Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis
Top Cited Papers
- 26 June 2014
- journal article
- research article
- Published by Massachusetts Medical Society in New England Journal of Medicine
- Vol. 370 (26), 2487-2498
- https://doi.org/10.1056/nejmoa1312884
Abstract
Cryptococcal meningitis accounts for 20 to 25% of acquired immunodeficiency syndrome–related deaths in Africa. Antiretroviral therapy (ART) is essential for survival; however, the question of when ART should be initiated after diagnosis of cryptococcal meningitis remains unanswered. We assessed survival at 26 weeks among 177 human immunodeficiency virus–infected adults in Uganda and South Africa who had cryptococcal meningitis and had not previously received ART. We randomly assigned study participants to undergo either earlier ART initiation (1 to 2 weeks after diagnosis) or deferred ART initiation (5 weeks after diagnosis). Participants received amphotericin B (0.7 to 1.0 mg per kilogram of body weight per day) and fluconazole (800 mg per day) for 14 days, followed by consolidation therapy with fluconazole. The 26-week mortality with earlier ART initiation was significantly higher than with deferred ART initiation (45% [40 of 88 patients] vs. 30% [27 of 89 patients]; hazard ratio for death, 1.73; 95% confidence interval [CI], 1.06 to 2.82; P=0.03). The excess deaths associated with earlier ART initiation occurred 2 to 5 weeks after diagnosis (P=0.007 for the comparison between groups); mortality was similar in the two groups thereafter. Among patients with few white cells in their cerebrospinal fluid (<5 per cubic millimeter) at randomization, mortality was particularly elevated with earlier ART as compared with deferred ART (hazard ratio, 3.87; 95% CI, 1.41 to 10.58; P=0.008). The incidence of recognized cryptococcal immune reconstitution inflammatory syndrome did not differ significantly between the earlier-ART group and the deferred-ART group (20% and 13%, respectively; P=0.32). All other clinical, immunologic, virologic, and microbiologic outcomes, as well as adverse events, were similar between the groups. Deferring ART for 5 weeks after the diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at 1 to 2 weeks, especially among patients with a paucity of white cells in cerebrospinal fluid. (Funded by the National Institute of Allergy and Infectious Diseases and others; COAT ClinicalTrials.gov number, NCT01075152.)This publication has 38 references indexed in Scilit:
- Integration of Antiretroviral Therapy with Tuberculosis TreatmentNew England Journal of Medicine, 2011
- Timing of Antiretroviral Therapy for HIV-1 Infection and TuberculosisNew England Journal of Medicine, 2011
- Clinical Features and Serum Biomarkers in HIV Immune Reconstitution Inflammatory Syndrome after Cryptococcal Meningitis: A Prospective Cohort StudyPLoS Medicine, 2010
- Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitionsThe Lancet Infectious Diseases, 2010
- Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndromeAIDS, 2010
- Paucity of Initial Cerebrospinal Fluid Inflammation in Cryptococcal Meningitis Is Associated with Subsequent Immune Reconstitution Inflammatory SyndromeThe Journal of Infectious Diseases, 2010
- Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected casesBMC Infectious Diseases, 2010
- Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of AmericaClinical Infectious Diseases, 2010
- Independent Association between Rate of Clearance of Infection and Clinical Outcome of HIV‐Associated Cryptococcal Meningitis: Analysis of a Combined Cohort of 262 PatientsClinical Infectious Diseases, 2009
- Outcomes of Cryptococcal Meningitis in Uganda Before and After the Availability of Highly Active Antiretroviral TherapyClinical Infectious Diseases, 2008