Optimal timing for Starting Antiretroviral Therapy in HIV-Infected Patients with Cryptococcal Meningitis

July 21, 2014

Physicians who treat patients with cryptococcal meningitis in untreated AIDS patients should be aware that early initiation of antiretroviral therapy is associated with increased mortality.

In most cases, early initiation of antiretroviral therapy after the diagnosis of an opportunistic infection is beneficial. However, starting antiretroviral therapy early in patients with opportunistic infections runs the risk of immune reconstitution syndrome.1

Cryptococcal meningitis accounts for up to one quarter of acquired immunodeficiency syndrome-related deaths in Africa.2,3 A recent study published in the New England Journal of Medicine examines the optimal timing of starting antiretroviral therapy in patients with cryptococcal meningitis. The study enrolled 117 HIV-infected patients in Uganda and South Africa who had cryptococcal meningitis and who had not previously received antiretroviral therapy. Participants were randomly assigned to receive either antiretroviral therapy within 1 to 2 weeks of diagnosis (early therapy) or at 5 weeks after diagnosis. In addition to antiretroviral therapy, participants received amphotericin B and fluconazole for treatment of cryptococcal meningitis.1

Interestingly, patients who were assigned to the early-initiation arm had a much higher mortality (45% [40 of 88 patients] vs30% [27 of 89 patients]; hazard ratio for death, 1.73; 95% CI, 1.06 to 2.82; P=0.03).1 Notably, clinical cryptococcal immune reconstitution inflammatory syndrome did not significantly differ between the earlier-ART group and the deferred-ART group (20% and 13%, respectively; P=0.32). In the subgroup of patients with a white cell count of less than 5 cells per cubic millimeter in the cerebrospinal fluid, mortality was particularly higher with earlier ART than with deferred ART (hazard ratio, 3.87; 95% CI, 1.41 to 10.58; P=0.008). The difference in outcomes between the two arms of the study was significant enough to stop the trial early by the data and safety monitoring board.

This study highlights the complex interaction between the immune system and different opportunistic infections that occur in AIDS. Even though untreated AIDS presenting with severe opportunistic infections may not be as common in the United States, physicians who treat patients with cryptococcal meningitis in untreated AIDS patients should be aware of the implications of this important study.


1. Boulware DR, Meya DB, Muzoora C, et al. COAT Trial Team. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014; 26;370:2487-2498.

2. Jarvis JN, Meintjes G, Williams A, et al. Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected cases.BMC Infect Dis. 2010;10-67.

3. Cohen DB, Zijlstra EE, Mukaka M, et al. Diagnosis of cryptococcal and tuberculous meningitis in a resource-limited African setting. Trop Med Int Health. 2010;15:910-917.