Restoration of immune responses against opportunistic pathogens after commencing antiretroviral therapy (ART) may cause immune restoration disease (IRD) in about 10%–40% of HIV patients with low CD4+ T-cell counts and usually presents clinically as a type of immune reconstitution inflammatory syndrome (IRIS).
IRIS may be associated with many different opportunistic pathogens, but types associated with Mycobacterium tuberculosis, BCG, cryptococci, JC polyomavirus (the cause of progressive multifocal leukoencephalopathy [PML]), hepatitis C virus and hepatitis B virus infection are the most informative about disease pathogenesis and management.
A CD4+ T-cell count of < 50/μL and a high pathogen load are the most commonly identified risk factors for IRIS.
Recovery of pathogen-specific T-cell responses and perturbations of innate immune responses before and after ART appear to cause immunopathological abnormality in tissues infected by the pathogen.
Prevention of IRIS may be influenced by the timing of ART:
The risk of tuberculosis (TB)-associated-IRIS can be reduced by commencing ART after 8 weeks of TB treatment, but rates of AIDS or death are lower if ART is commenced during the first 4 weeks of TB treatment.
Outcomes for patients with HIV and treated cryptococcal or TB meningitis may be improved by deferring ART until the opportunistic infection is fully suppressed, but data are inadequate.
As ART is currently the only effective treatment for PML in patients with HIV, PML-associated IRIS cannot be prevented by manipulating the timing of ART.
A greater understanding of the immunopathogenesis of IRIS may lead to targeted therapies.
- 1. French MA, Mallal SA, Dawkins RL. Zidovudine-induced restoration of cell-mediated immunity to mycobacteria in immunodeficient HIV-infected patients. AIDS 1992; 6: 1293-1297.
- 2. John M, Flexman J, French MA. Hepatitis C virus-associated hepatitis following treatment of HIV-infected patients with HIV protease inhibitors: an immune restoration disease? AIDS 1998; 12: 2289-2293.
- 3. French MA, Lenzo N, John M, et al. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV Med 2000; 1: 107-115.
- 4. Müller M, Wandel S, Colebunders R, et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis 2010; 10: 251-261.
- 5. Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008; 8: 516-523.
- 6. Conesa-Botella A, Loembé MM, Manabe YC, et al. Urinary lipoarabinomannan as predictor for the tuberculosis immune reconstitution inflammatory syndrome. J Acquir Immune Defic Syndr 2011; 58 : 463-468.
- 7. French MA. HIV/AIDS: immune reconstitution inflammatory syndrome: a reappraisal. Clin Infect Dis 2009; 48: 101-107.
- 8. World Health Organization. TB/HIV facts 2011. http://www.who.int/tb/publications/TBHIV_Facts_for_2011.pdf (accessed Mar 2012).
- 9. Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med 2011; 365: 1492-1501.
- 10. Blanc FX, Sok T, Laureillard D, et al; CAMELIA (ANRS 1295–CIPRA KH001) Study Team. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 2011; 365: 1471-1481.
- 11. Koenig SP, Riviere C, Leger P, et al. High mortality among patients with AIDS who received a diagnosis of tuberculosis in the first 3 months of antiretroviral therapy. Clin Infect Dis 2009; 48: 829-831.
- 12. Elliott JH, Vohith K, Saramony S, et al. Immunopathogenesis and diagnosis of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome during early antiretroviral therapy. J Infect Dis 2009; 200: 1736-1745.
- 13. Rabie H, Violari A, Duong T, et al. Early antiretroviral treatment reduces risk of bacille Calmette-Guérin immune reconstitution adenitis. Int J Tuberc Lung Dis 2011; 15: 1194-1200.
- 14. Haddow LJ, Colebunders R, Meintjes G, et al. Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis 2010; 10: 791-802.
- 15. Makadzange AT, Ndhlovu CE, Takarinda K, et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-Saharan Africa. Clin Infect Dis 2010; 50: 1532-1538.
- 16. Martin-Blondel G, Delobel P, Blancher A, et al. Pathogenesis of the immune reconstitution inflammatory syndrome affecting the central nervous system in patients infected with HIV. Brain 2011; 134: 928-946.
- 17. Crane M, Oliver B, Matthews G, et al. Immunopathogenesis of hepatic flare in HIV/hepatitis B virus (HBV)-coinfected individuals after the initiation of HBV-active antiretroviral therapy. J Infect Dis 2009; 199: 974-981.
- 18. Cameron BA, Emerson CR, Workman C, et al. Alterations in immune function are associated with liver enzyme elevation in HIV and HCV co-infection after commencement of combination antiretroviral therapy. J Clin Immunol 2011; 31: 1079-1083.
- 19. Barber DL, Mayer-Barber KD, Antonelli LR, et al. Th1-driven immune reconstitution disease in Mycobacterium avium-infected mice. Blood 2010; 116: 3485-3493.
- 20. Mahnke YD, Greenwald JH, Dersimonian R, et al. Selective expansion of polyfunctional pathogen-specific CD4+ T cells in HIV-1-infected patients with immune reconstitution inflammatory syndrome. Blood 2012 Jan 4. [Epub ahead of print.]
- 21. Meintjes G, Wilkinson KA, Rangaka MX, et al. Type 1 helper T cells and FoxP3-positive T cells in HIV-tuberculosis-associated immune reconstitution inflammatory syndrome. Am J Respir Crit Care Med 2008; 178: 1083-1089.
- 22. Oliver BG, Elliott JH, Price P, et al. Mediators of innate and adaptive immune responses differentially affect immune restoration disease associated with Mycobacterium tuberculosis in HIV patients beginning antiretroviral therapy. J Infect Dis 2010; 202: 1728-1737.
- 23. Boulware DR, Meya DB, Bergemann TL, et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med 2010; 7: e1000384.
- 24. Barber DL, Andrade BB, Sereti I, Sher A. Immune reconstitution inflammatory syndrome: the trouble with immunity when you had none. Nat Rev Microbiol 2012; 10 : 150-156.
- 25. Jones M, Núñez M. HIV and hepatitis C co-infection: the role of HAART in HIV/hepatitis C virus management. Curr Opin HIV AIDS 2011; 6: 546-552.
- 26. Meintjes G, Wilkinson RJ, Morroni C, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010; 24: 2381-2390.
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