Symptomatic Relapse of HIV‐Associated Cryptococcal Meningitis after Initial Fluconazole Monotherapy: The Role of Fluconazole Resistance and Immune Reconstitution

BACKGROUND: Cryptococcal meningitis (CM) in South Africa is often treated with fluconazole as initial therapy. Surveillance data suggest that the prevalence of fluconazole-resistant CM is increasing, and expanding access to antiretroviral therapy is resulting in increasing recognition of immune reconstitution inflammatory syndrome. Therefore, we conducted a study to assess the contribution of these factors to CM relapse in this context. METHODS: Patients with symptomatic relapse of CM were prospectively identified at 2 hospitals in Cape Town, South Africa, during the period of 2003-2005. Patients met the following criteria: (1) a previous laboratory-confirmed episode of CM, with resolution of symptoms after treatment; (2) reported adherence to fluconazole treatment; (3) recurrence of typical CM symptoms; (4) cerebrospinal fluid antigen test and/or culture positive for Cryptococcus neoformans; and (5) no alternative diagnosis. Data on patients' human immunodeficiency virus (HIV) and CM infections and treatment were collected and analyzed. RESULTS: Thirty-two episodes of relapse occurred among 27 patients. Episodes were classified into 3 groups: culture-positive episodes in antiretroviral therapy-naive patients (6 episodes), culture-positive episodes in patients receiving antiretroviral therapy (15 episodes), and culture-negative episodes in patients receiving antiretroviral therapy (11 episodes). Seventy-six percent of culture-positive relapses were associated with isolates that had reduced susceptibility to fluconazole. Drug-resistant cases required prolonged intravenous therapy with amphotericin B, and despite this treatment, the mortality rate was high (54% at a median of 6 months of follow-up). Despite a long interval between initiation of antifungal therapy and initiation of antiretroviral therapy (median interval, 144 days), immune reconstitution inflammatory syndrome contributed to at least one-third of relapses. CONCLUSIONS: After initial treatment with fluconazole, relapses of symptomatic CM are often associated with fluconazole resistance and immune reconstitution inflammatory syndrome. These data add to concern about the efficacy of fluconazole, compared with amphotericin B, for initial treatment of HIV-associated CM.