Cryptococcal Meningitis in The Tropics: Defining the Problem and Refining the Management

The basis of my thesis is the CryptoDex trial, a randomized controlled trial of adjunctive dexamethasone in HIV-associated cryptococcal meningitis, in 6 countries in Southeast Asia and Africa. This trial, which demonstrated harm from dexamethasone, is presented in detail in Chapter 6. To contextualize the trial, and to get a better sense of the burden of cryptococcal meningitis in Vietnam, I estimated the burden of all the major invasive fungal infections in Vietnam. An actuarial approach to making these estimates was used, and showed that the leading fungal pathogen is likely to be Aspergillus. The CryptoDex trial was stopped early on the basis of an excess of adverse events in the intervention arm. Therefore, in chapter 7, I investigate the ethical, statistical, and logistical issues around stopping clinical trials early, and provide a detailed case study of our experience with early termination. Finally, to better understand how the harmful effects of dexamethasone were mediated, I characterized markers of immune response in the cerebrospinal fluid of the study patients and described their relationship with clinical and microbiological outcomes. Here I found that dexamethasone shifted CSF cytokine concentrations from a Th1 to a Th2 profile, and that this was associated with poorer clearance of fungi.