Review
Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis

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Summary

In patients with HIV-1 infection who are starting combination antiretroviral therapy (ART), the incidence of immune reconstitution inflammatory syndrome (IRIS) is not well defined. We did a meta-analysis to establish the incidence and lethality of the syndrome in patients with a range of previously diagnosed opportunistic infections, and examined the relation between occurrence and the degree of immunodeficiency. Systematic review identified 54 cohort studies of 13 103 patients starting ART, of whom 1699 developed IRIS. We calculated pooled cumulative incidences with 95% credibility intervals (CrI) by Bayesian methods and did a random-effects metaregression to analyse the relation between CD4 cell count and incidence of IRIS. In patients with previously diagnosed AIDS-defining illnesses, IRIS developed in 37·7% (95% CrI 26·6–49·4) of those with cytomegalovirus retinitis, 19·5% (6·7–44·8) of those with cryptococcal meningitis, 15·7% (9·7–24·5) of those with tuberculosis, 16·7% (2·3–50·7) of those with progressive multifocal leukoencephalopathy, and 6·4% (1·2–24·7) of those with Kaposi's sarcoma, and 12·2% (6·8–19·6) of those with herpes zoster. 16·1% (11·1–22·9) of unselected patients starting ART developed any type of IRIS. 4·5% (2·1–8·6) of patients with any type of IRIS died, 3·2% (0·7–9·2) of those with tuberculosis-associated IRIS died, and 20·8% (5·0–52·7) of those with cryptococcal meningitis died. Metaregression analyses showed that the risk of IRIS is associated with CD4 cell count at the start of ART, with a high risk in patients with fewer than 50 cells per μL. Occurrence of IRIS might therefore be reduced by initiation of ART before immunodeficiency becomes advanced.

Introduction

Combination antiretroviral therapy (ART) substantially reduces the occurrence of opportunistic events and mortality in patients with HIV.1 The beneficial effects of ART result from gradual restoration of pathogen-specific immune responses, mediated by suppressed HIV-1 replication and increased CD4 cell count.2, 3 WHO estimates that by the end of 2008 about 4 million people were receiving ART in countries of low and middle income—ten-times more than at the end of 2003.4 However, many patients in resource-poor settings start ART at a late stage when they already have advanced immunodeficiency.5, 6

Complications related to ART-induced immune reconstitution include paradoxical worsening of treated opportunistic infections or the unmasking of previously subclinical, untreated infections—so-called immune reconstitution inflammatory syndrome (IRIS), also known as immune reconstitution disease.7, 8, 9, 10 The panel summarises common definitions for IRIS. The syndrome is usually a consequence of exaggerated activation of the immune system against persistent antigen (paradoxical IRIS) or viable pathogens (unmasking IRIS), but it can also develop as progression of proliferative disease in patients with cancers.14 IRIS has been associated with a wide range of pathologies, including mycobacterial and cryptococcal infections, Kaposi's sarcoma, non-Hodgkin lymphoma, and progressive multifocal leukoencephalopathy.8, 9, 10, 15, 16, 17 Non-AIDS-defining illnesses such as sarcoidosis18 and rheumatic diseases19 can also transiently deteriorate after starting of ART.

The proportion of patients starting ART who develop IRIS is not well known, with estimates ranging from less than 10% to more than 50%.20, 21, 22, 23, 24 Several studies,10, 17, 25, 26, 27 but not all,21, 28, 29 have reported an increased risk of the syndrome in patients starting ART who have advanced immunodeficiency. We did a systematic review and meta-analysis of cohort studies to better define the incidence and lethality of IRIS in patients starting ART in countries of low, middle, and high income.

Section snippets

Search strategy and selection criteria

We searched Medline and Embase from January, 1996, to October, 2009, for published reports with the terms “immune reconstitution syndrome”, “immune reconstitution disease”, “immune restitution syndrome”, “immune restitution disease”, “immune reconstitution inflammatory syndrome”, and “immune recovery uveitis”. No language restrictions were used. Articles, brief reports, and letters to editors were included. Reference lists of relevant papers were screened. We also searched abstracts from

Results

The search identified 856 reports and 118 abstracts, of which 54 cohort studies from 22 countries were eligible for analysis: 22 (41%) were full-text reports, 21 (39%) were abstracts, and 11 (20%) were letters to the editor (figure 1, table 1). 17 cohorts (31%) were in unselected groups of people that included patients with and without AIDS, and studied any type of IRIS (table 1). The remaining studies were in patients with previously diagnosed opportunistic infections and examined paradoxical

Discussion

The incidence of IRIS among people starting ART varies with the AIDS-defining illness. The proportion of patients developing IRIS was highest in those with cytomegalovirus retinitis, high in those with cryptococcal meningitis, progressive multifocal leukoencephalopathy, or tuberculosis, and least common in those with Kaposi's sarcoma or herpes zoster. Differences in the incidence of IRIS between these opportunistic infections seem to be related to CD4 cell counts at baseline. In unselected

Search strategy and selection criteria

These are described in detail in the Methods section.

References (85)

  • GE Poda et al.

    Immune reconstitution syndrome in the course of antiretroviral treatment in Senegal

    Med Mal Infect

    (2009)
  • B Autran et al.

    Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease

    Science

    (1997)
  • Towards universal access. Scaling up priority HIV/AIDS interventions in the health sector. 2009 progress report

    (2009)
  • Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries

    Lancet

    (2006)
  • O Keiser et al.

    Antiretroviral therapy in resource-limited settings 1996 to 2006: patient characteristics, treatment regimens and monitoring in sub-Saharan Africa, Asia and Latin America

    Trop Med Int Health

    (2008)
  • ISA Shelburne et al.

    Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy

    Medicine

    (2002)
  • MA French et al.

    Immune restoration disease after antiretroviral therapy

    AIDS

    (2004)
  • MP Karavellas et al.

    Immune recovery vitritis and uveitis in AIDS: clinical predictors, sequelae, and treatment outcomes

    Retina

    (2001)
  • MA French

    HIV/AIDS: immune reconstitution inflammatory syndrome: a reappraisal

    Clin Infect Dis

    (2009)
  • ISA Shelburne 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)
  • JA DeSimone et al.

    Inflammatory reactions in HIV-1-infected persons after initiation of highly active antiretroviral therapy

    Ann Intern Med

    (2000)
  • R Colebunders et al.

    Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources

    Int J Tuberc Lung Dis

    (2006)
  • J Berenguer et al.

    Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy

    Clin Infect Dis

    (2003)
  • M Bower et al.

    Immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma

    J Clin Oncol

    (2005)
  • N Kumarasamy et al.

    Incidence of immune reconstitution syndrome in HIV/tuberculosis-coinfected patients after initiation of generic antiretroviral therapy in India

    J Acquir Immune Defic Syndr

    (2004)
  • M Narita et al.

    Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS

    Am J Respir Crit Care Med

    (1998)
  • SD Lawn et al.

    Cryptococcocal immune reconstitution disease: a major cause of early mortality in a South African antiretroviral programme

    AIDS

    (2005)
  • G Ortega-Larrocea et al.

    Lower incidence and severity of cytomegalovirus-associated immune recovery uveitis in HIV-infected patients with delayed highly active antiretroviral therapy

    AIDS

    (2005)
  • MA French et al.

    Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy

    HIV Med

    (2000)
  • DJ Jevtović et al.

    The prevalence and risk of immune restoration disease in HIV-infected patients treated with highly active antiretroviral therapy

    HIV Med

    (2005)
  • A Bourgarit et al.

    Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients

    AIDS

    (2006)
  • G Breton 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)
  • Pulimood SA, Chandrasekharan J, Kannangai R. Incidence of immune reconstitution inflammatory syndrome (IRIS) in a...
  • Human development report

    (2008)
  • D Spiegelhalter et al.

    Bayesian approaches to clinical trials and health-care evaluations

    (2004)
  • SP Hozo et al.

    Estimating the mean and variance from the median, range, and the size of a sample

    BMC Med Res Methodol

    (2005)
  • E Navas et al.

    Paradoxical reactions of tuberculosis in patients with the acquired immunodeficiency syndrome who are treated with highly active antiretroviral therapy

    Arch Intern Med

    (2002)
  • C Michailidis et al.

    Clinical characteristics of IRIS syndrome in patients with HIV and tuberculosis

    Antivir Ther

    (2005)
  • Chew NS, Brannigan E, Nugent C, Lambert J. Immune reconstitution inflammatory syndrome of tuberculosis among...
  • Elliott JH, Sarun S, Mean CV. Tuberculosis-associated immune restoration disease is associated with increased...
  • SD Lawn et al.

    Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa

    AIDS

    (2007)
  • WB Park et al.

    Tuberculosis manifested by immune reconstitution inflammatory syndrome during HAART

    AIDS

    (2007)
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