Abstract
Cryptococcal meningitis is the leading cause of adult meningitis in patients with HIV, and accounts for 15% of all HIV-related deaths in sub-Saharan Africa. The mainstay of management is effective antifungal therapy, despite a limited arsenal of antifungal drugs, significant progress has been made developing effective treatment strategies by using combination regimens. The introduction of fluconazole as a safe and effective step-down therapy allowed for shorter courses of more fungicidal agents to be given as induction therapy, with higher doses achieving more rapid CSF sterilisation and improved treatment outcomes. The development of early fungicidal activity (EFA), an easily measured surrogate of treatment efficacy, has enabled rapid identification of effective combinations through dose ranging phase II studies, allowing further evaluation of clinical benefit in targeted phase III studies. Recent clinical trials have shown that shorter course induction regimens using one week of amphotericin paired with flucytosine are non-inferior to traditional two-week induction regimens and that the combination of fluconazole and flucytosine offers a viable treatment alternative when amphotericin is unavailable. Access to drugs in many low and middle-income settings remains challenging but is improving, and novel strategies based on single high dose liposomal amphotericin B promise further reduction in treatment complications and toxicities. This review aims to summarise the key findings of the principal clinical trials that have led to the success story of combination therapy thus far.
Highlights
Cryptococcal meningitis (CM) is a severe infection caused by the environmental yeasts Cryptococcus neoformans and Cryptococcus gattii
While rapid initiation of antiretroviral therapy (ART) reduces AIDS progression and death [34], these benefits must be weighed against the risk of immune reconstitution inflammatory syndrome (IRIS), a paradoxical reaction caused by immune recovery
There have been significant advances in the treatment of CM through optimisation of combination antifungal therapies, as summarised in Table 1, with phase III trial design based on prioritisation of combinations, dosages, and schedules of existing drugs using randomised phase II early fungicidal activity (EFA) trials, and support from animal PK/PD modelling
Summary
Cryptococcal meningitis (CM) is a severe infection caused by the environmental yeasts Cryptococcus neoformans and Cryptococcus gattii. CM is primarily seen in patients with impaired cell-mediated immunity, most commonly in the context of advanced HIV (CD4 count < 200) [1]. It remains the leading cause of adult meningitis in sub-Saharan. Antifungal therapy is the mainstay of management, with a mortality rate of 100% in untreated disease [1,2]. CM [3], considerable success has been achieved by optimising combinations of existing drugs. Optimised combination therapy can achieve rapid clearance of infection from the cerebrospinal fluid (CSF), reduce relapse rates, minimise emergent drug resistance, allow a reduction in the duration and toxicity of component agents, and improve patient outcomes when compared to monotherapy. Findings of the principal clinical studies that have led to the success story of combination therapy far
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