When Should ART Be Started in HIV-Infected Patients with Cryptococcal Meningitis?

June 25, 2014

When Should ART Be Started in HIV-Infected Patients with Cryptococcal Meningitis?

  1. Carlos del Rio, MD

In a randomized trial conducted in Africa, deferring antiretroviral therapy initiation for 5 weeks after diagnosis of meningitis was associated with significantly improved survival.

  1. Carlos del Rio, MD

Increasingly, studies have suggested benefit from early initiation of antiretroviral therapy (ART) after diagnosis of an opportunistic infection, including tuberculosis (NEJM JW AIDS Clin Care Jun 22 2009). However, early ART is seemingly not beneficial for patients with tuberculous meningitis, and the evidence remains mixed for those with cryptococcosis. In a recent trial conducted in Uganda and South Africa, researchers investigated the timing of ART initiation in HIV-infected patients with cryptococcal meningitis.

The 177 participants received induction therapy with 2 weeks of amphotericin B and high-dose fluconazole, followed by consolidation therapy with fluconazole. After 7 to 11 days of antifungal treatment, they were randomized to receive early ART (initiated ≤48 hours after randomization) or deferred ART (initiated 4 weeks after randomization). The ART regimens were predominantly AZT/3TC/efavirenz (80%) or d4T/3TC/efavirenz (19%).

The patients were randomized a median of 8 days after initiation of amphotericin B. The median time between diagnosis of cryptococcal meningitis and ART initiation was 9 days for the early-ART group and 36 days in the deferred-ART group. Mortality at 26 weeks — the primary study endpoint — was significantly higher in the early-ART group than in the deferred-ART group (45% vs. 30%; hazard ratio, 1.73; 95% confidence interval, 1.06–2.82). The between-group difference in mortality occurred early in therapy (2–5 weeks after diagnosis). Participants with low cerebrospinal fluid (CSF) white-cell counts (<5 cells/mm3) at randomization had particularly high mortality with early ART. No other participant characteristic, including a low CD4-cell count, affected between-group mortality differences. The timing of ART did not influence any of the secondary endpoints (survival at 46 weeks, cryptococcal immune reconstitution inflammatory syndrome, relapse of cryptococcal meningitis, fungal clearance, virologic suppression at 26 weeks, ART discontinuation for >3 days, or adverse events).


These findings should settle the question of when to begin ART in patients with cryptococcal meningitis: It should not be initiated until 5 weeks after the start of amphotericin B therapy. This delay is particularly important for patients with CSF white-cell counts <5 cells/mm3. The findings might also make clinicians reluctant to start ART early after other central nervous system infections in HIV-infected patients, such as coccidioidal or histoplasmic meningitis.

Editor Disclosures at Time of Publication

  • Disclosures for Carlos del Rio, MD at time of publication Grant / Research support NIH; NIH/National Institute of Allergy and Infectious Diseases; NIH/Fogarty International Center; CDC; NIH/National Institute on Drug Abuse; MANILA Consulting Group, Inc.; NIH/National Institute of Mental Health; Janssen Services; Addis Ababa University; George Washington University Editorial boards AIDS Research and Human Retroviruses; Journal of AIDS Leadership positions in professional societies HIV Medicine Association (Board of Directors); International AIDS Society-USA (Board of Directors)


Reader Comments (1)

JOVEN JEBIO ONGOLE Piet Retief Hospital, TB/HIV Integrated Wellness Clinic, Department of Health South Africa

The study give good insight into the impact of early ART initiation in first 6 months, which fades away in the one year. Thinking out of the box and knowing that it is ethically not acceptable with availability of treatment, could the mortality rate seen at 26 weeks in early initiation matched CCM patients who never received ART.

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