Independent Association between Rate of Clearance of Infection and Clinical Outcome of HIV-Associated Cryptococcal Meningitis: Analysis of a Combined Cohort of 262 Patients

• Published in: Clinical infectious diseases Vol. 49; no. 5; pp. 702 - 709
• Main Authors: Bicanic, Tihana, Muzoora, Conrad, Brouwer, Annemarie E., Meintjes, Graeme, Longley, Nicky, Taseera, Kabanda, Rebe, Kevin, Loyse, Angela, Jarvis, Joseph, Bekker, Linda-Gail, Wood, Robin, Limmathurotsakul, Direk, Chierakul, Wirongrong, Stepniewska, Kasia, White, Nicholas J., Jaffar, Shabbar, Harrison, Thomas S.
• Format: Journal Article
• Language: English
• Published: Oxford The University of Chicago Press 01.09.2009; University of Chicago Press; Oxford University Press
• Subjects: Adult; AIDS; AIDS-Related Opportunistic Infections - cerebrospinal fluid; AIDS-Related Opportunistic Infections - drug therapy; AIDS-Related Opportunistic Infections - mortality; Antifungal Agents - therapeutic use; Antifungals; Antiviral drugs; Articles and Commentaries; Biological and medical sciences; Cerebrospinal fluid; Cerebrospinal Fluid - microbiology; Clinical outcomes; Cohort Studies; Colony Count, Microbial; Cryptococcal meningitis; Cryptococcus; Cytokines; Data processing; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drugs; Female; Fluconazole - therapeutic use; Fungi; Fungicidal activity; gamma -Interferon; Health outcomes; HIV; Human immunodeficiency virus; Human mycoses; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunodeficiency; Immunopathology; Infection; Infections; Infectious diseases; Interferon; Interferon-gamma - cerebrospinal fluid; Male; Medical sciences; Meningitis; Meningitis, Cryptococcal - cerebrospinal fluid; Meningitis, Cryptococcal - drug therapy; Meningitis, Cryptococcal - mortality; Miscellaneous mycoses; Mortality; Mycoses; Prognosis; Proportional Hazards Models; Prospective Studies; Randomized Controlled Trials as Topic; South Africa; Statistics; Survival; Thailand; Therapy; Time Factors; Treatment Outcome; Uganda; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Thailand; South Africa; Uganda; Human; Immunopathology; Nervous system diseases; Prognosis; Mycosis; Cryptococcosis; Retroviridae; AIDS; Clearance; Immune deficiency; Lentivirus; Infection; Virus; Viral disease; Central nervous system disease; Meningitis; Human immunodeficiency virus
• ISSN: 1058-4838; 1537-6591; 1537-6591
• DOI: 10.1086/604716

Background. Progress in therapy for cryptococcal meningitis has been slow because of the lack of a suitable marker of treatment response. Previously, we demonstrated the statistical power of a novel endpoint, the rate of clearance of infection, based on serial quantitative cultures of cerebrospinal fluid, to differentiate the fungicidal activity of alternative antifungal drug regimens. We hypothesized that the rate of clearance of infection should also be a clinically meaningful endpoint. Methods. We combined data from cohorts of patients with human immunodeficiency virus-associated cryptococcal meningitis from Thailand, South Africa, and Uganda, for whom the rate of clearance of infection was determined, and clinical and laboratory data prospectively collected, and explored the association between the rate of clearance of infection and mortality by Cox survival analyses. Results. The combined cohort comprised 262 subjects. Altered mental status at presentation, a high baseline organism load, and a slow rate of clearance of infection were independently associated with increased mortality at 2 and 10 weeks. Rate of clearance of infection was associated with antifungal drug regimen and baseline cerebrospinal fluid interferon-γ levels. Conclusions. The results support the use of the rate of clearance of infection or early fungicidal activity as a means to explore antifungal drug dosages and combinations in phase II studies. An increased understanding of how the factors determining outcome interrelate may help clarify opportunities for intervention.