of CM and finally in an advocacy paper for CM to be recognised as a neglected tropical disease. In Cameroon, serum CrAg detection, a major risk factor for incident CM in AIDS patient is prevalent in 7.5% of patients initiating antiretroviral therapy (ART) at less than 100 CD4 cells/μL, of whom 45% have cerebrospinal fluid (CSF) evidence of asymptomatic CM. The new Biosynex CryptoPS test for CrAg detection is comparable to the IMMY lateral flow assay test and shows promise for correctly classifying patients with high serum CrAg titre, a predictor of confirmed CM. Post CrAg screening, enhanced adherence to ART and to fluconazole-based pre-emptive therapy to CrAg positive patients who present with no CM is effective in preventing incident CM within the first year of ART. In HIV patients presenting with symptoms of central nervous system disease, compared to Indian ink staining and/or culture of CSF, serum CrAg detection is highly presumptive of CM and CSF CrAg detection is diagnostic of first episode of CM. In African patients with confirmed CM, inductive therapy based on oral fluconazole-flucytosine combination or seven-day amphotericin B-flucytosine combination are as effective and more tolerated than standard fourteen-day amphotericin B-flucytosine combination. In spite advances in HIV care, mortality due to CM remains unacceptably high warranting CM to be recognised as a neglected tropical disease for which targeted resources need to be allocated to reduce HIV-related mortality. Overall, in Cameroon, putting in place of local pragmatic algorithms based on the availability of simple but highly performant diagnostic tools and sustainable recommended treatment are indispensable to decrease AIDS-associated CM-related morbidity and mortality.