Delayed HIV treatment may be beneficial in cryptococcal meningitis [COAT Trial]

1. For patients with cryptococcal meningitis and AIDS not previously treated with antiretrovirals, survival was better in the group starting antiretrovirals 5 weeks after diagnosis (delayed) vs. the group starting antiretrovirals 1 week after diagnosis (early). 

Evidence Rating Level: 1 (Excellent) 

Study Rundown: Cryptococcal infection begins in the lungs, but often spreads to the central nervous system (CNS) in immunosuppressed individuals, such as those with untreated human immunodeficiency virus infection / acquired immunodeficiency syndrome (HIV/AIDS). In such individuals, the benefits of antiretroviral therapy (ART) must be weighed against the risk of immune reconstitution inflammatory syndrome (IRIS), a condition in which the recovering immune system mounts a potentially harmful inflammatory response to pre-existing infections. IRIS may be particularly dangerous when involving the brain.

The Cryptococcal Optimal ART Timing (COAT) trial is the largest to address the question of whether early or delayed initiation of ART is better in the setting of cryptococcal meningitis. COAT found that mortality was higher in the group receiving ART one week after diagnosis versus the group receiving ART five weeks after diagnosis.

This result is likely to influence clinical practice as the trend has been towards earlier initiation of ART, largely based on evidence favoring early ART in AIDS patients with TB. However, it appears that this is not generalizable to cryptococcal CNS infections.

Click to read the study, published today in NEJM

Relevant Reading: Earlier versus Later Start of Antiretroviral Therapy in HIV-Infected Adults with Tuberculosis; Timing of Antiretroviral Therapy for HIV-1 Infection and Tuberculosis

In-Depth [randomized controlled trial]: 177 patients with cryptococcal meningitis were randomized to start ART either 1 week (early) or 5 weeks (delayed) after diagnosis of meningitis. All patients were treated for cryptococcal meningitis with a regimen of amphotericin and fluconazole. Flucytosine was not used because it is not available in low/middle-income countries.

Overall, the risk of death was higher in the early ART group (hazard ratio 1.73, p=0.03). Most of the mortality occurred during days 8 through 30 of the 26 week follow-up period. Interestingly, there was no significant difference in recognized IRIS between the two groups, though this may reflect issues with IRIS case definition rather than underlying pathophysiology. Also of note was the finding that mortality was greatest among those who received early ART and had low numbers of CSF white cells (<5mm/cm³) at randomization.

The trial was stopped early due to the clear difference between the delayed and early arms. However, this limits the size of the trial and the power to derive conclusions from the subgroup analyses.

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