June 2nd, 2012

Cryptococcal Meningitis Study Stopped — Early HIV Therapy Clearly Harmful

From NIAID, an important clinical trial has been stopped early:

The Phase IV study … was evaluating whether HIV-infected participants hospitalized with cryptococcal meningitis (CM) but not yet taking antiretroviral therapy (ART) would improve their chances of survival if they began ART while receiving CM treatment as inpatients compared with the standard practice of beginning ART as outpatients, approximately five weeks after receiving CM treatment. Two reviews of the COAT trial’s safety and effectiveness data last month by an independent data and safety monitoring board (DSMB) found substantially higher mortality rates among the 87 participants who received early ART compared with the 87 participants who received delayed HIV treatment.

More details on the study design can be found here, and we’ll undoubtedly hear and read additional details on the results in an upcoming meeting and when the paper is published. But since it was stopped after only 174 (out of a planned 500) enrolled, the difference between the two strategies must have been really huge. [See edit below.]

Until then, we can postulate that ART-induced immune response — IRIS — triggered inflammation, which could have worsened intracranial pressure and other manifestations of cryptococcal disease. Inflammation is just bad news in meningitis. This could explain why crypto and perhaps TB meningitis seem to be the exceptions to the rule that early ART is beneficial with acute OIs — a strategy confirmed now in several clinical trials (ACTG 5164 and these three TB studies: SAPIT, STRIDE, and CAMELIA).

Importantly, the study confirms the results of this other cryptococcal meningitis study (which amazingly was led by one of our ID fellows before she started fellowship — how’s that for impressive?), but differs in at least two important ways: First, initial therapy was with the standard-of-care amphotericin B and not fluconazole; and second, the ART was efavirenz- not nevirapine-based. Both of these address at least some of the concerns about the earlier study’s generalizability.  A5164 did not find that early ART was harmful in crypto meningitis; however, the number of study subjects with cryptococcosis was relatively small (35 out of 282).

Though the COAT trial was conducted in Uganda and South Africa, the results have immediate applicability to practice world-wide. Early ART in cryptococcal meningitis is clearly harmful, and clinicians should delay starting ART for at least 5-6 weeks in their patients with the disease.

And the study reminds us more broadly that critical studies on the optimal management of HIV-related OIs will necessarily need to come from outside the United States and Western Europe.

[Edit:  David Boulware, the PI of the COAT trial, kindly provided a bit more data on the study results. He noted that the “absolute difference in 6-month survival is approx. 15% between the two arms (with ongoing follow up still occurring through October 2012)”, which is perhaps not as big an effect as I had anticipated. However, the message remains the same – early ART after cryptococcal meningitis decreases survival, and should be avoided. He also noted that linkage to outpatient HIV care remains a very important consideration for delayed ART.]

3 Responses to “Cryptococcal Meningitis Study Stopped — Early HIV Therapy Clearly Harmful”

  1. Rob says:

    Thanks for an excellent synopsis on this tricky topic. Here where I practice in South Africa (238 bed regional hospital), we often see patients who respond clinically (improved headaches, better functional status, less visual disturbance, less vomiting) to appropriately dosed IV Amphoterocin B for 2/52, yet their CLATs often don’t respond and may be as high as 512 or 1024 after therapy. I have reasonable success starting ART once patients are improved/symptom free (usually about 3 weeks after diagnosis or (re)treatment), but it really is a tightrope you walk. Would be interested to hear your advice regarding starting of ART in a patient with Ampho B resistant CM. Regards

    • Paul Sax says:


      I wouldn’t necessarily consider the CM resistant to ampho b, but just slow-to-respond — and CM has always been tough to treat. The COAT study (plus the earlier one) say we should wait until 5-6 weeks of antifungal therapy before starting ART, and that’s what I’ll plan to do going forward.


  2. Kristin Darin says:

    Dr. Sax – Thank you for summarizing this important information, as well as providing the extra details from the PI on the observed mortality rates. By chance – do you happen to know if CSF pressures were checked routinely at baseline / during the study and subsequently if CSF drainage was performed as needed?

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

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NEJM Journal Watch
Infectious Diseases

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