Immune Reconstitution Inflammatory Syndrome (IRIS) HAIVN Harvard Medical School AIDS Initiative in Vietnam Peds Module 2, 2010

Outline of Presentation Definition of IRIS Pathogenesis of IRIS Clinical presentation of IRIS IRIS due to TB, Hepatitis B, CMV Diagnosis of IRIS Management of IRIS

Learning objectives At the end of this presentation, the trainee will be able to describe: The two forms of the Immune Reconstitution Inflammatory Syndrome (IRIS) The etiological agents and syndromes of IRIS The management of IRIS Commonly encountered forms of IRIS

IRIS: Definition IRIS = IRD: Immune Restoration Disease IRIS: symptoms or signs consistent with an inflammatory and/or atypical presentation of OIs or tumors Is not a side effect of ARV, Occur after initiation, reintroduction, or change of ARV In patients who have evidence of viral load suppression. Definition IRIS: Immune Reconstitution Inflammatory Syndrome Risk Factors and Treatment Implications Yukari C. Manabe, MD,*† James D. Campbell, MD, MS,‡ Emily Sydnor, MD,† and Richard D. Moore, MD, MHS†§ J Acquir Immune Defic Syndr _ 2007

IRIS: Definition IRIS is a pattern of diseases presenting soon after the initiation of ARV. Typically, it occurs in the first 2-12 weeks after starting ARV. IRIS is a “paradoxical” overreaction against a foreign antigen (alive or dead) in patients starting ARV.

IRIS: Pathogenesis IRIS is secondary to immunological changes after ARV: Rapid and potent suppression of HIV viraemia + Abundant microbial antigen (alive or dead) promotes a greater immune response when it encounters suddenly increased numbers of functionally active antigen-specific cells. Immune reconstitution inflammatory syndrome in HIV Marc Lipman and Ronan Breen. Current Opinion in Infectious Diseases 2006, 19:20–25

IRIS: Clinical presentations IRIS in patients already receiving therapy for an OI at the time at which ARV is initiated. Clinical deterioration of the disease: “paradoxical reaction”. IRIS may trigger the presentation of an OI that was sub-clinical prior ARV: “unmasking IRIS”. Immune reconstitution disease: recent developments and implications forantiretroviral treatment inresource-limitedsettings Stephen D. Lawna,b and Martyn A. Frenchc,d Current Opinion in HIV and AIDS 2007, 2:339–345

IRIS: Clinical presentations Inflammatory response that causes the unexpected worsening of the patient’s condition. Often there is no detectable evidence of the underlying pathogen. Mycobacterium Tuberculosis accounts for 1/3 of all IRIS events. BCG vaccine: very common in infants

Common Pathogens All infections have been reported to cause IRIS Mycobacteria: TB and MAC, BCG in children Fungal: Cryptococcosis, PCP, histoplasmosis, Penicilliosis Viral: CMV, VZV, HBV, HCV Parasites: Strongyloides stercoralis, cryptosporidium Cryptococcus: increased mortality rate. Some patients with an initial or recurrent episode of crypto meningitis during the first weeks of ARV. CSF: more prominent inflammatory cell reaction in patients on ARV. Often CSF sterile culture for crypto

IRIS Risk factors Low CD4 count before starting ARV Rapid reduction in HIV viral load with ARV High pathogen load at the beginning of ARV, i.e. starting ARV therapy in the setting of an active OI High number of prior OIs Minor criteria: increase in CD4 count. High pathogen load at the beginning of ARV, i.e. starting ARV therapy in the setting of an active OI: delaying ARV until the antigen load has been reduced by anti-microbial therapy will reduce the incidence of IRIS…………but more risks of further AIDS events. What is the best moment to start ARV in co-infected patients, especially with low CD4 counts, remain to be established Minor criteria: increase in CD4 count. Absolute CD4 T-cell increase did not correlate with increasing risk for IRIS. CD4+ T-cell increases are not found in all patients with IRIS. Immune Reconstitution Inflammatory Syndrome. Risk Factors and Treatment Implications Yukari C. Manabe, MD,*† James D. Campbell, MD, MS,‡ Emily Sydnor, MD,† and Richard D. Moore, MD, MHS†§ J Acquir Immune Defic Syndr _ 2007

IRIS TB Worsening of signs and symptoms of TB in patients being started on anti-TB chemo-therapy Described in the pre-HIV era but appear to be more frequent in HIV-infected patients Occur in 7 to 36% of patients More frequently when HAART is started within 2 months of beginning anti-TB treatment Occur in 7 to 36% of patients: data are very different because no very clear clinical definitions of IRIS.

IRIS TB Factors complicating ARV and TB therapy: Adherence to heightened pill burden Overlapping drug toxicities Drug/drug interactions

IRIS TB “Paradoxical reaction”: Initial clinical response to TB treatment, ARV introduction, New persistent symptoms or signs of TB, Adequate adherence to ARV and TB treatment. For patients on TB treatment at the moment to start ARV: Initial clinical response to TB treatment : cessation of fever, relief of pulmonary symptoms, decrease in lymph node size, termination of meningeal signs New persistent symptoms or signs of TB : fevers without an identifiable source or reason, worsening or emergence of dypnoea, increase in lymph node size, development of abscesses, abdominal pain = ultrasound: abdominal adenopathies, CNS symptoms

IRIS TB Diagnosis “Paradoxical reaction”: Chest X ray/Ultrasound: worsening or new lesions, Good virological response, Clear exclusion of other conditions: TB treatment failure, resistant TB others OI, Malabsortion, Drug reactions. Chest X ray/Ultrasound: showing worsening or emergence of intra-thoracic adenopathy, pulmonary infiltrates, pleural effusions, abdominal lymph nodes Good virological response: rapid and significant viral load decline at least > 1 log

IRIS TB Diagnosis “Unmasking IRIS”: Unapparent TB at the start of ARV Insufficient clinical symptoms to justify TB treatment, Chest X ray: normal Patients with cough at least 3 sputum: AFB negative

IRIS TB Diagnosis “Unmasking IRIS”: TB appeared within the first 6 months of ARV Good virological response to ARV Adequate adherence to ARV

CXR before ARV CXR 3 weeks after ARV

8 months old: Severe malnutrition Wt 5 kg; height 58cm Hepatosplenomegaly CD4 40.6%; 662 tb/mm3 PCR + ARV: D4T/3TC/NVP enlargement of the axillary lymph nodes. Left Axillary LN = BCG disease

IRIS TB Differential diagnosis For patients on TB treatment who develop IRIS after start ARV: “Paradoxical reaction” Side effects of ARV drug fevers TB infection not responding to treatment Resistant TB Poor adherence to TB treatment Other HIV or non-HIV related infections IRIS is a diagnosis of exclusion !!!

Overlapping Side Effects of Antituberculosis and Antiretroviral Drugs

Overlapping Side Effects of Antituberculosis and Antiretroviral Drugs

IRIS in Thai children Between May 2002-2004 (3 hospital) HIV-infected children enrolled: 153 ARV regimens: D4T + 3TC + NVP: 81 D4T + 3TC + EFV: 72 Mean Age: 8 years old Mean CD4 baseline: 5% No active OI Immune Reconstitution Syndrome After Highly ActiveAntiretroviral Therapy in Human ImmunodeficiencyVirus-Infected Thai Children Thanyawee Puthanakit, The Pediatric Infectious Disease Journal • Volume 25, Number 1, January 2006

IRIS in Thai children: results 153 enrolled children: 29 children (19%) had 32 episodes of IRIS Median time: 4 weeks after ARV IRIS: Mycobacterial: 14 episodes (43%) Atypical mycobacteria: 9 Mycobacterium Tuberculosis: 3 Mycobacterium Bovis: 2 Varicella-Zoster: 7 episodes Mycobacterium diseases: localized infections ( Lymph nodes, subcutaneous tissues, lungs) M Bovis: 2 patients with BCG vaccine years before The Pediatric Infectious Disease Journal • Volume 25, Number 1, January 2006

IRIS in Thai children: results (cont’) HSV: 7 episodes Cryptococcus: 3 Guillain Barre: 1 The Pediatric Infectious Disease Journal • Volume 25, Number 1, January 2006

IRIS in Thai children: outcomes One patient interrupted 8 weeks ARV during IRIS 3 patients died of IRIS or its complications The Pediatric Infectious Disease Journal • Volume 25, Number 1, January 2006

IRIS in infants (South Africa) Infants less than 24 months old: 169 ARV: D4T + 3TC + Aluvia Median age: 8 months old IRIS: 34 infants (21%) Median time: 2 weeks post-ARV BCG disease: 24/34 (71%) Local reaction and/or ipsilateral axillary lymph node Ipsilateral lymph nodes were the most common manifestation of the BCG AIDS 2009, 23:1097–1107

IRIS in infants (South Africa) Tuberculosis: 12 cases (6 co-infected with M. bovis) Outcomes: IRIS: 3/34 died (9%) BCG disease: 2 cases BCG and TB: 1 case AIDS 2009, 23:1097–1107

IRIS Management Continuation of primary therapy against the pathogen, Continuation of ARV, Judicious use of anti-inflammatory agents, To provide reassurance to the patients: With appropriate management, IRIS usually does not alter the patients long-term prognosis.

IRIS Management Corticosteroids (1mg/kg/day) might be necessary in case of severe symptoms: Worsening of meningeal, cerebral or mediastinal disease with compression of vital structure, Pain, prolonged fever. In case of life-threatening forms of IRIS, stopping ARV temporarily could be considered. * Rifampicin decrease 50% prednisolone concentrations

Managing ARV During IRIS Continue ARV Except in life-threatening situations Adjust for anti-mycobacterial treatment If rifampin is prescribed: Switch NVP to EFV Stop PIs and start EFV or a third NRTI, as appropriate Super boosted PI

Summary and Key Points Restoration of immunopathological response to antigens of opportunistic pathogens subclinical infections treated infections Usually presents during the first weeks (2-12 weeks) of ARV Less commonly presents after many months of ARV The most common agent inducing IRIS in Vietnam is TB/BCG 28

Summary and Key Points IRIS is a diagnosis of exclusion Treatment consists of antimicrobial + anti-inflammatory therapy or anti-inflammatory therapy alone IRIS is NOT treatment failure: ARV therapy should be continued The syndrome will be spontaneously resolved after months

Thank you! Questions?