June 24th, 2009

An Irrational Fear of IRIS?

One of the most important recent studies in HIV has just been “published” in (on?) PLoS ONE.  It’s ACTG 5164, led by Andrew Zolopa, which compared “early” versus “deferred” antiretroviral therapy in 282 patients presenting with acute opportunistic infections.

(Full disclosure: I am on the protocol study team — but am not an author on this paper.)

Take home message:  Starting antiretroviral therapy within 2 weeks of the OI diagnosis significantly reduced the risk of further AIDS complications or death, compared to the group that started 6-12 weeks later.  (For additional details of the study, here’s a nice summary in AIDS Clinical Care.)

When I discussed 5164 with some of my less clinically-inclined colleagues, they wonder why the study was even done — of course starting these severely immunocompromised patients on ART as soon as possible would be better than waiting.

But the clinicians, they were not so sure, and raised appropriate concerns about drug-drug interactions, pill burden, overlapping toxicities, reduced adherence, and — drum roll — the immune reconstitution inflammatory syndrome, or IRIS.

Some of us are terrified of IRIS, and I’m not quite sure why.  Yes, it can be difficult to manage (my sense is that we’re too reluctant to use steroids), and sometimes it’s very confusing exactly what is going on.  And of course there are occasional case reports of severe IRIS, some even leading to death — but always with such cases, I wonder whether the outcome would have been just as poor without ART, just with a different clinical manifestation.

So that’s why it’s particularly gratifying to see this finding in 5164:

IRIS was reported in 23 cases and confirmed in 20: 8 subjects in the immediate arm and 12 in the deferred arm.

In other words, no significant difference in IRIS rates between early and deferred therapy, and only about a 7% incidence overall.  As the authors note, this is likely to be closer to the true incidence of IRIS in patients starting therapy than the 15% or so widely reported in the literature, as the latter estimate often comes from retrospective studies.

So don’t let a fear of IRIS delay starting ART.  The alternative — opportunistic infections, advanced HIV disease, no ART — is “old fashioned AIDS”, and we all know how that turned out.

4 Responses to “An Irrational Fear of IRIS?”

  1. CM says:

    “Take home message: Starting antiretroviral therapy within 2 weeks of the OI diagnosis significantly reduced the risk of further AIDS complications or death, compared to the group that started 6-12 weeks later.”

    It should be recognized that these OIs were predominantly PCP, so it is probably true that we can safely start ARVs soon after initiating PCP therapy. But, I would still exercise caution in starting ARVs soon after Crypto meningitis or Tb where drug toxicities/interactions are legion and IRIS events have often proven to be lethal. Much of these data come from SSA where IRIS anecdotally seems so much more prevalent (less PCP and more Tb/Crypto there??).

    Oh, and what did you do with your “time for a switch?” patients?

  2. Paul Sax says:


    THANK YOU for your comments! In response:

    >>OIs were predominantly PCP …

    True enough, but there were also 12% crypto meningitis, and at least based on these small #’s (and in settings where ampho B and aggressive rx of raised intracranial pressure were both generally standard), this disease did not seem to impact outcome negatively. Regarding TB, I guess we’ll see what the SAPIT study tells us in the “early integrated” vs “late integrated” comparison, which is ongoing.

    Speaking of crypto, I am aware of only one study where “early” ART appears worse:


    This study from Zimbabwe used d4t/3TC/NVP and fluconazole for all; aggressive ICP management was not done.

    Based on this, my thoughts on the crypto meningitis cases is to wait until the initial ampho induction is practically complete, then start ART — typically around 2 weeks anyway.

    >>IRIS events have often proven to be lethal

    Maybe … but I wonder about case ascertainment bias on these severe IRIS cases, as prospective studies from such regions do not describe a high rate of lethal IRIS events (AIDS 2008 Mar 12;22(5):601-10). Plus, what is the alternative!

    (Still collecting “expert opinion” on “time for a switch” cases, which will be published in AIDS Clinical Care. Then I’ll give the f/u.)

  3. CM says:

    Re: crypto IRIS, see also Clin Infect Dis. 2008 Jun 1;46(11):1694-701. These pts in Uganda received 14 d ampho and ICP control. The numbers are admittedly small, but about half of pts starting ARVs got IRIS and half of these cases died.

    Of the 24 CM patients who started antiretroviral therapy, 7 subsequently developed cryptococcal-related IRIS manifest as aseptic meningitis (n=5), generalized lymphadenopathy (n=1), and severe pneumonitis with respiratory failure (n=1) within 2–33 weeks from HAART initiation. Among the 5 subjects with aseptic meningitis, presenting features were severe headache, vomiting, negative CSF cultures, and high opening pressures (range: 280–320 mm H2O). One subject experienced sudden onset of transient, bilateral blindness twice after 20 and 25 weeks of HAART in conjunction with aseptic meningitis and a normal ophthalmologic exam without papilledema. Another three subjects developed possible cryptococcal-related IRIS events including chorioretinitis, phlyctenular conjunctivitis, and lobar pneumonitis. IRIS also presented as unmasking of pulmonary TB in one patient and varicella zoster in another. Thus, suspected IRIS events occurred in 50% of CM patients (95% CI: 29% to 71%). Six persons subsequently died after starting HAART, four from cryptococcal-related IRIS, one from possible CM-IRIS after 12 days of HAART, and one from profound anemia (hemoglobin 1.4 g/dL) with lactic acidosis after 10 weeks of an AZT-3TC-efavirenz regimen.

    But, as you say if you are a pt that has an OI you in principle need ARVs post haste. Initiating ARVs after “induction” therapy for both crypto and Tb makes sense to me. PCP seems less controversial.

  4. Paul Sax says:

    Yep, crypto meningitis is a very tough beast indeed, with or without HIV treatment. It’s the exceptional case that goes smoothly from start to finish.

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

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