Welcome to the I-TECH HIV/AIDS Clinical Seminar Series February 25, 2010 Immune Reconstitution...

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

25/2/2010 Distance Learning Seminar Series 2

36 Yrs , F HIV +veWith no active OI’sCD4 : 46 Started on ART

Case Study-1


After 4 weeks

Dyspnoea and Fatigue

CD4 :124

Case Study-1


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.



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



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

25/2/2010 9Distance Learning Seminar Series


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


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


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


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



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


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



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


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


Ref:Huruy K et al Jpn J Infect Dis 2008; 61:205-8.


Bhrushundi M Mishra P, Nagpur, India, IAS conference 2006

IRIS in Adults


Total number on ART

2330

IRIS: Number & % 302 & 13%

IRIS in Children


TB associated IRIS and ART associated IRIS

TB diagnosed & treatment started before ART initiation


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)


IRIS : Clinical Spectrum

• Heterogeneous

• Onset; early/delayed

• Atypical symptoms; generalized/local

• Varying severity

• Infectious/ Non-infectious agents

• Site of infection


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)


Atypical symptoms


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


Case study-22 months after Anti-TB

Treatment:

Chest x-ray : Normal

Smear: Negative

ART initiated (ddI, 3TC, EFV)


Case study-2


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


Case study-2CXR after 6 months


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


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


AIDS Res Ther. 2007; 4: 9.


Differential Diagnosis

• Failure of HAART• ART toxicity• Active Opportunistic Infections• Failure of antimicrobial therapy


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.


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


Ref: Carine Salliot et al, Journal of the International Association of Physicians in AIDS Care; Vol 7 No 4 July/August 2008 ;178-181

IRIS-Cardiac tamponade



IRIS: Management

Temporary cessation of ART needs to

be considered if potentially life-

threatening forms of IRIS develop

Maraviroc beneficial in IRIS-PML??


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.


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


No. of Deaths

CID 2009: 49, 965-72 Barbara Castelnuovo et al


Clinical outcome


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, 2010Dr Laura Brandt – HIV Disclosure in Children

Welcome to the I-TECH HIV/AIDS Clinical Seminar Series February 25, 2010 Immune Reconstitution...

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