COMMENTARY

Immune Reconstitution Inflammatory Syndrome (IRIS): 'Why Is My Patient Getting Worse?'

James C.M. Brust, MD

Disclosures

July 29, 2021

Dr James Brust

Over the past 25 years, antiretroviral therapy (ART) has led to a dramatic decrease in HIV-associated morbidity and mortality. Patients who initiate ART today can now expect a nearly normal life expectancy.1 Despite the overwhelming benefits of ART, some patients experience immune reconstitution inflammatory syndrome (IRIS), a disease- or pathogen-specific immune response that can mimic the presentation of an active opportunistic infection (OI). IRIS can occur at any CD4 count. However, it is most often associated with the rapid increase in CD4 count and decrease in viral load that typically follows ART initiation in patients who are severely immunocompromised and have high viral loads. 2-6

IRIS manifests in two primary ways. Paradoxical IRIS refers to the worsening of a previously diagnosed disease after ART initiation, whereas unmasking IRIS refers to the appearance of a previously undiagnosed disease following ART initiation.

The Medical Care Criteria Committee of the New York State Department of Health AIDS Institute Clinical Guidelines Program recently published an update to its guideline, Management of IRIS . This update incorporates recent data and summarizes how to identify and manage IRIS associated with several OIs. Important goals of this update were to raise awareness among healthcare providers about IRIS, including its clinical presentation, and provide treatment recommendations.

For Most Patients, ART Should Be Started Quickly

Over the past few years, rapid initiation of ART has become the new standard of care, with same-day initiation on the day of HIV diagnosis recommended whenever possible. For many years, however, the presence of an active OI was felt to justify delaying ART initiation until the OI was completely treated. This approach changed in 2009 when a randomized trial by the AIDS Clinical Trials Group demonstrated that patients who initiated ART within 2 weeks of OI diagnosis did not experience more adverse events than those who waited.7 Moreover, although the finding did not reach statistical significance, participants in the early ART arm appeared to experience lower mortality and progression of AIDS than those in the delayed ART arm. Therefore, patients diagnosed with most OIs can start ART as soon as they are tolerating the treatment for the OI.

Some OIs Do Require a Delay in ART

Symptoms associated with IRIS are typically mild or moderate; life-threatening complications are rare. Most patients newly diagnosed with HIV who have an active OI can therefore initiate ART quickly. However, IRIS involving the central nervous system or eye carries a much greater risk of morbidity and mortality. OIs that do warrant a delay in ART initiation, therefore, include tuberculosis (TB) meningitis, cryptococcal meningitis, and cytomegalovirus (CMV) retinitis.

Several randomized clinical trials have found that in patients with HIV and pulmonary TB co-infection, ART should be started as soon as the patient is tolerating anti-TB therapy.8-10 What's more, in patients with CD4 counts <50 cells/microL, there is a mortality benefit when ART is initiated within 2 weeks of starting TB treatment (compared with waiting 8 weeks).

For TB meningitis, however, a clinical trial conducted in Vietnam did not show any mortality benefit when ART was started within 7 days (vs 2 months); however, severe adverse events were more common in the immediate ART group, raising the concern that patients in that group had experienced complications of IRIS of the central nervous system.11 Limited data are available to guide specific timing of ART in patients with TB meningitis, but based on the results of this trial, most clinicians wait approximately 2 months before initiating ART, and consultation with an expert is recommended.

Optimal timing of ART in patients with cryptococcal meningitis is also uncertain, and there have been contradictory results from several small studies. However, in 2014, the larger COAT trial, conducted in Uganda and South Africa, found 15% higher mortality in patients who initiated ART within 2 weeks (compared with >5 weeks).12 Although exactly how long to wait is still unknown, ART should be delayed by at least 2 weeks after a patient starts antifungal therapy.

CMV-IRIS can have devastating effects, including vision loss or blindness. Therefore, ART initiation should be delayed in patients with diagnosed or strongly suspected CMV.13 Importantly, however, patients with advanced HIV may have asymptomatic or subclinical CMV retinitis. As a result, all patients with HIV who have CD4 counts <100 cells/mm3 who do not have known or strongly suspected CMV should be screened for signs of CMV by dilated ophthalmologic examination as soon as possible after initiation of ART. If signs of CMV are seen on dilated exam, clinicians should consult with an experienced HIV care provider to determine if ART must be temporarily paused.

Diagnosing IRIS

Broadly, IRIS presents as a clinical deterioration after ART initiation, with localized tissue inflammation, with or without a systemic inflammatory response, but the presentation of IRIS varies depending on the underlying OI or illness. In most cases, IRIS occurs within 4 to 8 weeks of ART initiation or regimen change. A rise in CD4 count often but does not always precede IRIS and is not a diagnostic criterion. There is no diagnostic test for IRIS, and when assessing a patient for possible IRIS, clinicians should exclude HIV disease progression, new infections, OI drug resistance, OI treatment nonadherence, and drug reactions as possible causes for inflammatory signs or symptoms.

Treatment of IRIS

Most cases of IRIS are mild, and patients can be reassured that the symptoms will resolve with time. Clinicians should interrupt ART only if a patient has a severe, life-threatening case of IRIS. Unnecessary ART interruption may increase a patient's risk of new opportunistic infections, recurring IRIS upon resumption of ART, and development of HIV-drug resistance. Any newly unmasked OIs should be treated promptly while ART is continued. For patients with severe IRIS, clinicians can use prednisone to treat inflammatory symptoms — generally for 1 to 2 weeks, followed by a taper as needed. Prednisone, however, should not be used in patients with cryptococcal meningitis or Kaposi sarcoma as it is associated with worse outcomes.14-17

In patients newly diagnosed with HIV, prompt initiation of ART is, with the exceptions outlined above, the highest priority. IRIS is an unfortunate complication of ART, and patients may be discouraged when they find themselves feeling worse shortly after starting treatment. While providing supportive and symptomatic care, clinicians can reassure patients by explaining that immune reconstitution is, in fact, the goal of ART and that their symptoms do not represent the progression of HIV disease. It is hoped that with more frequent HIV testing, earlier diagnosis, and earlier ART initiation at higher CD4 counts, IRIS will become a less frequent nuisance to patients and providers. 

References

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  2. Breton G, Duval X, Estellat C, et al. Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis 2004;39:1709-12.

  3. Shelburne SA, 3rd, Darcourt J, White AC, Jr, et al. The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis 2005;40:1049-52.

  4. Shelburne SA, Visnegarwala F, Darcourt J, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005;19:399-406.

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  7. Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One 2009;4:e5575.

  8. Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med 2011;365:1482-91.

  9. Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med 2011;365:1492-501.

  10. Blanc FX, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 2011;365:1471-81.

  11. Torok ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)–associated tuberculous meningitis. Clin Infect Dis 2011;52:1374-83.

  12. Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014;370:2487-98.

  13. Ortega-Larrocea G, Espinosa E, Reyes-Teran G. Lower incidence and severity of cytomegalovirus-associated immune recovery uveitis in HIV-infected patients with delayed highly active antiretroviral therapy. AIDS 2005;19:735-8.

  14. Beardsley J, Wolbers M, Kibengo FM, et al. Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis. N Engl J Med 2016;374:542-54.

  15. Gill PS, Loureiro C, Bernstein-Singer M, Rarick MU, Sattler F, Levine AM. Clinical effect of glucocorticoids on Kaposi sarcoma related to the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989;110:937-40.

  16. Elliott AM, Luzze H, Quigley MA, et al. A randomized, double-blind, placebo-controlled trial of the use of prednisolone as an adjunct to treatment in HIV-1-associated pleural tuberculosis. J Infect Dis 2004;190:869-78.

  17. Volkow PF, Cornejo P, Zinser JW, Ormsby CE, Reyes-Teran G. Life-threatening exacerbation of Kaposi's sarcoma after prednisone treatment for immune reconstitution inflammatory syndrome. AIDS 2008;22:663-5.

Dr Brust reports no relevant financial relationships.

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