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N Engl J Med. 2014 Jun 26;370(26):2487-98. doi: 10.1056/NEJMoa1312884.

Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis.

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  • 1From the University of Minnesota, Minneapolis (D.R.B., D.B.M., M.A.R., K.H.H., D.A.W., R.R., J.R., M.W.L., K.N., T.L.B., P.R.B.); the Infectious Disease Institute (D.B.M., A.M., H.W.N., D.A.W., R.R., J.R., M.W.L., A.K., Y.C.M.) and School of Medicine, College of Health Sciences (D.B.M.), Makerere University, Kampala, and Mbarara University of Science and Technology, Mbarara (C.M., K.T.) - both in Uganda; the University of Cape Town, Cape Town, South Africa (C.S., F.T., G.M.); Johns Hopkins School of Medicine, Baltimore (Y.C.M.); the Mucosal and Vaccine Research Program Colorado (MAVRC), University of Colorado Denver, Aurora, and Denver Veterans Affairs Medical Center, Denver (E.N.J.); and Imperial College London, London (G.M.).

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.).

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