Therapy of AIDS-Related Cryptococcal Meningitis

Abstract

Cryptococcal meningitis is a common and severe opportunistic infection in advanced HIV, with the highest burden of disease in resource-poor settings in sub-Saharan Africa. It is invariably fatal if left untreated, and carries a high mortality even with treatment. High fungal burden, raised intracranial pressure, and reduced level of consciousness at presentation are associated with poorer outcomes. The recommended treatment strategy consists of a two-week induction phase, then eight weeks of consolidation therapy, followed by long-term maintenance therapy until restoration of immune function by antiretroviral therapy (ART) for HIV. Induction treatment should consist of a rapidly fungicidal drug. Amphotericin B has demonstrated superiority to fluconazole both in terms of fungicidal activity and mortality outcomes. A combination of amphotericin B at 1 mg/kg/day plus flucytosine 100 mg/kg/day has been associated with a reduction in mortality as compared to amphotericin B alone. This regimen should be used where available, with fluconazole as an acceptable alternative second agent if flucytosine is unavailable. In resource-limited settings where both amphotericin B and flucytosine are often unavailable, fluconazole monotherapy is still often used. In this setting, high-dose fluconazole at 1,200 mg/day should be used as induction therapy, although fungal clearance with this regimen is inferior to amphotericin B-based therapy. Consolidation and maintenance therapy with fluconazole is recommended. Aggressive management of raised intracranial pressure by repeated therapeutic lumbar puncture is an essential adjunct to antifungal chemotherapy. Surgical intervention, such as ventriculoperitoneal shunting for refractory raised intracranial pressure, is rarely required. In patients who are not already on ART, this should be commenced no earlier than four weeks after starting induction treatment for cryptococcal meningitis, as earlier initiation of ART may be associated with immune reconstitution inflammatory syndrome (IRIS). There are ongoing efforts to evaluate fluconazole and flucytosine combination therapy as an alternative induction regimen, as well as shorter courses of amphotericin B, in resource-poor settings with limited access to antifungal agents.