Deferred ART Could Improve Survival in HIV Meningitis

Veronica Hackethal, MD

June 27, 2014

Patients with HIV and cryptococcal meningitis have improved survival when the initiation of antiretroviral therapy is deferred until 5 weeks after the diagnosis, according to results from the Cryptococcal Optimal ART Timing (COAT) Trial, published in the June 26 issue of the New England Journal of Medicine.

Enrollment in the study was stopped early because of "substantial" excess mortality in the group with earlier ART initiation. During study days 8 through 30, 28% of participants who received earlier ART died compared with 10% who received deferred ART.

Cryptococcal meningitis causes 20% to 25% of AIDS-related deaths in Africa, according to David R. Boulware, MD, MPH, from the University of Minnesota, Minneapolis, and the Infectious Disease Institute, Makerere University, Kampala, and colleagues. Immune reconstitution inflammatory syndrome (IRIS) occurs in reaction to ART. Although the standard of care has shifted to early ART initiation, its benefits in meningitis are uncertain, as IRIS that occurs in the brain can be fatal. Some studies suggest early ART can improve meningitis outcomes, whereas others indicate the opposite.

The researchers looked at survival at 26 weeks in 177 HIV-infected adults in Uganda and South Africa. Participants had been diagnosed with cryptococcal meningitis and were naive to ART therapy. The researchers enrolled patients between November 2010 and February 2011 and ended early on the recommendation of the data and safety monitoring board

Researchers randomly assigned participants to earlier ART (1 - 2 weeks after meningitis diagnosis) or deferred ART (5 weeks after diagnosis). Participants received amphotericin B and fluconazole for 14 days, followed by extended treatment with fluconazole. Ninety-nine percent of participants remained in the study as outpatients.

At 26 weeks, the earlier ART group had significantly higher mortality compared with the deferred ART group (45% vs 30%; hazard ratio for death, 1.73; 95% confidence interval [CI], 1.06 - 2.82; P = .03). Excess death in the earlier ART group happened between 2 and 5 weeks after diagnosis (hazard ratio, 3.10; 95% CI, 1.37 - 7.00; P = .007).

Participants with few white cells in their cerebrospinal fluid had the highest risk for death from earlier ART compared with deferred ART (hazard ratio, 3.87; 95% CI, 1.41 - 10.58; P = .008).

The incidence of IRIS did not differ significantly between the 2 groups (P = 0.32). The authors mentioned that limitations in the IRIS definition could have underestimated earlier IRIS incidence. Differentiating between meningitis or IRIS as the cause of death in the earlier ART group was not always possible. IRIS events were more clear-cut among patients who started to improve and then deteriorated after starting ART.

Earlier ART could be "detrimental" in central nervous system infections, the authors hypothesize, as the confines of the system do not allow for compression caused by IRIS-associated inflammation. As a result, patients who have not fully recovered from the initial meningitis insult would receive a "second insult" from IRIS. Earlier ART, then, could be "most harmful" in high-risk patients, such as those predisposed to cryptococcal IRIS.

"With earlier ART, it was difficult to determine whether deterioration early after randomization was due to cryptococcal IRIS or to progressive sequelae of cryptococcal meningitis," the authors conclude. "Nevertheless, earlier ART initiation was associated with significant excess mortality."

Supported by grants from the National Institute of Allergy and Infectious Diseases, the Wellcome Trust, and the Veterans Affairs Research Service. The President's Emergency Plan for AIDS Relief supported HIV care and provided ART in Uganda; ART was provided by the Department of Health in South Africa. Merck Sharp & Dohme donated a reserve supply of efavirenz. Various authors have reported receiving grant support from the National Institutes of Health. Dr. Boulware has reported receiving nonfinancial support from Merck. One coauthor has reported receiving grant support from Fogarty International.

N Engl J Med. 2014;370:2487-2498. Abstract

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