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Welcome to the I-TECH HIV/AIDS Clinical Seminar Series
February 25, 2010Immune Reconstitution Inflammatory Syndrome
Dr.G.Manoharan
Medical Director, ITECH India
Case Study-1
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36 Yrs , F HIV +veWith no active OI’sCD4 : 46 Started on ART
Case Study-1
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After 4 weeks
Dyspnoea and Fatigue
CD4 :124
Case Study-1
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Follow-up : Pericardiocentesis Anti TB drugs & Steroids along with ARTFinal diagnosis: IRIS-TB pericardial Effusion
IRIS : Definition
The worsening of signs and symptoms due to known infections, or the development of disease due to occult infections, that results from an inflammatory response by a re-invigorated immune system following the initiation of anti-retroviral therapy.
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IRIS: Epidemiology
*HIV Med 2000, 1(2):107-115 **J Antimicrob Chemother 2006; 57(2):167–70
Authors Incidence
*French MA 10%-25%
**Shelburne SA et al. 15%-45%
Milind Bhrushundi et al (Nagpur, India)
9.4%
Government Hospital of Thoracic Medicine, Chennai
13%
IRIS: Epidemiology • Incidence in cohort
from India: 15.2 cases/100 p-y Kumarasamy N et al. JAIDS 2004; 37: 1574.
• Event rate 28% in TB/HIV with CD4<250 TRC, Chennai experience
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IRIS:Case Definition 1• HIV positive• Receiving HAART
– Decrease in HIV-1 RNA level from baseline– Increase in CD4 cells from baseline (may lag HIV-
1 RNA decrease)• Clinical symptoms consistent with inflammatory
process• Clinical course NOT consistent with:
– Expected course of previously diagnosed OI– Expected course of newly diagnosed OI– Drug toxicity
Ref: Samuel A. Shelburne, Martin Montes and Richard J.Hamill, Journal of Antimicrobial Chemotherapy (2006) 57, 167-170;
IRIS : Case definition - 2Major criteria(A)Atypical presentation of opportunistic infections or tumors in
patients responding to ART• Localized disease• Exaggerated inflammatory reaction• Atypical inflammatory response in affected tissues• Progressive organ dysfunction or enlargement of pre-existing
lesions after definite clinical improvement with pathogen specific therapy before the initiation of ART and exclusion of treatment toxicity and new alternative diagnoses
(B) Decrease in plasma HIV RNA concentration by more than 1 log10 copies per mL
Minor criteria• Increase in blood CD4 T-cell count after starting ART• Increase in an immune response specific to the relevant
pathogen—eg, delayed-type hypersensitivity skin test response to mycobacterium antigens
• Spontaneous resolution of disease without specific antimicrobial therapy or tumor chemotherapy with continuation of ART
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IRIS: Case Definition 3
Required criterion Supportive criterionWorsening symptoms of inflammation/infection
Increase in cd4 cell count of > 25 cells/cu.mm
Temporal relationship with starting antiretroviral treatment
Biopsy demonstrating well formed granulomatous inflammation or unusually exuberant inflammatory response
Symptoms not explained by newly acquired infection or disease or the usual course of a previously acquired disease
> 1 log10 decrease in plasma viral load CID J 2006;Jaime Robertson et al ;(1 June) 42: 1639-46
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National AIDS Control Organization-India
“Occurrence or manifestations of new OIs within six weeks to six months after initiating ART; with increase in
CD4 count”
National AIDS Control Organization, Antiretroviral Therapy Guidelines for HIV-infected Adults and Adolescents Including Post-exposure Prophylaxis. (May 2007)
Case definition specific for TB -associated IRIS
Suspected tuberculosis-associated IRIS case: Cases must meet the following three criteria:
• An initial clinical response to tuberculosis treatment, based on a combination of some of the following factors: cessation of fever, relief of pulmonary symptoms, decrease in lymph node size, termination of signs of meningeal irritation (depending on
presenting symptoms)
• New persistent fevers without another identifiable cause and/or one or more of the following: worsening or emergence of dyspnoea, stridor, an increase in lymph node size, development of abscesses, development of abdominal pain with ultrasound evidence of abdominal adenopathies, unexplained CNS symptoms
• Adequate adherence to ART and tuberculosis treatment
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Case definition specific for TB-associated IRIS
Confirmed tuberculosis-associated IRIS case: Cases must meet the following three criteria:
• Radiological examinations showing worsening or emergence of intrathoracic lymphadenopathy, pulmonary infiltrates, pleural
effusions, abdominal lymph nodes, hepatosplenomegaly
• A good virological response and/or increase in CD4+ lymphocyte count, and/or conversion of tuberculin skin test from negative to positive, and/or adequate adherence to ART and tuberculosis treatment
• A clear exclusion of other conditions that could explain the clinical manifestations of the patient, such as tuberculosis treatment failure or other concomitant infections, tumours, or allergic reactions
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INSHI (International Network for the Study of HIV associated IRIS) 2008 DefinitionTB associated IRIS : case definitions for use in
resource-limited settings Graeme Meintjes, Stephen D Lawn, Fabio Scano, Gary
Maartens, Martyn A French, William Worodria, Julian H Elliott, David Murdoch, Robert J Wilkinson, Catherine Seyler, Laurence john, Maarten Schim van der Loeff , Peter Reiss, Lut Lynen, Edward N Janoff , Charles Gilks, Robert Colebunders, for the International Network for the Study of HIV-associated IRIS.
Lancet Infect Dis 2008; 8: 516–23
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IRIS: Pathogenesis
• Improved Cell Mediated Immunity with restoration of both memory and naïve CD4 cells
• Increased CD4/CD8 cells detect hidden pathogens which were ignored with deficiency of immunity previously
• Result in inflammatory process at the area of occult/sub-clinical infections
• Usually improves with control of inflammation and specific treatment
IRIS: Categories Categories Antigen target
Infectious-unmasking Viable replicating infective antigen
Infectious-paradoxical Dead or dying organisms
Auto immune Host
Malignancies Possible tumor or associated pathogen
Other inflammatory conditions
Range of antigens
Ref: Devesh J. et al, Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients Receiving Antiretroviral Therapy Pathogenesis, Clinical Manifestations and Management:; Drugs 2008; 68 (2): 191-208
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IRIS: Etiology Infectious Causes
• Mycobacteria Mycobacterium
tuberculosis Mycobacterium avium complex• Cytomegalovirus • Herpes viruses • Cryptococcus neoformans• Pneumocystis jirovecii
pneumonia• Histoplasma capsulatum• Toxoplasmosis
• Hepatitis B Virus• Hepatitis C Virus• Progressive multifocal
leukoencephalopathy• Parvovirus B 19• Molluscum contagiosum
& genital warts• Sinusitis• Folliculitis • Strongyloides stercoralis
& other parasitic infections
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IRIS: Etiology Non Infectious Causes
Autoimmune IRIS• Rheumatoid arthritis• SLE• Graves disease• Autoimmune thyroid
diseaseSarcoid IRIS• Granulomatous
reactions
Other (Rare) manifestations
• Tattoo ink• Guillain-Barre’s
syndrome• Interstitial lymphoid
pneumonitis
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Bhrushundi M Mishra P, Nagpur, India, IAS conference 2006
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Bhrushundi M Mishra P, Nagpur, India, IAS conference 2006
IRIS in Adults
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Total number on ART
2330
IRIS: Number & % 302 & 13%
TB associated IRIS and ART associated IRIS
TB diagnosed & treatment started before ART initiation
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Not on TB treatment when ART is initiated
AntiRetroviral Therapy Paradoxical
reactionwithin 3 months
Active TB diagnosed on ART
Paradoxical IRIS-TB
ART-associated TB (a subset of these patients could
have unmasking IRIS-TB)
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IRIS : Clinical Spectrum
• Heterogeneous
• Onset; early/delayed
• Atypical symptoms; generalized/local
• Varying severity
• Infectious/ Non-infectious agents
• Site of infection
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Onset of IRIS
Source: AIDS 2005, Vol 19 No4 ;399-406, Samuel A. Shelburne et al
Onset of IRISS.No Authors, Year & Country Onset (SD)
1 Narita et al 1998 USA Mean 15 days (SD 11 days)
2 Breen et al 2004 UK Median 11 days (range 8–18 days)
3 Breton et al 2004 France Median 12 days (range 2–114 days)
4 Kumarasamy et al 2004 India Median 42 days (range 10–89 days)
5 Shelburne et al 2005 USA Median 46 days (range 3–658 days)
6 Michailidis et al 2005 UK Median 0-6 months; (IQR 0.1 to 9.1 months)
7 Manosuthi et al 2006 Thailand Median 32 days (IQR 14–115 days)
8 Lawn et al 2007 South Africa Median 2 weeks(IQR 1.5 –3.5 weeks)
9 Burman et al 2007 USA Median 34 days (IQR 8–97 days)
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Case study-2• M 34 Yrs, HIV+ : 2 months
of Cough and dyspnoea & Fever for 20 days
• Sputum smear +ve for AFB• Culture grew M.tuberculosis,
sensitive to all drugs• CD4 85 cells (13%)• HIV-1 Viral Load : >
100,000• TB treatment (CAT-1)
initiated
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Case study-22 months after Anti-TB
Treatment:
Chest x-ray : Normal
Smear: Negative
ART initiated (ddI, 3TC, EFV)
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Case study-2
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One month after ART, patient presented with chest pain, high fever
Case study-2Lab parameters at various time points
Baseline 2 months
ATT
1 month ART
4 months
ART
6 months
ART
9 months
ART
Weight in Kgs
50 52 55 63 66 70
Hb (gms%)
7.7 11.7 12.1 14.5 13.3 14
CD4% 8 9 16 11 14 14
CD4 (Absolute)
85 56 188 162 260 232
Viral Load (Lakhs)
1.07 1.73 <400 <400 <400
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Predictors for IRIS• Male gender (P = .02) • ARV-naive patients at the time of diagnosis of
their OI (P < .001)• Short interval (less than 50 days) between the
initiation of OI treatment and the beginning of HAART (P < .001)
• Dramatic decrease of the RNA viral load in the first 3 months of treatment (P < .001) but not an increase in the CD4 cell count
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Shelburne et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS. 2005;19:399-406.
Predictors for IRIS (cont’d)
• Younger age
• Lower CD4 cell count / CD4 % / CD4:CD8 ratio at ART initiation
• Higher viral load at ART initiation• Genetic susceptibility
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AIDS Res Ther. 2007; 4: 9.
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Differential Diagnosis
• Failure of HAART• ART toxicity• Active Opportunistic Infections• Failure of antimicrobial therapy
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IRIS: Management• Mild form (with ongoing ART)
– Observation
• Localized IRIS (with ongoing ART)– Local therapy such as minor surgical procedures for
lymph node abscesses
• Most of the situations (with ongoing ART)– Unmasking &/or Recognition of ongoing
infections >> Antimicrobial therapy to reduce the antigen load of the triggering pathogen;
– Reconstituting immune reaction to non-replicating antigens >> No antimicrobial therapy. Short term therapy with corticosteroids or non-steroidal anti inflammatory drugs to reduce the inflammation.
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Severe and diffuse tubulointerstitial nephritis with non-caseating granuloma
Ref: Carine Salliot et al; Journal of the International Association of Physicians in AIDS Care; Vol 7 No 4 July/August 2008 ;178-181
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Ref: Carine Salliot et al, Journal of the International Association of Physicians in AIDS Care; Vol 7 No 4 July/August 2008 ;178-181
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IRIS: Management
Temporary cessation of ART needs to
be considered if potentially life-
threatening forms of IRIS develop
Maraviroc beneficial in IRIS-PML??
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PML-IRIS with an unusually fast improvement after maraviroc adjunction. Mechanism: Modulating CNS leukocyte trafficking and attenuatingany deleterious inflammatory response
Author: Guillaume Martin-Blondela, France.
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IRIS : Prevention
• Identification of patients with risk-factors for infectious IRIS
• Measures taken to reduce pathogen load • Keeping high vigilance in patients who are at
risk of developing IRIS during the introduction phase of HAART
• Delaying initiation of HAART few weeks until pathogen load is decreased by using appropriate anti-microbial agents
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No. of Deaths
CID 2009: 49, 965-72 Barbara Castelnuovo et al
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Key Points
• IRIS is likely to occur when ART is not initiated early enough
• Clinicians need to know about this syndrome and its pathophysiology when working up the differential diagnosis of a wide variety of clinical symptoms in HIV-infected patients on ART **Important in countries where ART is prescribed for patients who already have advanced immunodeficiency.