Welcome to the I-TECH HIV/AIDS Clinical Seminar Series February 25, 2010 Immune Reconstitution Inflammatory Syndrome Dr.G.Manoharan Medical Director, ITECH India

Case Study-1 25/2/2010Distance Learning Seminar Series 2 36 Yrs, F HIV +ve With no active OI’s CD4 : 46 Started on ART

Case Study-1 25/2/2010Distance Learning Seminar Series 3 After 4 weeks Dyspnoea and Fatigue CD4 :124

Case Study-1 25/2/2010Distance Learning Seminar Series 4 Follow-up : Pericardiocentesis Anti TB drugs & Steroids along with ART Final 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. 25/2/2010Distance Learning Seminar Series 5

25/2/2010Distance Learning Seminar Series 6 IRIS: Epidemiology *HIV Med 2000, 1(2): **J Antimicrob Chemother 2006; 57(2):167–70 AuthorsIncidence *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: Event rate 28% in TB/HIV with CD4<250 TRC, Chennai experience 25/2/2010 Distance Learning Seminar Series7

25/2/2010Distance Learning Seminar Series 8 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, ;

IRIS : Case definition - 2 Major 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 25/2/ Distance Learning Seminar Series

25/2/2010Distance Learning Seminar Series 10 IRIS: Case Definition 3 Required criterionSupportive criterion Worsening 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:

25/2/2010Distance Learning Seminar Series 11 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 25/2/ Distance Learning Seminar Series

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 25/2/ Distance Learning Seminar Series

INSHI (International Network for the Study of HIV associated IRIS) 2008 Definition TB 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 25/2/2010Distance Learning Seminar Series 14

25/2/2010 Distance Learning Seminar Series 15 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

CD4 Dynamics during ART 25/2/2010Distance Learning Seminar Series 16

IRIS: Categories CategoriesAntigen target Infectious-unmaskingViable replicating infective antigen Infectious-paradoxicalDead or dying organisms Auto immuneHost MalignanciesPossible 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): /2/2010 Distance Learning Seminar Series 17

25/2/2010Distance Learning Seminar Series 18 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

25/2/2010Distance Learning Seminar Series 19 IRIS: Etiology Non Infectious Causes Autoimmune IRIS Rheumatoid arthritis SLE Graves disease Autoimmune thyroid disease Sarcoid IRIS Granulomatous reactions Other (Rare) manifestations Tattoo ink Guillain-Barre’s syndrome Interstitial lymphoid pneumonitis

25/2/2010Distance Learning Seminar Series 20 Ref:Huruy K et al Jpn J Infect Dis 2008; 61:205-8.

25/2/2010Distance Learning Seminar Series 21 Bhrushundi M Mishra P, Nagpur, India, IAS conference 2006

25/2/2010Distance Learning Seminar Series 22 Bhrushundi M Mishra P, Nagpur, India, IAS conference 2006

IRIS in Adults 25/2/2010Distance Learning Seminar Series 23 Total number on ART 2330 IRIS: Number & %302 & 13%

IRIS in Children 25/2/2010Distance Learning Seminar Series 24

TB associated IRIS and ART associated IRIS TB diagnosed & treatment started before ART initiation 25/2/2010Distance Learning Seminar Series 25 Not on TB treatment when ART is initiated AntiRetroviral Therapy Paradoxical reaction within 3 months Active TB diagnosed on ART Paradoxical IRIS- TB ART-associated TB (a subset of these patients could have unmasking IRIS-TB )

25/2/2010Distance Learning Seminar Series 26 IRIS : Clinical Spectrum Heterogeneous Onset; early/delayed Atypical symptoms; generalized/local Varying severity Infectious/ Non-infectious agents Site of infection

25/2/2010Distance Learning Seminar Series 27 Onset of IRIS Source: AIDS 2005, Vol 19 No4 ; , Samuel A. Shelburne et al

Onset of IRIS S.NoAuthors, Year & CountryOnset (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) 25/2/2010Distance Learning Seminar Series 28

Atypical symptoms 30/1/2010Distance Learning Seminar Series 29

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 30/1/2010Distance Learning Seminar Series30

Case study-2 2 months after Anti-TB Treatment: Chest x-ray : Normal Smear: Negative ART initiated (ddI, 3TC, EFV) 30/1/2010Distance Learning Seminar Series31

Case study-2 25/2/2010Distance Learning Seminar Series 32 One month after ART, patient presented with chest pain, high fever

Case study-2 Lab parameters at various time points Baseline2 months ATT 1 month ART 4 months ART 6 months ART 9 months ART Weight in Kgs Hb (gms%) CD4% CD4 (Absolute) Viral Load (Lakhs) <400 25/2/2010 Distance Learning Seminar Series33

Case study-2 CXR after 6 months 25/2/2010Distance Learning Seminar Series 34

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 25/2/2010Distance Learning Seminar Series 35 Shelburne et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS. 2005;19:

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 25/2/2010Distance Learning Seminar Series 36 AIDS Res Ther. 2007; 4: 9.

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25/2/2010Distance Learning Seminar Series 38 Differential Diagnosis Failure of HAART ART toxicity Active Opportunistic Infections Failure of antimicrobial therapy

25/2/2010Distance Learning Seminar Series 39 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.

25/2/2010Distance Learning Seminar Series 40 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 ;

25/2/2010Distance Learning Seminar Series 41 Ref: Carine Salliot et al, Journal of the International Association of Physicians in AIDS Care; Vol 7 No 4 July/August 2008 ;

IRIS-Cardiac tamponade 25/2/2010Distance Learning Seminar Series 42

25/2/2010Distance Learning Seminar Series 43 IRIS: Management Temporary cessation of ART needs to be considered if potentially life- threatening forms of IRIS develop

Maraviroc beneficial in IRIS-PML?? 25/2/2010Distance Learning Seminar Series 44 PML-IRIS with an unusually fast improvement after maraviroc adjunction. Mechanism: Modulating CNS leukocyte trafficking and attenuating any deleterious inflammatory response Author: Guillaume Martin-Blondela, France.

25/2/2010Distance Learning Seminar Series 45 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

25/2/2010Distance Learning Seminar Series 46 No. of Deaths CID 2009: 49, Barbara Castelnuovo et al

30/1/2010Distance Learning Seminar Series 47 Clinical outcome

25/2/2010Distance Learning Seminar Series 48 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.

Next session: March 11, 2010 Dr Laura Brandt – HIV Disclosure in Children